dossiÊ syrspend® sf
TRANSCRIPT
SyrSpend® SF DOSSIÊ
03
Índice
Estudo da Reologia SyrSpend® SF 220
Estudos de estabilidade
Compatibilidade comSondas Nasogástricas 214
Estudos de Estabilidade
Acetaminofeno (paracetamol) ______________________________________________________________Estudo 20,35Acetazolamida ________________________________________________________________________________Estudo 26,35Ácido fólico ___________________________________________________________________________________Estudo 15,35Alopurinol _____________________________________________________________________________________Estudo 20,35Alprazolam ____________________________________________________________________________________Estudo 25,35Amiodarona (HCl )____________________________________________________________________________Estudo 12Amitriptilina (HCl)____________________________________________________________________________Estudo 20,35Amlodipina (besilato) ________________________________________________________________________Estudo 13,35Atenolol________________________________________________________________________________________Estudo 16,35
Azatioprina ____________________________________________________________________________________Estudo 33,35Baclofen _______________________________________________________________________________________Estudo 26,30,35Cafeína ________________________________________________________________________________________Estudo 15,35Captopril ______________________________________________________________________________________Estudo 10Carbamazepina _______________________________________________________________________________Estudo 20,35Carvedilol _____________________________________________________________________________________Estudo 15,30,35Celecoxib______________________________________________________________________________________Estudo 27Cetoconazol __________________________________________________________________________________Estudo 20,35Cetoprofeno __________________________________________________________________________________Estudo 16
Ciprofloxacina (HCI) _________________________________________________________________________Estudo 27Clomipramina (HCl) __________________________________________________________________________Estudo 15,35Clonazepam___________________________________________________________________________________Estudo 16,35Clonidina (HCl )_______________________________________________________________________________Estudo 33,35Clopidogrel ___________________________________________________________________________________Estudo 33,35
Cloxacilina ____________________________________________________________________________________Estudo 18Colecalciferol (Vit. D3)_______________________________________________________________________Estudo 14,35Dapsone _______________________________________________________________________________________Estudo 13,35Darunavir e cobicistate ______________________________________________________________________Estudo 32Dexametasona ________________________________________________________________________________Estudo 16,35Diclofenaco de sódio ________________________________________________________________________Estudo 16,35Diltiazem (HCl) ________________________________________________________________________________Estudo 16,35Dipiridamol____________________________________________________________________________________Estudo 26,35Domperidona _________________________________________________________________________________Estudo 20,35Doxiciclina ____________________________________________________________________________________Estudo 34Enalapril (maleato )___________________________________________________________________________Estudo 16,35Esomeprazol (magnésio ) ____________________________________________________________________Estudo 21,35Espironolactona e hidroclorotiazida_______________________________________________________Estudo 27Espironolactona ______________________________________________________________________________Estudo 12,30,35Etambutol (HCl ) ______________________________________________________________________________Estudo 33,35Fenitoína_______________________________________________________________________________________Estudo 13,35Fenobarbital___________________________________________________________________________________Estudo 12,30
Fluoxetina (HCI )______________________________________________________________________________Estudo 34Furosemida____________________________________________________________________________________Estudo 12
Flecainida (acetato) __________________________________________________________________________Estudo 27
Atropina (sulfato) ____________________________________________________________________________ Estudo 25,35
Ciclosporina _________________________________________________________________________Estudo 27
Cloroquina (fosfato)__________________________________________________________________________Estudo 13,35
Gabapentina __________________________________________________________________________________Estudo 06Glicopirrolato (brometo de glicopirrônio) _________________________________________________Estudo 27Glutamina _____________________________________________________________________________________Estudo 25,35Griseofulvin ___________________________________________________________________________________Estudo 33,35Haloperidol____________________________________________________________________________________ Estudo 14,35Hidralazina (HCl)______________________________________________________________________________Estudo 33,35Hidrato de cloral______________________________________________________________________________Estudo 27Hidroclorotiazida _____________________________________________________________________________Estudo 15,27,30,35Hidrocortisona________________________________________________________________________________Estudo 12,27Hidroxicloroquina (Sulfato)__________________________________________________________________Estudo 31Imipramina (HCl) _____________________________________________________________________________Estudo 14,35Isoniazida______________________________________________________________________________________Estudo 20,35Itraconazol ____________________________________________________________________________________Estudo 27Labetalol (HCl) ________________________________________________________________________________Estudo 27Lamotrigina ___________________________________________________________________________________Estudo 16,35Lansoprazol ___________________________________________________________________________________Estudo 21,35Levodopa e carbidopa _______________________________________________________________________Estudo 14,35Levofloxacino _________________________________________________________________________________Estudo 25,35Lisinopril (di-hidratado) ______________________________________________________________________Estudo 20,35Loperamida (HCl)_____________________________________________________________________________Estudo 15,35Lorazepam ____________________________________________________________________________________Estudo 14,35
Metronidazol (benzoato)_____________________________________________________________________Estudo 01
Mebeverine (HCl) _____________________________________________________________________________Estudo 26,35Melatonina ____________________________________________________________________________________Estudo 27Mercaptopurina ______________________________________________________________________________Estudo 30,35Metadona (HCl) _______________________________________________________________________________Estudo 30
Metotrexato ___________________________________________________________________________________Estudo 15,35Metoprolol (tartarato) ________________________________________________________________________Estudo 25,35
Nadolol ________________________________________________________________________________________Estudo 15,35Naltrexona (HCl) ______________________________________________________________________________Estudo 15,35Naproxen ______________________________________________________________________________________Estudo 20,35Nifedipine _____________________________________________________________________________________Estudo 12Nitrendipina___________________________________________________________________________________Estudo 28 e 19Nitrofurantoína _______________________________________________________________________________Estudo 25,33,35Omeprazol ____________________________________________________________________________________Estudo 04,21,35Ondansetron (HCl) ___________________________________________________________________________Estudo 25,35Oseltamivir (fosfato) _________________________________________________________________________Estudo 02,24,30,35Oxandrolona __________________________________________________________________________________Estudo 25,35Pantoprazol (sódico) _________________________________________________________________________Estudo 21,35Penicilamina __________________________________________________________________________________Estudo 16,35Pentoxifilina ___________________________________________________________________________________Estudo 15,35Pirazinamida __________________________________________________________________________________Estudo 22,30,35Piridoxina (HCl) - Vit. B6 _____________________________________________________________________Estudo 13,35
Prednisona ____________________________________________________________________________________Estudo 29Pregabalina____________________________________________________________________________________Estudo 25,35
Midazolam (HCl) ______________________________________________________________________________Estudo 11,24Minociclina (HCl) _____________________________________________________________________________Estudo 14,35
Prednisolona (fosfato sódico)_______________________________________________________________Estudo 12
Propiltiouracil _________________________________________________________________________________Estudo 26,35Propranolol (HCl) _____________________________________________________________________________Estudo 07,24,30,35
Rabeprazol ____________________________________________________________________________________Estudo 21,35Riboflavina - Vit. B2___________________________________________________________________________Rifampicina ___________________________________________________________________________________Estudo 09Sildenafila (citrato) ___________________________________________________________________________Estudo 17Sinvastatina ___________________________________________________________________________________Estudo 12
Sotalol (HCl)___________________________________________________________________________________Estudo 30,35Sulfadiazina ___________________________________________________________________________________Estudo 13,35Sulfassalazina _________________________________________________________________________________Estudo 13,35Tacrolimus (monohidrato)___________________________________________________________________Estudo 14,30,35Terbinafina (HCl) _____________________________________________________________________________Estudo 14,35Tetraciclina (HCl) _____________________________________________________________________________Estudo 13,35Tiagabina (HCl) _______________________________________________________________________________Estudo 27Tioguanina ____________________________________________________________________________________Estudo 33,35
Topiramato ____________________________________________________________________________________Estudo 26,35Tramadol (HCl)________________________________________________________________________________Estudo 14,34,35Trimetoprim___________________________________________________________________________________Estudo 13,35Ursodiol________________________________________________________________________________________Estudo 08,35Valsartan ______________________________________________________________________________________Estudo 14,35Vancomicina (HCl) ___________________________________________________________________________Estudo 05,30,35Varfarina (sódica)_____________________________________________________________________________Estudo 23Verapamil (HCl) _______________________________________________________________________________Estudo 03,35Zonisamida____________________________________________________________________________________Estudo 13,35
Estudo 25,35
Quinidina (sulfato) ___________________________________________________________________________ Estudo 26,35
Tiamina (HCl) - Vit. B1 ________________________________________________________________________Estudo 16,35
Sertralina (HCl) _______________________________________________________________________________Estudo 20,35
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PEER REVIEWEDFORMULATIVE
Introduction Drug treatment in pediatric and aging patients poses specific pharmaceutical issues that are not, or to a lesser extent, seen in the general adult population. In the elderly, age-related physi-ological changes and alterations in pharmacokinetics, such as drug metabolism, distribution, and excretion, can require dose adjustments.1 Children go through extensive changes in body size and weight during their development, with a weight increase up to 20-fold from birth to maturity, and 100-fold dose variation throughout childhood.2-3 Furthermore, the rate and extent of drug bioavailability can variate in pediatric patients due to develop-mental changes in absorptive surfaces.4 Dysphagia or swallow-ing difficulty is another reason why children and elderly adults require customized medication. Solid dosage forms are frequently unsuitable until the age of 6 and 25% to 45% of the general pediat-ric population suffers from dysphagia.5-6 Despite the increasing availability of pediatric and elderly tai-lored dosage forms, there is still an extensive range of medicines that need to be compounded by the pharmacist on a small scale or individual basis. In these cases, pharmacists will generally prepare extemporaneous capsules or oral liquids, the latter often being a more convenient alternative to capsules and provides better adher-ence. Oral liquids are comparatively swift to prepare and can allow dosage flexibility, although pharmacists sometimes struggle to obtain physical and chemical stable formulations. As many active pharmaceutical ingredients (APIs) have limited solubility, most actives will be suspended rather than solubilized, which can result in irreversible sedimentation (“caking”) of the API. For oral suspen-sions, there is the additional concern with uniformity, particularly because of the potential for segregation during the compounding process and storage of the bulk suspension, especially in cases where an active ingredient is present in small quantities.7-9 Because of these factors, compounded capsules are sometimes seen as a bet-ter alternative to oral liquid medication. To ensure the safe and accurate administration of compounded medications, the drug substance content should be within the pre-determined range as defined by the current pharmacopeia. For solid preparations, pharmacists have two pharmacopoeia tests available to determine if the compounded medication meets the requirements: 1) weight variation and 2) uniformity of content.10-11
Always the Right Dose? Content Uniformity in Over 100 Different Formulations Tested
Eli Dijkers, PharmD, PhDHudson Polonini, BPharm, PhDAnderson de Oliveira Ferreira, BPharm, PhD
The authors’ affilia-tions are: Eli Dijkers (hospital pharmacist), Hudson Polonini and Anderson de Oliveira Ferreira, Fagron BV, Rotterdam, The Netherlands.
AbstractThere is still an evident need for nonsterile compounded medications for pediatric and elderly patients in cases where patients require dose adjustments or have swal-lowing difficulties. Pharmacists generally have the choice between compounding capsules or oral liquids. In daily pharmacy practice, extemporaneous capsules are from time to time seen as a better alternative to oral liquid medication, although various published studies indicate that weight variation and/or uniformity of content can be significantly out of specification for compounded cap-sules. In contrast, analyses with the ready-to-use oral liquid vehicle SyrSpend SF in 104 different formulations with 89 unique active pharmaceutical ingredients showed results that all 6.414 samples analyzed were within speci-fication. It can, therefore, be argued that SyrSpend SF could be a better way to assure content uniformity com-pared to manually compounded, small-batch extempora-neous capsules.
S P FS T A B I L I T Y P E N E T R A T I O N F O R M U L A T I V E C L I N I C A L S T U D Y O T H E RC O
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For liquids, only content uniformity (CU) applies, although the British Pharmacopoeia (BP) has a specific monograph on the CU of liquid dispersions.12 Between the various pharmacopoeias, the weight variation and uniformity of content tests have been gener-ally harmonized. SyrSpend SF is an oral liquid vehicle range that has specific rheological properties to ensure dose consistency throughout therapy. The thixotropy prevents APIs from settling by increasing the viscosity when left undisturbed; the pseudoplasticity facilitates homogenization by lowering viscosity when shaken.13
Our hypothesis is that SyrSpend SF can better assure dosing con-sistency than what has been shown in the literature for extempora-neous compounded capsules. Previously, the CU had been evaluated with a limited number of APIs.14 In this article, we present unifor-mity of content of over 100 different APIs in SyrSpend SF at refrig-erated and room temperature.
Methods All data presented were performed by a single, International Organization for Standardization (ISO) and Good Laboratory Practice (GLP) validated lab. The stability of each individual API in SyrSpend SF was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantifi-cation was performed by high-performance liquid chromatogra-phy (HPLC-UV) via a stability-indicating method. Methods and their acceptance criteria were established based on United States Pharmacopeia (USP) protocols15 and The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.16 During forced-degradation studies, samples were subjected to stress conditions (acid, base, ultraviolet, heating, oxidizing), to validate the HPLC method. Samples were assayed by HPLC at pre-determined time points to verify the stabil-ity of the APIs in SyrSpend SF. Samples were shaken manually for 1 minute to simulate patient dosing. Adequate volumetric aliquots for quantification were withdrawn from the middle of the bottles without contacting the inner surface of the bottle. They were appro-priately diluted to obtain work solutions, as described earlier.17-38 Samples were taken at several time points: day 0 (baseline), 7 days, 14 days, 30 days, 60 days, and 90 days, except for 11 samples which had already been evaluated earlier at a different concentration and had shown good physicochemical compatibility. These APIs were sampled at day 0, 30 days, 60 days, and 90 days and refrigerated temperature only. All suspensions were immediately assayed six times at each time point. The evaluation parameter was the percent recovery (%) with respect to T = 0 using HPLC. Mean and standard deviation were calculated for all data-points combined.17-38
To determine CU, the USP describes that no less than 30 units need to be selected, 10 of which should be assayed. The acceptance value (AV) for the CU was calculated as described earlier.14 The requirements for dosage uniformity are met if the acceptance value of the first 10 dosage units is less than or equal to L1. If one or more
samples have an acceptance value greater than L1, another 20 dos-age units need to be tested. The requirements are then met if the final acceptance value of the 30 dosage units is less than or equal to L1 and no individual dosage unit is less than 75% or more than 125% of the declared dose (L2). Practical Pharmaceutics39 describes the acceptability value for smaller sampling plans than described in the USP/European Pharmacopoeia. According to the BP monograph on the Content Uniformity of Liquid Dispersions, homogeneity and resuspendability of a liquid dispersion comply if each of the 10 doses is between 85% and 115% of the average dose. The preparation fails if more than one dose is outside of these limits or if one indi-vidual dose is outside the limits of 75% to 125%.12
Results In this study, 104 different formulations with 89 unique APIs were evaluated. In total, 6.414 different samples were analyzed, of which the majority was tested at both room temperature (15°C to 25°C) and controlled refrigerated temperature (2°C to 8°C). A complete overview of the different formulations tested and the dif-ferent API concentrations is provided (see TA B L E ). The dataset was analyzed in accordance with the USP Content Uniformity mono-graph, corrected for the sample number of 6. Calculations were only performed until the maximum beyond-use-date of the sample. The acceptance values were calculated for all the different APIs, at all time points and at both temperatures. The mean acceptance val-ues for room temperature and controlled refrigerated temperature are 3.12 and 3.17, respectively. As shown from all the acceptance values plotted in F I G U R E 1 , not a single acceptance value was more than L1, indicating that all APIs complied with the USP Content Uniformity monograph. When the dataset was also evaluated according to the BP Content Uniformity of Liquid Dispersions, all APIs were well within the first range (85% to 115% of the declared content). The mean concentra-tion of all samples was 100.30% and 100.34% for room and refriger-ated temperature, respectively. The 6.414 individual data-points are plotted in F I G U R E 2 .
Discussion There has been increased focus on safety of pediatric medica-tion.40-41 This is especially important since many medicines have a narrow therapeutic window, and small deviations in the content can significantly affect patient safety. This study has shown that with SyrSpend SF all samples are well within the specifications for CU, independent of the API used, storage conditions, or time of analysis. This is in contrast with some of the available data found on compounded capsules. Various published studies have shown that manually compounded small-scale batches of capsules can be out of specification for CU, even when requirements for weight variation have been met. Studies found in the literature are briefly discussed below.
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Markman and colleagues evaluated 40-mg simvastatin capsules from 18 different compounding pharmacies. Although the weight variation was out of specification in 22% of the cases, an even larger percentage did not comply to the specifications for CU: 72%.42 In another study with 20-mg simvastatin, 37% of the capsules failed to meet the criteria for CU.43 Colucci et al showed that 1-mg micro-dose captopril capsules were all within acceptable limits for weight variation described in the USP, but the actual dose administered to the patients could vary by as much as 25% when the content was analyzed.44 Raffl published that when 0.1-mg or 1-mg capsules with NaCl as a model API were evaluated, all samples met the USP requirements for weight variation, but 46% of the 1-mg capsules and 64% of the 0.1-mg capsules failed to meet the criteria for CU.45 Neuman et al randomly collected compounded hydrocortisone capsules from German children suffering from congenital adrenal hyperplasia. HPLC analysis of the 56 batches, containing 1125 cap-sules, revealed insufficiency in uniformity of net mass or drug con-
T A B L E . OVERVIEW OF FORMULATIONS TESTED IN SYRSPEND SF.
HCl = hydrochloride
Acetazolamide 25 mg/mL
Allopurinol 20 mg/mL
Alprazolam 1 mg/mL
Amitriptyline HCl 10 mg/mL
Amlodipine besylate 1 mg/mL
Atenolol 1 mg/mL
Atenolol 5 mg/mL
Atropine sulphate 0.1 mg/mL
Azathioprine 50 mg/mL (tablets)
Azathioprine 50 mg/mL (powder)
Baclofen 10 mg/mL
Baclofen 2 mg/mL
Carbamazepine 25 mg/mL
Carbidopa (as levodopa/carbidopa) 1.25 mg/mL
Carvedilol 1 mg/mL
Carvedilol 5 mg/mL
Chloroquine phosphate 15 mg/mL
Cholecalciferol (Vit D3) 50,000 UI
Clomipramine HCl 5 mg/mL
Clonazepam 0.2 mg/mL
Clonidine HCl 0.1 mg/mL (powder)
Clonidine HCl 0.1 mg/mL (tablets)
Clonidine HCl 0.1 mg/mL (tablets)
Clopidogrel bisulfate 5 mg/mL (tablets)
Caffeine 10 mg/mL
Dapsone 2 mg/mL
Dexamethasone 1 mg/mL
Diclofenac sodium 5 mg/mL
Diltiazem HCl 12 mg/mL
Dipyridamole 10 mg/mL
Domperidone 5 mg/mL
Enalapril maleate 1 mg/mL
Esomeprazole 3 mg/mL
Ethambutol 2 HCl 100 mg/mL (powder)
Ethambutol 2 HCl 50 mg/mL (powder)
Ethambutol 2 HCl 50 mg/mL (tablets)
Folic acid 1 mg/mL
Glutamine 250 mg/mL
Griseofulvin 25 mg/mL
Haloperidol 0.5 mg/mL
Hydralazine HCl 4 mg/mL (powder)
Hydralazine HCl 4 mg/mL (tablets)
Hydrochlorothiazide 2 mg/mL
Hydrochlorothiazide 5 mg /mL
Imipramine HCl 5 mg/mL
Isoniazid 10 mg/mL
Ketoconazol 20 mg/mL
Ketoprofen 20 mg/mL
Lamotrigine 1 mg/mL
Lansoprazole 3 mg/mL
Levodopa (as levodopa/carbidopa) 5 mg/mL
Levofloxacin 50 mg/mL
Lisinopril 1 mg/mL
Loperamide 1 mg/mL
Lorazepam 1 mg/mL
Mebevarine HCl 10 mg/mL
Mercaptopurine 10 mg/mL
Methotrexate 2.5 mg/mL
Metoprolol tartrate 10 mg/mL
Minocycline HCl 10 mg/mL
Nadolol 10 mg/mL
Naltrexone HCl 1 mg/mL
Naproxen 25 mg/mL
Nitrofurantoin 10 mg/mL
Nitrofurantoin 2 mg/mL
Omeprazole 5 mg/mL
Ondansetron HCl 0.8 mg/mL
Oseltamivir 6 mg/mL (tablets)
Oxandrolone 3 mg/mL
Pantoprazole 3 mg/mL
Paracetamol 50 mg/mL
Penicillamine D 50 mg/mL
Pentoxifylline 20 mg/mL
Phenytoin 15 mg/mL
Pregabalin 20 mg/mL
Propranolol 0.5 mg/mL
Propranolol 5 mg/mL
Propylthiouracil 5 mg/mL
Pyrazinamide 100 mg/mL (tablets)
Pyridoxine (Vit. B6) 50 mg/mL
Quinidine sulfate 10 mg/mL
Rabeprazole 3 mg/mL
Riboflavin (vit. B2) 10 mg/mL
Sertraline HCl 10 mg/mL
Sotalol HCl 5 mg/mL (tablets)
Spironolactone 2 mg/mL
Spironolactone 2.5 mg/mL
Sulfadiazine 100 mg/mL
Sulfasalazine 100 mg/mL
Tacrolimus monohydrate 0.5 mg/mL
Tacrolimus monohydrate 1 mg/mL
Terbinafine 25 mg/mL
Tetracycline HCl 25 mg/mL
Thiamine (Vit. B1) 100 mg/mL
Thioguanine 2.5 mg/mL
Topiramate 5 mg/mL
Tramadol HCl 10 mg/mL
Trimethoprim 10 mg/mL
Ursodiol 20 mg/mL
Valsartan 4 mg/mL
Vancomycin 25 mg/mL
Verapamil 50 mg/mL
Zonisamide 10 mg/mL
tent in 21.4% of the batches.46 Compounded veterinary trilostane capsules (15 mg, 45 mg, or 100 mg) were purchased from eight phar-macies and assayed for content. In total, 38% of the compounded batches were below the acceptance criteria for content.47 Finally, Morita and colleagues analyzed capsules with thyroid hormones levothyroxine (T4) and liothyronine (T3) from 5 different com-pounding facilities and showed that they were out of specification for CU in 40% to 100% of the cases.48
Conclusion There is still an evident need for nonsterile compounded medications for pediatric and elderly patients in cases where patients require dose adjustments or have swallowing difficulties. Pharmacists generally have the choice between compounding cap-sules or oral liquids. Although not compared head-to-head, based on the available information for compounded capsules and the current
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F I G U R E 1 . CONTENT UNIFORMITY DISPLAYED ACCORDING TO THE UNITED STATES PHARMACOPEIA.
study data, it can be argued that SyrSpend SF could be a better way to assure CU than manually compounded, small-batch extem-poraneous capsules.
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L1
L2
Acc
epta
nce
Valu
e
Upper L2
Upper L1
Cont
ent
0
Upper L1
Upper L2
L1
L2
Acc
epta
nce
Valu
e
Upper L2
Upper L1
Cont
ent
0
Upper L1
Upper L2
The dotted lines indicate the L1 and L2 criteria described in the United States Pharmacopeia; the closed dots represent samples stored at room temperature; the open dots represent samples stored at controlled refrigerated temperature.
F I G U R E 2 . CONTENT UNIFORMITY DISPLAYED ACCORDING TO THE BRITISH PHARMACOPOEIA’S “CONTENT UNIFORMITY OF LIQUID DISPERSIONS.”
The dotted lines indicate the 100% target and the first range (85% to 115%) and second range (75% to 125%) as described; the closed dots represent samples stored at room temperature; the open dots represent samples stored at controlled refrigerated temperature.
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30. Whaley PA, Voudrie MA 2nd. Stability of vancomycin in SyrSpend SF. IJPC. 2012; 16(2): 167–169.
31. Voudrie MA, Alexander B, Allen B. Stability of verapamil hydrochloride in SyrSpend SF compared to Sorbitol containing syrup and suspending vehicles. IJPC. 2011; 15(3): 255–258.
32. Polonini HC, Loures S, de Araujo ED et al. Stability of allopurinol, amitrip-tyline hydrochloride, carbamazepine, domperidone, isoniazid, ketocon-
azole, lisinopril, naproxen, paracetamol (acetaminophen), and sertraline hydrochloride in SyrSpend SF PH4 Oral Suspensions. IJPC. 2016; 20(5): 426–434.
33. Polonini HC, Silva SL, de Almeida TR et al. Compatibility of caffeine, carvedilol, clomipramine hydrochloride, folic acid, hydrochlorothiazide, loperamide hydrochloride, methotrexate, nadolol, naltrexone hydrochlo-ride and pentoxifylline in SyrSpend SF PH4 oral suspensions. Eur J Hosp Pharm. 2016; 23(6): 352–358.
34. Polonini HC, Silva SL, Loures S et al. Compatibility of proton pump inhib-itors in a preservative-free suspending vehicle. Eur J Hosp Pharm. 2018; 25(3): 150–156.
35. Dijkers E, Nanhekhan V, Thorissen A. Updated stability data for mi-dazolam, oseltamivir phosphate, and propranolol hydrochloride in SyrSpend SF and minoxidil in espumil. IJPC. 2017; 2(3): 240–241.
36. Ferreira AO, Polonini HC, Loures da Silva S et al. Stability of alprazolam, atropine sulfate, glutamine, levofloxacin, metoprolol tartrate, nitrofuran-toin, ondansetron hydrochloride, oxandrolone, pregabaline, and riboflavin in SyrSpend SF PH4 Oral Suspensions. IJPC. 2017; 21(3): 255–263.
37. Ferreira AO, Polonini HC, Loures da Silva S et al. Stability of acetazol-amide, baclofen, dipyridamole, mebevarine hydrochloride, propylthio-uracil, quinidine sulfate, and topiramate oral suspensions in SyrSpend SF PH4. IJPC. 2017; 21(4): 339–346.
38. Uriel M, Gómez-Rincón C, Marro D. Stability of regularly prescribed oral liquids formulated with SyrSpend® SF. Pharmazie. 2018; 73(4): 196–201.
39. Smeets O, Santillo M, van Rooij H. Quality requirements and analysis. In: Bouwman-Boer Y, Fenton-May V, Le Brun P, eds. Practical Pharmaceutics. First edition. Switzerland: KNMP and Springer International Publishing; 2015: 716–717.
40. Parrish RH 2nd. Current trends and emerging priorities in compounded preparations for children. IJPC. 2018; 22(5): 358–366.
41. Engels MJ, Ciarkowski SL, Rood J et al. Standardization of compounded oral liquids for pediatric patients in Michigan. Am J Health Syst Pharm. 2016; 73(13):981–990.
42. Markman BE, Rosa PC, Koschtschak MR. Assessment of the quality of simvastatin capsules from compounding pharmacies. Rev Saude Publica. 2010; 44(6): 1055–1062.
43. Marques-Marinho FD, da Costa Zanon JC, Sakurai E et al. Quality evalua-tion of simvastatin compounded capsules. Braz J Pharm Sci. 2011; 474(3): 495–502.
44. Colucci RD, Scavone JM, Auty R et al. Quality control of extemporane-ously prepared microdose captopril capsules: Weight variation versus content uniformity. Int J Clin Pharmacol Ther. 1994; 32(1): 24–25.
45. Raffl M. Quality in pharmaceutical compounding for paediatric patients. EJHP. 2012; 19(2): 100.
46. Neumann U, Burau D, Spielmann S et al. Quality of compounded hydro-cortisone capsules used in the treatment of children. Eur J Endocrinol. 2017; 177(2): 239–242.
47. Cook AK, Nieuwoudt CD, Longhofer SL. Pharmaceutical evaluation of compounded trilostane products. J Am Anim Hosp Assoc. 2012; 48(4): 228–233.
48. Morita L, Baldin R, Farias N. Avaliação da qualidade da informação nas requisições e condições das amostras biológicas nos Laboratórios de Saúde Pública Lapa e Ipiranga do município de São Paulo. BEPA, Bol. epi-demiol. paul. 2010; 7(79): 12–22.
Address correspondence to Eli Dijkers, BPharmD, PhD, Hospital Pharmacist, Fagron BV, Lichtenauerlaan 182, 3062 ME, Rotterdam, The Netherlands. E-mail: [email protected].
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Acknowledgment This work was conducted under the spon-sorship of Fagron and FrancePrep.
Introduction Compounding in veterinary medicine is intended to facilitate drug administra-tion and improve palatability and dosage. Administering medications using oral suspensions represents a suitable method in dogs and cats. These galenic formula-tions limit the risk of entrapment of the solid form, especially in cats that generally do not drink frequently, and allow easier adjustment of the dosage.1,2 Few studies have been published on the stability and quality of compounded formulations for veterinary patients. Additionally, adding other chemicals as flavors in a suspension may interfere with the stability or solubility of the drug, compromising its oral absorp-tion and efficacy.3
Outpatient pain management in dogs and cats could be difficult for veterinarians and owners.4 In France, the European Medicine Agency authorized only nonsteroidal anti-inflammatory drugs (NSAIDs) to control pain in pets, until the approval of tramadol in 2018. Due to the potential adverse effects of NSAIDs or lack of a clinical response, clinicians often prefer to prescribe com-pounded formulation of tramadol. Tramadol is indicated in the management of moderate to moderately severe pain in humans and in the reduction of acute and chronic mild pain in soft tissue and the musculoskeletal system in dogs only. Tramadol is a racemic mixture of two enantiomers, which are
S P F OS T A B I L I T Y P E N E T R A T I O N F O R M U L A T I V E C L I N I C A L S T U D Y O T H E RC
Stability of Extemporaneous Oral Tramadol, Fluoxetine, and Doxycycline Suspensions in SyrSpend SF PH4
B. EspanaF. Joseph-Tornabène, PharmDCécile Jaquet, PharmDS. Perrot, PharmDC. Prouillac, PharmD
The authors’ affiliations are: B. Espana, Analytical Chemical Engineer, Université de Lyon, Veta-gro Sup, Marcy l’Etoile, France; F. Joseph-Tornabène, Pharmacist, France-Prep, Marseille, France; Cécile Jaquet, Pharmacist, France-Prep, Marseille, France; S. Perrot, Université Paris-Est, École Natio-nale Vétérinaire d'Alfort, France; C. Prouillac, Université de Lyon, Vetagro Sup, Marcy l’Etoile, France.
AbstractExtemporaneous compounding in veterinary practice sometimes represents the only possibility for treating animals in the absence of appropriate commer-cial formulations, especially for particular species. This method involves manipulating pharmaceutical active ingredients to a suitable dosage and for-mulation for administration to humans or animals. However, veterinarians and pharmacists should focus on the risk of potential incompatibilities and instabil-ity of their preparations. To help practitioners in drug compounding, we inves-tigated the stability of oral suspensions of tramadol, fluoxetine, and doxycycline in a commercially ready-to-use vehicle (SyrSpend). A validated high-performance liquid chromatography method was developed to assay these active pharmaceutical ingredients. The oral suspensions were prepared at two concentration ranges and were stored in amber glass bottles under refrigerated conditions and at room temperature. After 90 days, the average recovery rates were between 90% and 110% for tramadol (5 mg/mL to 30 mg/mL) and doxycy-cline (2 mg/mL to 10 mg/mL) without organoleptic modification. For fluoxetine, only the formulation at 2 mg/mL was stable; at higher concentrations, the uni-formity of the suspension was compromised.
µ-opioid receptor agonists without affinity to δ- and κ-opioid receptors. Tramadol also inhibits neu-ronal serotonin reuptake, and the two enantiomers inhibit neuronal noradrenaline reuptake, leading to anti-nociceptive effects by enhancing inhibitory effects on pain transmission in the spinal cord.5 Tramadol is metabolized into different metabolites, among which only O-desmethyltramadol (ODM) and N,O-desmethyltramadol (DDM) have pharma-cologic effects.6 Pharmacokinetics studies in dogs and cats have shown interspecies differences in the metabolic pathway of tramadol. Dogs produce
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mostly DDM,7 whereas cats produce high concentrations of ODM, leading to more opioid effects than in dogs.8,9 Tramadol is associ-ated with high bioavailability after oral administration in cats with a similar pharmacokinetic profile of ODM. Additionally, the opioid-mediated adverse effects are more likely to appear in cats (sedation, mydriasis, dysphoria or euphoria, constipation, vomiting). Few clinical controlled trials have assessed the clinical efficacy of tram-adol in pets,10-12 leading to scarce evidence of its efficacy in animal pain management despite its significant use in clinical veterinary patients. Therefore, a compounded formulation of tramadol is cur-rently prescribed for cats. Fluoxetine is a selective serotonin reuptake inhibitor com-monly used to treat behavioral problems of dogs and cats. The drug Reconcile was approved for use in dogs for separation anxiety associated with behavioral problems.13 At the time of this study, Reconcile was not available in France and the U.S., encouraging practitioners to prescribe human medicines and compounded for-mulations for dogs and cats.14 The major canine behaviors for which fluoxetine is prescribed in dogs are separation anxiety, compulsive disorders, and aggression.15 For cats, inappropriate urination and anxiety are the major indications of fluoxetine. Doxycycline is a tetracycline antibiotic commercially available in veterinary medicine. Despite the high frequency of bacterial resistance to tetracyclines, they have clinical utility in many clini-cal indications, such as skin, soft tissue, and genital infections. Additionally, they have activity against Gram-positive and Gram-negative bacteria and against some atypical pathogens transmit-ted by ticks and other parasites (Rickettsia) and blood-borne pathogens. In birds, they are indicated especially for the treatment of Chlamydophila psittaci. Doxycycline hyclate is the form of doxy-cycline prescribed and available in tablet formulations. However, these formulations are not suitable for use in some species, particu-larly in birds or ferrets. For these species, no veterinary-approved formulations of doxycycline exist in France. The only approved antimicrobial in these species are critical antibiotics such as fluo-roquinolones. Liquid forms of doxycycline are not approved even in human medicine. Oral suspensions of doxycycline hyclate are stable for 14 days, as reported by Papich et al.16
Compounding without knowledge of the compatibility and stabil-ity of the active ingredient in the excipient is risky, particularly with suspensions if the suspended active pharmaceutical ingredients sediment after preparation. In that case, the sediment should be resuspended by shaking to guarantee the uniformity of the dose. The purpose of our study was to investigate the stability of current compounded formulations. The suspending vehicle selected was SyrSpend SF PH4, which is commonly used in the compounding of medicine for humans. We conducted this sta-bility study in accordance with the International Conference on Harmonisation (ICH) guidelines to ensure the quality and safety of these compounding formulations. Thus, we validated a high-performance liquid chromatographic (HPLC) method for the assay. We chose to examine only chemical stability and some
aspects of physical stability over 90 days at room temperature and under refrigerated conditions.
Materials and MethodsREAGENTS Tramadol powder was provided by Safic Alcan (Lot SLL/TDM/0615010, France), and chicken aroma (Lot 18L13-B03-PPR1903296, fluoxetine (Lot 17H04-B03-346103), doxycycline (Lot 18J04-B02-355882), and SyrSpend SF PH4 (Lot 1706761/1; 1812150/1; 1802653/3) were provided by Fagron (Thiais, France). Potassium phosphate, ammonium formate, ammonia, ortho-phosphoric acid (for analysis), methanol, and acetonitrile (HPLC gradient grade) used for the mobile phase were provided by VWR International (Fontenay-sous-Bois, France). Water for HPLC was supplied by a demineralized water system from aquadem (Veolia Water Technologies, Antony, France). Sodium hydroxide (NaOH), hydrochloric (HCl) acid, and hydrogen peroxide 30% (H2O2) solu-tions used for the degradation study were purchased from Merck (Darmstadt, Germany). The stability study was conducted in 60-mL brown polyethylene terephthalate flasks by Fagron.
INSTRUMENTATION AND CHROMATOGRAPHIC CONDITIONS The HPLC system comprised an Agilent 1260 affinity II sys-tem with a 100-µL sample loop and a G7117C diode array detec-tor at a wavelength of 230 nm for tramadol and fluoxetine and 270 nm for doxycycline (Agilent Technologies, les Ulis, France). Chromatography of tramadol was performed using partial-loop injection of the 10-µL sample in a Waters Nova Pak C18 system (4 µm; 75 × 3.9 mm) at 45°C. The mobile phase comprised 10 mM ammonium formate adjusted to pH 9.5 with 25% ammonium hydroxide (A) and methanol (B). A flow rate of 0.8 mL/min was maintained, and tramadol was eluted using the following program: 0 min to 0.2 min isocratic hold at 30% B, 0.2 min to 2 min linear gra-dient to 30% to 70% B; 2 min to 4 min isocratic hold at 70% B. For fluoxetine and doxycycline, an Excel ACE AR 100 C18 column (150 × 4.6 mm, 5 µm) (VWR International) maintained at 40°C was used. Mobile-phase acetonitrile (A) phosphate buffer (10 mM; pH=3); (B) was eluted at a flow rate of 1 mL/min with the following program: 0 min to 0.2 min isocratic hold at 98% B; 0.2 min to 5 min linear gradient to 40% B. Tramadol, fluoxetine, and doxycycline peaks had retention times of approximately 4.1 minutes, 4.7 minutes, and 4.0 minutes, respec-tively. The area of the peaks was used for quantification using open-lab software (Agilent Technologies Inc.).
PREPARATION OF SUSPENSION SAMPLES Six formulations were prepared for each storage and concentra-tion condition. The oral suspension of tramadol was prepared by adding 0.05 g or 0.3 g of tramadol powder with 0.1 g of chicken aroma
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completed with 10 mL of SyrSpend SF PH4 in a plastic amber bottle (5-mg/mL and 30-mg/mL final concentrations, respectively). The oral suspension of fluoxetine was prepared by adding 0.02 g or 0.1 g of fluoxetine powder with 0.1 g of chicken aroma com-pleted with 10 mL of SyrSpend SF PH4 in a plastic amber bottle (2-mg/mL and 10-mg/mL final concentrations, respectively). The oral suspension of doxycycline was prepared by homogenization of 0.02 g of doxycycline powder in 10 mL of SyrSpend Cherry in a plastic amber bottle (2-mg/mL final concentration) or by adding 0.5 g of doxycycline powder with 0.1 g of chicken aroma completed with 10 mL of SyrSpend SF PH4 in a plastic amber bottle (50-mg/mL final concentration). The product was homogenized and split into two controlled stor-age conditions, one at a refrigerated temperature (2°C to 8°C) and one at room temperature (18°C to 25°C). The stability of doxycy-cline was conducted only at refrigerated temperature.
STABILITY STUDY DESIGN For each storage condition, the time points of the concentration determination were as follows:
• 0 (initial point)• 1 day (T=1)• 3 days (T=3)• 7 days (T=7)• 15 days (T=15)• 30 days (T=30)• 60 days (T=60) • 90 days (T=90)
First, the bottles were shaken and the suspensions were inspected for organoleptic characteristics (consistency, color, and odor changes). In each bottle, 0.4 mL or 0.15 mL of 5 mg/mL or 30 mg/mL of tramadol, respectively, was sampled and diluted in 20 mL or 50 mL of HPLC water, respectively, and was vigor-ously mixed. Similarly, 0.5 mL or 0.1 mL of 2 mg/mL or 10 mg/mL of fluoxetine, respectively, was sampled and diluted in 20 mL of HPLC water and was vigorously mixed. Finally, 0.5 mL or 0.1 mL of 2 mg/mL and 50 mg/mL of doxycycline, respectively, was sampled and diluted in 20 mL or 100 mL of HPLC water, respectively, and was vigorously mixed. The concentrations were analyzed using a validated stability-indicating HPLC-UV method. The average and standard deviation of all replicates at each time point were calcu-lated to estimate the percent recovery.
ANALYTICAL VALIDATION Analytical validation was performed according to the recom-mendations of the ICH guidelines (Q2R1), SFPC (Société Française de Pharmacie Clinique) and GERPAC (Groupe d’Evaluation et de Recherche sur la Protection en Atmosphère Contrôlée) and included the assessment of system linearity, accuracy, precision
(repeatability, intermediate precision), and specificity. Linearity was performed using two types of ranges, one containing only the active ingredient (standard solutions) and one reconstituted with the suspending vehicle and aroma to investigate the interactions of the active ingredient with excipients. The range of concentrations was between 60% and 140% of tramadol, fluoxetine, and doxycycline in the final formulation according to ICH recommendations. Standard solutions were prepared in methanol and diluted in water to obtain the final working concentrations of the calibration standards. Three different curves of standard solutions and reconstituted prepara-tions were constructed on three different days. Linearity of the method was evaluated by linear regression of the responses obtained after the injection of the calibration samples and reconstituted sam-ples. The method was considered linear if the correlation coefficient was greater than 0.99 for the mean standard curve. Accuracy values were obtained by calculating the relative error (report between theo-retical and calculated concentration) from the linearity study. This report allows access to a recovery rate. To be accepted, the average recovery rate must be between 90% and 110%. For each run of analy-ses, system suitability samples (quality-control standards) were injected every 6 injections. The precision of the analytical method, including sample preparation, was also evaluated. Seven suspen-sions of each active ingredient were prepared on three different days to evaluate the repeatability and intermediate precision.
PREPARATION OF FORCED-DEGRADATION SAMPLES The formulations in SyrSpend SF PH4 using chicken aroma or SyrSpend Cherry were submitted to forced degradation to produce a degradation profile and determine the intrinsic stability of the different active ingredients in the formulations. Hydrolytic degrada-tion was evaluated by diluting the Oral Mix SF suspension and the excipients with water only, aqueous NaOH (1 N; 30%), aqueous HCl (1 N; 30%), or aqueous hydrogen peroxide (4.5%). These solutions were heated for 1 hour or 3 hours at 80°C and were cooled to room temperature. The sample preparation for HPLC injection was then neutralized prior to analysis using the HPLC-UV method.
STATISTICAL ANALYSIS All statistical tests were performed using Excel software (2007; Microsoft Office, Redmond, Washington) with a risk α of 5%. Statistical significance was defined as P<0.05. The linearity was eval-uated using a linear regression model estimated by the method of least squares. The peak area intercept of the regression line was assessed by Student's t-test. Cochran's test was used to assess the homogeneity of variance, and the Fischer-Snedecor's test was performed to assess the existence of a significant slope. The accuracy was tested using Cochran's and ANOVA tests. The confidence interval of the average recovery was determined by Student's t-test. Finally, the precision was validated by Cochran's test. The coefficients of variation were cal-culated for intermediate precision and repeatability.
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ResultsANALYTICAL VALIDATION The slope of the two types of curves and peak area intercept of the regression line were not statistically significant. The regres-sion slope test assessed the existence of a significant linear rela-tionship for all formulations with a correlation coefficient greater than 0.995. Accuracy was assessed with an average recovery rate between 90% and 108%. Repeatability was determined using a coef-ficient variation less than 2.1%. Finally, intermediate precision was characterized by a coefficient variation less than 5.5%. The specificity of the method is illustrated by representative chromatograms in F I G U R E S 1 T O 3 . No peak overlap was observed between the active ingredients and ingredients contained in the Oral Mix SF suspension, including the aroma. The retention times were 4.1 minutes, 4.6 minutes, and 4.04 minutes for tramadol, fluox-etine, and doxycycline, respectively.
F I G U R E 1 . REPRESENTATIVE CHROMATOGRAMS OF THE EXTEMPORANEOUS ORAL TRAMADOL (30 MG/ML) SUSPENSION IN SYRSPEND SF PH4.
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STABILITY OF THE ORAL SUSPENSIONPhysicochemical Stability No change in color was observed during the studied period as well as no precipitation or macroscopic changes concerning the tramadol and doxycycline oral suspensions. Visual inspection of the fluoxetine suspension stored at refrigerated temperature revealed a coalescence of the suspension on the bottle walls. This phenomenon was observed at room temperature to a lesser extent.
FORCED-DEGRADATION STUDY No degradation of tramadol was observed under neutral and alkaline forced-degradation conditions. Under acidic and oxi-dative forced-degradation conditions, 2% and 47% of tramadol degradation were observed, respectively. A major degradation product appeared at 4.5 minutes. No peak overlap was observed
A B
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F I G U R E 2 . REPRESENTATIVE CHROMATOGRAMS OF THE EXTEMPORANEOUS ORAL FLUOXETINE (10 MG/ML) SUSPENSION IN SYRSPEND SF PH4 WITH CHICKEN AROMA.
After preparation (A); after NaOH treatment (B); after hydrochloride treatment; (C) after hydrogen peroxide treatment (D).
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5.076
4.666
4.384
5.284
4.673
0 2 4 6 8 10
150
100
50
0
Minutes
mA
U
Tramadol 4.1
0 2 4 6 8 10
150
100
50
0
Minutes
mA
U
Tramadol 4.1
0 2 4 6 8 10
150
100
50
0
Minutes
mA
U
Tramadol 4.2
0 2 4 6 8 10
150
100
50
0
Minutes
mA
U
Tramadol 4.1
3.7
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.252 5.109
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U4.246
4.388
8.0275.089
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
5.1
4.671
4.392
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
5.076
4.666
4.384
5.284
4.673
among tramadol, its degradation products, and the excipients. The ultraviolet (UV) spectra of additional products are similar to that of tramadol, confirming that they are degradation products from tramadol. No degradation of fluoxetine was observed under all of the degradation conditions studied. Under acidic conditions, supplementary products were observed under the retention times of 3.89 minutes (48%), 4.38 minutes (11%), and 5.19 minutes (8%) for doxycycline; these new products showed different UV spectra from those of doxycycline. Under oxidative degradation condi-tions, doxycycline completely disappeared (-96%). Despite this result, doxycycline seems to be stable in the neutral and alkaline forced-degradation study.
STABILITY STUDY Temperature monitoring was conducted between 19.8°C ± 2.2 and 25.3°C ± 1.8, and between 3.0°C ± 1.6 and 7.5 °C ± 1.8 for the room
temperature and refrigerated conditions, respectively, during the study course. F I G U R E 4 shows the data in terms of the percentage of recovery of each formulation and storage conditions throughout the duration of the study, and F I G U R E 5 shows the mean of the deviation from the initial concentration. From days 0 through 90, the tramadol and doxycycline concen-trations in the compounded formulations were within the pre-defined acceptable range of 90% to 110% regardless of the storage conditions tested. During the 90 days of the stability study at 25°C and 4°C, the tramadol content remained greater than or equal to 98.0% of the initial content (F I G U R E 4 A A N D 4 B ). The stability of fluoxetine in SyrSpend SF PH4 at 10 mg/mL seemed to be compromised after only 3 days at room temperature and under refrigerated conditions. Indeed, the fluoxetine concen-tration variation reached more than 40% at 4°C storage, a finding that was likely correlated with the physical modification noted at the same time. This result was not observed at 2 mg/mL of fluox-
Peer Reviewed | StabilityESTUDO 34
332International Journal of Pharmaceutical CompoundingVol. 24 No. 4 | July | August | 2020
www.IJPC.com
Peer Reviewed | Stability
etine; the concentration variations were between 5% and 10% dur-ing the study (F I G U R E 4 C A N D 4 D ). Concerning doxycycline, the concentrations of doxycycline in SyrSpend SF PH4 (2 mg/mL) and SyrSpend Cherry (50 mg/mL) were significantly different from the initial dosage, even if they were in the acceptable ranges of 60 days at 2 mg/mL and 90 days at 50 mg/mL (F I G U R E 4 E ).
Discussion The conditions of the stability study were chosen based on the literature data and ICH guidelines. The concentrations of the active ingredients were established based on common prescrip-tions used by veterinarians. Considering all the parameters, the analytical method was validated without interference with excipient ingredients and aroma. Additionally, considering the palatability considerations is crucial to enhance compliance, which can be improved by incorporating flavor into the formula-
F I G U R E 3 . REPRESENTATIVE CHROMATOGRAMS OF THE EXTEMPORANEOUS ORAL DOXYCYCLINE (50 MG/ML) SUSPENSION IN SYRSPEND SF PH4 WITH CHICKEN AROMA.
After hydrochloride treatment (A); after NaOH (B); after hydrogen peroxide treatment (C); after preparation (D)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutesm
AU
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
A B
C D
tion. Because cats and dogs prefer meat-based flavors, we chose chicken aroma.17 Concerning birds and ferrets, no study has inves-tigated their preference; our choice of aroma was based on our practical experience. Concerning the vehicle, Visser et al reported that SyrSpend SF PH4 (liquid) is one of the best vehicles because of its rheologic properties with the sedimentation phenomenon, combined with good resuspension ability and pourability.18 Compatibility studies were investigated for more than 70 pharma-ceutical active ingredients, but none has investigated tramadol, fluoxetine, and doxycycline.19-36 One study reported the compat-ibility of SyrSpend SF PH4 with tablets or capsules when no raw pharmaceutical material is available.37
The present study showed that tramadol suspended in a vehicle such as SyrSpend SF PH4 retains its quality and stability in accor-dance with the ICH guidelines. Data on tramadol stability were not available, and our results confirmed the possibility of com-pounding tramadol in SyrSpend SF PH4 in a range of concentra-tions between 5 mg/mL and 30 mg/mL. These results agree with
ESTUDO 34
333International Journal of Pharmaceutical Compounding
Vol. 24 No. 4 | July | August | 2020www.IJPC.com
Peer Reviewed | Stability
F I G U R E 4 . CHEMICAL STABILITY OF THE ORAL FORMULATIONS.
(A) tramadol in SyrSpend SF PH4 5 mg/mL at room temperature, and the refrigerated temperature for 90 days; (B) tramadol in SyrSpend SF PH4 30 mg/mL at room temperature and the refrigerated temperature for 90 days; (C) fluoxetine in SyrSpend SF PH4 2 mg/mL for 90 days; (D) fluoxetine in SyrSpend SF PH4 10 mg/mL at room temperature and the refrigerated temperature for 90 days (the samples (n=6) were protected from light); (E) doxycycline in SyrSpend Cherry 2 and SyrSpend SF PH4 50 mg/mL at the refrigerated temperature for 90 days (the samples (n=6) were protected from light).
A B
C D
E
Wagner et al who demonstrated the stability of tramadol in syrup and a sugar-free vehicle (5 mg/mL).38
Considering the antimicrobial activity of doxycycline, the stabil-ity of the formulation is critical because any degradation may lead to subtherapeutic dosages and selection of bacterial resistance. The
duration of our stability assay was much longer, considering the rational use of antibiotics. In addition to the decreasing stability over time, this modification appeared in sufficient delay to allow the prescription of this antibiotic. Acidification of water has been reported to greatly improve doxycycline's stability.39 However,
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 2 4 6 8 10
200
150
100
50
0
Minutes
mA
U
3.883
4.038
4.2434.379
5.176
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.042
4.251
0 2 4 6 8 10
300
200
100
0
Minutes
mA
U
4.3864.0334.245
0 2 4 6 8 10
400
300
200
100
0
Minutes
mA
U
4.031
4.237
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%%
of R
ecov
ery
(% In
itial
S
D)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
-+-+
0 10 20 30 40 50 60 70 80 90
120%
110%
100%
90%
80%
% o
f Rec
over
y (%
Initi
al
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
Time (Day)
ESTUDO 34
334International Journal of Pharmaceutical CompoundingVol. 24 No. 4 | July | August | 2020
www.IJPC.com
F I G U R E 5 . MEAN OF THE DEVIATION FROM THE INITIAL CONCENTRATION.
(A) tramadol in SyrSpend SF PH4 5 mg/mL at room temperature and the refrigerated temperature for 90 days; (B) tramadol in SyrSpend SF PH4 30 mg/mL at room temperature, and the refrigerated temperature for 90 days; (C) fluoxetine in SyrSpend SF PH4 2 mg/mL for 90 days; (D) fluoxetine in SyrSpend SF PH4 10 mg/mL at room temperature, and the refrigerated temperature for 90 days; (E) doxycycline in SyrSpend Cherry 2 and SyrSpend SF PH4 50 mg/mL at the refrigerated temperature for 90 days (the samples (n=6) were protected from light).
0 10 20 30 40 50 60 70 80 90
10%
8%
6%
4%
2%
0%
-2%
-4%
-6%
Time (Day)
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
0
-10%
-20%
-30%
-40%
-50%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
A B
C D
E
0 10 20 30 40 50 60 70 80 90
10%
8%
6%
4%
2%
0%
-2%
-4%
-6%
Time (Day)
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
0
-10%
-20%
-30%
-40%
-50%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 10 20 30 40 50 60 70 80 90
10%
8%
6%
4%
2%
0%
-2%
-4%
-6%
Time (Day)
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
0
-10%
-20%
-30%
-40%
-50%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 10 20 30 40 50 60 70 80 90
10%
8%
6%
4%
2%
0%
-2%
-4%
-6%
Time (Day)
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
0
-10%
-20%
-30%
-40%
-50%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
0 10 20 30 40 50 60 70 80 90
10%
8%
6%
4%
2%
0%
-2%
-4%
-6%
Time (Day)
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
-20%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
0
-10%
-20%
-30%
-40%
-50%
Mea
n of
Dev
iatio
n fr
om In
itial
Conc
entr
atio
n (
SD
)-+
0 10 20 30 40 50 60 70 80 90
10%
5%
0%
-5%
-10%
-15%
Mea
n of
Dev
iatio
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om In
itial
Conc
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)-+
Time (Day)
Time (Day)
Time (Day)
Time (Day)
under forced conditions with acidification, we noticed the forma-tion of new derivatives. Naveed et al conducted a degradation study of a commercial prep-aration of doxycycline and demonstrated that acid treatment has
the most degradation impact.40 These degradation products may also be the result of epimerization already described by Jutglar et al.41 One study reported that doxycycline remained stable in water for one week at 37°C; this temperature condition does not reflect
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real storage conditions. We have chosen to investigate the stability of doxycycline hyclate only at 4°C.42 Our results tend to confirm the stability of our formulation until 30 days with a concentration of less than 5% compared with the initial concentration. Similar to previous results reported by Papich et al,16 we have improved the stability of doxycycline using another vehicle. However, the range of concentrations studied were not the same. Finally, it is important to guarantee that the tetracycline formulations are protected from light in tinted bottles to minimize photodegradation, which is a well-known characteristic of tetracyclines.43,44 This phenomenon may not be important for doxycycline, as reported by Jutglar et al.41
Finally, the stability of fluoxetine in SyrSpend SF PH4 was also explored. Under our conditions, considering fluoxetine formula-tions and the conditions of storage, only the formulation at 2 mg/mL was stable. For the highest concentration, after 3 days of storage, the quality of the compounded formulations decreased, as determined by the lack of uniformity in consistency. This phenomenon was more important at the refrigerated temperature. The stability of fluoxetine was already studied in many common aqueous pharma-ceutical vehicles (1 mg/mL and 2 mg/mL) without significant deg-radation.45 Additionally, our results agreed with those at equivalent dosages. No data exist concerning higher concentrations of fluox-etine. We noticed some physical modifications of the preparation that seemed to become thicker. To assess the uniformity problem of the formulations, the samples were heated at 40°C and analyzed. Under these conditions, the percentage of recovery was better and near 95% at the refrigerated temperature and 83% at room tempera-ture. Compounding fluoxetine in SyrSpend SF PH4 might not be recommended for high concentration.
Conclusion Formulas were developed for tramadol, fluoxetine, and doxy-cycline in the oral suspending vehicle SyrSpend to allow easy palatability and rapid extemporaneous preparation. The extempo-raneously prepared oral suspensions were stable for 3 months at the refrigerated and controlled room temperature. These oral suspen-sions may provide an option in situations where the marketed tab-lets are not adapted, particularly for feline treatment. Nevertheless, the bioavailability of these formulations remains unknown and must be explored.
References1. Carlborg B, Densert O. Esophageal lesions caused by orally
administered drugs. An experimental study in the cat. Eur Surg Res. 1980; 12(4): 270–282.
2. Frowde PE, Battersby IA, Whitley NT et al. Oesophageal disease in 33 cats. J Feline Med Surg. 2011; 13(8): 564–569.
3. Papich MG. Drug compounding for veterinary patients. AAPS J. 2005; 7(2): E281–E287.
4. KuKanich B. Outpatient oral analgesics in dogs and cats beyond nonsteroidal anti-inflammatory drugs: An evidence-based
approach. Vet Clin North Am Small Anim Pract. 2013; 43(5): 1109–1125.
5. Raffa RB, Friderichs E, Reimann W et al. Complementary and synergistic antinociceptive interaction between the enantio-mers of tramadol. J Pharmacol Exp Ther. 1993; 267(1): 331–340.
6. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004; 43(13): 879–923.
7. KuKanich B, Papich MG. Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in grey-hounds. Am J Vet Res. 2011; 72(2): 256–262.
8. Pypendop BH, Ilkiw JE. Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats. J Vet Pharmacol Ther. 2008; 31(1): 52–59.
9. Perez Jimenez TE, Mealey KL, Grubb TL et al. Tramadol metab-olism to O-desmethyl tramadol (M1) and N-desmethyl tramadol (M2) by dog liver microsomes: Species comparison and identi-fication of responsible canine cytochrome P-450s (CYPs). Drug Metab Dispos. 2016; 44(12): 1963–1972.
10. Malek S, Sample SJ, Schwartz Z et al. Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis. BMC Vet Res. 2012; 8: 185.
11. Brondani JT, Loureiro Luna SP, Beier SL et al. Analgesic effi-cacy of perioperative use of vedaprofen, tramadol or their com-bination in cats undergoing ovariohysterectomy. J Feline Med Surg. 2009; 11(6): 420–429.
12. Monteiro BP, Klinck MP, Moreau M et al. Analgesic efficacy of tramadol in cats with naturally occurring osteoarthritis. PLoS One. 2017; 12(4): e0175565.
13. Simpson BS, Landsberg GM, Reisner IR et al. Effects of recon-cile (fluoxetine) chewable tablets plus behavior management for canine separation anxiety. Vet Ther. 2007; 8(1): 18–31.
14. Kaur G, Voith VL, Schmidt PL. The use of fluoxetine by veteri-narians in dogs and cats: A preliminary survey. Vet Rec Open. 2016; 3(1): 1–7.
15. Dodman NH, Donnelly R, Shuster L et al. Use of fluoxetine to treat dominance aggression in dogs. J Am Vet Med Assoc. 1996; 209(9): 1585–1587.
16. Papich MG, Davidson GS, Fortier LA. Doxycycline concentra-tion over time after storage in a compounded veterinary prepa-ration. J Am Vet Med Assoc. 2013; 242(12): 1674–1678.
17. Thombre AG. Oral delivery of medications to companion ani-mals: Palatability considerations. Adv Drug Delivery Rev. 2004; 56(10): 1399–1413.
18. Visser JC, Ten Seldam IE, van der Linden IJ et al. Comparison of rheological and sedimentation behavior of commercially available suspending vehicles for oral pharmaceutical prepara-tions. IJPC. 2018; 22(3): 247–251.
19. Polonini HC, Silva SL, Loures S et al. Compatibility of proton pump inhibitors in a preservative-free suspending vehicle. Eur J Hosp Pharm. 2018; 25(3): 150–156.
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20. Binson G, Beuzit K, Migeot V et al. Preparation and physico-chemical stability of liquid oral dosage forms free of poten-tially harmful excipient designed for pediatric patients. Pharmaceutics. 2019; 11(4): 190.
22. Polonini H, da Silva SL, Brandäo MA et al. Compatibility of baclofen, carvedilol, hydrochlorothiazide, mercaptopurine, methadone hydrochloride, oseltamivir phosphate, phenobarbi-tal, propranolol hydrochloride, pyrazinamide, sotalol hydrochlo-ride, spironolactone, tacrolimus monohydrate, ursodeoxycholic acid, and vancomycin hydrochloride oral suspensions com-pounded with SyrSpend SF PH4. IJPC. 2018; 22(6): 516–526.
22. Uriel M, Gómez-Rincón C, Marro D. Stability of regularly pre-scribed oral liquids formulated with SyrSpend® SF. Pharmazie. 2018; 73(4): 196–201.
23. Ferreira AO, Polonini HC, Loures da Silva S et al. Stability of alprazolam, atropine sulfate, glutamine, levofloxacin, metopro-lol tartrate, nitrofurantoin, ondansetron hydrochloride, oxan-drolone, pregabaline, and riboflavin in SyrSpend SF PH4 oral suspensions. IJPC. 2017; 21(3): 255–263.
24. Dijkers E, Nanhekhan V, Thorissen A. Updated stability data for midazolam, oseltamivir phosphate, and propranolol hydrochlo-ride in SyrSpend SF and minoxidil in espumil. IJPC. 2017; 21(3): 240–241.
25. Polonini HC, Loures S, Lima LC et al. Stability of atenolol, clonazepam, dexamethasone, diclofenac sodium, diltiazem, enalapril maleate, ketoprofen, lamotrigine, penicillamine-d, and thiamine in SyrSpend SF PH4 oral suspensions. IJPC. 2016; 20(2): 167–174.
26. Polonini HC, Silva SL, Cunha CN et al. Compatibility of chole-calciferol, haloperidol, imipramine hydrochloride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacrolimus monohydrate, terbinafine, tramadol hydrochloride and valsar-tan in SyrSpend SF PH4 oral suspensions. Pharmazie. 2016; 71(4): 185–191.
27. Polonini HC, Loures S, de Araujo EP et al. Stability of allopuri-nol, amitriptyline hydrochloride, carbamazepine, domperidone, isoniazid, ketoconazole, lisinopril, naproxen, paracetamol (acet-aminophen), and sertraline hydrochloride in SyrSpend SF PH4 oral suspensions. IJPC. 2016; 20(5): 426–434.
28. Ferreira AO, Polonini HC, Silva SL et al. Feasibility of amlodip-ine besylate, chloroquine phosphate, dapsone, phenytoin, pyri-doxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions. J Pharm Biomed Anal. 2016; 118: 105–112.
29. Geiger CM, Sorenson B, Whaley PA. Stability of midazolam in SyrSpend SF and SyrSpend SF cherry. IJPC. 2013; 17(4): 344–346.
30. Geiger CM, Sorenson B, Whaley PA. Stability of captopril in SyrSpend SF. IJPC. 2013; 17(4): 336–338.
31. Sorenson B, Whaley P. Stability of rifampin in SyrSpend SF. IJPC. 2013; 17(2): 162–164.
32. Geiger CM, Voudrie MA 2nd, Sorenson B. Stability of proprano-lol hydrochloride in SyrSpend SF. IJPC. 2012; 16(6): 513–515.
33. Sorenson B, Voudrie MA 2nd, Gehrig D. Stability of gabapentin in SyrSpend SF. IJPC. 2012; 16(4): 347–349.
34. Whaley PA, Voudrie MA 2nd. Stability of vancomycin in SyrSpend SF. IJPC. 2012; 16(2): 167–169.
35. Whaley PA, Voudrie MA 2nd, Sorenson B. Stability of omeprazole in SyrSpend SF Alka (reconstituted). IJPC. 2012; 16(2):164–166.
36. Voudrie MA II, Allen DB. Stability of oseltamivir phosphate in SyrSpend SF, cherry syrup, and SyrSpend SF (for reconstitu-tion). IJPC. 2010; 14(1): 82–86.
37. Dijkers E, Nanhekhan V, Thorissen A et al. Limited influence of excipients in extemporaneous compounded suspensions. Hosp Pharm. 2017; 52(6): 428–432.
38. Wagner DS, Johnson CE, Cichon-Hensley BK et al. Stability of oral liquid preparations of tramadol in strawberry syrup and a sugar-free vehicle. Am J Health Syst Pharm. 2003; 60(12): 1268–1270.
39. Marx JO, Vudathala D, Murphy L et al. Antibiotic administra-tion in the drinking water of mice. J Am Assoc Lab Anim Sci. 2014; 53(3): 301–306.
40. Safila N, Hina Q, Wardha J et al. Degradation study of six dif-ferent brands of doxycycline using UV spectrophotometer. The Global Journal of Pharmaceutical Research. 2014; 3(3): 1978–1984.
41. Jutglar M, Foradada M, Caballero F et al. Influence of the sol-vent system on the stability of doxycycline solutions. J Pharm Biomed Anal. 2018; 159: 60–65.
42. Honnorat-Benabbou VC, Lebugle AA, Sallek B et al. Stability study of tetracyclines with respect to their use in slow release systems. J Mater Sci Mater Med. 2001; 12(2): 107–110.
43. Chen Y, Li H, Wang Z et al. Photoproducts of tetracycline and oxytetracycline involving self-sensitized oxidation in aqueous solutions: Effects of Ca2+ and Mg2+. J Environ Sci (China). 2011; 23(10): 1634–1639.
44. Zakeri B, Wright GD. Chemical biology of tetracycline antibiot-ics. Biochem Cell Biol. 2008; 86(2): 124–136.
45. Peterson JA, Risley DS, Anderson PN et al. Stability of fluox-etine hydrochloride in fluoxetine solution diluted with com-mon pharmaceutical diluents. Am J Hosp Pharm. 1994; 51(10): 1342–1345.
Address correspondence to Dr. C. Prouillac, Université de Lyon, Vetagro Sup, Marcy l’Etoile, France. E-mail: [email protected]
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Stability of Azathioprine, Clonidine Hydrochloride, Clopidogrel Bisulfate, Ethambutol Hydrochloride, Griseofulvin, Hydralazine Hydrochloride, Nitrofurantoin, and Thioguanine Oral Suspensions Compounded with SyrSpend SF PH4
Hudson Polonini, BPharm, PhDSharlene Loures da Silva, BBiomedCarolina Neves Cunha, BPharmAnderson de Oliveira Ferreira, BPharm, PhDKorina Anagnostou, PharmD, MScEli Dijkers, PharmD, PhD
The authors Hudson Polonini, An-derson de Oliveira Ferreira, Korina Anagnostou, and Eli Dijkers are affiliated with Fagron BV, Rotterdam, The Netherlands. The authors Sharlene Loures da Silva and Carolina Neves Cunha are affiliated with Ortofarma – Quality Control Laboratories, Matias Barbosa, MG, Brazil.
AbstractTo allow for tailored dosing and overcome swallowing difficulties, compounded liquid medication is often required in pediatric patients. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients azathioprine (powder) 50 mg/mL, azathioprine (from tablets) 50 mg/mL, clonidine hydrochlo-ride (powder) 0.1 mg/mL, clopidogrel bisulfate (from tablets) 5 mg/mL, ethambu-tol hydrochloride (powder) 50 mg/mL, ethambutol hydrochloride (from tablets) 50 mg/mL, ethambutol hydrochloride (powder) 100 mg/mL, griseofulvin (powder) 25 mg/mL, hydralazine hydrochloride (powder) 4 mg/mL, nitrofuran-toin (powder) 10 mg/mL, and thioguanine (powder) 2.5 mg/mL. Suspensions were compounded at the concentrations listed above and stored at controlled room and refrigerated temperatures. Stability was assessed by measuring the percentage recovery at 0 day (baseline), and at 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography, via a stability-indicating method. The follow-ing oral suspensions compounded using SyrSpend SF PH4 as the vehicle showed a beyond-use date of 90 days when stored both at room or refrigerated tempera-tures: clonidine hydrochloride 0.1 mg/mL, ethambutol hydrochloride 50 mg/mL and 100 mg/mL, griseofulvin 25 mg/mL, nitrofurantoin 10 mg/mL, and thiogua-nine 2.5 mg/mL, all compounded from the active pharmaceutical ingredients in powder form. Suspensions compounded using the active pharmaceutical ingredi-ents from tablets presented a lower beyond-use date: 30 days for ethambutol hydrochloride 50 mg/mL and hydralazine hydrochloride 4 mg/mL, stored at both temperatures, and for clopidogrel bisulfate 5 mg/mL when stored only at refriger-ated temperature. Azathioprine suspensions showed a beyond-use date of 14 days when compounded using active pharmaceutical ingredients in powder form at both temperatures. This suggests that SyrSpend SF PH4 is suitable for compound-ing active pharmaceutical ingredients from different pharmacological classes.
S P F OS T A B I L I T Y P E N E T R A T I O N F O R M U L A T I V E C L I N I C A L S T U D Y O T H E RC
Acknowledgment Compatibility studies were per-formed by Ortofarma under the spon-sorship of Fagron.
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Introduction Drug treatment in children can be more challenging than that seen in adults; age-appropriate drug formulations are required because of the wide age range seen in pediatric patients. Additionally, many children have difficulty swallow-ing tablets and capsules. A suitable liquid alternative with acceptable taste and palatability can help to overcome both hurdles and allow for maximal dosing flex-ibility over different ages. Although many liquid formulations are commercially available, there is still a broad range of drugs that need to be compounded by the pharmacist. To assure accurate treatment of the compounded medication, the dos-ing needs to be in accordance to what is defined in the various pharmacopoeias. In the perception of many doctors and pharmacists, compounded capsules offer a safer alternative to suspensions, as they bypass the risk of sedimentation and cak-ing. An earlier study has shown that for many extemporaneously compounded capsules, a routine weight-variation check does not seem to be enough to guarantee the right content. Compounded oral liquids with SyrSpend SF PH4 (liquid) (Fagron, St. Paul, Minnesota) have shown little variation in content for 74 different active pharmaceutical ingredients (APIs), and were all well within the criteria defined by the United States Pharmacopeia (USP), the European Pharmacopoeia, and the British Pharmacopoeia. Compounding oral liquids were therefore considered to be a valuable alternative when compounding individual-ized medication for patients.1
The purpose of the current study was to determine the stability of different active pharmaceutical ingredients in SyrSpend SF, a vehicle for the compounding of oral liquid dosage forms, providing consistent, individual dosing throughout treatment. This paper focuses on the stability of aza-thioprine, clonidine hydrochloride (HCl), clopidogrel bisulfate, ethambutol HCl, gris-eofulvin, hydralazine HCl, nitrofurantoin, and thioguanine oral suspensions com-pounded with SyrSpend SF PH4.
T A B L E 1 . CONCENTRATIONS OF THE SUSPENSIONS USED IN THE STUDY.
A C T I V E P H A R M A C E U T I C A L I N G R E D I E N T S
Azathioprine
Clonidine hydrochloride
Clopidogrel bisulfate
Ethambutol hydrochloride
Griseofulvin
Hydralazine hydrochloride
Nitrofurantoin
Thioguanine
C O N C E N T R A T I O N I N S U S P E N S I O N
( M G / M L )
50.0
0.1
5.0
50.0 and 100.0
25.0
4.0
10.0
2.5
A C T I O N / I N D I C A T I O N
Immunosuppressant
Alpha-2-adrenoceptor agonist; treatment of hypertension
Inhibitor of adenosine diphosphate-mediated platelet aggregation
Antituberculosis drug
Antifungal
Vasodilator; treatment of hypertension
Antibacterial
Treatment of acute myeloid leukemia; acute lymphocytic leukemia; and chronic myeloid
leukemia
MethodsREAGENTS, REFERENCE STANDARDS, AND MATERIALS All API raw powders and SyrSpend SF PH4 (liquid) (Batch number 14F02-U59-019404) were obtained from Fagron. Concentrations and intended use are listed in TA B L E 1 . High-performance liquid chromatographic (HPLC)-grade reagents (Panreac, Barcelona, Spain) were used. Ultrapure water obtained with an AquaMax-Ultra 370 Series (Young Lin, Anyang, Korea) (18.2 MΩ·cm resistivity at 25°C) was used throughout the experi-ments. The reference standards used were all work standards obtained using primary USP (Rockville, MD) reference materials. All the mobile phases and receptor media were filtered through a 0.45-µm filter membrane (RC-45/15 MS; Chromafil, Düren, Germany) and degassed using an ultrasonic apparatus (Model 1600A; Unique, Indaiatuba, Brazil) for 30 minutes immediately before use. All volumetric glassware and the analytical balance used were previously calibrated.
EQUIPMENT HPLC analyses were performed on a qualified and calibrated chromatography system (Young Lin) composed of a quaternary gradient pump (YL 9110), a photodiode array (PDA) detector (YL 9160), a 96-vial programmable autosampler (YL 9150), a column oven compartment (YL 9130), a variable sample loop up to 200 mL, and a software controller (Clarity).
CHROMATOGRAPHIC CONDITIONS The chromatographic determinations were based upon USP methods for the APIs or their final products, with minor modifica-tions when necessary. The exact chromatographic conditions used
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T A B L E 2 . CHROMATOGRAPHIC CONDITIONS USED IN THE COMPATIBILITY STUDY.
A C T I V E P H A R M A C E U T I C A L I N G R E D I E N T S
Azathioprine
Clonidine hydrochloride
Clopidogrel bisulfate
Ethambutol hydrochloride
Griseofulvin
Hydralazine hydrochloride
Nitrofurantoin
Thioguanine
M O B I L E P H A S E C O M P O S I T I O N
1.1 g of sodium heptanesulfonate in 700 mL of water and 300 mL of methanol; pH adjusted to 3.5 with hydrochloric acid
Acetonitrile and 1 mL/L triethylamine in water (32:68); pH adjusted to 6.9 with phosphoric acid
Acetonitrile and 1.36 g/L potassium phosphate monobasic in water (25:75)
Acetonitrile and 1 mL/L triethylamine in water (50:50); pH adjusted to 7.0 with phosphoric acid
Acetonitrile, tetrahydrofuran, and water (35:5:60)
1.44 g of sodium dodecyl sulfate and 0.75 g of tetrabutylammonium bromide in 770 mL water and 230 mL of acetonitrile. pH adjusted to 3.0 with 0.1N sulfuric acid
Acetonitrile and buffer (12:88). Buffer = 6.8 g of potassium phosphate monobasic in 1000 mL of water; pH adjusted to 7.0 with 1N sodium hydroxide
6 g of sodium phosphate monobasic in 1 L of water; pH adjusted to 3.0 with phosphoric acid
W O R K C O N C E N T R A T I O N
(µG / M L ) *
100; 20-µL injection
50.0; 50-µL injection
100.0, in methanol; 10-µL injection
300.0; 50-µL injection
125; 20-µL injection
40.0; 25-µL injection
250.0, in water and dimethylformamide (2:8);
15-µL injection
40.0, in 0.01M sodium hydroxide; 10-µL injection
C O L U M N
L1, 4.6-mm × 25-cm; at 25°C
L1, 3.9-mm × 30-cm, at 25°C
L1, 4.6-mm × 25-cm, at 25°C
L10, 4.6-mm × 15-cm, at 25°C
L10, 4.6-mm × 25-cm, at 40°C
L10, 4.0-mm × 25-cm, at 25°C
L1, 3.9-mm × 30-cm; at 40°C
L1, 4.6-mm × 5-cm, at 25°C
F L O W ( M L /M I N )
2.0
2.0
1.0
1.0
1.0
1.0
1.2
2.0
U L T R A V I O L E T D E T E C T I O N
W A V E L E N G T H ( N M )
254
220
220
200
254
230
254
248
*Diluted with mobile phase, unless specified otherwise
for each API are stated in TA B L E 2 . The columns were connected with a pre-column with the same packing (4.0 × 3.0 mm, 5 µm) from the same vendor as the columns.
VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD Validation protocol and the acceptance criteria were established based upon USP and International Conference for Harmonisation (ICH) guidelines.2,3 Specificity of the method was determined by running HPLC analyses of a standard solution, a SyrSpend SF PH4 (liquid) blank solution, and a mobile phase/diluents blank solution. The acceptance criterion was defined as a percentage of discrep-ancy between the peak areas of less than 2% (Eq. 1). In addition, the specificity of the method was obtained through comparison of standard chromatograms with and without the SyrSpend SF PH4 (liquid) matrix. All analyses were run in triplicate.
% discrepancy = 100
(standard area - sample area ) Eq. 1 standard area
Precision was evaluated as repeatability and intermediate preci-sion. Repeatability was determined by consecutively analyzing six replicates by a single analyst in a single day. Intermediate precision was also performed in six replicates, but over two days, by different analysts. An injection precision of more than 95% (coefficient of variation (CV) <5%) was considered acceptable. The accuracy of the method was determined through spike-recovery of the SyrSpend SF PH4 (liquid) matrix, diluted within the range used for final sample measurements (to the calibration curves). Percent recovery was calculated from the concentration measured relative to the theoretical concentration spiked. For linearity, concentrations from 70% to 130% of the working concentration of the API in SyrSpend SF PH4 (liquid) were pre-pared and analyzed. The data from each experiment was fitted by ordinary least squares method and was evaluated by analysis of variance (ANOVA). The limit of detection (LOD) and limit of quantification (LOQ) were determined from three standard calibration curves of the APIs in the presence of the SyrSpend SF PH4 (liquid) matrix and were calculated as shown in Eq. 2 and Eq. 3, respectively:
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LOD = s 3 Eq. 2 a
LOQ = s 10 a
Eq. 3
where a is the slope of the calibration curve, and s is the standard deviation of the y-intercept. The LOD and LOQ were con-firmed by the analysis of chromatograms generated by injecting solutions in their respective limit concentrations.
PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS SUSPENSION SAMPLES The suspensions compounded with raw powders were prepared using the following general protocol:
1. The required quantity of each ingredient for the total amount to be prepared was calculated.
2. Each ingredient was accurately weighed.
3. The API was placed in a mortar and triturated until a fine powder was obtained.
4. A small amount of the SyrSpend SF PH4 (liquid) was added to the powder and mixed to form a uni-form paste.
5. The SyrSpend SF PH4 (liquid) was further added in approxi-mately geometric portions almost to volume, mixing thoroughly after each addition.
6. Sufficient SyrSpend SF PH4 (liquid) was added to bring the volume to 300 mL, and then mixed well.
7. The final product was packaged in low-actinic, light-resistant pre-scription bottles and labeled.
8. The suspensions were then imme-diately assayed at T = 0.
9. The suspensions were then sepa-rated into two different 150-mL bottles: one sample was stored at controlled refrigerated (2ºC to 8ºC) and the other at room tem-
Peer Reviewed | Stability
perature (20ºC to 25ºC), for the duration of the study.
10. Temperature and humidity were checked in real-time throughout the duration of the experiment, using a calibrated, digital thermo-hygrometer (Incoterm).
The suspensions compounded with tab-lets were prepared using the following gen-eral protocol:
1. The required quantity of tablets for the total amount to be pre-pared was calculated.
2. The tablets were crushed using a mortar and pestle until a fine pow-der was obtained.
3. The exact quantity of powder needed to prepare the suspension was accurately weighed.
4. A small amount of the SyrSpend SF PH4 (liquid) was added to the powder and mixed to form a uni-form paste.
5. The SyrSpend SF PH4 (liquid) was further added in approxi-mately geometric portions almost to volume, mixing thoroughly after each addition.
6. Sufficient SyrSpend SF PH4 (liquid) was added to bring the volume to 100 mL, and then mixed well.
7. The final product was packaged in low-actinic, light-resistant pre-scription bottles and labeled.
8. The suspensions were then imme-diately assayed at T = 0.
9. The suspensions were then sepa-rated into two different 150-mL bottles: one sample was stored at controlled refrigerated (2ºC to 8ºC) and the other at room tem-perature (20ºC to 25ºC), for the duration of the study.
10. Temperature and humidity were checked in real time throughout the duration of the experiment, using a calibrated, digital thermo-hygrometer (Incoterm).
FORCED-DEGRADATION STUDIES: STABILITY-INDICATING CHARACTERISTICS API samples were subjected to the fol-lowing stressing conditions for 24 hours to determine the capacity of the HPLC method and to detect any possible degradation products that may arise during storage of the oral suspension:
1. Dilution in acid (0.1M HCl, at 25°C);
2. Dilution in base (0.1M NaOH, at 25°C);
3. Exposure to ultraviolet (UV) light at 365 nm (at 25°C);
4. Heating to 70°C; and5. Dilution in H2O2 35% (v/v)
(at 25°C).
These solutions were prepared for each API at its respective work concentra-tion by means of serial dilution from a stock-solution and using suitable diluents (see TA B L E 2 ). The stock solutions were sonically dispersed by 10 minutes, and the final solutions were filtered (15-mm regenerated cellulose syringe filters, with 0.45-µm pore size) before injection onto the HPLC system. Any extraneous peaks found in the chromatograms were labeled. A resolution of 1.5 between the peaks of the degradation products and the API was considered full separation. Also, a discrepancy greater than 2% between the stressed sample peak and the standard, non-stressed sample peak was considered indicative of API decomposition.
STABILITY STUDY The API samples were assayed by HPLC at pre-determined time points to verify the stability of the API in SyrSpend SF PH4 (liquid). Before analyses, the bottles were shaken until the API was uniformly dispersed by visual inspection. Aliquots for quantification (variable for each API) were withdrawn from the middle of the bottles, without contact with the inner surface of the bottle, and diluted in order to obtain work solutions in the concentra-
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Acceptance criteria were: R2 >0.99; F (significance of regression) >>4.67; discrepancy <2%; repeatability and intermediate precision <5%; and recovery = 100% ± 2%. All analytical ranges (µg/mL) were adequate to quantify the APIs in the concentrations used in the suspensions (mg/mL).API = active pharmaceutical ingredient; CV = Coefficient of Variation; HCl = hydrochloride; LOD = Limit of Detection; LOQ = Limit of Quantification (20-µL injections).
T A B L E 3 . SUMMARY OF VALIDATION RESULTS OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC METHODS.
A P I
Azathioprine
Clonidine HCl
Clopidogrel bisulfate
Ethambutol HCl
Griseofulvin
Hydralazine HCl
Nitrofurantoin
Thioguanine
R A N G E (µG / M L )
70.84 – 131.56
7.35 – 13.65
140.00 – 260.00
174.86 – 324.74
87.71 – 162.89
75.00 – 130.00
350.14 – 650.26
28.00 – 52.00
A N A L Y T I C A L C U R V E
y = 47.40x – 50.92
y = 664.80x + 40.27
y = 2.14x - 26.49
y = 233.04x – 926.95
y = 39.20x – 89.57
y = 513.98x – 6598.25
y = 71.24x + 1374.98
y = 6.19x + 29.12
R 2
0.9988
0.9993
0.9931
0.9988
0.9957
0.9909
0.9964
0.9941
ANOVA’S SIGNIFI-
CANCE OF RE-
GRESSION ( F )
10964.58
18826.39
1888.93
10552.86
3053.82
1426.33
3568.05
1095.34
L O D (µG /M L )
1.85
66.73
21.52
4.72
9.15
7.60
0.005
0.06
L O Q (µG / M L )
6.16
222.44
71.72
15.74
30.49
25.32
0.02
0.19
SPECIFICITY
DISCREP-ANCY (%)
|0.89|
|1.67|
|1.02|
|1.76|
|0.44|
|0.67|
|1.97|
|0.95|
PRECISION
REPEAT-ABILITY
(CV, %)
0.12
0.03
0.73
0.31
0.10
0.06
0.35
3.44
INTERMEDI-ATE
PRECISION(CV, %)
0.71
0.45
3.76
0.51
1.11
2.17
0.64
3.39
ACCURACY
RECOVERY (%)
100.11
99.76
100.02
99.94
99.41
99.41
99.39
100.25
L I N E A R I T Y
T A B L E 4 . SUMMARY OF THE STABILITY-INDICATING STUDY FOR THE ACTIVE PHARMACEUTICAL INGREDIENTS.
A C T I V E P H A R M A C E U T I C A L I N G R E D I E N T S
Azathioprin
Clonidine HCl
Clopidogrel bisulfate
Ethambutol HCl
Griseofulvin
Hydralazine HCl
Nitrofurantoin
Thioguanine
HCL
%D*
6.81
-94.38
38.03
-37.94
-34.18
3.79
-73.55
37.52
NAOH
%D*
-34.31
1.29
ND
ND
-2.90
ND
ND
63.44
UV
%D*
-0.51
-9.78
30.15
-1.81
0.34
2.14
1.01
76.89
HEAT
%D*
0.58
10.84
11.75
0.35
-0.67
-1.11
0.82
80.14
H2O 2
%D*
-1.97
-17.53
-27.14
-9.43
-10.04
-2.79
-9.54
ND
Results are presented as the average of 3 replicates, at the work concentration.*%d = percentage of discrepancy between the active pharmaceutical ingredient peak without submission to stressing factors (negative control) and the peak of a sample subjected to one of the cited accelerated-degradation factors.Areas given as mV. Maximum acceptable = 2% (values higher than this are in bold and they represent significant resuts).HCl = hydrochloride; NaOH = sodium hydroxide solution; ND = non-detected; UV = ultraviolet
tion described in TA B L E 1 . Sampling times were: 0 days (T = 0), 7 days (T = 7), 14 days (T = 14), 30 days (T = 30), 60 days (T = 60), and 90 days (T = 90). All suspensions were assayed six times, and the results expressed as the mean from six independent measurements. For that purpose, samples were diluted, sonicated for 10 minutes, and then filtered in 15-mm regenerated cellulose syringe filters, with 0.45-µm pore size before injection onto the HPLC system. The evaluation parameter was the percent recovery with respect to T = 0, using the HPLC method (results given as percentage ± standard deviation).
Results and Discussion Validation studies of all methods of analysis were performed and all results (TA B L E 3 ) met the respective acceptance criteria, confirm-ing the suitability of the methods for the objectives of this work. Stability-indicating studies were also conducted to determine if the used methods were fully validated and adequate to identify decom-position of the APIs by chromatographic analysis. The decom-position profile of the APIs notably varied for different stressing conditions. Acidic stress affected all APIs tested; alkaline stress also affected all APIs except for clonidine HCl; UV-light exposure and heat exposure decomposed clonidine HCl, clopidogrel bisulfate, griseofulvin, and thioguanine; and oxidative stress impacted all but azathioprine and griseofulvin. Once the forced-degradation profiles of the APIs were determined, the stability of the APIs in SyrSpend
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Peer Reviewed | Stability
SF PH4 (liquid) was assessed. Results are summarized in TA B L E 4 . At each sampling time, the visual appearance of the suspensions was also evaluated to verify their homogeneity and physical stability (data not shown). Throughout the whole study, no phenom-ena such as precipitation, turbidity, mac-roscopically visible crystal growth, odor generation, phase separation, flocculation, or caking were observed when the drug content was within specifications. The chemical stability results are shown in TA B L E 5 and are expressed as relative percent of recovery (initial sampling time = 100%). For the suspensions to be consid-ered stable, the relative percentage recovery should lie within 90% to 110%.4
AZATHIOPRINE In our study, a beyond-use date (BUD) of 14 days was observed when the suspensions were compounded from powder and stored at both room and refrigerated temperatures. The suspensions compounded from tablets showed a BUD of 7 days at room temperature. Azathioprine suspensions compounded from tablets were also studied by Dressman and Poust (1983)5 and Allen and Erickson (1996).4 In the first study, little or no loss occurred in 56 days at room temperature or in 84 days at 5ºC, but assay was performed using UV spectrophotometry, which is low sensitive to detect degradation products. By their turn, Allen and Erickson detected losses lower than 4% through HPLC analy-sis after 60 days of storage at room or refrig-erated temperature, when compounded using Ora-Sweet and Ora-Plus.
CLONIDINE HYDROCHLORIDE The clonidine suspensions prepared with SyrSpend SF PH4 in this work presented a BUD of 90 days when stored both at refrig-erated and at room temperatures. This is a higher stability than the one reported by Levinson and Johnson (1992),6 which evaluated clonidine suspension prepared from tablets and with simple syrup: their BUD was reported as 28 days, when stored at 4ºC in the dark.
CLOPIDOGREL BISULFATE Clopidogrel bisulfate 5-mg/mL suspensions com-pounded from tablets and using SyrSpend SF PH4 as the vehicle showed stability for 30 days when stored under refrigeration, and the storage at room tempera-ture is not recommended due to instability. Skillman et al7 evaluated suspensions with the same API, in the same concentration, and in the same storage conditions, but, in that study, the suspen-sions were prepared with Ora-Plus and Ora-Sweet and using Plavix tablets as the raw material. They found that the suspensions remained stable for 60 days in both storage conditions, although the bitter aftertaste of the product intensified between 28 days and 60 days. Tynes et al8 complemented the study of Skillman et al and verified that during this period the oral suspension of clopidogrel retained at least 98% of the active S-enantiomer for 60 days (more chiral inversion was noted in the clopidogrel suspension stored at room temperature).
ETHAMBUTOL HYDROCHLORIDE Three ethambutol suspensions were evaluated in the present study, all compounded using SyrSpend SF PH4 as the vehicle, with 50 mg/mL and 100 mg/mL prepared from the API as powder and 50 mg/mL pre-pared from tablets (Combutol 800). The suspensions prepared from the powder remained stable for the 90-day period of study, with no physical or chemical intercurrences. The suspensions prepared from the tablets remained stable for 30 days, indicating a pos-sible reaction between the vehicle and the excipients of this particular tablet used. According to the USP,9 a 100-mg/mL suspension compounded with equal parts of Ora-Plus and Ora-Sweet SF has a BUD of 90 days, but no specific stability study was found in the literature.
GRISEOFULVIN Griseofulvin 25-mg/mL suspensions compounded with SyrSpend SF PH4 presented a BUD of at least 90 days when stored at refrigerated or room tempera-tures. Losses of less than 2% were found throughout the study, and no physical change was detected. No other report from literature was found for a parameter for comparison.
HYDRALAZINE HYDROCHLORIDE Hydralazine HCl 4-mg/mL oral suspensions com-pounded using SyrSpend SF PH4 as the vehicle pre-
sented a BUD of at least 30 days when stored both at refriger-ated and at room temperatures. Hydralazine HCl oral suspen-sions were extensively studied. Alexander et al10 evaluated various potential adjuvants for compounding the suspen-sion with syrup and tablets, but HPLC analyses calculated a shelf life of only 5.13 days at room temperature and 14 days at 5ºC, and they have found that hydralazine HCl was incompat-ible with sodium edetate and sodium bisulfite. Gupta et al11 investigated the stability of 1% hydralazine HCl with vari-ous aqueous agents, and they verified losses of 30% to 70% in 24 hours when stored at 24ºC. In the same study, they evaluated the 1% API in 85% sucrose solution, and losses of 10% occurred in about 7 days at 24ºC; in 0.28 mM mannitol, no loss occurred after 21 days of storage at 24ºC. Allen and Erickson12 evaluated the API at 4 mg/mL in Ora-Sweet and Ora-Sweet SF, but losses of 22% and 13% were observed in 1 day for Ora-Sweet and Ora-Sweet SF, respectively; at refrigerated temperature, losses lower than 10% were observed in 1 day for Ora-Sweet and 2 days for Ora-Sweet SF.
NITROFURANTOIN Nitrofurantoin 10-mg/mL oral suspensions compounded using SyrSpend SF PH4 as the vehicle presented less than 1% of loss in the API amount dur-ing the duration of the study, which accounts for a BUD of 90 days. A previous study from Ferreira et al13 observed the same BUD, but for a 2-mg/mL suspension in the same vehicle
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Peer Reviewed | Stability
T A B L E 5 . STABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID).
E L A P S E D T I M E ( D A Y S )
AZATHIOPRINE (FROM POWDER) 50.0 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
AZATHIOPRINE (FROM TABLETS) 50.0 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
CLONIDINE HYDROCHLORIDE (FROM POWDER) 0.1 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
CLOPIDOGREL BISULFATE (FROM TABLETS) 5 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
ETHAMBUTOL HYDROCHLORIDE (FROM POWDER) 50 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
ETHAMBUTOL HYDROCHLORIDE (FROM TABLETS) 50 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
% RECOVERY
REFRIGERATED TEMPERATURE
(2ºC TO 8ºC)
100 ± 1.69
99.35 ± 0.60
100.81 ± 0.66
82.33 ± 0.81
NP
NP
100 ± 0.38
77.90 ± 0;39
ND
NP
NP
NP
100 ± 0.27
95.20 ± 0.10
95.75 ± 0.98
96.82 ± 0.83
96.34 ± 0.55
95.99 ± 0.47
100 ± 0.90
103.02 ± 0.81
96.18 ± 0.45
101.14 ± 0.72
ND
NP
100 ± 0.35
101.54 ± 0.79
98.58 ± 0.27
98.66 ± 0.20
99.69 ± 0.42
99.14 ± 0.23
100 ± 0.77
94.03 ± 0.16
93.09 ± 1.10
96.54 ± 0.32
70.88 ± 0.21
NP
CONTROLLED ROOM TEMPERATURE
(20ºC TO 25ºC)
100 ± 1.69
99.94 ± 0.51
100.64 ± 0.61
77.83 ± 1.61
NP
NP
100 ± 0.38
100.29 ± 0.22
82.96 ± 0.34
ND
NP
NP
100 ± 0.27
94.52 ± 0.76
96.17 ± 1.14
95.56 ± 0.71
95.88 ± 0.60
98.23 ± 0.45
100 ± 0.90
ND
NP
NP
NP
NP
100 ± 0.35
97.53 ± 1.92
99.61 ± 2.52
98.82 ± 0.31
95.45 ± 0.53
98.09 ± 0.40
100 ± 0.77
93.45 ± 0.20
91.69 ± 0.60
94.37 ± 0.36
80.15 ± 0.14
NP
E L A P S E D T I M E ( D A Y S )
REFRIGERATED TEMPERATURE
(2ºC TO 8ºC)
CONTROLLED ROOM TEMPERATURE
(20ºC TO 25ºC)
% RECOVERY
T A B L E 5 C O N T I N U E D . STABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID).
ETHAMBUTOL HYDROCHLORIDE (FROM POWDER) 100 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
GRISEOFULVIN (FROM POWDER) 25 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
HYDRALAZINE HYDROCHLORIDE (FROM POWDER) 4 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
NITROFURANTOIN (POWDER) 10 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
THIOGUANINE (FROM POWDER) 2.5 MG/ML
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
100 ± 0.26
94.84 ± 0.38
94.99 ± 0.19
94.31 ± 0.78
94.96 ± 0.46
94.91 ± 0.63
100 ± 0.17
100.03 ± 0.23
98.51 ± 0.18
99.28 ± 0.25
98.81 ± 0.10
98.42 ± 0.29
100 ± 0.57
100.25 ± 0.26
102.32 ± 0.40
101.90 ± 0.21
67.32 ± 0.53
NP
100 ± 0.34
96.77 ± 0.82
98.59 ± 0.58
100.12 ± 0.65
99.67 ± 0.26
99.89 ± 0.39
100 ± 1.03
101.05 ± 0.24
101.76 ± 0.38
101.79 ± 0.31
100.88 ± 2.33
101.37± 0.37
100 ± 0.26
97.78 ± 0.59
96.66 ± 0.23
98.23 ± 0.55
98.89 ± 0.56
97.91 ± 0.75
100 ± 0.17
101.20 ± 0.20
101.48 ± 0.19
101.87 ± 0.34
101.68 ± 0.16
100.83 ± 0.25
100 ± 0.57
101.75 ± 0.50
97.10 ± 0.41
98.05 ± 0.45
65.02 ± 2.02
NP
100 ± 0.34
100.26 ± 0.89
99.32 ± 0.29
100.07 ± 0.40
100.11 ± 0.38
99.88 ± 0.45
100 ± 1.03
100.43 ± 0.13
102.04 ± 0.24
101.59 ± 0.11
99.15 ± 1.68
100.03 ± 1.06
ND = not detected; NP = not performed
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259International Journal of Pharmaceutical Compounding
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(losses of less than 1.5%), which indicates that this API has a good stability in SyrSpend SF PH4. No other report using other vehicles was found in available literature.
THIOGUANINE Thioguanine suspensions (2.5 mg/mL) compounded with SyrSpend SF PH4 and stored at room or refrigerated temperatures showed no significant loss of API during the period of 90 days of evaluation. Dressman and Poust5 previously evaluated the stability of thioguanine 40 mg/mL in a suspension prepared from tablets and Cologel (Lilly) and a 2:1 mixture of simple and cherry syrups. Their suspension was stored in amber glass bottles at 5ºC and at ambient temperature, and remained stable for 84 days. A plot of the APIs in SyrSpend SF PH4 throughout the compat-ibility study is represented in F I G U R E 1 .
Conclusion The following oral suspensions compounded using SyrSpend SF PH4 as the vehicle and compounded from the API in powder form showed a BUD of 90 days when stored both at room or refrigerated temperatures: clonidine HCl 0.1 mg/mL, ethambutol HCl 50 mg/mL and 100 mg/mL, griseofulvin 25 mg/mL, nitrofurantoin 10 mg/mL, and thioguanine 2.5 mg/mL. Suspensions compounded using the API from tablets presented a lower BUD: 30 days for ethambutol HCl 50 mg/mL and hydralazine HCl 4 mg/mL, stored at both tempera-tures, and for clopidogrel bisulfate 5 mg/mL when stored only at refrigerated temperature. Azathioprine suspensions showed a BUD of 14 days when compounded using API in powder form, at both temperatures. In an earlier publication with SyrSpend SF PH4 liq-uid, no influence of excipients of tablets and capsules on the BUD of several APIs was found.1 This new publication suggests that raw pharmaceutical materials can be the preferred source for certain APIs. Considering this new result and the previous ones from litera-ture,13-39 it is noteworthy that SyrSpend SF is one the most studied oral vehicles worldwide, with over 100 different API compatibility combinations studied.
References1. Dijkers E, Nanhekhan V, Thorissen A et al. Suspensions as a
valuable alternative to extemporaneously compounded cap-sules. IJPC. 2017; 21(2): 171–175.
2. United States Pharmacopeial Convention, Inc. United States Pharmacopeia–National Formulary. [USP Website.] Available at: https://online.uspnf.com/uspnf/document/GUID-E2C6F9E8-EA71-4B72-A7BA-76ABD5E72964_4_en-US?highlight=validation. Accessed 2019.
3. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Validation of Analytical Procedures: Text and Methodology Q2(R1). (ICH Website.] Available at: www.ich.org. Accessed 2019.
Peer Reviewed | Stability
F I G U R E 1 . PLOT OF ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 THROUGHOUT THE COMPATIBILITY STUDY.
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
Time (Days)
0 30 60 90
0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
120
110
100
90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
Time (Days)
0 30 60 90
0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
120
110
100
90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
Time (Days)
0 30 60 90
0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
120
110
100
90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
Dashed lines represent the lower and upper limits, corresponding to 90% and 100% of labeled concentration; blue lines represent results from storage at controlled refrigerated temperature (2°C to 8°C); orange lines correspond to storage at controlled room temperature (20°C to 25°C). Values represent the relative average recovery, as mg/mL (n=6).
ESTUDO 33
260International Journal of Pharmaceutical CompoundingVol. 24 No. 3 | May | June | 2020
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F I G U R E 1 C O N T I N U E D . PLOT OF ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 THROUGHOUT THE COMPATIBILITY STUDY.
Peer Reviewed | Stability
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Pow
der)
Time (Days)
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60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
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0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
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120
110
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90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
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0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
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60
55
50
45
40
35[Aza
thio
prin
e] m
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L (f
rom
Pow
der)
Time (Days)
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60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
Time (Days)
0 30 60 90
0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
120
110
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90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
Time (Days)
0 30 60 90
0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
120
110
100
90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
Time (Days)
0 30 60 90
0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
120
110
100
90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
60
55
50
45
40
35[Aza
thio
prin
e] m
g/m
L (f
rom
Tab
lets
)
Time (Days)
0 30 60 90
0.12
0.11
0.10
0.09
0.08[Clo
nidi
ne H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
[Clo
pido
grel
bis
ulfa
te]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
60
55
50
45
40
35
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m T
able
ts)
Time (Days)
0 30 60 90
120
110
100
90
80
[Eth
ambu
tol H
Cl]
mg/
mL
(fro
m P
owde
r)Time (Days)
0 30 60 90
30
28
26
24
22
20[Gris
eofu
lvin
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
4.5
4.0
3.5
3.0
2.5
[Hyd
rala
zine
HCl
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
12
11
10
9
8[Nitr
ofur
anto
in]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
3.0
2.8
2.6
2.4
2.2
2.0[Thi
ogua
nine
] m
g/m
L (f
rom
Pow
der)
Time (Days)
Dashed lines represent the lower and upper limits, corresponding to 90% and 100% of labeled concentration; blue lines represent results from storage at controlled refrigerated temperature (2°C to 8°C); orange lines correspond to storage at controlled room temperature (20°C to 25°C). Values represent the relative average recovery, as mg/mL (n=6).
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4. Allen LV Jr., Erickson MA 3rd. Stability of acetazolamide, allopurinol, azathioprine, clonazepam, and flucytosine in extemporaneously compounded oral liquids. Am J Health Syst Pharm. 1996; 53(16): 1944–1949.
5. Dressman JB, Poust RI. Stability of allopurinol and of five antineoplastics in suspension. Am J Hosp Pharm. 1983; 40(4): 616–618.
6. Levinson ML, Johnson CE. Stability of an extemporaneously compounded clonidine hydrochloride oral liquid. Am J Hosp Pharm. 1992; 49(1): 122–125.
7. Skillman KL, Caruthers RL, Johnson CE. Stability of an extemporaneously prepared clopidogrel oral suspension. Am J Health Syst Pharm. 2010; 67(7): 559–561.
8. Tynes CR, Livingston B, Patel H et al. Chiral stability of an extemporaneously prepared clopidogrel bisulfate oral suspen-sion. J Pediatr Pharmacol Ther. 2014; 19(1): 25–29.
9. United States Pharmacopeial Convention, Inc. United States Pharmacopeia–National Formulary. [USP Website.] Available at: https://online.uspnf.com/uspnf/document/GUID-B88ED6EE-7E72-400E-8D65-56554C0DC25B_1_en-US?highlight=ethambutol. Accessed 2019.
10. Alexander KS, Pudipeddi M, Parker GA. Stability of hydrala-zine hydrochloride syrup compounded from tablets. Am J Hosp Pharm. 1993; 50(4): 683–686.
11. Das Gupta V, Stewart KR, Bethea C. Stability of hydralazine hydrochloride in aqueous vehicles. J Clin Hosp Pharm. 1986; 11(3): 215–223.
12. Allen LV Jr., Erickson MA 3rd. Stability of alprazolam, chloro-quine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids. Am J Health Syst Pharm. 1998; 55(18): 1915–1920.
13. Ferreira AO, Polonini HC, da Silva Loures S et al. Stability of alprazolam, atropine sulfate, glutamine, levofloxacin, meto-prolol tartrate, nitrofurantoin, ondansetron hydrochloride, oxandrolone, pregabaline, and riboflavin in SyrSpend SF pH4 oral suspensions. IJPC. 2017; 21(3): 255–263.
14. Geiger CM, Sorenson B, Whaley P. Stability assessment of 10 active pharmaceutical ingredients compounded in SyrSpend SF. IJPC. 2015; 19(5): 420–427.
15. Ferreira AO, Polonini HC, Silva SL et al. Feasibility of amlodip-ine besylate, chloroquine phosphate, dapsone, phenytoin, pyri-doxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend® SF PH4 oral suspensions. J Pharm Biomed Anal. 2016; 118: 105–112.
16. Polonini HC, Loures S, Lima LC et al. Stability of atenolol, clonazepam, dexamethasone, diclofenac sodium, diltiazem, enalapril maleate, ketoprofen, lamotrigine, penicillamine-d, and thiamine in SyrSpend SF PH4 oral suspensions. IJPC. 2016; 20(2): 167–174.
17. Geiger CM, Sorenson B, Whaley PA. Stability of captopril in SyrSpend SF. IJPC. 2013; 17(4): 336–338.
Peer Reviewed | Stability
Dashed lines represent the lower and upper limits, corresponding to 90% and 100% of labeled concentration; blue lines represent results from storage at controlled refrigerated temperature (2°C to 8°C); orange lines correspond to storage at controlled room temperature (20°C to 25°C). Values represent the relative average recovery, as mg/mL (n=6).
F I G U R E 1 C O N T I N U E D . PLOT OF ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 THROUGHOUT THE COMPATIBILITY STUDY.
0 30 60 90
4.5
4.0
3.5
3.0
2.5
[Hyd
rala
zine
HCl
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
12
11
10
9
8[Nitr
ofur
anto
in]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
3.0
2.8
2.6
2.4
2.2
2.0[Thi
ogua
nine
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
4.5
4.0
3.5
3.0
2.5
[Hyd
rala
zine
HCl
] m
g/m
L (f
rom
Pow
der)
Time (Days)
0 30 60 90
12
11
10
9
8[Nitr
ofur
anto
in]
mg/
mL
(fro
m P
owde
r)
Time (Days)
0 30 60 90
3.0
2.8
2.6
2.4
2.2
2.0[Thi
ogua
nine
] m
g/m
L (f
rom
Pow
der)
Time (Days)
ESTUDO 33
262International Journal of Pharmaceutical CompoundingVol. 24 No. 3 | May | June | 2020
www.IJPC.com
Peer Reviewed | Stability
18. Polonini HC, Silva SL, Cunha CN et al. Compatibility of cholecalciferol, haloperidol, imipramine hydrochlo-ride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacrolimus monohydrate, terbinafine, trama-dol hydrochloride and valsartan in SyrSpend SF PH4 oral suspensions. Pharmazie. 2016; 71(4): 185–191.
19. Sorenson B, Voudrie MA III, Gehrig D. Stability of gabapentin in SyrSpend SF. IJPC. 2012; 16(4): 347–349.
20. Vu NT, Aloumanis V, Ben MJ et al. Stability of metronidazole benzoate in SyrSpend SF One-step Suspension System. IJPC. 2008; 12(6): 558–564.
21. Geiger CM, Sorenson B, Whaley PA. Stability of midazolam in SyrSpend SF and SyrSpend SF Cherry. IJPC. 2013; 17(4): 344–346.
22. Whaley PA, Voudrie MA III, Sorenson B. Stability of Omeprazole in SyrSpend SF Alka (Reconstituted). IJPC. 2012; 16(2): 164–166.
23. Voudrie MA, Allen B. Stability of osel-tamivir phosphate in SyrSpend SF, Cherry Syrup and SyrSpend SF (for reconstitution). IJPC. 2010; 14: 82–85.
24. Geiger CM, Voudrie MA III, Sorensen B. Stability of propranolol hydrochlo-ride in SyrSpend SF. IJPC. 2012; 16(6): 513–515.
25. Sorenson B, Whaley P. Stability of rifampin in SyrSpend SF. IJPC. 2013; 17(2): 162–164.
26. Geiger CM, Voudrie MA, Sorenson B. Stability of ursodiol in SyrSpend SF Cherry Flavored. IJPC. 2012; 16(6): 510–512.
27. Whaley PA, Voudrie MA. Stability of vancomycin in SyrSpend SF. IJPC. 2012; 16(2): 167–169.
28. Voudrie MA, Alexander B, Allen DB. Stability of verapamil hydrochloride in SyrSpend SF compared to sorbitol con-taining syrup and suspending vehicles. IJPC. 2011; 15(3): 255–258.
29. Polonini HC, Loures S, de Araujo ED et al. Stability of allopurinol, amitrip-tyline hydrochloride, carbamazepine, domperidone, isoniazid, ketoconazole, lisinopril, naproxen, paracetamol
(acetaminophen), and sertraline hydrochlo-ride in SyrSpend SF PH4 Oral Suspensions. IJPC. 2016; 20(5): 426–434.
30. Polonini HC, Silva SL, de Almeida TR et al. Compatibility of caffeine, carvedilol, clo-mipramine hydrochloride, folic acid, hydro-chlorothiazide, loperamide hydrochloride, methotrexate, nadolol, naltrexone hydro-chloride and pentoxifylline in SyrSpend SF PH4 oral suspensions. Eur J Hosp Pharm. 2016; 23(6): 352–358.
31. Polonini HC, Silva SL, Loures S et al. Compatibility of proton pump inhibitors in a preservative-free suspending vehicle. Eur J Hosp Pharm. 2018; 25(3): 150–156.
32. Dijkers EC, Nanhekhan V, Thorissen A. Updated stability data of midazolam, osel-tamivir phosphate, and propranolol hydro-chloride in SyrSpend SF and Minoxidil in Espumil. IJPC. 2017; 21(3): 240–241.
33. De Oliveira FA, Polonini HC, Loures da Silva S et al. Stability of acetazolamide, baclofen, dipyridamole, mebeverine hydrochloride, propylthiouracil, quinidine sulfate, and topiramate oral suspensions in SyrSpend SF PH4. IJPC. 2017; 21(4): 339–346.
34. Uriel M, Gómez-Rincón C, Marro D. Stability of regularly prescribed oral liquids formulated with SyrSpend® SF. Pharmazie. 2018; 73(4): 196–201.
35. Barbazan C, Le Daré B, Lester MA et al. Etude de Stabilité D’une Suspension Buvable de Cloxacilline a Usage Pédiatrique. Poster presentation at 11th Rencontres Convergences Santé Hôpital 2016.
36. Bonnaure AC, Bellay R, Rault P et al. Stabilité dúne suspension buvable de nitrendipine 5 mg/mL. Poster presenta-tion at 11th Rencontres Convergences Santé Hôpital 2016.
37. Bonnaure AC, Bellay R, Rault P et al. Stability Study of 5 mg/mL Pediatric Prednisone Oral Suspension in Syrspend®. 20th European GERPAC Conference 2017.
38. Boivin PN, Geffroy C, Tron C et al. PP-054 Stability study of 100 mg/mL paediatric pyrazinamide oral suspension in SyrSpend. Eur J Hosp Pharm. 2017; 24(Suppl 1): A225.
39. Guillois G, Fetique L, Perovic I et al. PP-028 Stability study of 1 mg/mL paediatric warfa-rin oral suspension in SyrSpend. Eur J Hosp Pharm. 2017; 24(Suppl 1): A214.
Address correspondence to Hudson Polonini, Fagron BV, Rotterdam, The Netherlands. E-mail: [email protected]
ESTUDO 33
Data in Brief 30 (2020) 105552
Contents lists available at ScienceDirect
Data in Brief
journal homepage: www.elsevier.com/locate/dib
Data Article
Data on the stability of darunavir/cobicistat
suspension after tablet manipulation
D. Zanon a , A. Manca b , A. De Nicolòb , A. D’Avolio b , U.M. Musazzi c , F. Cilurzo c , N. Maximova a , C. Tomasello d , P. Minghetti c , ∗
a Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy b Laboratory of Clinical Pharmacology and Pharmacogenetics, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy c Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Giuseppe Colombo, 71, 20133 Milan, Italy d S.C. Farmacie Ospedaliere - Ospedale M. Vittoria - Asl Città di Torino, Turin, Italy
a r t i c l e i n f o
Article history: Received 27 March 2020 Revised 3 April 2020 Accepted 6 April 2020 Available online 12 April 2020
Keywords: Covid-19 Medicament manipulation Nasogastric tube Darunavir Cobicistat
a b s t r a c t
The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treat- ments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortu- nately, for most of them, the drug products available on the market are not designed to be administered by a naso- gastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the prod- uct quality, is necessary for the preparation of suspension to meet patients’ need. In this situation, it is urgent to pro- vide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by phar- macists using as active ingredient a commercially available tablet can be stable at least for one week.
© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
∗ Corresponding author. E-mail address: [email protected] (P. Minghetti).
https://doi.org/10.1016/j.dib.2020.105552 2352-3409/© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
ESTUDO 32
2 D. Zanon, A. Manca and A. De Nicolò et al. / Data in Brief 30 (2020) 105552
Specifications table
Subject Pharmacology, Toxicology and Pharmaceutical Science Specific subject area Pharmaceutical Science Type of data Table, Figure, Text How data were acquired High pressure liquid chromatography (HPLC) Data format Raw and analysed Parameters for data collection Data on darunavir/cobicistat stability in suspension through one week from
the preparation after storage at 4 ° and room temperature (RT) Description of data collection The drug suspension was prepared in a hospital pharmacy by manipulating the
darunavir/cobicistat tablet. The drug stability in two-vehicle suspensions was tested at different storage conditions (4 °C, RT) for one week. The samples at different time points were analysed by HPLC.
Data source location Turin, Italy Data accessibility Analysed data with the article.
Raw data and chromatogram with supplementary materials.
Value of the data
• The data provide evidence on the darunavir/cobicistat chemical stability when they are sus- pended in different vehicles and stored for one week at different conditions.
• The data can be useful to healthcare professionals that are trying to fight against the COVID- 19 outbreak.
• These data can support further clinical studies focused on investigating the effectiveness of darunavir/cobicistat against COVID-19, especially when the commercially available drug prod- uct has to be manipulated to meet clinical needs.
• The data are insights for further studies focused on the development of new dosage forms indicated for inpatients of intensive care units.
1. Data description
One of the possible pharmacological treatment of COVID-19 patients resides in the admin- istration of antiretroviral medicines [1] . The situation is complicated by the absence of ad hoc authorised pharmacological therapies. Many antivirals, including darunavir and cobicistat, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortu- nately, their manipulation is sometimes necessary because they are not always formulated to be administered to non-cooperative patients, like those in intensive care units. Thus, the activity of hospital pharmacists for the compounding of extemporaneous suspensions by manipulation of authorized medicinal products is crucial to provide such life-treating treatments to the hospital wards [2] . However, the manipulation of medicines can alter their quality profile with potential impact on the efficacy and safety of the pharmacological treatment. Therefore, such compound- ing activities must be guided by the provisions of the Good Compounding Practice and by other available technical guidelines to assure the required quality and the stability of the preparation over time [3] .
For example, the darunavir/cobicistat fixed combination was authorised in the EU as film- coated tablets (i.e. Rezolsta R ©), which cannot be administered to inpatients by using a naso- gastric tube. The compounding activity of pharmacists consists of the grinding of the dosage forms and the preparation of a stable suspension. Herein, the chemical stability data of darunavir and cobicistat suspended in two different vehicles, namely a commercially available base vehicle (Syrspend R ©) and a 1% w/v carboxymethyl cellulose (CMC) aqueous suspension, is presented.
Tables 1 and 2 reported the data on both drug assay obtained storing extemporaneous sus- pensions of the powder obtained by the manipulation of the fixed drug combination at 4 °C and room temperature (RT).
ESTUDO 32
D. Zanon, A. Manca and A. De Nicolò et al. / Data in Brief 30 (2020) 105552 3
Table 1 Data on the chemical stability of darunavir and cobicistat in Syrspend R ©-based extemporaneous suspension when stored through one week at 4 °C or at room temperature (RT; ≈25 °C) expressed as mean percentage and relative standard deviation (RSD%).
Storage condition Sampling times (days) Drug assay (%) RSD (%)
Darunavir Cobicistat Darunavir Cobicistat
at 4 °C
0 100.0 100.0 7.4% 7.0% 3 120.2 121.8 12.5% 7.8% 7 120.4 120.0 8.5% 8.2%
at RT
0 100.0 100.0 7.4% 7.0% 3 112.5 111.4 17.9% 9.0% 7 104.3 104.6 1.9% 2.1%
Table 2 Data on the chemical stability of darunavir and cobicistat in CMC-based extemporaneous suspension when stored through one week at 4 °C or RT ( ≈25 °C) expressed as mean percentage and relative standard deviation (RSD%).
Storage condition Sampling times (days) Drug assay (%) RSD (%)
Darunavir Cobicistat Darunavir Cobicistat
at 4 °C
0 100.0 100.0 1.9% 2.5% 3 93.4 92.8 11.4% 4.2% 7 105.4 91.1 22.4% 2.4%
at RT.
0 100.0 100.0 1.9% 2.5% 3 115.6 113.7 3.6% 2.8% 7 123.0 106.4 13.3% 7.3%
The high-variability of data obtained by Syrspend R ©-based extemporaneous suspension can be justified since its sampling resulted more complex than CMC one due to the higher viscosity. Nevertheless, the data show that both drugs remained within ± 20% of the initial value. Such data are a proof-of-concept that both drug substances are chemically stable in the suspension over one week, regardless of the vehicle and the storage condition.
2. Experimental design, materials, and methods
2.1. Materials
Rezolsta R © 800 mg/150 mg film-coated tablets (Janssen-Cilag International NV, I). Tablet core : hypromellose, colloidal silicon dioxide, silicified microcrystalline cellulose, crospovidone, magne- sium stearate. Tablet film-coat : polyvinyl alcohol–partially hydrolysed, macrogol 3350, titanium dioxide, talc, iron oxide red, iron oxide black [4] .
Sodium carboxymethyl cellulose (CMC), trisodium citrate dihydrate, and citric acid were purchased by Farmalabor (I). Syrspend R © was purchased by Fagron Italia. All other chemi- cals/solvents used in the study were either analytical grade and used without further purifi- cation.
2.2. Suspension preparation
Two tablets of Rezolsta R © were crushed in a mortar to obtain a fine and homogenous powder. Then, the powder was precisely weighed and loaded in a 50-ml syringe. Using a female-female Luer-lock connector, the syringe was linked to another one containing 20-mL of the suspension vehicle. Syrspend R © and 1% w/v CMC solution in pH 4.2 citrate buffer were used as vehicles. The vehicle volume was set up to obtain a final suspension containing 20 mg/ml of darunavir and 3.75 mg/ml of cobicistat. Moving the syringe plungers, the powder and the solution had mixed each other to reach a homogenous whitish suspension (appx. 50 syringe complete movements).
ESTUDO 32
4 D. Zanon, A. Manca and A. De Nicolò et al. / Data in Brief 30 (2020) 105552
Table 3 Chromatographic condition (Gradient).
Time (min) Solvent A% Solvent B% Flow (mL/min)
0.0 70 30 1 5.0 61 39 1 7.0 56 44 1 10.0 54 46 1 11.0 51 49 1 13.0 48 52 1 15.5 47 53 1 18.0 47 53 1 19.8 46 54 1 19.9 41 59 1 20.0 30 70 1 23.9 30 70 1 24.0 70 30 1 28.0 70 30 1
2.3. Stability studies
Aliquots of the suspensions (1.5 mL each) were stored at both 4 °C and RT for one week. At fixed sampling times (0, 3, 7 days), the aliquots of each suspension were heated to RT, if necessary, and mixed by a vortex. The samples were diluted 1:1 with a mixture of acetoni- trile/water (40/60 % v/v), mixed by vortex and, then, sonicated until a homogeneous suspension was obtained. The sample was split into three replicates diluted 1:125 with a mixture of ace- tonitrile/water (40/60 % v/v). The obtained dilutions were sonicated and mixed by mechanical agitator for 30 min before being analysed in HPLC.
2.4. HPLC method
The method was developed and validated modifying a previous published method for plasma analyses [5] . The analysis was carried out with a liquid chromatographer Waters 2695 HPLC sys- tem (Milan, Italy) coupled with a 2998 PDA detector. HPLC-PDA system was controlled by Em- power 2 Pro-software (version year 2005; Waters). A chromatographic column Luna 5 µm C18 (150 ×4.6 mm; Phenomenex, US), protected by a C18 security guard (4.0 ×3.0 mm; Phenomenex, US) was used for chromatographic separation. The temperature Control Module II (Waters) was set at 45 °C. The run was performed at 1 mL/min and the temperature was set at 45 °C; the mo- bile phase was composed of solvent A (KH 2 PO 4 50 mM with orthophosphoric acid, pH = 3.23) and solvent B (acetonitrile). The selected wavelength to quantify each drug was: 267 nm for Darunavir and 241 nm for Cobicistat. The runtime was 28 min. Chromatographic Condition (Gra- dient) were set as shown in Table 3 . Chromatograms of placebo and drug-loaded suspension vehicles were reported in Supplementary materials.
Preliminary, stress tests were performed on aliquots of the obtained extemporaneous suspen- sions to identify degradation patterns of both drugs. Aliquots of both suspensions were stored in the following conditions: at 96 °C, at RT and 96 °C after the addition of phosphoric acid pH 2.5, at RT and 96 °C after the addition of ammonia pH 10. Chromatograms of the observed degrada- tion products during stress tests were included in Supplementary materials.
Conflict of Interest
The authors declare that they have no known competing financial interests or personal rela- tionships which have, or could be perceived to have, influenced the work reported in this article.
ESTUDO 32
D. Zanon, A. Manca and A. De Nicolò et al. / Data in Brief 30 (2020) 105552 5
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.dib.2020.105552 .
References
[1] WHO, Q&a on COVID-19, HIV Aantiretrovirals. https://www.who.int/news-room/q-a-detail/q-a-on-covid-19-hiv- and-antiretrovirals (accessed: 21 March 2020).
[2] Council of Europe, Resolution CM/Res(2016)1 on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients. https://www.edqm.eu/sites/default/files/resolution _ cm _ res _ 2016 _ 1 _ quality _ and _ safety _ assurance _ requirements _ for _ medicinal _ products _ prepared _ in _ pharmacies.pdf (accessed: 20 December 2019).
[3] P. Minghetti , D. Pantano , C.G.M. Gennari , A. Casiraghi , Regulatory framework of pharmaceutical compounding and actual developments of legislation in Europe, Health Policy (New York) 117 (2014) 328–333 .
[4] EMA, Rezolsta R ©. https://www.ema.europa.eu/en/medicines/human/EPAR/rezolsta (accessed: 21 March 2020). [5] A. D’Avolio , L. Baietto , M. Siccardi , M. Sciandra , M. Simiele , V. Oddone , S. Bonora , G. Di Perri , An HPLC-PDA method
for the simultaneous quantification of the HIV integrase inhibitor raltegravir, the new nonnucleoside reverse tran- scriptase inhibitor etravirine, and 11 other antiretroviral agents in the plasma of HIV-infected patients, Ther. Drug Monit. 30 (2008) 662–669 .
ESTUDO 32
Journal Pre-proof
Preparation and physicochemical stability of 50 mg/mlhydroxychloroquine oral suspension in Syrspend pH4 dry
Guillaume Binson , Nicolas Venisse , Alexis Sauvaget ,Astrid Bacle , Pauline Lazaro , Antoine Dupuis
PII: S0924-8579(20)30407-6DOI: https://doi.org/10.1016/j.ijantimicag.2020.106201Reference: ANTAGE 106201
To appear in: International Journal of Antimicrobial Agents
Please cite this article as: Guillaume Binson , Nicolas Venisse , Alexis Sauvaget , Astrid Bacle ,Pauline Lazaro , Antoine Dupuis , Preparation and physicochemical stability of 50 mg/ml hydroxy-chloroquine oral suspension in Syrspend pH4 dry, International Journal of Antimicrobial Agents (2020),doi: https://doi.org/10.1016/j.ijantimicag.2020.106201
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ESTUDO 31
Highlights
Hydroxychloroquine has been proposed as a potential agent to treat COVID-19
patients
Oral drug administration of solid forms may be comprised in many patients
Liquid formulation of hydroxychloroquine is not commercially available
Compounded hydroxychloroquine oral suspension is stable over 60 days
ESTUDO 31
Preparation and physicochemical stability of 50 mg/ml
hydroxychloroquine oral suspension in Syrspend pH4 dry
Guillaume Binson1,2, Nicolas Venisse2,3, Alexis Sauvaget1,2, Astrid Bacle4, Pauline Lazaro1,
Antoine Dupuis1,2*
1University Hospital of Poitiers, Pharmacy department, 2 rue de la milétrie, 86021 Poitiers,
France
2CIC Inserm 1402, HEDEX Group, 2 rue de la milétrie, 86021 Poitiers, France
School of Medicine and Pharmacy, University of Poitiers, Poitiers, France
3University Hospital of Poitiers, Pharmacokinetics department, 2 rue de la milétrie, 86021
Poitiers, France
4Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et
travail) - UMR_S 1085, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France; Pôle
Pharmacie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, 35033 Rennes, France.
*Corresponding author. Tel: +33 5 49 43 37 68; fax: +33 5 49 45.39 72
E-mail address: [email protected]
ESTUDO 31
Abstract
In the context of the SARS-CoV-2 pandemic, hydroxychloroquine has been proposed as a
potential agent to treat COVID-19 patients. Older adults are more susceptible to COVID-19
and some patients may require admission in intensive care units, where oral drug
administration of solid forms may be compromised in many COVID-19 patients. However,
liquid formulation of hydroxychloroquine is not commercially available. This study describes
how to prepare a 50 mg/mL hydroxychloroquine oral suspension using hydroxychloroquine
sulfate powder and Syrspend SF dry pH4 suspending vehicle. Moreover, a fully validated
stability indicating method has been developed to demonstrate the physicochemical stability
of the compounded hydroxychloroquine oral suspension over 60 days under refrigeration (5
± 3°C). Finally, use of the proposed oral suspension provides a reliable solution to perform
safe and accurate administration of hydroxychloroquine to patients with SARS-CoV-2
infection.
Keywords: hydroxychloroquine; oral suspension; SARS-CoV-2 infection; stability-indicating
assay
ESTUDO 31
1. Introduction
Hydroxychloroquine, a derivative of chloroquine first synthesized in the 1950s, belongs to the
group of antimalarial agents exhibiting therapeutic effects in other diseases besides malaria
[1]. Both drugs are mainly used in the treatment of numerous rheumatic diseases, including
systemic lupus erythematosus. While hydroxychloroquine has similar chemical structure and
mechanisms of action it has been shown to be much less toxic than chloroquine. Among its
numerous therapeutic effects, hydroxychloroquine was found to be effective against some
viral infections. Recently, in vitro evaluation of the antiviral effect of hydroxychloroquine
showed that it can efficiently inhibit SARS-CoV-2 infection [2,3]. Starting in China in
December 2019, the outbreak of coronavirus disease 2019 (COVID-19) caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) has become a
pandemic, posing a serious threat to global public health. Therefore several publications
have proposed hydroxychloroquine as a potential agent to treat COVID-19, even though
robust clinical data are still needed to support its efficacy [2,4-7]. Accordingly, several
treatment strategies including hydroxychloroquine are being considered and evaluated in
numerous clinical trials [8] and hydroxychloroquine has been included in some national
guidelines for treating COVID-19 in certain situations [9–11].
To our knowledge hydroxychloroquine is only available as 200 mg film-coated tablets.
However, for many patients (seniors, difficulty swallowing, intensive care unit), the use of a
liquid formulation is required but no commercially liquid formulations of hydroxychloroquine
are currently available. Only one paper reports the preparation of a liquid hydroxychloroquine
formulation but at a strength not optimal to treat COVID-19 patients [12]. Therefore, the aim
of this study was to evaluate the feasibility of compounding a 50 mg/mL hydroxychloroquine
oral suspension and to demonstrate its physicochemical stability.
ESTUDO 31
2. Materials and methods
2.1. Chemicals and reagents
Syrspend® SF PH4 Dry (batch number: 1742-B02-344675) was purchased from Fagron
(France), and hydroxychloroquine sulfate powder (batch number: 1811P018) from Inresa
(France). Sterile water was purchased from Fresenius (Versylene®, France) and ammonium
acetate from Sigma-Aldrich (France). HPLC-grade acetonitrile and methanol were purchased
from Carlo Erba (France) and ultrapure water was provided using a Direct-Q UV3 water
purification system (Millipore®, France).
2.2. Feasibility study
Oral liquid dosage forms were compounded by a pharmacist at a target concentration of 50
mg/mL. Since hydroxychloroquine sulfate is poorly soluble in water, use of a suspending
vehicle was mandatory in order to prepare a liquid dosage form. The oral suspensions were
prepared according to the following standard operating procedure. First, the exact amount of
hydroxychloroquine sulfate powder was weighed in order to obtain the targeted
concentration. Then,hydroxychloroquine sulfate powder was added to 13 g of Syrspend® SF
PH4 Dry and triturated in a mortar until homogeneity was achieved. Subsequently, sterile
water was gently added, while stirring continuously, until reaching a final volume of 200 mL in
a class A volumetric flask (200 ± 0.5 mL). Finally, the suspension was bottled in a 100 mL
amber type I glass container.
The entire procedure was carried out in a clean area, in order to limit microbiological
contamination.
In order to verify that the formulations were providing correct dispersion of
hydroxychloroquine sulfate powder in the suspending vehicle, hydroxychloroquine strengths
in the compounded preparations were assessed. In this way, concentrations (n=3) of three
different batches were determined for the oral liquid dosage form, using high performance
ESTUDO 31
liquid chromatography coupled to ultraviolet spectrometry (HPLC-UV) methods described
below. One milliliter oral suspension samples (n=3), collected after shaking (30 s) in order to
obtain uniform dispersion of the hydroxychloroquine sulfate powder, were diluted in water
(1:10, v:v), centrifuged at 3500 g for 10 min and supernatants were then diluted in water
(1:100, v:v) before injection onto the column. According to the United States Pharmacopoeia,
dose content uniformity is verified if every compounded preparation contains no less than
90% and no more than 110% of theoretical strength [13].
2.3. Stability study
In order to investigate the physical and chemical stability of hydroxychloroquine oral
suspension, three bottles from different batches of hydroxychloroquine suspensions were
stored throughout the study duration under controlled refrigeration (5 ± 3 °C) (temperature
was monitored daily).
Hydroxychloroquine concentrations were determined at days 0, 3, 7, 11, 14, 30 and 60, using
the HPLC-UV methods described below. One milliter oral suspension samples (n=3),
collected after shaking (30 s) in order to obtain uniform dispersion of hydroxychloroquine
sulfate powder, were diluted in water (1:10, v:v), centrifuged at 3500 g for 10 min and the
supernatants were then diluted in water (1:100, v:v) before injection onto the column.
According to the US Pharmacopoeia, compounded preparations are considered to be stable
if the drug concentration remains within 90-110% of the initial value (day 0) [13].
In addition, physical appearance was investigated by visual inspection performed in a
transparent glass vial, in order to check the initial color and opalescent aspect of the
suspension.
2.4. Analytical method development and validation
A stability-indicating method, using isocratic high performance liquid chromatography
coupled to u.v. spectrometry (HPLC-UV), has been developed, validated and performed to
ESTUDO 31
determine hydroxychloroquine concentrations. Separation was performed using a
Purospher® 5 µm RP-18 endcapped column (150 x 4.6 mm, Merck). The mobile phase
consisted of a mixture of 0.1M ammonium acetate:acetonitrile:methanol (40:15:45; v:v:v),
and the flow rate was set at 1 mL/min. The chromatographic system consisted of a Waters
1525® solvent delivery pump and a Waters 717® autosampler (set at 30 µL) connected to a
Waters 2996® photodiode array detector (Waters, France). Wavelength of the detector was
set at 340 nm. Chromatographic data were recorded and processed using Empower®
software integrator. The system was operated at ambient temperature.
Stability-indicating capability of the method was evaluated by verifying that degradation
products did not coelute with intact hydroxychloroquine. Hydroxychloroquine oral suspension
was subjected to severe stress (heat, acidic and basic conditions, oxidation) in accordance
with ICH Q1 (R2) international guidelines [14]. To ensure that no degradation products were
coeluting with hydroxychloroquine, a photodiode array detector was used to obtain a three-
dimensional (3-D) chromatogram and to perform a peak purity check test The 3-D
chromatograms obtained from stored suspensions were then compared to those obtained
with initial extemporaneous suspensions.
Validation of the analytical method was performed in accordance with ICH Q2 R(1)
international guidelines using the following criteria: linearity and accuracy (precision and
trueness) and specificity of the method [14].
2.4.1. Calibration curve
A calibration method was performed to assess hydroxychloroquine concentration in the
compounding vehicles. Initial 100 µg/mL hydroxychloroquine solution was prepared in water.
This latter was then diluted in water to obtain a six-point calibration curve (0, 6.25, 12.5, 25,
50, and 100 µg/mL). The calibration curve range was chosen according to the target
concentration of hydroxychloroquine in diluted oral suspension set at 50 µg/mL. Calibration
curves were generated by linear least-squares regression of the peak area versus
hydroxychloroquine concentration profiles.
ESTUDO 31
2.4.2. Linearity and matrix effect
Five calibration curves were prepared on five different days. Linearity was assessed through
the analysis of the coefficient of determination (r2), y-intercept and slope of the linear
regression line and residual values (expressed as the percentage of the theoretical value).
Matrix effect was assessed comparing calibration curves prepared in water versus calibration
curves obtained using Syrspend® SF PH4 Dry. Dilution was performed using water solution
containing 0.1% of the suspending vehicle in order to mimic the exact composition of
samples obtained after dilution of the oral suspensions before HPLC-UV analysis. The y-
intercept and slope of linear regression lines were compared using a Student t test (α = 0.05)
to assess matrix effect.
2.4.3. Accuracy and limit of quantification
Accuracy was investigated by assessing precision and trueness of the method. Quality
controls (QC) were prepared in water at a level of 50 µg/mL, according to diluted oral
suspension concentrations. Precision was assessed through determination of the relative
standard deviation (RSD) of the mean concentration determined for each QC, on the same
day for repeatability (n=5) and over five days for intermediate precision (n=15). Trueness
was assessed by determination of the percent recovery of the expected concentrations of
QC used during precision study. Quantitation limit was calculated based on the standard
deviation of the y-intercept and the slope in order to set the limit of quantification.
ESTUDO 31
3. Results
3.1. Method validation
Calibration curves obtained with water working solutions provided adequate linearity over the
studied range since correlation coefficients were greater than 0.9999 and residual values
were lower than 4% of the nominal value. The mean equation of the linear regression line
was:
y = 57303 (± 936) x + 18064 (± 5234)
and correlation coefficients (r²) of the linear regression line were equal to 0.99996 (±
0.00002), on average.
The slope and y-intercept values provided by calibration curves prepared in Syrspend® SF
PH4 Dry (57284 ± 250 and 23297 ± 14377 for slope and y-intercept, respectively) were not
statistically different from those provided by calibration curves obtained using water (p = 0.97
and p = 0.52 for slope and y-intercept, respectively). These results are in accordance with
the absence of matrix effect due to the suspending vehicles, which implies that calibration
curves may be performed using hydroxychloroquine water solutions.
The analytical method was accurate as demonstrated by precision (repeatability and
intermediate precision) and trueness studies. Indeed, relative standard deviation obtained at
the quality control level during repeatability and intermediate precision studies were equal to
4.5% and 2.9%, respectively. The mean percent recoveries obtained at the quality control
level during the trueness study were equal to 100.7% and 101.3% for repeatability and
intermediate precision, respectively. The quantitation limit was equal to 0.91 mg/mL.
However, to be more conservative, the limit of quantification was set as the lowest point of
the calibration curve (6.25 mg/mL).
During the forced degradation study, no degradation products interfered with the
hydroxychloroquine peak in terms of retention time and according to UV spectrum analysis
ESTUDO 31
and purity check test of the peaks (Fig. 1). Therefore, the method can be considered as a
stability-indicating method according to international guidelines [14].
3.2. Feasibility and stability studies
Subsequent to the preparation, the mean hydroxychloroquine concentration of the
compounded oral suspensions was equal to 50.13 ± 0.69 mg/mL. Thereby, these results
demonstrate reliability of the compounding and that no drug loss occurred during
preparation.
Regarding chemical stability, no significant degradation of hydroxychloroquine occurred in
the compounded oral suspensions (Fig. 2). Indeed, at day 60 the mean percentage drug
remaining was equal to 97.3 ± 1.3 %, 98.4 ± 1.3 % and 96.5 ± 0.4 %, for oral suspension #1,
#2 and #3, respectively. During the period of testing, the proportion of the initial
hydroxychloroquine concentration remaining was higher than 95%, meaning that oral
suspensions were chemically stable up to at least 60 days under refrigerated storage (5 ± 3
°C). In addition, according to FDA guidelines [15], an estimated shelf life of 100 days may be
established since the earliest time at which the lower one-sided 95 percent confidence limit
of the linear regression intersects the acceptance criterion of 90% at this time (Fig. 2). In
accordance with this result, no degradation products were observed over the assessed
period and according to 3-D chromatogram analysis and purity check test of the peaks, no
degradation products were coeluting with hydroxychloroquine (Fig. 3). Moreover, for all
samples, hydroxychloroquine concentration remained within 95 to 104% of the targeted
strength, highlighting the fact that dose content remained uniform over time for all the
compounded suspensions.
According to the physical stability study, no color modification was observed and no
precipitates or suspendability were retained over the storage period.
Overall, these results attest to the physical and chemical stability of the oral liquid dosage
form stored at 5 ± 3 °C over at least 60 days.
ESTUDO 31
4- Discussion
Liquid formulation of hydroxychloroquine is not commercially available and only one paper
from McHenry et al. reported the extemporaneous preparation of a liquid dosage form of
hydroxychloroquine for oral use [12].
According to the doses proposed for COVID-19 patients (from 100 mg to 600 mg per dose)
we chose to prepare oral liquid dosage forms at a target concentration (50 mg/mL) higher
than the formulations proposed by McHenry et al., thereby reducing by a factor of two the
volume of administration required. Hydroxychloroquine is a hydrophobic compound,
displaying poor solubility in water. Consequently, we had to compound suspension in order
to provide an oral liquid dosage form. One major disadvantage of suspension dosage form is
the risk of the settling of drug particles, producing non-homogeneous preparation leading to
inaccuracy in dosage measurement. However, according to the feasibility study, dose
content uniformity of the suspension was established since deviation of the concentration of
the drug in the compounded preparations was never higher than 5% of expected drug
strength. Thereby, these results demonstrate that the oral formulation compounded using
Syrspend® SF PH4 Dry as a suspending vehicle provides reliable dosage of
hydroxychloroquine. Moreover, under our conditions, no significant degradation of
hydroxychloroquine occurred in compounded oral suspensions. Indeed, during the period of
testing, the proportion of the initial hydroxychloroquine concentration remaining was within
the limit set by the U.S. Pharmacopeia [13], meaning that hydroxychloroquine oral
suspension was stable up to at least 60 days under refrigeration (5 ± 3°C). In addition, an
estimated shelf life of 100 days may be proposed, supported by statistical analysis of the
data. However, according to the manufacturer, the microbiological stability of oral
suspensions compounded in Syrspend® SF PH4 Dry has been demonstrated under same
storage conditions and under the condition that the suspension is hygienically compounded
and used, for up to 60 days (statements provided by Fagron). Therefore, hydroxychloroquine
oral suspension compounded in Syrspend® SF PH4 Dry can be assigned a maximum
ESTUDO 31
beyond-use date of 60 days. These results, the first to be obtained using a stability-indicating
method, are in accordance with the durations of the different treatment strategies reported in
the literature.
Syrspend® SF PH4 Dry, a powder ensuring correct drug suspension and designed to
prepare oral liquid dosage form, was chosen since this marketed product is formulated
mostly with starch, which is considered as an inert excipient. In contrast to many other
vehicles, it does not contain any potentially harmful excipients such as alcohol, propylene
glycol, or benzoic acid, which render other formulations unsuitable for many patients.
Thereby, the compounded oral suspension is particularly suitable for children requiring
hydroxychloroquine administration. In addition, Syrspend® SF PH4 Dry does not contain any
divalent cations, such as calcium or magnesium, which may interfere with the absorption of
hydroxychloroquine and reduce its effectiveness [16]. Moreover, the low osmolality (< 100
mOsm/kg, data not shown) displayed by our compounded liquid formulation of
hydroxychloroquine minimises the risk of gastrointestinal side effects.
Older adults are more susceptible to COVID-19 and some patients may require admission in
intensive care units [17], where oral drug administration of solid forms may be compromised
in many COVID-19 patients. In case of lack of commercially available liquid formulation,
crushing the solid oral form is a common practice to facilitate easier medication
administration [18]. However, drug loss is frequently observed when tablets are crushed [19].
In addition, drug administration via enteral feeding tubes may be necessary for COVID-19
patients. Once again, crushed tablets may result in clogged tubing, leading to increased
adverse events and decreased medication efficacy [20].
Finally, in contrast with commercially available tablets, the liquid formulation of
hydroxychloroquine compounded by our team is suitable to perform personalization of an
optimal dosing regimen, particularly in view of reaching appropriate target blood level in
COVID-19 patients [21].
In light of all this, the compounded oral liquid formulation proposed in this study provides an
appropriate and easy to use dosage form for oral hydroxychloroquine treatment, enabling
ESTUDO 31
safe and accurate hydroxychloroquine dose administration to patients with SARS-CoV-2
infection.
ESTUDO 31
Acknowledgment
We wish to thank Jeffrey Arsham, an American scientific translator, for his highly
helpful reading of our original text.
Declarations
Funding: This work was supported by internal funding.
Competing Interests: All authors report no potential conflicts of interest.
Ethical Approval: Not required.
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[7] Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020:101663. https://doi.org/10.1016/j.tmaid.2020.101663.
[8] Zhai P, Ding Y, Wu X, Long J, Zhong Y, Li Y. The epidemiology, diagnosis and treatment of COVID-19. Int J Antimicrob Agents 2020. https://doi.org/10.1016/j.ijantimicag.2020.105955.
[9] Nicastri E, Petrosillo N, Bartoli TA, Lepore L, Mondi A, Palmieri F, et al. National Institute for the Infectious Diseases “L. Spallanzani”, IRCCS. Recommendations for COVID-19 clinical management. Infect Dis Rep 2020;12. https://doi.org/10.4081/idr.2020.8543.
[10] Avis relatif aux recommandations thérapeutiques dans la prise en charge du COVID-19(complémentaire à l’avis du 5 mars 2020) n.d.:23. [https://www.hcsp.fr/Explore.cgi/Telecharger?NomFichier=hcspa20200323_coronsarscovrecomthrap.pdf.]
[11] Hinton DM. Food and Drug Administration. FDA Emergency use authorization (EUA) of chloroquine and hydroxychloroquine. 28 Mar 2020. [https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization]
[12] McHenry AR, Wempe MF, Rice PJ. Stability of Extemporaneously Prepared Hydroxychloroquine Sulfate 25-mg/mL Suspensions in Plastic Bottles and Syringes. Int J Pharm Compd 2017;21:251–4.
[13] Allen, L.V., Jr.; Bassani, G.S.; Elder, E.J.; Parr, A.F. Strength and Stability Testing for Compounded Preparations. US Pharmacop. 2014, pp. 1–7. [https://www.usp.org/sites/default/files/usp/document/FAQs/strength-stability-testing-compounded-preparations.pdf]
[14] Abraham, J. International Conference on Harmonisation of Technical Requirements For Registration of Pharmaceuticals for Human Use. In Handbook of Transnational Economic Governance Regimes; Brouder, A., Tietje, C., Eds.; Brill: Leiden, The Netherlands, 2009; pp. 1041–1054. ISBN 978-90-04-16330-0.
[15] Guidance for industry #219 (VICH GL51) Statistical Evaluation of Stability Data. US Food Drug Adm 2019. [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-219-vich-gl51-statistical-evaluation-stability-data][16] McElnay JC, Mukhtar HA, D’Arcy PF, Temple DJ, Collier PS. The effect of magnesium trisilicate and kaolin on the in vivo absorption of chloroquine. J Trop Med Hyg 1982;85:159–63.
[17] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020;323:1061. https://doi.org/10.1001/jama.2020.1585.
[18] Bourdenet G, Giraud S, Artur M, Dutertre S, Dufour M, Lefèbvre-Caussin M, et al. Impact of recommendations on crushing medications in geriatrics: from prescription to administration. Fundam Clin Pharmacol 2015;29:316–20. https://doi.org/10.1111/fcp.12116.
[19] Stubbs J, Haw C, Dickens G. Dose form modification – a common but potentially hazardous practice. A literature review and study of medication administration to older psychiatric inpatients. Int Psychogeriatr 2008;20:616–27. https://doi.org/10.1017/S1041610207006047.
[20] Matysiak-Luśnia K, Lysenko Ł. Drug administration via enteral feeding tubes in intensive therapy - terra incognita? Anaesthesiol Intensive Ther 2014;46:307–11. https://doi.org/10.5603/AIT.2014.0050.
[21] Perinel S, Launay M, Botelho-Nevers É, Diconne É, Louf-Durier A, Lachand R, et al. Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients. Clin Infect Dis 2020:ciaa394. https://doi.org/10.1093/cid/ciaa394.
Figure captions
Fig. 1. Three-dimensional chromatograms obtained for hydroxychloroquine (HCQ) oral
suspensions after applying different stress conditions: no stress(a), HCl 0.75 M for 5 min (b),
NaOH 0.5 M for 5 min (c), H2O2 1% for 2.5 h (d) and 80°C for 1.5 h (e). Dark line indicates
the control absorbance at 340 nm.
Fig. 2 . Chemical stability of hydroxychloroquine in compounded oral suspensions stored at 5
± 3 °C. The plots represent the mean percentage drug remaining (n=3) for each batch. The
solid dark line represents the linear regression of the percentage drug remaining versus time
profile (y = - 0.0554 x). The grey lines represent the 95 percent confidence limits for the
linear regression. The dashed line represents the limit for the acceptance criterion of 90%.
Fig. 3. Three-dimensional chromatograms obtained for hydroxychloroquine (HCQ) oral
suspension #2 at day 0 (a) and at day 60 (b) and two-dimensional chromatograms obtained
at day 0 (c) and at day 60 (d).
76International Journal of Pharmaceutical CompoundingVol. 22 No. 6 | November | December | 2018
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ACKNOWLEDGMENT Compatibility studies were per-formed by Ortofarma under the spon-sorship of Fagron.
INTRODUCTION Drug treatment in children poses specific pharmaceutical issues that are not, or to a lesser extent, seen in adults. The wide age range (0 to 16 years) requires age-appropriate drug formula-tions. The use of liquid formulations is encouraged in children as it provides maximal dosing flexibility and allows the use of a single formulation over different ages. As many children have swallowing difficulties with tablets and capsules, a suitable liquid alternative with acceptable taste and palatability can help to overcome these hurdles. To ensure the safe and accurate adminis-tration of liquid drugs, the use of appro-priate measuring devices (preferably oral syringes) is advised.1 Although many liquid formulations are commercially available, there is still a broad range of drugs that need to be compounded by the pharmacist
Stability of Baclofen, Carvedilol, Hydrochlorothiazide, Mercaptopurine, Methadone Hydrochloride, Oseltamivir Phosphate, Phenobarbital, Propranolol Hydrochloride, Pyrazinamide, Sotalol Hydrochloride, Spironolactone, Tacrolimus Monohydrate, Ursodeoxycholic Acid, and Vancomycin Hydrochloride Oral Suspensions Compounded with SyrSpend SF PH4
Hudson Polonini, BPharm, PhDSharlene Loures da Silva, BBiomedMarcos Antônio Fernandes Brandão, BPharm, PhDTiene Bauters, PharmD, PhDBarbara De Moerloose, MD, PhDAnderson de Oliveira Ferreira, BPharm, PhD Candidate
The authors’ affiliations are: Hudson Poloni-ni, Sharlese Loures da Silva, Marcos Antônio Fernandes Brandão, and An-derson de Oliveira Ferreira, Ortofarma – Quality Control Labora-tories, Matias Barbosa, MG, Brazil; Tiene Bauters, Pharmacy and Pediatric Hema-tology-Oncology and Stem Cell Transplan-tation, Ghent Univer-sity Hospital, Ghent, Belgium; Barbara De Moerloose, Pediatric Hematology-Oncology and Stem Cell Trans-plantation, Ghent Uni-versity Hospital, Ghent, Belgium. Marcos Antô-nio Fernandes Brandão is also affiliated with the Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil.
ABSTRACTCompounded liquid medication is frequently required in children to allow easy dose adjustment and overcome swallowing difficulties. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients baclofen 2.0 mg/mL, arvedilol 5.0 mg/mL, hydrochlorothiazide 2.0 mg/mL, mercaptopu-rine 10.0 mg/mL, methadone hydrochloride 10.0 mg/mL, oseltamivir phosphate 6.0 mg/mL, phenobarbital 9.0 mg/mL and 15.0 mg/mL, propranolol hydrochloride 0.5 mg/mL and 5.0 mg/mL, pyrazinamide 100.0 mg/mL, spirono-lactone 2.0 mg/mL and 2.5 mg/mL, sotalol hydrochloride 5.0 mg/mL, tacrolimus monohydrate 0.5 mg/mL, ursode-oxycholic acid 20.0 mg/mL, and vancomycin hydrochlo-ride 25.0 mg/mL. Suspensions were compounded with raw powders, except for mercaptopurine, pyrazinamide, and sotalol hydrochloride, which were made from commercial tablets. Stability was assessed by measuring the percent-age recovery at 0 (baseline), 60 days, and 90 days after compounding for suspensions made with raw powders, which were stored at 2°C to 8°C. The stability of tablets, which were stored at 2°C to 8°C and 20°C to 25°C, was assessed by measuring the percentage recovery at 0 (baseline), 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was per-formed by ultraviolet high-performance liquid chromatog-raphy via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions in the con-ditions tested. This suggests that SyrSpend SF PH4 is suit-able for compounding active pharmaceutical ingredients from different pharmacological classes.
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T A B L E 1 . CONCENTRATIONS OF THE SUSPENSIONS USED IN THE STUDY.
A C T I V E PHARMACEUTICAL I N G R E D I E N T Baclofen
Carvedilol
Hydrochlorothiazide
Mercaptopurine
Methadone hydrochloride
Oseltamivir phosphate
Phenobarbital
Propranolol hydrochloride
Pyrazinamide
Sotalol hydrochloride
Spironolactone
Tacrolimus monohydrate
Ursodeoxycholic acid
Vancomycin hydrochloride
A C T I O N A N D U S E
Skeletal muscle relaxant
Beta-adrenoceptor antagonist;
arteriolar vasodilatador
Thiazide diuretic
Thiopurine cytotoxic
Opioid receptor agonist; analgesic
Treatment of influenza
Barbiturate
Beta-adrenoceptor antagonist
Antituberculosis drug
Beta-adrenoceptor antagonist;
Class II and Class III antiarrhythmic
Aldosterone receptor antagonist;
potassium-sparing diuretic
Immunosuppressive agent
Bile acid; treatment of gallstones
Glycopeptide antibacterial
C O N C E N T R A T I O N I N S U S P E N S I O N
( M G / M L )2.0
5.0
2.0
10.0
10.0
6.0
9.0 and 15.0
0.5 and 5.0
100.0
5.0
2.0 and 2.5
0.5
20.0
25.0
if a liquid form is required. Apart from a lack of sta-bility data in many cases, availability (especially in case of drug shortages) and drug reimbursement are of concern in many countries. A liquid formulation with known stability that can be compounded by the pharmacist might help to overcome these problems. As an example, this is the case for mercaptopurine, a cornerstone of maintenance treatment in acute lymphoblastic leukemia. In many countries, where the commercial solution is not available or not reim-bursed, pharmacists rely on the pharmaceutical compounding of capsules starting from the marketed mercaptopurine 50-mg tablet (Puri-Nethol, Aspen Australia). This is time consuming and impractical, as the dose varies according to the body surface area of the child and to hematological parameters. Apart from children, liquid formulations can also be of benefit in terms of adherence and adjustment for geriatric patients and for patients with physiological, visual, or motoric dysfunctions and swallowing capa-bilities. The purpose of the current study was to deter-mine the stability of different active pharmaceuti-cal ingredients in SyrSpend SF (Fagron, St. Paul, Minnesota), a vehicle for the compounding of oral liquid dosage forms, providing consistent, individual dosing throughout treatment. This paper focuses on the stability of baclofen, carvedilol, hydrochlorothia-zide, mercaptopurine, methadone hydrochloride, oseltamivir phosphate, phenobarbital, propranolol hydrochloride, pyrazinamide, sotalol hydrochloride, spironolactone, tacrolimus monohydrate, ursodeoxy-cholic acid, and vancomycin hydrochloride oral sus-pensions compounded with SyrSpend SF PH4.
METHODSREAGENTS, REFERENCE STANDARDS, AND MATERIALS All active pharmaceutical ingredient (API) raw powders and SyrSpend SF PH4 (liquid) (Batch 14F02-U59-019404) were obtained from Fagron. High-performance liquid chromatographic (HPLC)-grade reagents (Panreac, Barcelona, Spain) were used (Table 1). Ultrapure water obtained with an AquaMax-Ultra 370 Series (Young Lin, Anyang, Korea) (18.2 MΩ·cm resistivity at 25°C) was used throughout the experiments. The reference standards used were all work standards obtained using primary United States Pharmacopeia (USP) (Rockville, Maryland) reference materials, with the exception of metha-done hydrochloride and phenobarbital, which were
supplied by Fagron (Rotterdam, The Netherlands). All the mobile phases and receptor media were filtered through a 0.45-µm fil-ter membrane (RC-45/15 MS; Chromafil, Düren, Germany) and degassed using an ultrasonic apparatus (Model 1600A; Unique, Indaiatuba, Brazil) for 30 min-utes, immediately before use. All volumetric glassware and the analytical balance used were pre-viously calibrated.
EQUIPMENT HPLC analyses were performed on a qualified and calibrated chromatography system (Young Lin) composed of a quaternary gradient pump (Model YL 9110), a photodiode array (PDA) detec-tor (Model YL 9160), a 96-vial programmable autosampler (Model YL 9150), a column oven compartment (Model YL 9130), a variable sample loop
up to 200 µL, and a software controller (Clarity, Sewickley, Pennsylvania). For methadone hydrochloride and phenobar-bital, an Alliance 2695/Acquity H-class chromatograph was used (Waters, Milford, Massachusetts), composed of a column heater, PDA detector Model 2998, and data system Empower 3.
CHROMATOGRAPHIC CONDITIONS The chromatographic determinations were based upon USP methods for the APIs or their final products, with minor modifications when necessary. Methods for baclofen, carvedilol, hydrochlorothiazide, and tacrolimus monohydrate were previ-ously developed and validated by our group and were used in this work.2-4 The exact chromatographic conditions used for each API are stated in Table 2. The columns were connected with a pre-column with the same packing (4.0 × 3.0 mm, 5 µm), from the same vendor of the columns.
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T A B L E 2 . CHROMATOGRAPHIC CONDITIONS USED IN THE COMPATIBILITY STUDY.
A C T I V E P H A R M A C E U T I C A L I N G R E D I E N T
Baclofen
Carvedilol
Hydrochloro-thiazide
Mercaptopurine
Methadone hydrochloride
Oseltamivir phosphate
Phenobarbital
Propranolol hydrochloride
Pyrazinamide
Sotalol hydrochloride
Spironolactone
Tacrolimus monohydrate
Ursodeoxycholic acid
Vancomycin hydrochloride
U L T R A V I O L E T D E T E C T I O N
W A V E L E N G T H ( N M )
220
254
254
260
201
207
196
290
215
235
230
210
201
240
F L O W ( M L /M I N )
1.5
1.0
2.0
1.0
0.4
1.5
0.8
1.0
0.8
1.0
1.5
2.0
1.5
0.9
W O R K C O N C . (µg / m L ) *5.0, in water;
20-µL injection
40.0; 10-µL injection
150.0; 20-µL injection
250.0, in 0.77 g/L
aqueous ammonium
acetate;
20-µL injection
50; 1-µL injection
480.0; 20-µL injection
50.0, in methanol;
1-µL injection
100.0, in methanol;
20-µL injection
100.0, in acetonitrile
and water (1:1); 20-µL
injection
20.0; 20-µL injection
100.0, in acetonitrile;
20-µL injection
100.0, in methanol;
20-µL injection
1000.0, in methanol;
20-µL injection
210.0; 20-µL injection
M O B I L E P H A S E C O M P O S I T I O N
Acetonitrile and 0.05M monobasic
sodium phosphate (2:8) (pH adjusted to
3.5 with phosphoric acid).
2.72 g of potassium phosphate
monobasic in 1000 mL of water (pH
adjusted to 2.0 with phosphoric acid)
Acetonitrile and 0.1M sodium phosphate
monobasic (1:9); pH adjusted to 3.0 with
phosphoric acid.
Solution B (methanol and 0.77 g/L
aqueous ammonium acetate, 5:9,5)
and Solution C (methanol and 0.77 g/L
aqueous ammonium acetate, 3:7) (8:2)
Methanol and 3.4 g of potassium
phosphate monobasic in 1000 mL
of water (pH adjusted to 4.0 with
phosphoric acid) (75:25)
Methanol, acetonitrile and 6.8 g/L
potassium phosphate monobasic
(245:135:620)
Water and methanol (1:1)
0.5 g of sodium dodecilsulphate in 18
mL of 0.15M phosphoric acid, 90 mL
of methanol, 90 mL of acetonitrile and
water to 250 mL
Acetonitrile and 10 mM monobasic
sodium phosphate (1:9)
Acetonitrile and 5 mM octanosulphonic
acid (25:75); pH adjusted to 3.2 with
hydrochloric acid
Methanol and water (60:40)
Acetonitrile and 0.1% phosphoric acid
(6.5:3.5)
Methanol and 0.01 M monobasic
potassium phosphate (75:25)
Acetonitrile, tetrahydrofuran and Buffer
(triethylamine and water, 1:500, pH
adjusted to 3.2 with phosphoric acid)
(29:1:70)
C O L U M NL1, 4.6-mm × 25-cm
L7, 4.6-mm × 15-cm, at 55ºC
L1, 4.6-mm × 25-cm
L1, 4.6-mm × 25-cm, at 30ºC
L11, 2.1-mm × 10-cm, at 40ºC
L7, 4.6-mm × 25-cm, at 50ºC
L1, 4.6-mm × 10-cm; at 40ºC
L7, 4.6-mm × 25-cm, at 55ºC
L7, 4.6-mm × 25-cm
L1, 4.6-mm × 25-cm
L1, 4.6-mm × 25-cm
L1, 4.6-mm × 25-cm, at 50ºC
L1, 4.6-mm × 25-cm
L1, 3.9mm × 30-cm
*Diluted with mobile phase, unless specified otherwise.
Conc. = concentration
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VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD Validation protocol and the acceptance criteria were established based upon USP5 and International Conference on Harmonization (ICH) guidelines.6
Specificity of the method was determined by running HPLC anal-yses of a standard solution, a SyrSpend SF PH4 (liquid) blank solu-tion, and a mobile phase/diluents blank solution. The acceptance criterion was defined as a percentage of discrepancy between the peak areas of less than 2% (Equation 1). In addition, the specificity of the method was obtained through comparison of standard chro-matograms with and without the SyrSpend SF PH4 (liquid) matrix. All analyses were run in triplicate.
Equation 1
% discrepancy = 100 standard area - sample area standard area Precision was evaluated as repeatability and intermediate preci-sion. Repeatability was determined by consecutively analyzing six replicates by a single analyst in a single day. Intermediate precision was also performed in six replicates, but over two days, by different analysts. An injection precision of more than 95% (coefficient of variation, CV <5%) was considered acceptable. The accuracy of the method was determined through spike-recovery of the SyrSpend SF PH4 (liquid) matrix, diluted within the range used for final sample measurements (to the calibration curves). Percent recovery was calculated from the concentration measured relative to the theoretical concentration spiked. For linearity, concentrations from 70% to 130% of the working concentration of the API in SyrSpend SF PH4 (liquid) were pre-pared and analyzed. The data from each experiment was fitted by ordinary least squares method and was evaluated by analysis of variance (ANOVA). The limit of detection (LOD) and limit of quantification (LOQ) were determined from three standard calibration curves of the APIs in the presence of the SyrSpend SF PH4 (liquid) matrix and were calculated as shown in Equation 2 and Equation 3, respectively:
Equation 2
LOD = s 3
a
Equation 3
LOQ = s 10
a
where a is the slope of the calibration curve, and s is the standard deviation of the y-intercept. The LOD and LOQ were confirmed by the analysis of chromatograms generated by injecting solutions in their respective limit concentrations.
PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS SUSPENSION SAMPLES The suspensions compounded with raw powders were prepared using the following general protocol:
1. The required quantity of each ingredient for the total amount to be prepared was calculated.
2. Each ingredient was accurately weighed.3. The API was placed in a mortar and triturated until a fine pow-
der was obtained.4. A small amount of the SyrSpend SF PH4 (liquid) was added to
the powder and mixed to form a uniform paste.5. The SyrSpend SF PH4 (liquid) was further added in approxi-
mately geometric portions almost to volume, mixing thor-oughly after each addition.
6. Sufficient SyrSpend SF PH4 (liquid) was added to bring the volume to 300 mL, and then mixed well.
7. The final preparation was packaged in low-actinic, light-resis-tant prescription bottles and labeled.
These suspensions were then immediately assayed at T = 0 and then stored at a controlled refrigerated temperature (2ºC to 8ºC) for the duration of the study (temperature and humidity were checked in real time throughout the whole experiment, using a calibrated, digital thermo-hygrometer [Incoterm, São Paulo, Brazil]). For the suspensions compounded with tablets, the suspensions were prepared using the following general protocol:
1. The required quantity of tablets for the total amount was calcu-lated.
2. The tablets were crushed using a mortar and pestle until a fine powder was obtained.
3. The exact quantity of powder obtained from the crushed tab-lets needed to prepare the suspension was accurately weighed.
4. A small amount of the SyrSpend SF PH4 (liquid) was added to the powder and mixed to form a uniform paste.
5. The SyrSpend SF PH4 (liquid) was further added in approxi-mate geometric portions almost to volume and mixed thor-oughly after each addition.
6. Sufficient SyrSpend SF PH4 (liquid) was added to bring the volume to 100 mL, and then mixed well.
7. The final product was packaged in low-actinic, light-resistant prescription bottles and labeled.
These suspensions were then immediately assayed at T = 0, and then separated into two different 150-mL bottles: one sample was stored at controlled refrigerated (2ºC to 8ºC) and the other at room temperature (20ºC to 25ºC), for the duration of the study (tem-perature and humidity were checked in real time throughout the whole experiment, using a calibrated, digital thermo-hygrometer [Incoterm]).
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FORCED-DEGRADATION STUDIES: STABILITY-INDICATING CHARACTERISTICS API samples were subjected to the following stressing conditions to determine the capacity of the HPLC method to detect any pos-sible degradation products that may arise during storage of the oral suspension:
• Dilution in acid (0.1M HCl, at 25°C)• Dilution in base (0.1M NaOH, at 25°C)• Exposure to ultraviolet light at 365 nm (at 25°C)• Heating at 70°C• Dilution in H2O2 35% (v/v) (at 25°C).
For methadone hydrochloride, stressing conditions were:
• 50 mg of sample was heated to boiling in 100 mL HCl 1M, then cooled at room temperature, and a 1000-mcL aliquot was diluted to 10 mL in a mixture of methanol and water (50:50, v/v)
• 50 mg of sample was heated to boiling in 100 mL NaOH 1M, then cooled at room temperature, and a 1000-mcL aliquot was diluted to 10 mL in a mixture of methanol and water (50:50, v/v)
• 50 mg of sample was heated to boiling in 100 mL H2O2 3%, then cooled at room temperature, and a 1000-mcL aliquot was diluted to 10 mL in a mixture of methanol and water (50:50, v/v)
• 100 mL of reference standard was exposed to UV light at 365 nm for 24 hours
For phenobarbital, stressing conditions were:
• 250 mg of sample was heated to boiling in 50 mL HCl 1M, then cooled at room temperature, and a 100-mcL aliquot was diluted to 10 mL in methanol
• 250 mg of sample was heated to boiling in 50 mL NaOH 1M, then cooled at room temperature, and a 100-mcL aliquot was diluted to 10 mL in methanol
• 250 mg of sample was heated to boiling in 50 mL H2O2 3%, then cooled at room temperature, and a 100-mcL aliquot was diluted to 10 mL in methanol
• 100 mL of reference standard was exposed to UV light at 365 nm for 24 hours
All conditions were performed for 24 hours. These solutions were prepared for each API at its respective work concentration by means of serial dilution from a stock solution and using suitable diluents (see Table 2). The stock solutions were sonically dispersed by 10 minutes, and the final solutions were filtered (15-mm regener-ated cellulose syringe filters, with 0.45-µm pore size) before injec-tion onto the HPLC system. Any extraneous peaks found in the chromatograms were labeled. A resolution of 1.5 between the peaks of the degradation products and the API was considered full sepa-ration. Also, a discrepancy greater than 2% between the stressed sample peak and the standard, non-stressed sample peak was con-
sidered indicative of API decomposition.
STABILITY STUDY The API samples were assayed by HPLC at pre-determined time points to verify the stability of the API in SyrSpend SF PH4 (liquid). Before analyses, the bottles were shaken until the API was uni-formly dispersed by visual inspection. Aliquots for quantification (variable for each API) were withdrawn from the middle of the bot-tles, without contact with the inner surface of the bottle, and diluted in order to obtain work solutions in the concentration described in Table 1. Sampling times were: initial (T = 0), 60 days (T = 60), and 90 days (T = 90) for baclofen 2.0 mg/mL, carvedilol 5.0 mg/mL, hydro-chlorothiazide 2.0 mg/mL, oseltamivir phosphate 6.0 mg/mL, pro-pranolol hydrochloride 0.5 mg/mL and 5.0 mg/mL, Spironolactone 2.0 mg/mL and 2.5 mg/mL, tacrolimus monohydrate 0.5 mg/mL, ursodeoxycholic acid 20.0 mg/mL, and vancomycin hydrochloride 25.0 mg/mL. Limited sampling was used for the APIs that had previ-ously been studied in SyrSpend SF PH4 and had shown beyond-use dates (BUDs) of 66 days (for ursodeoxycholic acid) or 90 days or more (for the remaining APIs). Because mercaptopurine, pyrazin-amide, and sotalol hydrochloride had not been studied in SyrSpend SF PH4 before, more extensive sampling was applied. The mercap-topurine 10.0 mg/mL, methadone hydrochloride 10.0 mg/mL, phe-nobarbital 9.0 mg/mL and 15.0 mg/mL, pyrazinamide 100.0 mg/mL, and sotalol hydrochloride 5.0 mg/mL, sampling times were initial (T = 0), 7 days (T = 7), 14 days (T = 14), 30 days (T = 30), 60 days (T = 60), and 90 days (T = 90). All suspensions were assayed six times, and the results expressed as the mean from six independent measurements. For that purpose, samples were diluted, sonicated for 10 minutes, and then filtered in 15-mm regenerated cellulose syringe filters, with 0.45-µm pore size, before injection onto the HPLC system. The evaluation parameter was the percent recovery with respect to T = 0, using the HPLC method (results given as percentage ± standard deviation).
RESULTS AND DISCUSSION Validation studies of all methods of analysis (chromatographic conditions are described in Table 3) were performed, and all results (Table 4) met the respective acceptance criteria, confirming the suitability of the methods for the objectives of this work. Stability-indicating studies were also conducted, and the results are summa-rized in Table 4. This type of study is important to determine if the used methods are fully validated and adequate to identify decompo-sition of the APIs by chromatographic analysis. The decomposition profile of the APIs notably varied for different stressing conditions.
• Acidic stress affected carvedilol, hydrochlorothiazide, mercap-topurine, oseltamivir phosphate, propranolol hydrochloride, spironolactone, and vancomycin hydrochloride.
• Alkaline stress affected all APIs with the exception of baclofen.• UV-light exposure decomposed carvedilol, hydrochloro-
thiazide, propranolol hydrochloride, sotalol hydrochloride,
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spironolactone, ursodeoxycholic acid, and vancomycin hydro-chloride.
• Heat exposure led to decomposition of carvedilol, hydrochlo-rothiazide, oseltamivir phosphate, propranolol hydrochloride, pyrazinamide, sotalol hydrochloride, spironolactone, tacro-limus monohydrate, ursodeoxycholic acid, and vancomycin hydrochloride.
• Oxidative stress impacted all but oseltamivir phosphate and ursodeoxycholic acid.
Once the forced-degradation profiles of the APIs were deter-mined, the stability of the APIs in SyrSpend SF PH4 (liquid) was assessed. At each sampling time, the visual appearance of the suspensions was also evaluated to verify their homogeneity and physical stability (data not shown). Throughout the whole study, none of the follow-ing phenomena were observed:
• Caking• Flocculation• Macroscopically visible crystal growth• Odor generation• Phase separation• Precipitation• Turbidity
The chemical stability results are shown in Table 4 and are expressed as relative percent of recovery (initial sampling time = 100%). For the suspensions to be considered stable, the relative per-centage recovery should lie within 90% to 110%.5
BACLOFEN Baclofen 10.0-mg/mL suspension in SyrSpend SF PH4 was already evaluated by our group.4 In this study, storage was per-formed at 2ºC to 8ºC and 20ºC to 25ºC, and the BUD was at least 90 days with regards to both temperatures. Allen and Erickson7 reported the stability of baclofen 10.0-mg/mL oral suspension. The suspensions were compounded using crushed tablets, using:
• Ora-Sweet and Ora-Plus (50:50, v/v)• Ora-Sweet SF and Ora-Plus (50:50, v/v)• Cherry syrup and simple syrup (1:4, v/v)
At either temperature, all suspensions remained stable for up to 60 days of storage (for baclofen, 4% of loss in content was found; for dipyridamole, 8%).
CARVEDILOL Similar to baclofen, carvedilol suspension in SyrSpend SF PH4 was already evaluated by our group, in a concentration of 1.0 mg/mL.2 Suspensions were stored at 2ºC to 8ºC and 20ºC to 25ºC, and
no decomposition greater than 10% was found until 90 days, at both temperatures, suggesting the vehicle evaluated has a positive com-patibility with this API regardless of its concentration, possibly due to the composition of SyrSpend, which contains starch, an excipient with little interaction with APIs. Yamreudeewong et al8 evaluated 0.625-mg/mL suspensions com-pounded from tablets and containing water and sorbitol 70% and found out that the suspension stored at room temperature remained stable for 8 weeks, but the refrigerated sample indicated a loss of 10% in 4 weeks.
HYDROCHLOROTHIAZIDE Hydrochlorothiazide 5.0 mg/mL in SyrSpend SF PH4 was also already evaluated by our group, stored at 2ºC to 8ºC and 20ºC to 25ºC.2 Stability was found to be at least 90 days for both storage conditions. Totterman et al9 evaluated a hydrochlorothiazide 2.0-mg/mL oral suspension, prepared from powder and a vehicle com-posed of water, citric acid, and Methocel E50 and stored at ambient temperature protected from light. HPLC analysis found an 8% loss after 10 weeks. Allen and Erickson10 reported the stability of a 5.0-mg/mL hydrochlorothiazide oral suspension in Ora-Sweet and found less than a 3% loss over 60 days at room temperature, through HPLC analysis.
MERCAPTOPURINE Dressman and Poust11 evaluated mercaptopurine 50.0 mg/mL in oral suspensions prepared from tablets and a mixture of Cologel (Lilly), cherry syrup, and simple syrup. The suspensions stored at room temperature and at 5ºC tended to cake, and the authors rec-ommended a BUD of 14 days for room temperature storage. Aliabadi et al12 evaluated four mercaptopurine 50.0-mg/mL oral suspensions made from Purinethol tablets; they have found that the better sta-bility was obtained in the suspension prepared with water, simple syrup, cherry syrup, and ascorbic acid, which exhibited a drug con-tent of 93% after 11 weeks at room temperature and 10 weeks at 4ºC to 8ºC.
METHADONE HYDROCHLORIDE Methadone oral liquids were studied by Little et al13 and Eggers.14 The study by Little et al used a mixture of methadone hydrochloride injection and hydroxyzine pamoate suspension in cherry syrup, and samples were stable for 2 weeks at ambient and refrigerated tem-perature. Eggers compounded a methadone hydrochloride 0.25-mg/mL suspension from a commercial elixir of prolintane and vitamins, and little loss of the API was detected up to 111 weeks of storage at 20ºC.
OSELTAMIVIR PHOSPHATE The manufacturer of the oseltamivir phosphate stated that 15.0 mg/mL compounded in HUMCO cherry syrup or Ora-Sweet SF is
ESTUDO 30
82International Journal of Pharmaceutical CompoundingVol. 22 No. 6 | November | December | 2018
www.IJPC.com
Peer Reviewed
RE
-C
OV
ER
Y
(%)
100.
18
98.8
7
99.8
3
100.
35
99.9
4
99.9
1
99.7
7
100.
60
100.
69
96.6
1
98.9
2
100.
01
100.
79
99.9
6
TABL
E 3.
SU
MM
ARY
OF
VA
LID
ATI
ON
RES
ULT
S O
F TH
E H
IGH
-PER
FORM
AN
CE L
IQU
ID C
HRO
MA
TOG
RAPH
IC M
ETH
OD
S.
AC
TIV
E
PH
AR
MA
-C
EU
TIC
AL
ING
RE
-D
IEN
TB
aclo
fen
Car
vedi
lol
Hyd
roch
loro
thia
zide
Mer
capt
opur
ine
Met
hado
ne
hydr
ochl
orid
e
Ose
ltam
ivir
phos
phat
e
Phen
obar
bita
l
Prop
rano
lol
hydr
ochl
orid
e
Pyra
zina
mid
e
Sota
lol
hydr
ochl
orid
e
Spiro
nola
cton
e
Tacr
olim
us
mon
ohyd
rate
Urs
odeo
xych
olic
acid
Vanc
omyc
in
hydr
ochl
orid
e
A
CCURA
CY
RA
NG
E
(µG
/ML
)3.
64 –
6.7
6
28.2
1 – 5
2.35
105.
14 –
195.
26
70.7
7 –
131.4
3
5.0
0 –
65.
04
335.
66 –
623
.76
4.95
– 6
4.42
70.2
8 –
130.
52
70.0
3 –
130.
00
35.0
0 –
75.
00
70.0
7 –
136.
60
70.0
0 –
130.
00
701.4
0 –
130
3.12
175.
28 –
325
.52
AN
AL
YT
ICA
L C
UR
VE
y =
79.7
7x –
43.
98
y =
79.13
x –
34.2
2
y =
10.4
1x +
26.
61
y =
17.6
1x –
150.
09
y =
1198
45x
+ 31
94.3
2
y =
478.
73x
– 33
75.4
6
y =
8878
.85x
+ 11
46.6
2
y =
25.3
3x –
497
.70
y =
84.15
x +
984.
07
y =
46.17
x –
454.
39
y =
26.3
3x +
163.
08
y =
6.68
x +
26.13
y =
2.42
x –
131.5
6
y =
364.
85x
+ 53
68.4
9
R2
0.99
38
0.99
03
0.99
73
0.99
07
0.99
98
0.99
95
0.99
97
0.99
08
0.99
14
0.99
25
0.99
23
0.99
79
0.99
02
0.99
42
AN
OV
A’S
S
IGN
IF-
ICA
NC
E O
F
RE
GR
ES
-S
ION
(F
)20
92.9
1
1277
.82
4848
.66
1387
.37
6669
9.69
2923
4.68
2690
14.2
4
1394
.89
1496
.17
1728
.46
1682
.09
6358
.90
1314
.71
2240
.47
AN
OV
A’S
L
AC
K O
F
FIT
(F
)2.
57
2.58
2.81
2.21
2.77
3.29
2.71
0.55
1.28
2.0
4
3.61
3.66 1.35
1.24
LO
D
(µG
/M
L)
0.50
0.12
0.0
2
3.84
0.27
16.0
8
0.25
16.16
8.82
7.53
8.25
0.0
1
153.
02
39.2
8
LO
Q
(µG
/M
L)
1.67
0.40
0.07
12.7
8
0.90
53.6
0
0.84
53.8
6
29.4
0
25.11
27.5
1
0.0
3
510.
08
130.
93
DIS
-C
RE
P-
AN
CY
(%
)|0
.59|
|0.2
3|
|0.0
1|
|0.6
5|
|0.0
0|
|1.26
|
|0.0
0|
|0.0
4|
|1.59
|
|0.8
1|
|1.87
|
|0.4
2|
|1.10
|
|1.47
|
RE
PE
AT
-A
BIL
ITY
(C
V, %
)0.
59
1.97
1.00
0.29
0.58
0.07
1.06
1.44
2.18
1.06
0.46
0.51
2.51
0.48
INT
ER
-M
ED
IAT
E
PR
E-
CIS
ION
(C
V, %
)3.
11
2.07 1.4
1
3.40
0.44
0.19
1.03
0.82
2.37
0.88
2.27
1.03
1.90
1.08
LINEA
RITY
SPEC
IFICITY
PREC
ISIO
N
CV
= c
oeff
icie
nt o
f var
iatio
n; L
OD
= L
imit
of D
etec
tion;
LO
Q =
Lim
it of
Qua
ntifi
catio
n (2
0-µ
L in
ject
ions
);
Acc
epta
nce
crite
ria w
ere:
R2
> 0.
99; F
(Si
gnifi
canc
e of
Reg
ress
ion)
>>
4.67
; F (
Lack
of F
it) <
3.7
1; D
iscr
epan
cy <
2%
; Rep
eata
bilit
y an
d In
term
edia
te P
reci
sion
< 5
%; R
ecov
ery
= 10
0%
± 2
%. A
ll an
alyt
ical
rang
es (
µg/m
L) w
ere
adeq
uate
to
quan
tify
the
activ
e ph
arm
aceu
tical
ingr
edie
nts
in t
he c
once
ntra
tions
use
d in
the
sus
pens
ions
(m
g/m
L).
stable for 5 days at controlled room temperature and for 5 weeks under refrigeration.15 Winiarski et al16 also evalu-ated 15.0 mg/mL oseltamivir phosphate compounded from tablets and with Ora-Sweet SF and reported a stability of 35 days, both at refrigerated and room temperature. These two studies presented lower BUDs than was found in this study for SyrSpend SF.
PHENOBARBITAL Phenobarbital was previously evaluated in SyrSpend SF PH4 at 9.26 mg/mL and 8.98 mg/mL, and both retained above 90% of initial concentration for at least 154 days at room temperature.17
Dietz et al18 evaluated a series of oral liquids contain-ing phenobarbital 4.0 mg/mL (emulsions or aqueous solu-tions) Products compounded with an addition of propylene glycol were stable for 56 weeks (unspecified temperature), and products without propylene glycol exhibited losses of 34% in 4 weeks (emulsion) and 10% in 12 weeks (solution). Cober and Johnson19 compounded alcohol-free phenobarbital 10.0-mg/mL suspensions from crushed tablets using Ora-Plus mixed either with Ora-Sweet of Ora-Sweet SF and evaluated their stability. Losses lower than 2% were found after 115 days of storage at room tem-perature.
PROPRANOLOL HYDROCHLORIDE Henry et al20 evaluated a 1-mg/mL propranolol hydro-chloride suspension prepared from tablets and Diluent Flavored for Oral Use (Roxane)
ESTUDO 30
83International Journal of Pharmaceutical Compounding
Vol. 22 No. 6 | November | December | 2018www.IJPC.com
*%d = percentage of discrepancy between the active pharmaceutical ingredient peak without submission to stressing factors (negative control) and the peak of a sample subjected to one of the cited accelerated-degradation factors; ND = Not detected; NP – Not performed.Results presented as average of 3 replicates at the work concentration.
Areas given as mV. Maximum acceptable = 2% (values higher than this are in bold).
T A B L E 4 . SUMMARY OF THE STABILITY-INDICATING STUDY FOR THE ACTIVE PHARMACEUTICAL INGREDIENTS.
A C T I V E P H A R M A C E U T I C A L I N G R E D I E N TBaclofen
Carvedilol
Hydrochlorothiazide
Oseltamivir phosphate
Methadone hydrochloride
Mercaptopurine
Phenobarbital
Propranolol hydrochloride
Pyrazinamide
Sotalol hydrochloride
Spironolactone
Tacrolimus monohydrate
Ursodeoxycholic acid
Vancomycin hydrochloride
H Y D R O -C H L O R I D E
% d *|0.04|
|-8.05|
|8.56|
|-5.11|
|16.39|
|-11.23|
|-68.6|
|42.60|
|0.04|
|4.19|
|-77.34|
|-1.71|
|-0.33|
|4.94|
N a O H% d *|-1.47|
|-28.70|
|8.50|
ND
|-88.02|
|-100.00|
|-90.75|
|-45.71|
|-85.64|
|-56.11|
ND
ND
ND
|5.15|
U L T R A -V I O L E T
% d *|0.08|
|5.46|
|13.04|
|0.59|
NP
|-1.16|
NP
|15.42|
|0.60|
|2.10|
|6.21|
|0.79|
|-4.29|
|3.49|
H E A T% d *|0.39|
|2.17|
|-27.50|
|2.56|
NP
|1.60|
NP
|6.44|
|4.37|
|3.66|
|-27.65|
|4.41|
|4.66|
|7.33|
H 2O 2% d *
|-6.10|
ND
ND
|-0.12|
0.45
|-100.00|
|-73.44|
|-3.62|
|-44.43|
|5.84|
|5.36|
|-10.43|
|-1.37|
|-89.31|
Peer Reviewed
and reported a BUD of 4 months both at 5ºC and 25ºC. Gupta and Stewart21 prepared 0.5-mg/mL oral suspensions from tablets and with simple syrup and sodium benzoate 0.1%, stored at 25ºC in amber glass bottles, and analyzed by HPLC a BUD of over 238 days; no loss occurred through this period.
PYRAZINAMIDE Allen and Erickson22 evalu-ated pyrazinamide 10.0-mg/mL oral suspensions compounded from tablets and using Ora-Sweet and Ora Plus and found less than 3% of loss after 60 days of storage under room and refrigerated temperatures, using HPLC analysis. Nahata et al23 performed a stability study
temperatures. The BUD was found to be 90 days for both temperatures, similar to the result found here, indicating that this API in SyrSpend SF PH4 was stable regardless of the concentration used. A longer BUD was also found for tacro-limus monohydrate in SyrSpend SF PH4 (liquid) (at least 90 days at both studied temperatures) when compared to a previ-ous study by Jacobson et al.26 In this work, a tacrolimus 0.5-mg/mL oral suspension was prepared from capsules using a mixture of equal parts of Ora-Plus and simple syrup. This suspension was found to be stable for 56 days when stored at 25°C.
URSODEOXYCHOLIC ACID Mallet et al27 studied a 25.0-mg/mL oral suspension prepared from capsules and Ora-Plus. It was stored protected from light at 4ºC and 23ºC; no loss was detected after 60 days. Nahata et al28 evaluated oral sus-pensions prepared from capsules and using a 1:1 mixture of Ora-Sweet and Ora-Plus and found a 3% loss after 91 days of storage at room or refrigerated temperatures.
VANCOMYCIN HYDROCHLORIDE Mallet et al29 evaluated the stability of oral solutions reconstituted at 0ºC, 4ºC and 25ºC over 90 days of storage and found out that refrigerated samples presented no loss on drug content by HPLC analysis. The sample at room temperature precipitated on the sixth day and a 17% drug loss after 90 days.
CONCLUSION As the results have shown, SyrSpend SF PH4 is compatible with the 14 APIs tested here, under a 90-day period of storage at refrigerated temperature. This suggests that SyrSpend SF PH4 is suitable for compound-ing APIs from different pharmacological classes.
REFERENCES1. Batchelor HK, Marriott JF. Formulations
of 100.0-mg/mL oral suspensions compounded from tablets and simple syrup and reported a BUD of 60 days at 4ºC and 25ºC.
SOTALOL HYDROCHLORIDE Nahata and Morosco24 evaluated the stability of oral suspensions compounded from tablets and using Ora-Sweet and Ora-Plus (1:1), stored at 4ºC and 25ºC. The BUD was determined as 91 days, equivalent to what was found in the present study.
SPIRONOLACTONE Allen and Erickson25 evaluated the stability of 25.0 mg/mL oral suspensions compounded from tablets and using as vehicle Ora-Sweet and Ora-Plus. HPLC analy-sis showed not more than 7% of drug loss after 60 days of storage at 5 ºC or 25 ºC.
TACROLIMUS MONOHYDRATE Our group evaluated the stability of tacrolimus monohydrate in SyrSpend SF PH43 at a concentration of 1.0 mg/mL and stored both at refrigerated and room
ESTUDO 30
84International Journal of Pharmaceutical CompoundingVol. 22 No. 6 | November | December | 2018
www.IJPC.com
C O N T R O L L E D R O O M
T E M P E R A T U R E ( 2 0 º C T O 2 5 º C )
NP
NP
NP
NP
NP
NP
NP
NP
NP
100 ± 0.47
99.80 ± 0.63
100.68 ± 0.81
102.40 ± 0.38
99.64 ± 0.33
99.96 ± 0.48
100 ± 0.42
96.66 ± 0.90
99.49 ± 0.82
97.09 ± 1.01
98.87 ± 0.45
99.02 ± 2.57
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
T A B L E 5 . STABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID).
E L A P S E D T I M E ( D A Y S )Baclofen 2.0 mg/mL
T = 0
T = 60
T = 90
Carvedilol 5.0 mg/mL
T = 0
T = 60
T = 90
Hydrochlorothiazide 2.0 mg/mL
T = 0
T = 60
T = 90
Mercaptopurine 10.0 mg/mL
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
Methadone Hydrochloride 10.0 mg/mL
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
Oseltamivir Phosphate 6.0 mg/mL
T = 0
T = 60
T = 90
Phenobarbital 9.0 mg/mL
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
Phenobarbital 15.0 mg/mL
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
% R E C O V E R Y
R E F R I G -E R A T E D
T E M P -E R A T U R E
( 2 º C T O 8 º C )
100 ± 0.65
100.22 ± 0.15
99.52 ± 0.39
100 ± 0.45
101.70 ± 0.57
101.08 ± 0.25
100 ± 0.81
100.44 ± 0.79
101.62 ± 3.41
100 ± 0.47
99.54 ± 0.82
103.17 ± 0.78
101.88 ± 0.81
99.46 ± 0.32
100.08 ± 0.20
100 ± 0.42
96.05 ± 0.74
100.14 ± 0.68
97.80 ± 0.65
98.15 ± 0.19
97.18 ± 2.29
100 ± 0.19
103.39 ± 0.07
102.32 ± 0.67
100 ± 0.82
100.15 ± 1.20
100.90 ± 1.14
100.90 ± 3.57
105.89 ± 2.60
102.59 ± 0.62
100 ± 1.00
103.05 ± 1.97
101.75 ± 0.84
100.22 ± 0.83
107.80 ± 1.19
100.35 ± 0.94 NP = Not performed
Propranolol Hydrochloride 0.5 mg/mL
T = 0
T = 60
T = 90
Propranolol Hydrochloride 5.0 mg/mL
T = 0
T = 60
T = 90
Pyrazinamide 100.0 mg/mL
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
Sotalol Hydrochloride 5.0 mg/mL
T = 0
T = 7
T = 14
T = 30
T = 60
T = 90
Spironolactone 2.0 mg/mL
T = 0
T = 60
T = 90
Spironolactone 2.5 mg/mL
T = 0
T = 60
T = 90
Tacrolimus Monohydrate 0.5 mg/mL
T = 0
T = 60
T = 90
Ursodeoxycholic Acid 20.0 mg/mL
T = 0
T = 60
T = 90
Vancomycin Hydrochloride 25.0 mg/mL
T = 0
T = 60
T = 90
100 ± 0.55
98.95 ± 0.30
98.35 ± 0.41
100 ± 0.17
97.55 ± 0.16
98.78 ± 1.18
100 ± 0.84
103.00 ± 0.82
98.69 ± 0.81
96.02 ± 0.71
101.65 ± 0.37
102.49 ± 0.20
100 ± 0.89
98.89 ± 0.71
96.78 ± 0.97
103.66 ± 0.33
101.59 ± 0.43
101.48 ± 0.14
100 ± 0.38
101.20 ± 0.42
99.69 ± 0.47
100 ± 0.52
105.06 ± 0.42
103.75 ± 0.39
100 ± 0.17
98.77 ± 0.60
100.08 ± 0.19
100 ± 0.85
95.35 ± 3.42
96.95 ± 0.88
100 ± 0.16
103.28 ± 0.22
101.87 ± 0.21
NP
NP
NP
NP
NP
NP
100 ± 0.84
101.54 ± 1.13
101.15 ± 0.14
101.33 ± 0.95
101.32 ± 0.69
102.12 ± 0.15
100 ± 0.89
98.21 ± 0.63
100.61 ± 0.78
103.21 ± 0.16
102.48 ± 0.38
101.40 ± 0.16
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
NP
E L A P S E D T I M E ( D A Y S )
R E F R I G -E R A T E D
T E M P -E R A T U R E
( 2 º C T O 8 º C )
% R E C O V E R Y
C O N T R O L L E D R O O M
T E M P E R A T U R E ( 2 0 º C T O 2 5 º C )
T A B L E 5 . STABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID) CONTINUED.
Peer ReviewedESTUDO 30
85International Journal of Pharmaceutical Compounding
Vol. 22 No. 6 | November | December | 2018www.IJPC.com
Peer Reviewed
[Bac
lofe
n] m
g/m
L
0 30 60 90
2.4
2.2
2.0
1.8
1.6
Time (Days)
[Car
vedi
lol]
mg/
mL
0 30 60 90
6.0
5.5
5.0
4.5
4.0
Time (Days)
[Hyd
roch
loro
thia
zide
] m
g/m
L
0 30 60 90
2.4
2.2
2.0
1.8
1.6
Time (Days)
[Mer
capt
opur
ine]
m
g/m
L
0 30 60 90
12
11
10
9
8
Time (Days)
[Met
hado
ne]
mg/
mL
0 20 40 60 80 100
12
11
10
9
8
Time (Days)
[Ose
ltam
ivir
phos
phat
e]
mg/
mL
0 30 60 90
7.2
6.6
6.0
5.4
4.8
Time (Days)
[Phe
noba
rital
] m
g/m
L
0 30 60 90
10.8
9.9
9.0
8.1
7.2
Time (Days)
[Phe
noba
rbita
l] m
g/m
L
0 30 60 90
18
16
14
12
10
Time (Days)
[Pro
pran
olol
HCl
] m
g/m
L
0 30 60 90
6.0
5.5
5.0
4.5
4.0
Time (Days)
[Pro
pran
olol
HCl
] m
g/m
L
0 30 60 90
6.0
5.5
5.0
4.5
4.0
Time (Days)
[Pyr
azin
amid
e] m
g/m
L
0 30 60 90
120
110
100
90
80
Time (Days)
[Sot
alol
HCl
] m
g/m
L
0 30 60 90
6.0
5.5
5.0
4.5
4.0
Time (Days)
[Spi
rono
lact
one]
mg/
mL
0 30 60 90
2.4
2.2
2.0
1.8
1.6
Time (Days)
[Spi
rono
lact
one]
mg/
mL
0 30 60 90
2.8
2.6
2.4
2.2
2.0
Time (Days)[T
acro
limus
mon
ohyd
rate
] m
g/m
L
0 30 60 90
0.60
0.55
0.50
0.45
0.40
Time (Days)
[Urs
odeo
xych
olic
Aci
d]
mg/
mL
0 30 60 90
24
22
20
18
16
Time (Days)
[Van
com
ycin
HCl
] m
g/m
L
0 30 60 90
28
26
24
22
20
Time (Days)
F I G U R E 1 . PLOT OF ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 THROUGHOUT THE COMPATIBILITY STUDY.
ESTUDO 30
86International Journal of Pharmaceutical CompoundingVol. 22 No. 6 | November | December | 2018
www.IJPC.com
for children: Problems and solutions. Br J Clin Pharmacol 2015; 79(3): 405–418.
2. Polonini HC, Silva SL, de Almeida TR, et al. Compatibility of caffeine, carvedilol, clomipramine hydrochloride, folic acid, hydrochlorothiazide, loperamide hydro-chloride, methotrexate, nadolol, naltrex-one hydrochloride and pentoxifylline in SyrSpend SF PH4 oral suspensions. Eur J Hosp Pharm 2016; 23(6): 352–358.
3. Polonini HC, Silva SL, Cunha CN et al. Compatibility of cholecalciferol, haloperi-dol, imipramine hydrochloride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacrolimus monohydrate, terbinafine, tramadol hydrochloride and valsartan in SyrSpend SF PH4 oral sus-pensions. Pharmazie 2016; 71(4): 185–191.
4. Ferreira AO, Polonini H, da Silva SL et al. Stability of acetazolamide, baclofen, dipyridamole, mebeverine hydrochloride, propylthiouracil, quinidine sulfate, and topiramate oral suspensions in SyrSpend SF PH4. IJPC 2017; 21(4): 339–346.
5. United States Pharmacopeial Convention, Inc. United States Pharmacopeia–National Formulary. Rockville, MD: US Pharmacopeial Convention, Inc.; Current Edition.
6. International Conference on Harmonisation. Technical Requirements for Registration of Pharmaceuticals for Human Use (2005). Validation of Analytical Procedures: Text and methodol-ogy Q2(R1). [ICH Website.] Available at: www.ich.org. Accessed December 2017.
7. Allen LV Jr., Erickson MA III. Stability of acetazolamide, allopurinol, azathioprine, clonazepam, and flucytosine in extempo-raneously compounded oral liquids. Am J Health Syst Pharm 1996; 53(16): 1944–1949.
8. Yamreudeewong W, Dolence EK, Pahl D. Stability of two extemporaneously pre-pared oral metoprolol and carvedilol liq-uids. Hosp Pharm 2006; 41(3): 254–259.
9. Tötterman AM, Luukkonen P, Riukka L et al. Formulation of enteral hydrochloro-thiazide suspension for premature infants. Eur J Hosp Pharm 1994; 4(2): 65–69.
10. Allen LV Jr., Erickson MA III. Stability of labetalol hydrochloride, metoprolol tartrate, verapamil hydrochloride, and spi-ronolactone with hydrochlorothiazide in
extemporaneously compounded oral liq-uids. Am J Health Syst Pharm 1996; 53(19): 2304–2309.
11. Dressman JB, Poust RI. Stability of allo-purinol and of five antineoplastics in suspension. Am J Hosp Pharm 1983; 40(4): 616–618.
12. Aliabadi HM, Romanick M, Desai S, Lavasanifar A. Effect of buffer and antioxi-dant on stability of a mercaptopurine sus-pension. Am J Health Syst Pharm 2008; 65(5): 441–447.
13. Little TL, Tielke VM, Carlson RK. Stability of methadone pain cocktails. Am J Hosp Pharm 1982; 39(4): 646–647.
14. Eggers NJ. Stability of a methadone and prolintane mixture. Aust J Hosp Pharm 1978; 8: 91–92.
15. [No author listed.] Physicians’ Desk Reference. 61st ed. Montvale, NJ: Medical Economics Company; 2007.
16. Winiarski AP, Infeld MH, Tscherne R et al. Preparation and stability of extemporane-ous oral liquid formulations of oseltamivir phosphate using commercially available capsules. J Am Pharm Assoc 2007; 47(6): 747–755.
17. Geiger CM, Sorenson B, Whaley P. Stability assessment of 10 active phar-maceutical ingredients compounded in SyrSpend SF. IJPC 2015; 19(5): 420–427.
18. Dietz NJ, Cascella PJ, Houglum JE et al. Phenobarbital stability in different dosage forms: Alternatives for elixirs. Pharm Res 1988; 5(12): 803–805.
19. Cober MP, Johnson CE. Stability of an extemporaneously prepared alcohol-free phenobarbital suspension. Am J Health Syst Pharm 2007; 64(6): 644–646.
20. Henry DW, Repta AJ, Smith FM et al. Stability of propranolol hydrochloride suspension compounded from tablets. Am J Hosp Pharm 1986; 43(6): 1492–1495.
21. Gupta VD, Stewart KR. Stability of pro-pranolol hydrochloride suspension and solution compounded from injection or tablets. Am J Hosp Pharm 1987; 44(2): 360–361.
22. Allen LV Jr., Erickson MA. Stability of bethanechol chloride, pyrazinamide, quinidine sulfate, rifampin, and tetracy-cline hydrochloride in extemporaneously compounded oral liquids. Am J Health Syst Pharm 1998; 55(17): 1804–1809.
23. Nahata MC, Morosco RS, Peritore SP. Stability of pyrazinamide in two suspen-sions. Am J Health Syst Pharm 1995; 52(14): 1558–1560.
24. Nahata MC, Morosco RS. Stability of sotalol in two liquid formulations at two temperatures. Annals Pharmacother 2003; 37(4): 506–509.
25. Allen LV Jr., Erickson MA III. Stability of ketoconazole, metolazone, metronidazole, procainamide hydrochloride, and spirono-lactone in extemporaneously compounded oral liquids. Am J Health Syst Pharm 1996; 53(17): 2073–2078.
26. Jacobson PA, Johnson CE, West NJ et al. Stability of tacrolimus in an extempora-neously compounded oral liquid. Am J Health Syst Pharm 1997; 54(2): 178–180.
27. Mallett MS, Hagan RL, Peters DA. Stability of ursodiol 25 mg/mL in an extemporane-ously prepared oral liquid. Am J Health Syst Pharm 1997; 54(12): 1401–1404.
28. Nahata MC, Morosco RS, Hipple TF. Stability of ursodeoxycholic acid in two extemporaneously prepared oral suspen-sions. J Appl Ther Res 1999; 2: 221–224.
29. Mallet L, Sesin PG, Ericson J. Storage of vancomycin hydrochloride oral solution. J Human Pharmacol Drug Ther 1982; 2(5): 285.
Address correspondence to Hudson Polonini, Ortofarma – Quality Control Laboratories, BR 040, N. 39, Empresarial Park Sul. 36120-000. Matias Barbosa – MG. Brazil. E-mail address: [email protected]
Peer ReviewedESTUDO 30
Anne-Claire Bonnaure*, Romain Bellay, Pauline Rault, Marie-Antoinette Lesterand Pierre-Nicolas Boivin
Physicochemical Stability of 5mg/mL PediatricPrednisone Oral Suspension in Syrspend® SF PH4
https://doi.org/10.1515/pthp-2018-0001Received January 5, 2018; revised February 14, 2018; acceptedFebruary 15, 2018
Abstract
Background: Prednisone is a corticosteroid used in sev-eral inflammatory diseases and cancers. In France, noavailable prednisone drinkable formulation exists.Instead, an oral syrup of prednisone with ethanol,sodium benzoate and simple syrup is produced.However, sodium benzoate can induce neonatal icterusand alcohol is not authorized for children below 3 yearsof age. The aim of this study was to determine the stabi-lity of 5mg/mL prednisone oral suspension in a commer-cial compounding excipient: Syrspend® SF PH4.Methods: Three batches of oral suspensionswere prepared,using micronized prednisone and Syrspend® SF PH4. Theywere packaged in amber glass vials and stored at roomtemperature. On day 0, 1, 4, 10, 30, 60 and 90, we observedphysical and chemical stability (pH measurement, osmol-ality measurement, residual concentrations of prednisoneand degradation product identification). A stability indicat-ing method was developed using high performance liquidchromatography with Ultraviolet detection at 254 nm.Results: Prednisone concentrations remained stablewithin ± 5% of nominal values for 60 days. No degrada-tion product and change of physicochemical propertieswere detected.Conclusion: This study showed that 5mg/mL prednisoneoral suspension in Syrspend® SF PH4 is stable for 60days, at room temperature and protected from light.
Keywords: suspension, formulation, excipient, stability,HPLC (Hight Perfomance/Pressure LiquidChromatography), pediatric
Introduction
Prednisone (Figure 1) is a glucocorticosteroid usuallyused in several inflammatory pathologies and cancers.Low dose prednisone is used for anti-inflammatory activ-ities, while high dose prednisone is employed for immu-nosuppressive purposes [1].
This drug is usually used in pediatric oncology andhematology units. To facilitate the pediatric use, drink-able formulations of prednisone are preferred over oralsolid forms. However, no available prednisone drinkableformulation exists (no commercial syrup or ATU:Temporary Authorization for Use) in France and onlytablets of prednisone are available [1].
Despite this, a few studies on liquid oral formulationshave been reported [2, 3]. For several years, an oral syrup ofprednisone with alcohol (ethanol), sodium benzoate, andsimple syrup [4] was prepared in our hospital. The stabilityof this preparation was maintained for 56 days under refrig-eration ( + 2 °C+ 8 °C) in amber glass vials. However, alco-hol is not recommended for use in pediatric therapeutics oris used at a percentage of less than 5% [5]. Moreover,sodium benzoate can induce neonatal icterus [6].
To avoid these excipients with known effects, wedecided to rely on a commercial compounding vehicle:Syrspend® SF PH4, a product that is frequently used inoral suspension drugs. Many studies have approved thecompatibility between active pharmaceutical ingredients(API) and this vehicle [7, 8].
Furthermore, the stability of prednisolone suspen-sion (Figure 2) in Syrspend® SF PH4 was studied [8],while it remains unknown for prednisone.
Materials and methods
Analytical method
Reagents
Micronized prednisone was bought to Inresa(Bartenheim, France) and Syrspend® SF PH4 to Fagron
*Corresponding author: Anne-Claire Bonnaure, CHU de Rennes, 2rue Henri Le Guilloux, 35000 Rennes, France, E-mail: [email protected] Bellay, Pauline Rault, Marie-Antoinette Lester,Pierre-Nicolas Boivin, CHU de Rennes, 2 rue Henri Le Guilloux,35000 Rennes, France, E-mail: [email protected]; [email protected]; [email protected];[email protected]
Pharm Technol Hosp Pharm 2018; 3(2): 49–57
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ESTUDO 29
(Thiais, France). Methanol was of HPLC grade and waspurchased from VWR Chemicals (Fontenay-sous-Bois,France). Prednisone and prednisolone standards wereprocured from Merck (Darmstadt, Germany).
Water for HPLC was distilled and passed through areverse osmosis system. Hydrochloric acid (HCl) solutions0.1M and 1M were purchased from VWR Chemicals(Fontenay-sous-Bois, France), sodium hydroxide (NaOH)0.1M and 1M were bought to Merck (Darmstadt,Germany), oxygen peroxide (H2O2) 10 volumes wasacquired from Gifrer (Decines-Charpieu, France).
Instrumentation and chromatographic conditions
The HPLC system included a 717 plus autosampler, 2487UV detector, and a HPLC 515 pump (Waters, Milford,USA). Chromatographic separation of the analytes wascarried out on Waters Xterra RP C18 5 µm column(4.6*150mm). The volume injection of the sample was10 µL. The flow rate was kept at 1mL/min and prednisonewas detected at 254 nm [9, 10]. The oven temperature waskept at 45 degrees Celsius.
Multiple mobile phases were tested to achieve anoptimal elution. Fourteen different combinations oforganic solvent and water were tried: acetonitrile/water,acetonitrile/methanol/water and methanol/water, each atvarious proportions.
Data were acquired and processed with EMPOWERSoftware (Warers, Milford, USA). All calculations wereperformed using Microsoft Excel 2010 (MicrosoftCorporation, USA).
Preparation of oral suspensions
Three batches of 5mg/mL oral suspension were prepared,using 350mg of micronized prednisone and 70 mL ofSyrspend® SF PH4. These were packaged in amber glassvials (60 mL) to protect from light and stored at roomtemperature throughout the study. According to theEuropean Pharmacopoeia [11], prednisone could be pro-tected from light. That why, the study was realized withamber glass.
Prednisone concentrations were determined on days0, 1, 4, 10, 30, 60, 90 after the first day of production.
Method parameters validation
The HPLC method was validated according to theInternational Conference on Harmonization (ICH) guide-lines (Q2R1) [12] including the assessment of system lin-earity, accuracy, precision (repeatability, intermediateprecision) and specificity [13].
Standard stock solutions of prednisone were pre-pared in methanol to obtain a concentration of 5mg/mL. Six calibration curves were prepared using this solu-tion. The work concentrations of calibration standardswere 75 µg/mL, 100 µg/mL, 125 µg/mL, 150 µg/mL and175 µg/mL and the work concentrations of the three qual-ity controls (QC) were 75 µg/mL, 125 µg/mL and 175 µg/mL. An assay range between 60% and 140% of the targetvalue (125 µg/mL) was respected according to the ICH.
Linearity
The response function was performed on three differentdays with the six calibrations curves. In order to checkwhether an excipient effect existed, two types of rangeswere produced: a range only containing the API and areconstituted range, with Syrspend® SF PH4. The method
Figure 1: chemical structure of prednisone.
Figure 2: chemical structure of prednisolone.
50 A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension
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ESTUDO 29
was considered as linear if the coefficient of determina-tion was over 0.99 for the mean standard curve.
Accuracy
The accuracy was determined using the data obtainedduring study of the response function. For each QC, theaccuracy was measured by calculating the report betweentheoretical and calculated concentrations. This reportallows the access to a recovery rate, whereby, it had tobe less than 5% in order to be accepted.
Precision
To determine the repeatability of this method, six pointsof the middle of the range was performed (125 µg/mL),and each point was prepared by independent weighing.Then, the intermediate precision was determined on threedifferent days, using the relative standard variation(RSD), which had to be less than 5%.
Stability indicating method
A stability indicating method is a process that is able todistinguish the API from its degradation products. Themethod has to be sufficiently sensitive to detect thesedegradation products in low quantity and sufficientlyresolute to distinguish products with potentially closestructures [13, 14].
Forced degradation experiments were carried out onprednisone under various conditions explained in the ICHguideline: heat, acid, alkaline and oxidative conditions.
A thermal degradation study was performed at twodifferent temperatures: room temperature (24 °C ± 1 °C)and 80 °C in a water bath. The exposure time was onehour in both conditions.
Acid hydrolysis was studied by adding HCl solutions at0.1M, 0.5M and 1M in prednisone solution. At one hour ofexposure time, neutralization was performed with respec-tively 0.1M, 0.5M, and 1M NaOH solutions. The alkalinehydrolysis was performed by doing the opposite procedureof acid hydrolysis (exposition with NaOH, then neutraliza-tion with HCl). Acid and alkaline degradation was per-formed in a water bath heated to 80 °C, for one hour.
Oxidative degradation was assessed by exposed pre-dnisone solution in 10 volumes of H2O2 for three hours ina water bath heated to 100 °C.
The degradation was confirmed if a reduction ofmore 5% of prednisone concentration was observed.
Related substances
A solution of prednisolone was prepared in methanol toobtain a concentration of 5mg/mL to differentiate pre-dnisone to prednisolone. A work concentration of 125 µg/mL of prednisolone was compared to the same concen-tration of prednisone solution by HPLC. The same analy-sis method was used for the two molecules.
The resolution between these two peaks had to bemore than 1.5 to validate the separation.
Analysis during the studied period
Three prednisone oral suspensions were prepared at day0. During each time of the study (days 0, 1, 4, 10, 30, 60,90) physical and chemical parameters were observed onthe three batches.
Visual and odour inspection
A visual inspection was done in order to detect precipita-tion or variation of colour with time. A control of odoursuspension was also performed.
Osmolality
The osmolality of the suspension was measured withAdvanced Instruments Model 3250 Osmometer(Radiometer, Neuilly-Plaisance, France). A 250 µL aliquotof each suspension were taken and diluted (1:2 v/v) inwater for injection before measurement.
pH
The pH was determined with a pH-meter: pHenomenalVWR® (VWR Chemicals, Fontenay-sous-Bois, France).
Measure of concentration
Prednisone concentration was quantified in triplicatesimmediately after preparation and after 1, 4, 10, 30, 60and 90 days. Before removing samples, the containers
A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension 51
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were handshaken manually to ensure a homogeneoussuspension, according to the 9th edition of theEuropean Pharmacopoeia [11]. Then, 400 µL sample ofeach preparation was diluted (1:10 v/v) in methanoland centrifuged at 4000 rpm for five minutes to sedi-ment insoluble excipients. Another dilution (1:4 v/v) ofsupernatant was performed in methanol for HPLC ana-lysis. The chemical stability was determined by calcu-lating the percentage of the initial concentrationremaining at each time interval: prednisone concentra-tion in subsequent samples greater than 95% wereconsidered stable.
Statistical and data analysis Statistical tests wereperformed by Excel® software (Microsoft Office, USA,2007) with a risk α set at 5%. Statistical significancewas specified as p < 0.05.
Before using the Student t-test, the Shapiro-Wilk testwas performed to show a normality test data (α=0.05).
Results
Analytical method
The chosen mobile phase has been composed of metha-nol/water (45:55 v/v).
Method parameters validation
Linearity
The coefficients of determination were 0.9999, 0.9994and 0.9998, for days 1, 2 and 3, respectively, in thesuspension without Syrspend® SF PH4.
For the suspension with Syrspend® SF PH4, the coef-ficients of determination were 0.9999, 0.9999 and 0.9998,for days 1, 2 and 3, respectively.
The average of regression equations was without andwith Syrspend® SF PH4: y = 22096x-1129 (r2 = 0.9997) andy = 22791x-35,573 (r2 = 0.9998), respectively. Student sta-tistical test did not show significant differences betweenthe slopes and the y-intercepts (α = 5%). No excipienteffect was observed between curves with and withoutSyrspend® SF PH4.
Accuracy
The accuracy rates for the 75 µg/mL, 125 µg/mL and175 µg/mL QC were estimated to be 0.50%, 0.59% and1.12%, respectively. These results related to ranges withexcipient.
Precision
This method is repeatable because of a RSD of 1.64%,2.16% and 1.37%, for days 1, 2 and 3, respectively.
The results of the intermediate precision for threedays showed a RSD of 1.72%.
Stability indicating method
No degradation was observed at room temperature (20 °C)(Figure 3) and heating at 80 °C (Figure 4).
The acid hydrolysis showed a reduction of predni-sone concentration of 8.7% with HCl 1M (Figure 5). Nodegradation was observed with 0.1 and 0.5M of HCl(0.8% and 4% respectively).
AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Minutes
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00
Figure 3: chromatogram ofprednisone at roomtemperature.
52 A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension
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The alkaline hydrolysis was observed with low concentra-tion of NaOH. In fact, a reduction of 80% of prednisoneconcentration was visible with NaOH 0.1M (Figure 6). Thesame result was noted with 0.5 and 1M of NaOH.
No variation was observed with H2O2 (reduction of4.5%).
The prednisone degradation is poor in acid environ-ment but major in basic environment.
AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Minutes
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00
Figure 4: chromatogram of prednisone heating at 80 °C.
AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Minutes1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00
Figure 5: chromatogram of prednisone and products of degradation with HCl 1M.
AU
0.000
0.005
0.010
0.015
0.020
0.025
Minutes
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00
Figure 6: chromatogram of prednisone and products of degradation with NaOH 0.1M.
A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension 53
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Related substances
The resolution between peaks of prednisone and predni-solone was calculated at 2.9 (Figure 7).
Analysis during the studied period
Visual and odour inspection
No precipitation, no variation of colour or odour on thesuspension was observed in the three batches.
Osmolality
During the study period, all osmolality measurementswere included between 42 and 46 mOsm/Kg (Table 1).No significant variation of osmolality was observed.
pH
During the study, all pH measurements were includedbetween 4.18 and 4.22 (Table 1). No significant variationof pH was observed.
Measure of concentration
After validation of the analytical method, prednisoneconcentrations remained stable within more or less 5%of nominal value over 60 days. Two of the three batchesshowed a concentration more than 5% of nominal valueon the day 90 (Table 2). Results of the Shapiro-testshowed that samples followed a normality test data(p-value = 0.9638). Student test did not show a significantdifference from day 0 to day 60 (t calc < t table). However,a significant difference from the day 90 was observed(t calc = 5.3 and t table = 2.92).
Discussion
A suspension of prednisone dosing at 5mg/mL inSyrspend® SF PH4 was tested using a simple method:high performance liquid chromatography (HPLC).
After the fourteen tests, the mobile phase methanol/water (45:55 v/v) seemed more efficient than the othermixtures: the retention time was optimal (approximatelyseven minutes) and the peak was optimal (tailingfactor = 1.1). Other mixtures that could have been testedwere various combinations of methanol/water/tetrahy-drofuran [15, 16].
The chemical structure of prednisone is similar to theprednisolone structure. The difference is the molecular
Table 1: pH and Osmolality values of prednisone in oral suspension. pH and Osmolality expressed as mean ± standard deviation (SD) oftriplicate measurements of one test suspension (n= 3).
Day Day Day Day Day Day Day
pH . ±. . ± . . ±. . ± . . ± . . ±. . ± .Osmolality . ±. . ± . . ±. . ± . . ± . . ±. . ± .
AU
0.00
0.05
0.10
0.15
Minutes
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00
Figure 7: chromatogram of prednisone (on the left) and prednisolone (on the right).
54 A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension
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chemical group on the Carbon number 12: an alcoholgroup is substituted by a ketone group in prednisolone.A chromatographic separation of prednisone and predni-solone confirmed that the retention time of these twomolecules are different.
The validation of the analytical method confirmedthe use of this method to measure the concentration ofprednisone with HPLC. A good linearity with a coefficientof determination constantly more than 0.999 wasobtained. The accuracy and the precision rates weremeasured to be less than 5%, suggesting that thismethod is highly repeatable. The stability indicatingmethod has permitted to bring out degradation productsof prednisone [13].
The study of prednisone suspension in Syrspend® SFPH4 showed a stability of 60 days. Any variation of pHmeasurement and osmolality measurement wasobserved. Concentrations of prednisone remained stablewithin more or less 5% of nominal values over 60 days.No degradation product was detected throughout thestudied period.
A variation of concentration is fixed to 5% for drugswith narrow therapeutic window, and 10% for othertherapeutic [13]. Even if prednisone is not a drug withnarrow therapeutic window, we preferred to secure thereduction of concentration to 5% of the nominal valuesbecause this suspension is reserved for children.
The microbiological stability is recommended toshow the conservation over time within limits for con-tamination (ie: germs, moulds, yeasts) as according to theEuropean Pharmacopoeia [12, 14]. However, the micro-biological stability of this suspension was not evaluatedbecause of lake of materials in the laboratory.
Viscosity analysis is a limit of this study [13]. Thefriction force was not evaluated because no rotating visc-ometer was available in our laboratory.
Taken together, the results of this study showed thatthis new suspension is easier to produce than the syrupof prednisone with alcohol, sodium benzoate and simple
syrup. Indeed, the fabrication time is shorter and thenumber of compounds is smaller.
Conclusion
This study showed that 5mg/mL prednisone oral suspen-sion in Syrspend® SF PH4 was stable for 60 days, at roomtemperature and protected from light. This new suspen-sion would provide an interesting alternative to the syrupwith alcohol and sodium benzoate, especially for pedia-tric use.
Conflict of interest statement: Authors state no conflictof interest. All authors have read the journal’sPublication ethics and publication malpractice statementavailable at the journal’s website and hereby confirm thatthey comply with all its parts applicable to the presentscientific work.
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Table 2: concentration of prednisone in oral suspension over 90 days. Concentration expressed as mean ± RSD of triplicate assays of onesuspension (n= 3).
Test solution Drug concentration in sample (mg/mL) % initial concentration remaining ± relative deviation standard (RSD)
Nominal Day Day Day Day Day Day Day
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Note: drug concentration in samples taken at time zero was designated as 100%.
A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension 55
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8. Geiger CM, Sorenson B, Whaley P. Stability assessment of 10active pharmaceutical ingredients compounded in syrspendSF. Int J Pharm Compd 2015;19:420–27.
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10. Kwak HW, D’Amico DJ. Determination of dexamethasonesodium phosphate in the vitreous by high performance liquidchromatography. Korean J Ophthalmol 1995;9:79–83.
11. Pharmacopée européenne 9ème édition 9.0, 9.1, 9.2: :9789287181329 Edqm/conseil de l’europe, Gestion -Règlementation [Internet]. 2017 Available at: https://www.unitheque.com/Livre/edqm_-_conseil_de_l_europe/Pharmacopee_europeenne_9eme_edition_9.0_9.1_9.2-97053.html#gallery-1. Accessed 16 Nov 2017.
12. ICH Expert Working Group. ICH guideline Q1A(R2) stabilitytesting of new drug substances and products. In: InternationalConference on Harmonization [Internet]. 2003 p. 24. Availableat: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdf. Accessed 5 Nov 2017.
13. Sautou V, Bossard D, Chedru-Legros V, Crauste-Manciet S,Fleury-Souverain S, Lagarce F, et al. Methodological guidelinesfor stability studies of hospital pharmaceutical preparations[Internet]. 2013 Available at: https://www.gerpac.eu/IMG/pdf/guide_stabilite_anglais.pdf. Accessed 5 Nov 2017.
14. Blessy MN, Patel RD, Prajapati PN, Agrawal YK. Development offorced degradation and stability indicating studies of drugs—Areview. J Pharm Anal 2014;4:159–65.
15. Williamsx PA, Biehl ER. High-pressure liquid chromatographicdetermination of corticosteroids in topical pharmaceuticals. JPharm Sci 2017;70:530–34.
16. Lou H, Liu M, Wang L, Mishra SR, Qu W, Johnson J, et al.Development of a mini-tablet of co-grinded prednisone-Neusilin complex for pediatric use. AAPS PharmSciTech2013;14:950–58.
Bionotes
Anne-Claire BonnaureCHU de Rennes, 2 rue Henri Le Guilloux,35000 Rennes, France, [email protected]
After graduating from the Faculty of Pharmacy at the University ofRennes1, Anne-Claire Bonnaure chose a hospital career and becameresident pharmacist in 2014. She spent her residency in theUniversity Hospital and the Anticancer Centre of Rennes, and in theHospitals of Lorient and Saint-Brieuc in Brittany (France). Herinterests in the field of pharmaceutical technology include qualitycontrol units and chemotherapy production.
Romain BellayCHU de Rennes, 2 rue Henri Le Guilloux,35000 Rennes, France, [email protected]
Romain Bellay is currently a pharmD candidate working at thePharmacy Department of the University Hospital of Rennes, France.In 2017, he obtained his university degree in clinical pharmacy. Inthe field of pharmaceutical technology his special interests includenew oral formulations, quality control as well as physicochemicalstability of drug suspensions.
Pauline RaultCHU de Rennes, 2 rue Henri Le Guilloux,35000 Rennes, France, [email protected]
Pauline Rault, pharmD candidate, has two years of internship leftbefore her graduation. Currently working at the sterilization ward ofthe Rennes University Hospital, she is also specializing inpharmacoeconomics thanks to the Paris Descartes’ diploma. Herlast semester in paediatric nutrition allowed her to conduct astability study of vitamin formulations. In the meantime, she isteaching pharmacology to students at Pharmacy University and atnursing school.
56 A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension
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Marie-Antoinette LesterMarie-Antoinette Lester is a hospital pharmacist at RennesUniversity Hospital. Since 2006 she has been senior pharmacistinvolved in sterile preparations (cytotoxic and parenteral nutrition)and unsterile preparations. She became head of the pharmaco-technology unit in 2014.
Pierre-Nicolas BoivinCHU de Rennes, 2 rue Henri Le Guilloux,35000 Rennes, France,[email protected]
Pierre-Nicolas Boivin is a hospital pharmacist in the manufacturingand quality control laboratory at the Pharmacy Department of theUniversity Hospital of Rennes. His work is focused on sterilepreparations (cytotoxic, eye drops and parenteral nutrition) andunsterile preparations. He is involved in the development andvalidation of analytical methods and implementation of stabilitystudies.
A.-C. Bonnaure et al.: Stability of 5 mg/mL Prednisone oral suspension 57
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Romain Bellay*, Anne-Claire Bonnaure, Pauline Rault, Sophie Pertuisel,Marie-Antoinette Lester and Pierre-Nicolas Boivin
Stability of 5 mg/mL Nitrendipine Oral Suspensionin Syrspend® SF PH4
https://doi.org/10.1515/pthp-2017-0030Received December 4, 2017; revised January 21, 2018; acceptedJanuary 22, 2018
Abstract
Background: Nitrendipine is prescribed to children for thetreatment of primary hypertension (off-label use). Availablespecialties (Nidrel®, Baypress® and others generic drugs)are only marketed in tablet form, which is unsuitable forpediatric use. A hospital preparation of nitrendipine oralsuspension at 5mg/mLwas developed. The aim of the studywas to determine physicochemical and microbiological sta-bility of the nitrendipine oral suspension in order to set ashelf life for the preparation.Methods: A validated high-performance liquid chromato-graphic (HPLC) method was developed for the assay ofnitrendipine. Nitrendipine oral suspensions were preparedusing 20mg Nidrel® tablets and suspending vehicleSyrspend® SF PH4. These preparations were packaged inamber glass bottles and stored at room temperature. Thephysicochemical (pH, osmolality, nitrendipine concentra-tion, macroscopic changes) and microbiological stability ofthe preparation was tested over 90 days. Nitrendipineconcentration at day 0 was considered as 100% andnitrendipine concentration in subsequent samples greaterthan 95% were considered stable.Results: The developed HPLC method was validated interms of linearity, accuracy, precision and specificity.After 90 days, no significant pH and osmolality variationwas observed. No microbial growth was noted.
Concentrations of nitrendipine were found to be alwayshigher 95% of the initial concentration.Conclusions: Nitrendipine oral suspensions 5mg/mL arestable for at least 90 days when stored at temperatureroom and in amber glass bottles. This suspension is moresuitable for children than tablets and allows obtainingaccurate doses based on patient’s body weight.
Keywords: pediatrics, hypertension, calcium-channelblockers, stability, HPLC
Introduction
Nitrendipine is a dihydropyridine calcium channel blockerused in treatment of primary hypertension. When the drugis absorbed, it diffuses into smooth muscle cells membraneand inactivate L-type calcium channel [1]. The reducedlevels of calcium prevent smooth muscle contraction anddilation of the vasculature reduces total peripheral resis-tance, which decreases blood pressure.
Although it was an unlicensed drug, nitrendipine iswidely used in pediatrics. The daily dose of nitrendipineused in children is in the range of 1–3mg per kg, two orthree times daily. Available specialties (Nidrel®, 10 or20mg; Baypress® 10mg and others generic drugs) areonly marketed in tablet form, which is unsuitable forpediatric use because younger children are unable toswallow tablets. Moreover, available dosages do notallow obtaining low dosages precisely.
In the absence of a ready-made product, a hospitalpreparation of nitrendipine oral suspension at 5mg/mLwas developed. The suspending vehicle selected wasSyrspend® SF PH4 because this suspension base hasmany benefits: ready-to-use, buffered to pH 4.2 for max-imum active pharmaceutical ingredient (API) compatibil-ity, gently preserved with < 0.1% sodium benzoate whichis suitable for pediatrics, low osmolality (compatible withcommon enteral feeding tube). Syrspend SF PH4 is sugarfree and suitable for diabetics or children treated with aketogenic diet. In addition, this cherry flavored suspend-ing vehicle masks the unpleasant taste of nitrendipinepowder. However, there were no data about nitrendipine
*Corresponding author: Romain Bellay, Pharmacy, CHU de Rennes,2 rue Henri Le Guilloux, 35000 Rennes, France,E-mail: [email protected] Bonnaure, Pauline Rault, Pharmacy, CHU de Rennes,2 rue Henri Le Guilloux, 35000 Rennes, France,E-mail: [email protected]; [email protected] Pertuisel, Pediatric Oncology, CHU de Rennes, 2 rue Henri LeGuilloux, 35000 Rennes, France,E-mail: [email protected] Lester, Pierre-Nicolas Boivin, Pharmacy, CHU deRennes, 2 rue Henri Le Guilloux, 35000 Rennes, France,E-mail: [email protected];[email protected]
Pharm Technol Hosp Pharm 2018; 3(1): 31–37
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stability in the suspending vehicle, Syrspend® SF PH4 [2].A stability study was carried out according to the recom-mendations of the International Conference onHarmonization (ICH) to set a shelf life in order to deliverthe drug product to patients with quality and safety [3].The purpose of this study was to determine physicochem-ical and microbiological stability of the oral suspension.Many of analytical methods for nitrendipine in biologicalsamples were reported in the scientific literature [4, 56]but not for assay in hospital preparation. Moreover, therewere some problems for reproducing those methods inour laboratory: different instrumentation, economic rea-sons and unavailable reagents. For these reasons, wedecided to develop and to validate a high-performanceliquid chromatographic (HPLC) method for the assay ofnitrendipine.
Materials and methods
Reagents
Nitrendipine (Nidrel®) 20mg tablets were bought to UCBPharma (Colombes, France) and Syrspend® SF PH4 toFagron (Thiais, France). The composition of the suspen-sion base is as follows: sucralose (sweetener), citric acidand sodium citrate (acidifier/buffer), modified foodstarch (suspending agent), sodium benzoate ( < 0.1%,preservative), malic agent (buffer), simethicone (anti-foam agent), and purified water (approximately 95%).Methanol and acetonitrile were of HPLC grade and wereprocured respectively from VWR Chemicals (Fontenay-sous-Bois, France) and from Fisher Chemical (Illkirch-Graffenstaden, France). Water for HPLC was distilledand passed through a reverse osmosis system. Sodiumhydroxide (NaOH) and hydrochloric acid (HCl) solutionsused for the degradation study were purchased fromMerck (Darmstadt, Germany) and oxygen peroxide(H2O2) 10 volumes to Gifrer (Decines-Charpieu, France).
Formulations preparation
Nitrendipine oral suspension (5mg/mL) was prepared,according to the Good Manufacturing Practices (7), usingnitrendipine 20mg tablets (Nidrel®) and the suspendingvehicle Syrspend® SF PH4. Tablets were ground to finepowder and combined with the vehicle. These prepara-tions were packaged in amber glass bottles because, like
most 1,4-dihydropyridines derivatives, nitrendipine showshigh photosensitivity (8–10). The products were stored atroom temperature (24 °C ± 1 °C) because nitrendipine isnot a thermolabile active ingredient [11].
Instrumentation and chromatographicconditions
Nitrendipine concentrations of each sample were mea-sured by HPLC with UV detection. The chromatographicsystem included a 515 HPLC pump, an autosampler717plus and a 2487 UV detector (Waters, Milford, USA).The separation of the analytes was performed on a C-18reversed phase column Atlantis T3 column (4.6 × 150mm,5 µm) that was kept as 25 °C. The mobile phase was pre-pared by a mixture of methanol/water/acetonitrile(40:20:40 v/v). The injection volume of sample was10μL, the mobile phase flow rate was set at 1mL/min,and detection was done at 280nm. Data collection andanalysis were performed using Empower® Software(Waters, Milford, USA). All the HPLC equipment is avail-able in the control laboratory of the hospital pharmacy:this facilitates the preparations’ control extemporaneously.
Analytical validation
The analytical validation was performed according to therecommendations of ICH Q2R1 [3] including the assess-ment of system linearity, accuracy, precision (repeatabil-ity, intermediate precision) and specificity [12].
The linearity was checked for nitrendipine assay inthe concentration range from 75 to 175 µg/mL (75 µg/mL,100 µg/mL, 125 µg/mL, 150 µg/mL, 175 µg/mL). In order tocheck if there were interactions of excipients, two typesof range were realized: one containing only the API andone reconstituted with the suspending vehicle. In sum-mary, six different curves were performed on three differ-ent days. The method was considered as linear if thecorrelation coefficient was over 0.99 for the mean stan-dard curve.
To assess the accuracy, the results obtained duringthe evaluation of the linearity were used. Accuracyvalues were obtained by calculating relative error(report between theoretical and calculated concentra-tion) for three quality control samples (75 µg/mL,125 µg/mL, 175 µg/mL). This report allows to access to arecovery rate. To be accepted, this rate has to be lessthan 5%.
32 R. Bellay et al.: Stability of 5 mg/mL Nitrendipine Oral Suspension
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To study the repeatability of the method, six determi-nations of the 125 µg/mL solutions were achieved. Toevaluate intermediate precision, the protocol applied tothe study of repeatability was reproduced two other daysby different operators. Repeatability and intermediateprecision were determined using relative standard devia-tion and the threshold value for acceptability was 5%.
A stability-indicatingmethod is amethod able to distin-guish theAPI from its degradationproducts. Themethodhasto be sufficiently sensitive to detect these degradation pro-ducts in low quantity and sufficiently resolute to distinguishproducts with potentially close structures [13, 14]. Differentdegradative conditionswere tested: alkaline, acidic, thermaland oxidative [15]. Alkaline hydrolysis was studied by add-ing different concentration of NaOH (0.1M, 0.5M, 1M, and12M) in the nitrendipine solution (1:4 v/v). After one hour,neutralizationwas performedwith respectively 0.1M, 0.5M,1M and 12M HCl solutions. The acidic hydrolysis was per-formed by doing the opposite procedure. Thermal degrada-tion was assessed by placing the solution at 80 °C during 1hour. The oxidative degradation was studied by adding aH2O2 10 volumes solution to the nitrendipine solution.
Stability of oral suspension
Assay
Three nitrendipine oral suspensions were prepared at day 0.Nitrendipine concentration was quantified in triplicateimmediately after preparation and after 3, 7, 10, 15, 30, 60and 90 days. Before removing samples, the containers werehandshakemanually to ensure a homogeneous suspension.According to the9th editionof theEuropeanPharmacopoeia[11], nitrendipine is practically insoluble in water and fairlysoluble in methanol. For this reason, a 400µL sample ofeach preparation were diluted (1:10 v/v) in methanol andcentrifuged at 4000 rpm for 5min to sediment insolubleexcipients. Another dilution (1:4 v/v) of supernatant wasperformed in methanol in order to inject into the HPLCsystem. The chemical stability was determined by calculat-ing the percentage of the initial concentration remaining ateach time interval: nitrendipine concentration in subse-quent samples greater than 95% were considered stable.
In order to obtain standard solutions for HPLC ana-lysis, a 20mg/mL nitrendipine solution was prepared bycrushing Nidrel® 20mg tablets and dissolving the powderinto methanol. Then, this stock solution was diluted withmethanol to obtain standard solutions in the rangebetween 75 and 175 µg/mL.
pH determination
The pH of the suspension was determined initially and oneach study day using a pHenomenal® pHmeter (VWRChemicals, Fontenay-sous-Bois, France). Three measure-ments were performed on each study day (one on eachsuspension vial). The pH was considered as stable is thevariation of pH did not exceed 0.5 units.
Osmolality determination
Osmolality measurements were performed with AdvancedInstruments Model 3250 osmometer (Radiometer, Neuilly-Plaisance, France). Osmolality were determined in tripli-cate (one experiment on each suspension vial) at day 0and on each study day. A 250 µL aliquot of each suspen-sion were taken and diluted (1:2 v/v) in water for injectionbefore measurement. A variation of the initial measure-ment less than 10 mOsm/kg was considered as stable (theprecision of the osmometer was 2 mOsm/kg).
Physical stability
A visual examination was performed along the stabilitystudy in order to detect a precipitation, color change orother macroscopic manifestations (e. g. smell change).The preparation was considered physically stable ifthose characteristics were not changed.
Microbiological stability
According to the European Pharmacopoeia [11], themicrobiological quality of oral preparations must satisfythe following tests: enumeration of total viable aerobicgerms with a maximum of 103 bacteria and 102 molds andyeasts per milliliter and absence of Escherichia coli.Microbiological stability was assessed at each study dayby manual counting of colony-forming units on mediaplates. Because the suspensions were purposed for use asa multiple dose regimen, it was necessary to determinethe microbiological stability of the preparations whetherthey retained the quality once the containers wereopened under ambient conditions. Previously, a fertilitytest was performed in order to ensure that one of theproducts present in the vehicle Syrspend SF PH4 didnot inhibit microbial sprouting.
R. Bellay et al.: Stability of 5 mg/mL Nitrendipine Oral Suspension 33
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Statistical analysis/data analysis
The results are represented as the mean value of nineindependent experiments ± 95% confidence interval.All statistical tests were performed by the Excel®
software (Microsoft Office, USA, 2007) with a risk α of5%. Statistical significance was defined as p < 0.05.
Results
Analytical validation
Linearity
Three curves were performed on three different days. Thesame manipulation was done without and with excipi-ents in order to appreciate the influence of excipients onnitrendipine detection. Correlation coefficients of thestandard curves were 0.9925, 0.9992 and 0.9987 forcurves without excipients. Concerning curves with exci-pients, correlation coefficients values were 0.9977, 0.9993and 0.9998. The difference was not statistically signifi-cant (p = 0.7804).
Accuracy
The accuracy of the method was estimated to 2.27%,3.86% and 2.95% respectively on the 75, 125 and175 μg/mL concentrations of quality control samples.Those results were obtained using ranges with excipients.
Precision
Precision was tested on two levels: repeatability andintermediate precision. Relative standard deviation ofthe results was 0.93% for the repeatability and 1.03%for the intermediate precision.
Specificity
The retention time of nitrendipine was approximatively3.6min (Figure 1A). In this method, alkaline degradationseems to be the major route of degradation. We observeda major degradation product at 3.2min (Figure 1B). Thedegradation product was well-resolved from the nitrendi-pine peak. Resolution between nitrendipine peak and themajor degradation product peak identified was 1.6. This
A. Nitrendipine standard solution
B. Nitrendipine stressed sample using NaOH 12N.
AU
0.00
0.20
0.40
0.60
0.80
Minutes
0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00
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0.00
0.10
0.20
0.30
0.40
0.50
Minutes
0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00
Figure 1: Representative chro-matograms of nitrendipinestandard solution, in test sam-ples (A) and under stressedconditions (B).
34 R. Bellay et al.: Stability of 5 mg/mL Nitrendipine Oral Suspension
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resolution value, greater than 1.5, ensures that nitrendi-pine and his degradation product are well separated.
Stability of oral suspension
Chemical stability
Regarding to chemical stability, the nitrendipine mea-sured concentrations were within more or less 5% ofthe nominal concentration (Table 1).
pH and osmolality
During the whole study, all pH measurements were com-prised between 4.20 and 4.27 (Figure 2). No significant var-iation was observed. In the same way, osmolality were notmodified, varying between 44 and 48 mOsm/kg (Figure 3).
Physical stability
Visual inspections revealed no change in color during thestudied period (all suspensions maintained their initial
yellow color). No precipitation or macroscopic changeswere observed.
Microbiological stability
No antimicrobial properties were observed with the sus-pending vehicle. Nitrendipine suspensions preparedusing good manufacture practice was found to be freeof germs (no colony-forming units were found during thestudy). Those results show that the microbiological qual-ity of the suspensions is not impaired during the repeatedopening of the bottle over a period of 90 days, allowingthe manufacture of a multidose vial.
Discussion
Regarding to the method validation, all the parameterswere acceptable. The method was considered as linearbecause the correlation coefficient was over 0.99 for themean. No interference of the excipients was observed.Moreover, accuracy and precision were validated becausevalues were inferior to 5%. The method is stability indicat-ing and reliable to detect and quantify any potential degra-dation in the drug product during stability studies. Thisproposed HPLC method was found to be simple, rapid,sensitive, precise, linear, accurate, and stability indicating.Thus, it can be used for the assay of nitrendipine duringthe stability study and for routine quality control analysis.For economic reasons, no pure sample of nitrendipine ordegradation products was used so excipients of the spe-cialty used can be observed in the chromatogram.Preliminary tests have showed that the suspension washomogeneous (no significant variation were observed inassays of API in the top, middle or bottom of the bottle,with and without agitation). Moreover, because a lack of
Table 1: Chemical stability of nitrendipine suspension after storageat room temperature and protected from light (n=9).
Studyday
Percent of nitrendipine initial concentration remaining(%, confidence interval)
Day (.–.)Day . (.–.)Day . (.–.)Day . (.–.)Day . (.–.)Day . (.–.)Day . (.–.)Day . (.–.)
3.5
3.7
3.9
4.1
4.3
4.5
4.7
4.9
0 10 20 30 40 50 60 70 80 90 100
pH
Time (days)
pH evolution as a function of time
Figure 2: pH evolution of nitrendipineoral suspension as a function of time(n= 3).
R. Bellay et al.: Stability of 5 mg/mL Nitrendipine Oral Suspension 35
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available material, no photodegradation was tested, thiscould have been interesting with this photosensitive API.
Along 90 days, no significant variation of the nitrendi-pine concentration was observed in the oral suspension.This concentration was always higher than 95% of theinitial concentration. A 95% threshold was establishedbecause dosages in pediatrics are sometimes low and agood precision of the prepared dose is needed to ensure agood management of hypertension. Osmolality and pHwere also stable along time and no macroscopic changeswere highlighted. Those results are in accordance with theabsence of degradation products observed in chromato-grams. It would have been interesting to highlight if theappearance of degradation products cause a change in thepH of the suspension and thus induce a hydrolytic degrada-tion of nitrendipine. To complete the physical study ofthis oral suspension, measurement of viscosity should beinteresting. In fact, the viscosity can change either givingmore fluid or, conversely, more viscous products. Duringthis study, only the appearance and the consistency of theformulation were assessed with a visual inspection becauseno qualified viscometer was available in our laboratory.
Conclusion
Nitrendipine oral suspensions 5mg/mL are stable for at least90 days when stored at temperature room and in amberglass bottles. Indeed, pH and osmolality did not changesignificantly over 90 days. All the preparations retain mini-mum 95% of the initial concentration after 90 days and nophysical changes were highlighted. This suspension is moresuitable for children than tablets and allows obtaining accu-rate doses based on patient’s body weight.
Conflict of interest statement: Authors state no conflict ofinterest. All authors have read the journal’s Publication
ethics and publication malpractice statement available atthe journal’s website and hereby confirm that they complywith all its parts applicable to the present scientific work.
References
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2. Fagron. Syrspend SF PH4 liquid. Informations produits. Table decompatibilités. Available at: https://fr.fagron.com/fr/product-innovations/syrspendr-sf-ph4-liquid. Accessed: 1 Feb 2018.
3. International Conference of Harmonization (ICH). Guidelinesfor stability Q1A à Q1F. Available at: http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html.Accessed: 1 Feb 2018.
4. Oh SY, Kim KY, Kim YG, Kim HG. High-performance liquidchromatographic analysis of nitrendipine in human plasmausing ultraviolet detection and single-step solid-phase samplepreparation. J Pharm Biomed Anal 2003;32:387–92.
5. Shi X, Liu M, Sun M, Wang Q, Liu W, Cao D. Development of aLC-ESI-MS3 method for determination of nitrendipine in humanplasma. J Pharm Biomed Anal 2011;56:1101–05.
6. Shang D, Wang X, Zhao X, Huang F, Tian G, Lu W, et al.Simultaneous determination of nitrendipine and hydrochlor-othiazide in spontaneously hypertensive rat plasma usingHPLC with on-line solid-phase extraction. J Chromatogr BAnalyt Technol Biomed Life Sci 2011;879:3459–64.
7. International Conference of Harmonization (ICH). GoodManufacturing Practices. Guide for active pharmaceuticalingredients Q7. Available at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q7/Step4/Q7_Guideline.pdf. Accessed: 1 Feb 2018.
8. Kawabe Y, Nakamura H, Hino E, Suzuki S. Photochemicalstabilities of somedihydropyridine calcium-channel blockers inpowdered pharmaceutical tablets. J Pharm Biomed Anal2008;47:618–24.
9. Mukharya A, Patel PU, Chaudhary S. Effect assessment of “filmcoating andpackaging” on the photo-stability of highly photo-labile antihypertensive products. Int J Pharm Investig 2013;3:77–87.
20
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80
0 10 20 30 40 50 60 70 80 90 100
Osm
ola
lity
(m
Osm
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g)
Time (days)
Osmolality evolution as a function of time
Figure 3: Osmolality evolution ofnitrendipine oral suspension as afunction of time (n= 3).
36 R. Bellay et al.: Stability of 5 mg/mL Nitrendipine Oral Suspension
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10. Albini A, Fasani E. Photochemistry of drugs: an overview andpractical problems. Drugs Photochem Photostability 1998;4:1–65.
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Bionotes
Romain BellayPharmacy, CHU de Rennes, 2 rue Henri LeGuilloux, 35000 Rennes, France,[email protected]
Romain Bellay is currently a pharmD candidate working at thePharmacy Department of the University Hospital of Rennes, France.In 2017, he obtained his university degree in clinical pharmacy. Inthe field of pharmaceutical technology, his special interests includenew oral formulations, quality control as well as physicochemicalstability of drug suspensions.
Anne-Claire BonnaurePharmacy, CHU de Rennes, 2 rue Henri LeGuilloux, 35000 Rennes, France,[email protected]
After graduating from the Faculty of Pharmacy at the University ofRennes1, Anne-Claire Bonnaure chose a hospital career and becameresident pharmacist in 2014. She spent her residency in theUniversity Hospital and the Anticancer Centre of Rennes, and in theHospitals of Lorient and Saint-Brieuc in Brittany (France). Herinterests in the field of pharmaceutical technology include qualitycontrol units and chemotherapy production.
Pauline RaultPharmacy, CHU de Rennes, 2 rue Henri LeGuilloux, 35000 Rennes, France, [email protected]
Pauline Rault, pharmD candidate, has two years of internship left beforeher graduation. Currently working at the sterilization ward of the RennesUniversity Hospital, she is also specializing in pharmacoeconomicsthanks to the Paris Descartes’ diploma. Her last semester in paediatricnutrition allowed her to conduct a stability study of vitaminformulations. In the meantime, she is teaching pharmacology tostudents at Pharmacy University and at nursing school.
Sophie PertuiselPediatric Oncology, CHU de Rennes, 2 rueHenri Le Guilloux, 35000 Rennes, France,[email protected]
Sophie Pertuisel received her medical degree in 2016 and herpaediatrics specialization in the following year. She is qualified inpaediatrics oncology since 2016 and works as senior registrar andmedical assistant in the paediatrics hematology and oncologydepartment of the CHU of Rennes in France.
Marie-Antoinette LesterMarie-Antoinette Lester is a hospital pharmacist at RennesUniversity Hospital. Since 2006 she has been senior pharmacistinvolved in sterile preparations (cytotoxic and parenteral nutrition)and unsterile preparations. She became head of the pharmaco-technology unit in 2014.
Pierre-Nicolas BoivinPharmacy, CHU de Rennes, 2 rue Henri LeGuilloux, 35000 Rennes, France,[email protected]
Pierre-Nicolas Boivin is a hospital pharmacist in the manufacturing andquality control laboratory at the Pharmacy Department of the UniversityHospital of Rennes. His work is focused on sterile preparations(cytotoxic, eye drops and parenteral nutrition) and unsterilepreparations. He is involved in the development and validation ofanalytical methods and implementation of stability studies.
R. Bellay et al.: Stability of 5 mg/mL Nitrendipine Oral Suspension 37
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ORIGINAL ARTICLES
Pharmazie 73 (2018)196
Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain
Stability of regularly prescribed oral liquids formulated with SyrSpend® SF
M. URIEL*, C. GÓMEZ-RINCÓN, D. MARRO
Received January 10, 2017, accepted November 30, 2017
*Corresponding autor : Marta Uriel, Universidad San Jorge, Campus Universitario Villanueva de Gálleg, Autov.A-23 Zaragoza-Huesca, Km-299, 50830 Villanueva de Gállego, Zaragoza, [email protected]
Pharmazie 73: 196–201 (2018) doi: 10.1691/ph.2018.7008
The purpose of this research was to evaluate the stability of 12 oral liquid formulations frequently compounded in hospital and community settings formulated in a specific vehicle: SyrSpend® SF. The stability of melatonin, glycopyrrolate, ciclosporin, chloral hydrate, flecainide acetate, tiagabine HCl, labetalol HCl, ciprofloxacin HCl, spironolactone/hydrochlorothiazide, hydrocortisone, itraconazole and celecoxib in SyrSpend SF PH4 (liquid) was investigated at 0, 30, 60 and 90 days and stored at both controlled room temperature and refrigerated. Itraconazole samples were also investigated at 15 and 45 days. No change in odor, color or appearance was observed in the formulations during the test period. Based on the results, a beyond-use date of 30 days can be assigned to tiagabine HCl 1.0 mg/ml in SyrSpend SF when stored at controlled room temperature, and 90 days under refrigeration, improving stability data previously published using other vehicles. A beyond-use date of 60 days can be assigned to chloral hydrate 100.0 mg/ml. In this case, stability is not enhanced by refrigeration. With the rest of the formulations, less than 10% API loss occurred over 90 days at either controlled room tempera-ture or under refrigeration. Including for example itraconazole 20.0 mg/ml, thus providing extended stability compared to simple syrup and other oral liquid vehicles. The findings of this study show that SyrSpend SF is an appropriate suspending vehicle to be used for personalized formulations of the APIs studied here.
1. IntroductionOral medications are usually dispensed as capsules or tablets, neither of which allows for easy dose individualization (Allen 2012). Oral liquids are prescribed for children to permit easy customization of the dose and for children and adults to address difficulties in swallowing tablets or capsules (Allen 2012; Aliot et al. 2011; Nahata et al. 2003; Nahata 1991; Zerbit et al. 2014). Therefore, personalized formulations of oral suspensions are often required in today’s therapeutics, emphasizing the need for appro-priate compounding formulas and stability data. SyrSpend SF is a ready-for-use suspending vehicle designed for the compounding of oral liquid personalized formulations. Based on modified food starch, SyrSpend SF has shown beneficial suspending properties and good compatibility with a broad range of active pharmaceutical ingredients (APIs) (Vu et al. 2008; Geiger
et al. 2012a; Sorenson and Whaley 2013; Geiger et al. 2013a; Whaley et al. 2012a; Voudrie and Allen 2010; Whaley et al. 2012b; Voudrie et al. 2011; Geiger et al. 2012b, 2015; Ferreira et al. 2016; Polonini et al. 2016a, b). In this study, we have focused on oral liquid formulations which are regularly prescribed in hospital and community practice and that have not been studied to date in SyrSpend SF. Table 1 summa-rizes the 12 formulations selected for this study, their therapeutic indication and the main reasons that justify the preparation of personalized oral liquids for each of these APIs.The objective here was to evaluate the stability of these formula-tions in SyrSpend SF and, more specifically, to assess their stability over a period of 90 days, under two different storage conditions: controlled room temperature (25±2 ºC) and controlled refrigerated temperature (5±3 ºC).
Table 1: Description of the 12 formulations selected for this study, their indication in therapeutics and the main reasons that justify the preparation of a personalized oral liquids in each case
Oral liquid formulation Indication Justification for personalization
Melatonin 3.0 mg/ml Treatment for initial insomnia in children with ADHD taking stimulant medication (15)
Young children may need suspension, not commercially available (1, 2, 4)
Glycopyrrolate 0.5 mg/ml A synthetic anticholinergic that acts at peripheral mus-carinic receptors, has been used off-label for excessive drooling in children with neurodevelopmental disabilities for years (17)
Due to the need for accurate dose adjustments in pediatric populations, a liquid dosage form (not commercially avail-able) may be required (17)
Ciclosporin 100.0 mg/ml Inmunosupressor, in transplantations and some autoim-mune diseases (2)
Young children may need a liquid dosage form, not com-mercially available (2)
Chloral hydrate 100.0 mg/ml Nonbarbiturate sedative and hypnotic in paediatric popu-lation (2)
Young children may need a liquid dosage form, not com-mercially available (2)
Flecainide acetate 20.0 mg/ml Pediatric arrhytmias (3) Dose adjustment required according to age, body weight, symptoms and other factors (3)
Tiagabine HCl 1.0 mg/ml Tiagabine is used for adjunctive therapy for the treatment of refractory partial seizures (4)
Young children may need a liquid dosage form, not com-mercially available (1-3)
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2. Investigations and results High-performance liquid chromatography was used for both the stability study and a forced degradation study that was also performed with the aim of identifying all degradation products that may be produced during storage of the samples.The stability of melatonin, glycopyrrolate, ciclosporin, chloral hydrate, flecainide acetate, tiagabine HCl, labetalol HCl, cipro-floxacin HCl, spironolactone/hydrochlorothiazide, hydrocorti-sone, itraconazole and celecoxib in SyrSpend SF PH4 (liquid) was investigated at 0, 30, 60 and 90 days and stored at both controlled room temperature and refrigerated. Itraconazole samples were also investigated at 15 and 45 days.
With respect to methods validation, the analytical characteristics are summarized in Table 2, including linearity, limit of detection (LOD), limit of quantification (LOQ), and accuracy. All analytical methods met their respective acceptance criteria (Table 2).API degradation was studied after having subjected the formula-tions to stress conditions (forced degradation studies). The API degradation results are shown in Table 3, with a description of the conditions applied. This information, together with spectral analysis, was used to optimize the resolution and specificity of the analytical methods used in the stability assay, and to gain insight on the degradation processes taking place in the formulations.
Oral liquid formulation Indication Justification for personalization
Ciprofloxacin HCl 50.0 mg/ml Adults: infections of the respiratory, genital, urinary and gastro-intestinal tracts, skin and soft tissues and some bone and joint infections. Paediatrics: cystic fibrosis, complicat-ed urinary tract infections and other severe infections (20)
Dose adjustment required according to age, body weight, the severity of the infection and the patient’s creatinine clearance (20)
Hydrocortisone 1.0 mg/ml Cortisol is an essential stress hormone and replacement with oral hydrocortisone is lifesaving in patients with adre-nal insufficiency. Loss of cortisol rhythmicity is associated with fatigue, depression and insulin resistance (19)
Tailoring hydrocortisone dose to circadian rhythm, weight-related and clinical pharmacokinetics monitoring (19)
Itraconazole 20.0 mg/ml Systemic fungal infections (18) Flexibility to tailored itraconazole treatment for use in all patients, including children and those requiring intensive care (18)
Celecoxib 10.0 mg/ml Celecoxib is a selective cyclo-oxygenase 2 inhibitor that relieves pain without affecting platelet function (19)
Young children and some adults with swallowing diffi-culties may need a liquid dosage form, not commercially available (19)
Spironolactone 5.0 mg/ml + Hydrochlorothiazide 5.0 mg/ml
Diuretics used in treatment of edematous statesassociated with cardiac, renal, and hepatic failure and thetreatment of hypertension (21)
Two drug association non commercially available (21). Commonly used in the pediatric and adult populations which may have difficulties swallowing the solid form (22)
Table 2: Summary of analytical characteristics of the methods developed
Compd. Linear range (µg/ml) y - intercept Slope R2 LODa (µg/ml) LOQb(µg/ml) Accuracy (Recovery, %)
Melatonin 4.64 - 18.37 33.66 161.54 0.9999 0.01 0.02 100.2
Glycopyrrolate 4.90 - 19.10 46.97 198.50 0.9998 0.02 0.06 101.3
Ciclosporin 9.79 - 83.69 -16.70 26.50 0.9995 1.03 3.45 100.4
Chloral hydrate 6.79 – 25.67 -3345 1305 0.9947 0.64 2.12 103.6
Flecainide acetate 5.57 - 20.94 0.36 5.13 1.000 0.01 0.04 100.2
Tiagabine HCl 4.29 - 23.63 5.01 47.02 0.9998 0.03 0.11 98.6
Labetalol HCl 4.62 - 20.17 14.56 96.01 0.9975 0.03 0.09 104.9
Ciprofloxacin HCl 3.89 - 20.50 -20.79 88.45 0.9990 0.03 0.09 98.3
Hydrocortisone 5.76 - 21.05 5.76 18.88 1.000 0.01 0.04 99.5
Itraconazole 4.71 - 19.93 -35.71 47.59 1.000 0.08 0.27 99.7
Celecoxib 4.11 - 21.59 -18.40 89.51 0.9998 0.01 0.03 99.7
Spironolactone 4.73 - 19.42 -1.33 26.48 0.9999 0.02 0.05 100.8
Hydrochlorothiazide 4.53 - 19.36 1.04 52.78 0.9998 0.01 0.04 100.3
a) LOD: limit of detection. b) LOQ: limit of quantification (20 µl injections).All analytical ranges (µg/ml) were adequate to quantify the compounds in the concentrations used in the formulations (mg/ml). Acceptance criteria were: R2 > 0.99, accuracy = 100% ± 5%
Table 3: Conditions of the forced degradation studies
Compd. Forced degradation conditions Effectiveness of drug degradation
Melatonin UV light (365 nm) for 7 days 22% (±2.4 RSDa; n=2)
Glycopyrrolate UV light (365 nm) and pH 12 for 7 days Fully degraded
Ciclosporin UV light (365 nm) for 7 days 44% (±37 RSD; n=2)
Chloral hydrate pH 12 + UV light(365 nm) during 1 hour 33% (±48 RSD; n=3)
Flecainide acetate UV light (365 nm) and heat (70 ºC) for 7 days 13% (±7 RSD; n=2)
Tiagabine HCl UV light (365 nm) and heat (70 ºC) for 7 days 81% (±13 RSD; n=2)
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Finally, the results of the stability assays are shown in Table 4. It was observed that the oral suspensions exhibited no change in odor, color or appearance during the test period. The stability results are expressed as relative percent of recovery (time 0 = 100%).
Table 4: Stability assay of the SyrSpend SF formulations, stored at both controlled room temperature and refrigerated. Acceptance crite-ria were: 90-110% of initial concentration at time 0
Room temperature Refrigerated
Formulation Time (days) Drug recovery (%) SD Drug recovery (%) SD
Melatonin 0 100.0 1.6 100.0 0.7
3.0 mg/ml 30 96.9 8.7 98.3 2.6
60 93.5 5.4 95.8 3.4
90 97.6 2.1 102.1 6.7
Glycopyrrolate 0 100.0 6.4 100.0 0.2
0.5 mg/ml 30 95.1 1.3 95.1 1.1
60 98.5 1.3 97.9 0.2
90 92.1 1.4 90.9 0.9
Ciclosporin 0 100.0 5.0 100.0 1.4
100.0 mg/ml 30 98.2 4.8 97.6 5.9
60 102.5 3.1 96.9 2.7
90 103.1 2.3 97.4 1.9
Chloral hydrate 100.0 mg/ml
0 100.0 3.2 100.0 10.9
30 97.5 1.7 94.3 6.4
60 91.8 14.6 92.1 12.6
90 88.1 12.4 88.4 9.1
Flecainide acetate 20.0 mg/ml
0 100.0 3.2 100.0 1.8
30 94.3 0.8 92.1 1.1
60 98.3 0.9 98.9 1.4
90 97.0 2.4 100.4 2.6
Tiagabine HCl 0 100.0 1.5 100.0 1.0
1.0 mg/ml 30 93.0 1.7 98.7 1.2
60 87.9 0.7 96.6 1.2
90 83.3 0.7 94.8 1.9
Labetalol HCl 0 100.0 2.7 100.0 2.2
40.0 mg/ml 30 96.5 1.3 97.5 2.8
60 97.9 2.4 97.5 0.6
90 98.0 1.6 96.0 2.0
Ciprofloxacin HCl 0 100.0 1.8 100.0 1.4
50.0 mg/ml 30 99.9 2.0 95.8 1.9
60 104.7 0.7 99.7 0.3
90 110.4 3.9 97.9 1.3
Room temperature Refrigerated
Formulation Time (days) Drug recovery (%) SD Drug recovery (%) SD
Hydrocortisone 0 100.0 0.6 100.0 3.6
1.0 mg/ml 30 99.6 2.7 96.6 1.1
60 96.1 1.9 96.9 2.2
90 97.9 1.6 96.3 1.6
Itraconazole 0 100.0 8.4 100.0 13.7
20.0 mg/ml 15 96.3 3.4 97.5 7.8
30 105.1 2.4 99.1 2.8
45 92.1 14.8 103.5 1.5
60 95.2 2.4 104.0 8.9
90 91.2 8.3 91.7 5.8
Celecoxib 0 100.0 1.3 100.0 0.8
10.0 mg/ml 30 101.5 3.0 102.9 1.1
60 100.5 2.7 102.1 2.4
90 101.3 4.9 104.8 1.1
Spironolactonea 0 100.0 8.0 100.0 1.6
5.0 mg/ml 30 98.8 3.4 95.7 9.5
60 89.9 7.2 84.4 1.4
90 102.8 6.5 100.7 7.6
Hydrochloro-thiazidea
0 100.0 2.2 100.0 18.2
5.0 mg/ml 30 103.6 12.0 131.0 6.7
60 114.3 22.8 114.3 12.6
90 102.6 10.0 112.7 11.9
a) Spironolactone and hydrochlorothiazide were combined in the same formulation
3. DiscussionThe acceptance criteria for the oral liquid formulations to be considered stable were that the relative percentage of recovery should lie within 90-110% (Trissel 2012). With this criteria in mind, data in Table show that tiagabine HCl 1.0 mg/ml when stored at controlled room temperature fell out of specifications at 60 days and above, and thus, according to these results, a beyond-use date of 30 days is recommended. However, when stored under refrigeration, tiagabine HCl 1.0 mg/ml was stable throughout the whole time of the study (90 days). When compared with previously published data in other vehicles, these findings suggest that the stability of tiagabine is improved when formulated in SyrSpend SF (Nahata and Morosco 2003). Also, in the case of chloral hydrate 100.0 mg/ml, stability-indicating HPLC analysis of API concentration found a chloral hydrate loss >10% at 90 days at either controlled room temperature and under refrigeration. Therefore a beyond-use date of 60 days is recom-
Compd. Forced degradation conditions Effectiveness of drug degradation
Labetalol HCl pH 9 (with phosphate buffer) + UV light (365 nm) for 3 days
67% (±7 RSD; n=2)
Ciprofloxacin HCl pH 9 (with phosphate buffer) + UV light at 365 nm for 4 days
65% (±2.4 RSD; n=2)
Hydrocortisone pH 12 for 1 day 50% (±4.2 RSD; n=2)
Itraconazole UV light (365 nm) and heat (50 ºC) for 7 days 47% (±14.6 RSD; n=2)
Celecoxib UV light (365 nm) and heat (70 ºC) for 7 days 39% (±1.5 RSD; n=2)
Spironolactone UV light (365 nm) and heat (40 ºC) for 7 days 68% (±12 RSD; n=2)
Hydrochlorothiazide UV light (365 nm) and heat (70 ºC) for 4 days 85% (±4.7 RSD; n=2)
a) RSD: Relative Standard DeviationThe objective was to chromatographically identify all degradation products that may be produced during storage of the samples.
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mended. In the case of itraconazole, the concentration average at 90 days at either controlled room temperature and under refriger-ation was >90% but when considering its standard deviations, the % recovered drops below the cutoff value of 90.0%. Therefore a beyond-use date of 60 days is recommended for both temperatures. In contrast to these three cases (tiagabine HCl, itraconazole and chloral hydrate), with the rest of the formulations it was observed that less than 10% API loss occurred over 90 days at either controlled room temperature or under refrigeration. In the case of hydrochlorothiazide and spironolactone (formulated together in the same formulation) the heterogeneity of the results obtained needs further discussion. Although the formulation of hydrochlorothiazide/spironolactone in SyrSpend SF was stable throughout the whole time of the study (90 days), it was observed that some crystals formed after some time on the 1:500 sample dilutions, a required step when preparing the samples for HPLC injection. These dilutions were made with water. The dilutions were prepared shortly before HPLC injection and then were kept for a few days before discarding. Some crystalization was observed and noted down at the moment of discarding the spironolactone/hydrochlorothiazide dilutions of the SyrSpend SF suspensions. Our hypothesis is that this crystal formation process observed on the diluted spironolactone/hydrochlorothiazide samples may have had an impact on the API concentration actually in suspension. This fact would explain the heterogeneity in API concentration among the samples, with data above 100% of recovery and greater SD than in any other case. However, as stated above, no crystalli-zation was observed on the non-diluted SyrSpend SF formulations of spironolactone/hydrochlorothiazide.In summary, the stability obtained in SyrSpend SF was comparable (Johnson et al. 2011; Gupta 2001; Gupta 2003) or superior (Nahata and Morosco 2003; Allen and Erickson 1996a, b; Jacobson et al. 1995; Johnson et al. 2011) to what has previously been reported with the same APIs formulated in other oral liquids. These findings support, for example, that compounding itraconazole 20.0 mg/ml oral suspensions in SyrSpend SF may provide extended stability compared to simple syrup (Jacobson et al. 1995) and other oral liquid vehicles (Johnson et al. 2011).The findings of this study show that SyrSpend SF is an appropriate suspending vehicle to be used for personalized formulations of the APIs studied here. Since SyrSpend SF contains an effective preservative system, microbiological instability is not expected to become an issue. Therefore, a beyond-use date of 90 days can be assigned to tiagabine HCl 1.0 mg/ml in SyrSpend SF when stored under refrigeration and 30 days at controlled room temperature based on our physical-chemical study results. A beyond-use date of 60 days can be assigned to chloral hydrate 100.0 mg/ml and itraconazole20.0 mg/ml. In this case, stability is not enhanced by refrigeration. Finally, the results suggest that a beyond-use date of at least 90
days could be assigned to any of the other SyrSpend SF formu-lations studied in this work, even when stored at controlled room temperature. In summary, the stabilities obtained with SyrSpend SF were comparable or superior to what has been previously reported in the literature for the same compounds in other phar-maceutical vehicles.
4. Experimental
4.1. Chemical reagentsAPIs and analytical standards used in this study are listed in Table. SyrSpend SF PH4 (Liquid. composition: purified water, modified food starch, sodium citrate, citric acid, sucralose, sodium benzoate (<0.1 %, preservative), malic acid and simethicone) (batch 14E02E) was provided by Fagron. High-performance liquid chromatographic (HPLC)-grade water (resistivity 18.2 MW, obtained with ARIUM 611UV equipment), acetonitrile (Sigma Aldrich, batch SZBC150SV), and phosphoric acid (PanReac, batch 96684HFR) were used in this study.
4.2. Equipment and chromatographic conditionsHigh-performance liquid chromatography with diode array detection (HPLC-DAD) HP Agilent Series 1100 was used for both the stability study and a forced degradation study that was also performed with the aim of identifying all degradation products that may be produced during storage of the samples. A 10 μg/g solution of the corre-sponding analytical standard for each API was used for optimization of the analytical methods.Specific chromatographic conditions are listed in Table 6. The analytical charac-teristics of the methods developed for each compound are summarized in Table2. All preparations were filtered with 0.45 mm Sartorius nylon syringe filters prior to injection.
4.3. Forced degradation studiesForced degradation studies were performed prior to the stability assay. The objective was to identify each API together with all degradation products that may be produced during storage of the samples. This information was used for proper characterization of the degradation phenomena occurring during the stability phase of the study, thus allowing for optimization of the analytical methods, checking for significant over-lapping.The forced degradation conditions applied to each compound were determined from the literature (Trissel 2012). These conditions are summarized in Table 3. The purity of the peaks was confirmed by spectral analysis, using the corresponding API unstressed analytical standard as reference.
4.4. Stability assayThe appropriate amount of API was levigated with SyrSpend SF using geometric dilution to form a smooth suspension. The dispersion was then transferred to a 100 ml volumetric flask and brought to volume with SyrSpend SF to achieve the desired final concentration for each oral liquid formulation. The 100 ml of sample was then distributed into 4 low actinic glass bottles (20 ml each). These bottles were labeled for each of the time points considered in the assay (0, 30, 60 and 90 days), and assayed for API concentration after the corresponding elapsed time, then discarded. In the case of itraconazole, the 100 ml sample was distributed into 6 low actinic glass bottles (15 ml each). These bottles were labeled for each of the time points consid-ered in the itraconazole assay (0, 15, 30, 45, 60 and 90 days). The rationale for these specific time points (intermediate points at 15 and 45 days) was the faster degradation rates expected for itraconazole based on available literature (Jacobson et al. 1995; Johnson et al. 2011).
Table 5: Source of drug substances and analytical standards used in this study
Drug Drug Source Analytical Standard
Melatonin Melatonin raw powder (Fagron, batch 13H29-B03-293065) Sigma Aldrich, SLBK0706V
Glycopyrrolate Glycopyrrolate raw powder (Fagron, batch 14A14-B06-292838) Eurofins, batch JOJ363
Ciclosporin Ciclosporin raw powder (Fagron, batch 13B19NO2) Eurofins, batch I11Z033
Chloral hydrate Chloral hydrate raw powder (Fagron, batch 20130903) Eurofins, batch SZBE0150V
Flecainide acetate Apocard 100 mg tablets (MedaPharma S.A.U., batch GPG073A) Eurofins, batch G0K124
Tiagabine HCl Gabitril 15 mg oral tablets (TevaPharma B.V., batch W020406) Eurofins, batch F0E178
Labetalol HCl Trandate 200 mg tablets (Kern Pharma, S.L., batch H002 CAD 06/2017) Fluka, batch LRAA1069
Ciprofloxacin HCl Ciprofloxacin HCl raw powder (Fagron, batch 14B25-B02-292846) Eurofins, batch P500167
Hydrocortisone Hydrocortisone raw powder (Fagron, batch 13L31-B06-294874) Eurofins, batch 8.1
Itraconazole Itraconazole raw powder (Fagron, batch L14070008OF194389) Eurofins, batch G0K425
Celecoxib Celebrex 200 mg capsules (Pfizer, S.L., batch E10351530) Sigma Aldrich, batch 2558935
Spironolactone Spironolactone raw powder (Fagron, batch 12E07-U06-005744) Eurofins, batch LOL557
Hydrochlorothiazide Hydrochlorothiazide raw powder (Fagron, batch 10G21-B02) Eurofins, batch 7
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The whole process, including the elaboration of the samples as described above, was replicated 3 times per time point and storage condition: controlled room temperature (25±2 ºC) and controlled refrigerated (5±3 ºC).The chemical stability of the oral suspension was assessed by comparing API concen-tration over time with respect to specifications (90-110% of initial concentration at time 0) at the end of shelf-life.
4.5. Chloral hydrateChloral hydrate was derivatized with 1,2-benzenedithiol prior to injection, yielding a new compound that absorbs at the ultraviolet region (220 nm). 30 µL of 1,2-benzen-edithiol reactive (1000 ppm) was sufficient for the complete derivatization of chloral hydrate in the diluted samples. The reaction took place at 70 °C (for 1 h). Then, it was allowed to cool down before injected into the HPLC (Bruzzoniti et al. 2001; Kraemer et al. 1997).
Acknowledgements: The authors wish to thank Davinson Pezo and Salvador Valero for their analytical input, and Eli Dijkers, Maurits Vissers and Astrid Thorissen for reviewing the manuscript and the fruitful discussions. The work was conducted under the sponsorship of Fagron.
Conflicts of interest: see above, others not declared.
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Kaukonen AM, Vuorela P, Vuorela H, Mannermaa JP (1998) High-performance liquid chromatography methods for the separation and quantitation of spironolactone and its degradation products in aqueous formulations and of its metabolites in rat serum. J Chromatogr A 797: 271–281.
Kraemer HJ, Gehrke R, Breithaupt A (1997) Simultaneous quantification of cefo-taxime, desacetylcefotaxime, ofloxacine and ciprofloxacine in ocular aqueous humor and in plasma by high-performance liquid chromatography. J Chromatogr B 700: 147-153.
Malaekeh-Nikouei B, Banaee T, Aghamohammadian J (2011) Quantitative LC anal-ysis of cyclosporine A in ocular samples. Chromatographia 73: 817-821.
Nahata MC (1991) Stability of labetalol hydrochloride in distilled water, simple syrup and three fruit juices. DICP Ann Pharmacother 25: 465-469.
Nahata MC, Morosco R (2003) Stability of tiagabine in two oral liquid vehicles. Am J Health Syst Pharm 60: 75-77.
Polonini HC, Loures S, Lima LC, Ferreira AO, Brandão MA (2016a) Stability of atenolol, clonazepam, dexamethasone, diclofenac sodium, diltiazem, enalapril
Table 6: Summary of chromatographic conditions of the methods developed.
Drug Mobile phase Flow (ml/min) Wavelength (nm) Ref.
Melatonin 75/25 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 225 (26)
Glycopyrrolate 65/35 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 192 (27)
Ciclosporin 15/65/20 (0.12 M H3PO
4pH 2 /Acetonitrile /Methanol) 1.5 205 (28-30)
Chloral hydrate (derivatized)a 60/40 (0.12 M H3PO
4 pH 2/Acetonitrile) 1 220 (42,43)
Flecainide acetate 60/40 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 298 (31)
Tiagabine HCl 50/50 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 260 (32)
Labetalol HCl 70/30 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 233 (33)
Ciprofloxacin HCl 75/25 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 280 (34)
Hydrocortisone 40/60 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 254 (37-38)
Itraconazole 40/60 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 262 (39)
Celecoxib 20/80 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 254 (40)
Spironolactone 40/60 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 238 (35-36)
Hydrochlorothiazide 85/15 (0.12 M H3PO
4 pH 2/Acetonitrile) 0.5 225 (52)
a) Chloral hydrate had to be derivatized prior to injection. See text for details (section 2.5).The columns were thermostathised at 30 °C in all cases, except in ciclosporin analysis (70 °C). Volume of injection was 20 μL. An Ultrabase C18 silica 100 x 4.6 mm, 5 μm particle size column was used in all cases except for ciclosporin and chloral hydrate, where a 250 mm length column of the same kind was used.
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ORIGINAL ARTICLES
Pharmazie 73 (2018) 201
maleate, ketoprofen, lamotrigine, penicillamine-D and thiamine in SyrSpend SF PH4 oral suspensions. Int J Pharm Compd 20: 167-174.
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INTRODUCTION Dysphagia or swallowing difficulty is common among patients and one of the main reasons why vulnerable hospitalized patients such as children, oncology patients, neurologically impaired pa-tients, and the elderly frequently require customized medication.1 Studies have also shown that solid dosage forms are frequently unsuitable for children until the age of six.2-4 Dose adjustments due to metabolic impairment are a second common reason for per-
sonalized medication among hospitalized patients. Custom-ized capsules offer a possible solution, although the dosage cannot be adapted easily and they do not offer a solution for the hospitalized patients or children with dysphagia.5 In these situations, tailor-made oral liquid medications that can be easily administered to hospitalized patients can be of great benefit. While compounding liquid dosage forms, pharmacists are often required to manufacture a suspension instead of an oral solution, as many active
Stability of Acetazolamide, Baclofen, Dipyridamole, Mebevarine Hydrochloride, Propylthiouracil, Quinidine Sulfate, and Topiramate Oral Suspensions in SyrSpend SF PH4
Hudson Polonini, BPharm, PhDSharlene Loures da Silva, BBiomedNatália Cristina Buzinari Aglio, BCHJordana Abreu, BPharm, MScMarcos Antônio Fernandes Brandão, BPharm, PhDAnderson de Oliveira Ferreira, BPharm, PhD Candidate
ABSTRACTThe objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally u s e d s u s p e n d i n g v e h i c l e ( S y r S p e n d S F P H 4 ) : acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipydiramole 10.0 mg/mL, mebevarine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed b y u l t r a v i o l e t ( U V ) h i g h - p e r f o r m a n c e l i q u i d chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.
The authors’ affiliations are as follows: Hudson Polonini, Sharlene Loures da Silva, Natália Cristina Buzinari Aglio, Marcos Antônio Fernandes Brandão, and Anderson de Oliveira Ferreira, Ortofarma – Quality Control Laboratories, Matias Barbosa, MG, Brazil; Jordana Abreu, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil. Marcos Antônio Fernandes Brandão is also affiliated with the Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil.
pharmaceutical ingredients (APIs) are not sufficiently soluble in aqueous solutions. In addition, a suspension might be needed to avoid taste or stability-related issues of solutions.5 However, as suspensions are disperse systems, it can be challenging to achieve chemically and physically stable safe compounds that allow for consistent dosing.
OBJECTIVES In this study, we investigated the combined physical and chemical stability of different APIs into the ready-to-use suspending vehicle SyrSpend SF PH4. SyrSpend SF is a starch-based suspension which employs “active suspending technology:” the low viscosity
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when shaken eases re-homogenization and the high viscosity at rest keeps the APIs suspended. This enables (hospital) pharmacists to compound a homogeneous suspension that remains uniform in time. Additionally, SyrSpend SF is free of numerous excipients best avoided in vulnerable, hospitalized patients. These excipients include but are not limited to:
• Benzyl alcohol• Carrageenan• Colorants• Ethanol• Glycerol• Parabens• Propylene glycol• Sorbitol• Sucrose• Food allergens
The starch used in SyrSpend SF is considered mostly inert for chemical reactions. This allows the pharmacist to use SyrSpend SF with a wide range of APIs.6-18 Although the compatibility of SyrSpend SF has already been shown with various APIs, it is impor-tant to determine the stability for a wide range of APIs. In this com-patibility study, we focused on seven APIs that are frequently used in the hospital, and a single concentration of the APIs was selected based on commonly prescribed medications:
• Acetazolamide 25.0 mg/mL (carbonic anhydrase inhibitor)• Baclofen 10.0 mg/mL (skeletal muscle relaxant)• Dipirydamole 10.0 mg/mL (adenosine reuptake inhibitor)• Mebeverine hydrochloride 10.0 mg/mL (smooth muscle
relaxant)• Propylthiouracil 5.0 mg/mL (thiourea antithyroid)• Quinidine sulfate 10.0 mg/mL (Class I antiarrhythmic)• Topiramate 5.0 mg/mL (sulfamate; migraine prophylaxis)
The suspensions were stored both at controlled refrigerated temperature (2°C to 8°C) and at room temperature (20°C to 25°C) throughout the stability study.
METHODSREAGENTS, REFERENCE STANDARDS, AND MATERIALS All API raw materials and SyrSpend SF PH4 (liquid) (Lot 14F02-U59-019404) were obtained from Fagron (St. Paul, Minnesota). High-performance liquid chromatography (HPLC)-grade reagents (Panreac, Barcelona, Spain) were used. Ultrapure water obtained with an AquaMax-Ultra 370 Series (Young Lin, Anyang, Korea) (18.2 MΩ·cm resistivity at 25°C and <10 ppb total organic carbon) was used throughout the experiments. The reference standards used were all work standards obtained using primary United States Pharmacopeia (USP; Rockville, Maryland) reference materials. Immediately before use, all the mobile phases and receptor media
were filtered through a 0.45-µm filter membrane (RC-45/15 MS; Chromafil, Düren, Germany) and degassed using an ultrasonic ap-paratus (Model 1600A, Unique, Indaiatuba, Brazil) for 30 minutes. All volumetric glassware and analytical balance used were previ-ously calibrated.
EQUIPMENT HPLC analyses were performed on a qualified and calibrated chromatography system (Young Lin, Anyang, Korea) composed of a quaternary gradient pump (YL 9110), a photodiode array (PDA) detector (YL 9160), a 96-vial programmable autosampler (YL 9150), a column oven compartment (YL 9130), a variable sample loop up to 200 µL, and a software controller (Clarity).
CHROMATOGRAPHIC CONDITIONS The chromatographic determinations were based upon USP methods for the APIs or their final products, with minor modifica-tions when necessary. The exact chromatographic conditions used for each API are stated in Table 1. The columns were connected with a pre-column with the same packing (4.0 × 3.0 mm, 5 µm) from the same vendor of the columns.
VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD Validation protocol and the acceptance criteria were established based upon United States Pharmacopeia (USP)19 and International Conference on Harmonization (ICH) guidelines.20
Specificity of the method was determined by running HPLC analyses of a standard solution, a SyrSpend SF PH4 (liquid) blank solution, and a mobile phase/diluents blank solution. The accep-tance criterion was defined as a percentage of discrepancy between the peak areas of less than 2% (Eq. 1). In addition, the specificity of the method was obtained through comparison of standard chro-matograms with and without the SyrSpend SF PH4 (liquid) matrix. All analyses were run in triplicate.
% discrepancy = 100 ( standard area – sample area) (Eq. 1) standard area
Precision was evaluated as repeatability and intermediate. Repeatability was determined by consecutively analyzing six replicates by a single analyst in a single day. Intermediate precision was also performed in six replicates, but over two days, by different analysts. An injection precision of more than 95% (coefficient of variation [CV]) was considered acceptable. The accuracy of the method was determined through spike recovery of the SyrSpend SF PH4 (liquid) matrix, diluted within the range used for final sample measurements (to the calibration curves). Percent recovery was calculated from the concentration measured relative to the theoretical concentration spiked.
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ULTRAVIOLETDETECTIONWAVELENGTH(NM)254
220
288
263
276
235
Refractive index, at
50°C
T A B L E 1 . CHROMATOGRAPHIC CONDITIONS USED IN THE COMPATIBILITY STUDY.
ACTIVEPHARMACEUTICALINGREDIENTAcetazolamide
Baclofen
Dipyridamole
Mebeverine hydrochloride
Propylthiouracil
Quinidine sulfate
Topiramate
MOBILE PHASECOMPOSITION4.1 g of anhydrous sodium acetate, 20 mL
of methanol and 30 mL of acetonitrile in
950 mL of water (pH adjusted to 4.0 with
acetic acid).
Acetonitrile and 0.05 M monobasic
sodium phosphate (2:8) (pH adjusted to
3.5 with phosphoric acid).
Methanol and 1mg/mL dibasic sodium
phosphate (pH 4.6) (75:25)
Acetonitrile and 0.05M ammonium
acetate buffer (55:45) (pH adjusted to 5.2
with acetic acid)
5 mM 1-heptanosulfonic acid, 1% acetic
acid and methanol (40:45:15)
Acetonitrile, solution A, solution B and
water (192:19:19:770) (solution A: 35 mL
of methanesulfonic acid to 20 mL of
acetic acid, and diluted to 500 mL with
water; solution B: 10 mL of diethylamine
and 90 mL of water)
Acetonitrile and water (1:1)
WORK CONCENTRATION(µG/ML)*250.0, in 0.5 N sodium
hydroxide; 20-µL injection
5.0, in water; 20-µL
injection
100.0; 20-µL injection
100.0, in methanol; 20-µL
injection
100.0; 20-µL injection
100.0; 20-µL injection
2,000.0; 20-µL injection
COLUMNL1, 4.6-mm × 25-cm1
L1, 4.6-mm × 25-cm2
L1, 4.6-mm × 15-cm3
L1, 4.6-mm × 25-cm4
L1, 4.6-mm × 25-cm;
at 40°C5
L1, 4.6-mm × 15-cm6
L1, 4.6-mm × 25-cm;
at 50°C7
FLOW(ML/MIN)2.0
1.5
1.3
1.0
1.8
1.0
0.6
*Diluted with mobile phase, unless specified otherwise. 1-6Luna 100A 5µ (Phenomenex). 7Zorbax Eclipse XDB. 5µ (Agilent).
For linearity, concentrations from 70% to 130% of the work-ing concentration of the API in SyrSpend SF PH4 (liquid) were prepared and analyzed. The data from each experiment was fitted by ordinary least squares method and was evaluated by analysis of variance (ANOVA). The limit of detection (LOD) and limit of quantification (LOQ) were determined from three standard calibration curves of the APIs in the presence of the SyrSpend SF PH4 (liquid) matrix and were calculated as shown in Equations (2) and (3), respectively:
LOD = s 3
(Eq. 2) a
LOQ = s 3
(Eq. 3) a
where a is the slope of the calibration curve, and s is the standard deviation of the y-intercept. The LOD and LOQ were confirmed by the analysis of chromatograms generated by injecting solutions in their respective limit concentrations.
PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENT SUSPENSION SAMPLES The API suspensions were prepared using the following general protocol:
1. The required quantity of each ingredient for the total amount to be prepared was calculated.
2. Each ingredient was accurately weighed.3. The API was placed in a mortar and triturated until a fine pow-
der was obtained.4. A small amount of the SyrSpend SF PH4 (liquid) was added to
the powder and mixed to form a uniform paste.5. Additional SyrSpend SF PH4 (liquid) was geometrically added
almost to volume, mixing thoroughly after each addition.6. Sufficient SyrSpend SF PH4 (liquid) was added to bring the
volume to 300 mL, and then mixed well.7. The final product was packaged in low-actinic, light-resistant
prescription bottles and labeled.8. The suspensions were immediately assayed at T = 0.9. The suspensions were separated into two different 150-mL
bottles: one sample was stored at controlled refrigerated (2°C
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ACCURACY
Recovery (%)
100.09
100.18
100.05
100.06
100.00
100.26
99.85
Active Pharmaceutical Ingredient
Acetazolamide
Baclofen
Dipyridamole
Mebeverine
hydrochloride
Propylthiouracil
Quinidine
sulfate
Topiramate
T A B L E 2 . SUMMARY OF VALIDATION RESULTS OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHODS.
LINEARITY
Range (µg/mL)
175.42 – 325.78
3.64 –
6.76
70.84 –
131.56
700.28 –
1300.52
71.68 –
133.12
70.56 –
131.04
1402.52 –
2604.68
Analytical curve
y =16.67x –
118.43
y = 79.77x
– 43.98
y = 41.81x +
34.30
y = 2.74x –
36.89
y = 52.76x
– 376.55
y = 29.71x +
26.82
y = 0.16x +
4.16
R2
0.9985
0.9938
0.9988
0.9970
0.9969
0.9974
0.9949
ANOVA’s Significance of Regression (F)
8595.70
2092.91
11073.37
4307.91
4261.72
5071.33
2566.96
ANOVA’s Lack of Fit (F)
0.21
2.57
1.73
0.09
1.19
0.53
2.69
LOD (µg/mL)
9.19
0.50
5.18
37.61
11.11
2.86
26.731
LOQ (µg/mL)
30.63
1.67
17.28
125.36
37.03
9.54
222.438
SPECIFICITY
Discrepancy (%)
|0.82|
|0.59|
|0.14|
|1.20|
|1.47|
|1.43|
|1.74|
PRECISION
Repeatability (CV, %)
0.47
0.59
0.31
0.27
0.63
0.53
0.71
Intermediate Precision (CV, %)
0.47
3.11
1.00
0.69
0.81
0.63
0.80
Acceptance criteria were: R2 >0.99, F (significance of regression) >>4.67, F (lack of fit) <3.71, discrepancy <2%, repeatability and intermediate precision <5%, and recovery = 100% ± 2%. All analytical ranges (µg/mL) were adequate to quantify the active pharmaceutical ingredients in the concentrations used in the suspensions (mg/mL).CV = coefficient of variation; LOD = limit of detection; LOQ = limit of quantification (20-µL injections)
to 8ºC) and the other at room temperature (20°C to 25ºC), for the duration of the study (temperature and humidity were checked in real time throughout the whole experiment, using a calibrated, digital thermo-hygrometer [Incoterm]).
FORCED-DEGRADATION STUDIES: STABILITY-INDICATING CHARACTERISTICS API samples were subjected to the following stress conditions to determine the capacity of the HPLC method to detect any pos-sible degradation products that may arise during storage of the oral suspension:
1. Dilution in acid (0.1M HCl, at 25°C)2. Dilution in base (0.1M NaOH, at 25°C)3. Exposure to UV light at 365 nm (at 25°C)4. Heating at 70°5. Dilution in H2O2 35% (v/v) (at 25°C).
These solutions were prepared for each API at its respective work concentration by means of serial dilution from a stock-solution and using suitable diluents (see Table 1). The stock-solutions were sonically dispersed by 10 minutes, and the final solutions were filtered (15 mm regenerated cellulose syringe filters, with 0.45-µm pore size) before injection onto the HPLC system. Any extrane-ous peaks found in the chromatograms were labeled. A resolution of 1.5 between the peaks of the degradation products and the API was considered full separation. Also, a discrepancy greater than 2%
between the stressed sample peak and the standard, non-stressed sample peak was considered indicative of API decomposition.
STABILITY STUDY The API samples were assayed by HPLC at pre-determined time points to verify the stability of the API in SyrSpend SF PH4 (liquid). Before analyses, the bottles were shaken until the API was uniform-ly dispersed by visual inspection. Aliquots for quantification (vari-able for each API) were withdrawn from the middle of the bottles, without contact with the inner surface of the bottle, and diluted in order to obtain work solutions in the concentration described in Table 1. Sampling times were:
• Initial (T = 0)• 7 days (T = 7)• 14 days (T = 14)• 30 days (T = 30)• 60 days (T = 60)• 90 days (T = 90)
All suspensions were immediately assayed six times, and the results expressed as the mean from six independent measurements. For that purpose, samples were diluted, sonicated for 10 minutes, and then filtered in 15-mm regenerated cellulose syringe filters, with 0.45-µm pore size, before injection onto the HPLC system. The evaluation parameter was the percent recovery with respect to T = 0, using the HPLC method (results given as percentage ± standard deviation).
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Results are presented as the average of 3 replicates, at the work concentration.*%d = percentage of discrepancy between the active pharmaceutical ingredient peak without submission to stressing factors (negative control) and the peak of a sample subjected to one of the cited accel-erated-degradation factors. Areas given as mV. Maximum acceptable = 2% (Values higher than this are in bold.).HCl = hydrochloride; UV = ultraviolet
T A B L E 3 . SUMMARY OF THE STABILITY-INDICATING STUDY FOR THE ACTIVE PHARMACEUTICAL INGREDIENTS.
Active HCL NAOH UV HEAT H2O2Pharmaceutical Ingredient Area %d* Area %d* Area %d* Area %d* Area %d*
Acetazolamide 3790.08 |-0.67| 3748.81 |-1.76| 4032.27 |5.67| 3934.26 |3.10| 3253.90 |-14.73|
Baclofen 241.952 |0.047| 238.279 |-1.47| 242.033 |0.08| 242.776 |0.39| 227.084 |-6.10|
Dipyridamole 0.00 |-100.00| 0.00 |-100.00| 4123.42 |-2.26| 4145.30 |-1.74| 3850.99 |-8.72|
Mebeverine hydrochloride 2583.88 |-0.33| 0.00 |-100.00| 2481.36 |-4.29| 2713.29 |4.66| 2556.93 |-1.37|
Propylthiouracil 4894.78 |4.94| 4904.77 |5.15| 4827.38 |3.49| 5006.42 |7.33| 498.79 |-89.31|
Quinidine sulfate 2636.56 |-10.13| 1193.70 |-59.31| 2939.63 |0.20| 2979.60 |1.57| 2846.18 |-2.98|
Topiramate 317.50 |-4.06| 0.00 |-100.00| 0.00 |-100.00| 335.12 |1.26| 316.92 |-4.24|
RESULTS AND DISCUSSION Validation studies of all methods of analysis (chromatographic con-ditions described in Table 1) were performed and all results (Table 2) met the respective acceptance criteria, confirming the suitability of the methods for the objectives of this work. Stability-indicating studies were also conducted, and the results are summarized in Table 3. These types of studies are important to determine if the used meth-ods are fully validated and adequate to identify decomposition of the APIs by chromatographic analysis. The decomposition profile of the APIs notably varied for different stress conditions:
• Acidic stress affected dipyridamole, propylthiouracil, quini-dine sulfate, and topiramate
• Alkaline stress did not affect acetazolamine and baclofen• UV-light exposure did not decompose baclofen and quini-
dine sulfate• Heat exposure led to decomposition of acetazolamide, me-
bevarine hydrochloride, and propylthiouracil• Oxidative stress did not affect mebevarine hydrochloride
Once the forced-degradation profiles of the APIs were deter-mined, the stability of the APIs in SyrSpend SF PH4 (liquid) was assessed. At each sampling time, the visual appearance of the suspensions was evaluated to verify their homogeneity and physical stability (data not shown). Throughout the study, none of the following phe-nomena were observed:
• Precipitation• Turbidity• Macroscopically visible crystal growth• Odor generation• Phase separation• Flocculation• Caking
The chemical stability results are shown in Table 4 and are expressed as relative percent of recovery (initial sampling time = 100%). For the suspensions to be considered stable, the relative percentage recovery should lie within 90% to 110%.19,21,22 Figure 1 graphically represents the stability of the APIs in SyrSpend SF PH4 (liquid) in terms of absolute nominal concentration. All sus-pensions remained stable for 90 days, regardless of the tempera-ture of storage. For comparison, Alexander et al23 evaluated the stability of an acetazolamide suspension made from crushed tablets and contain-ing the following:
• Sorbitol• Carboxymethylcellulose• Aluminum magnesium silicate• Syrup USP• Glycerin• Methylparaben• Propylparaben• FD&C Red No. 40• Water
When stored at 5°C, 22°C, and 30°C during 79 days, the samples presented losses in acetazolamide content of 2%, 3%, and 5%, respectively. Allen and Erickson24 also evaluated the stability of acetazolamide in 25-mg/mL oral suspensions extemporaneously prepared from tablets, using Ora-Sweet and Ora-Plus (50:50, v/v), Ora-Sweet SF and Ora-Plus (50:50, v/v), and cherry syrup and simple syrup (1:4, v/v). The samples were stored at 5°C and 25°C in the dark. At either temperature, both suspensions remained stable for up to 60 days of storage. In another study, Allen and Erickson25 reported the stability of baclofen 10-mg/mL and dipyridamole 10-mg/mL oral suspensions. The suspensions were compounded using crushed tablets, and
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T A B L E 4 . STABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID).
% RECOVERY
ELAPSED REFRIGERATED CONTROLLED ROOMTIME TEMPERATURE TEMPERATURE(DAYS) (2ºC TO 8ºC) (20ºC TO 25ºC)Acetazolamide 25.0 mg/mL
T = 0 100.00 ± 0.27 100.00 ± 0.35T = 7 99.18 ± 0.66 99.41 ± 0.48T = 14 98.34 ± 0.33 99.78 ± 0.75T = 30 100.12 ± 0.14 99.96 ± 0.28T = 60 98.32 ± 0.22 99.77 ± 0.45T = 90 99.65 ± 0.44 99.73 ± 0.33
Baclofen 10.0 mg/mL
T = 0 100.00 ± 0.25 100.00 ± 0.25T = 7 102.33 ± 0.77 100.87 ± 0.93T = 14 101.09 ± 0.80 100.49 ± 0.61T = 30 98.27 ± 0.40 100.63 ± 0.57T = 60 102.21 ± 0.46 99.86 ± 0.34T = 90 99.85 ± 0.24 100.39 ± 0.30
Dipyridamole 10.0 mg/mL
T = 0 100.00 ± 0.27 100.00 ± 0.25T = 7 97.91 ± 0.26 100.68 ± 0.45T = 14 98.33 ± 0.44 99.85 ± 0.59T = 30 100.67 ± 0.24 100.41 ± 0.24T = 60 98.35 ± 0.13 100.68 ± 0.08T = 90 99.59 ± 0.36 101.28 ± 0.14
Mebeverine Hydrochloride 10.0 mg/mL
T = 0 100.00 ± 0.73 100.00 ± 0.73T = 7 102.21 ± 0.40 99.93 ± 0.38T = 14 98.93 ± 0.78 101.00 ± 0.39T = 30 101.26 ± 0.33 101.05 ± 0.32T = 60 101.92 ± 0.45 101.42 ± 0.33T = 90 99.99 ± 0.18 101.03 ± 0.34
Propylthiouracil 5.0 mg/mL
T = 0 100.00 ± 0.61 100.00 ± 0.61T = 7 99.45 ± 0.68 100.64 ± 0.78T = 14 100.42 ± 0.21 100.61 ± 0.21T = 30 100.07 ± 0.40 100.23 ± 0.34T = 60 100.07 ± 0.31 99.96 ± 0.20T = 90 99.36 ± 0.24 99.37 ± 0.34
Quinidine Sulfate 10.0 mg/mL
T = 0 100.00 ± 0.56 100.00 ± 0.56T = 7 98.64 ± 0.75 100.90 ± 0.63T = 14 102.38 ± 0.65 101.34 ± 0.53T = 30 101.17 ± 0.28 101.19 ± 0.51T = 60 101.74 ± 0.68 101.33 ± 0.69T = 90 100.34 ± 0.34 101.12 ± 0.55
Topiramate 5.0 mg/mL
T = 0 100.00 ± 0.84 100.00 ± 0.84T = 7 99.30 ± 0.78 99.78 ± 1.07T = 14 101.10 ± 0.65 99.48 ± 1.96T = 30 100.22 ± 0.48 100.80 ± 0.93T = 60 100.14 ± 0.79 98.70 ± 0.51T = 90 102.34 ± 0.18 100.30 ± 0.42
Ora-Sweet and Ora-Plus (50:50, v/v), Ora-Sweet SF and Ora-Plus (50:50, v/v), and cherry syrup and simple syrup (1:4, v/v). At either temperature, all suspensions remained stable for up to 60 days of storage (for baclofen, 4% of loss in content was found; for dipyri-damole, 8%). Nahata et al26 evaluated propylthiouracil 5-mg/mL suspensions compounded from tablets and using Ora-Plus and Ora-Sweet (1:1, v/v) or methylcellulose 1% and simple syrup (1:1, v/v). The suspen-sions remained stable for up to 91 days, with a 4% loss when stored under refrigeration at 4°C, and 6% to 7% loss when stored at room temperature near 25°C. These findings are in accordance with the study of Alexander and Mitra,27 who found the same period of sta-bility, but using a formula containing:
• Water• Carboxymethylcellulose sodium• Veegum• Syrup USP• Sorbitol• Saccharin• EDTA disodium• Paraben concentrate• Flavor blend
For quinidine sulfate, Allen and Erickson evaluated three 10-mg/mL oral suspensions compounded from tablets and using Ora-Sweet and Ora-Plus (50:50, v/v), Ora-Sweet SF and Ora-Plus (50:50, v/v), and cherry syrup and simple syrup (1:4, v/v). They reported that the suspensions remained stable for 60 days of storage, both at room and refrigerated temperature. For mebevarine hydrochloride and topiramate, there is no previ-ous reports towards their stability with an oral suspension, to the best of the authors’ knowledge. As for the other works found, our results show that SyrSpend SF PH4 (liquid) possesses equal to or better stability for the APIs tested in comparison to other formula-tions described in current literature.
CONCLUSION As the results showed, SyrSpend SF PH4 is compatible with the APIs tested within this study. Given the percentage of recovery of the APIs within the suspensions, the beyond-use date of the final products (API + vehicle) was at least 90 days for all suspensions with regards to both controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). This suggests that SyrSpend SF PH4 is suitable for compounding APIs from different pharmacological classes.
REFERENCES1. Colomer R, Alba E, González-Martin A et al. Treatment of can-
cer with oral drugs: A position statement by the Spanish Society of Medical Oncology (SEOM). Ann Oncol 2010; 21(2): 195–198.
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2. European Medicines Agency; Committee for Medicinal Prod-ucts for Human Use (CHM). Reflection Paper: Formulations of Choice for the Paediatric Population. [EMEA Website.] July 28, 2006. Available at: http://emea.europa.eu/pdfs/human/paediatrics/19481005en.pdf. Accessed May 23, 2016.
3. Schirm E, Tobi H, de Vries TW et al. Lack of appropriate for-mulations of medicines for children in the community. Acta Paediatr 2003; 92(12): 1486–1489.
4. Tent M. Kind vind pil vies, eng en veel te groot. Pharm Weekbl 2009; (14): 11–13.
5. Bouwman-Boer Y, Fenton-May V, Le Brun P. Practical Pharma-ceutical: An International Guideline for the Preparation, Care and Use of Medicinal Products. Switzerland: Springer Interna-tional Publishing AG; 2015; 77–99.
6. Geiger CM, Sorenson B, Whaley P. Stability assessment of 10 active pharmaceutical ingredients compounded in SyrSpend SF. IJPC 2015; 19(5): 420–427.
7. Ferreira AO, Polonini HC, Silva SL et al. Feasibility of amlodip-
30
27.5
25.0
22.5
20.0 Time (Days)[Ace
tazo
lam
ide]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)
[Dip
yrid
amol
] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
6.0
11
10
9
8 Time (Days)[Pro
pylth
iour
acil]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
6.0
5.5
5.0
4.5
4.0 Time (Days)
[Top
iram
ate]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)
[Pre
gaba
line]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)
[Bac
lofe
n] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)[Meb
ever
ine
HCl
] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
2.4
2.2
2.0
1.8
1.6 Time (Days)[Qui
nidi
ne s
ulfa
te]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
3.6
3.3
3.0
2.7
2.4 Time (Days)
[Oxa
ndro
lone
] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)
[Rib
oflav
in]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
A – Acetazolamide 25.0 mg/mL B – Baclofen 10.0 mg/mL
C – Dipyridamole 10.0 mg/mL D – Mebeverin Hydrochloride 10.0 mg/mL
E – Propylthiouracil 5.0 mg/mL F – Quinidine Sulfate 10.0 mg/mL
G – Topiramate 5.0 mg/mL H – Oxandrolone 3.0 mg/mL
I – Pregabaline 20.0 mg/mL J – Riboflavin 10.0 mg/mL
F I G U R E 1 . PLOT OF ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID) THROUGHOUT THE COMPATIBILITY STUDY.
Note: Dashed lines represent the lower and upper limits, corresponding to 90% and 110% of labeled concentration. Values represents mean ± SD (n=6).
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ine besylate, chloroquine phosphate, dapsone, phenytoin, pyri-doxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend® SF PH4 oral suspensions. J Pharm Biomed Anal 2016; 118: 105–112.
8. Geiger CM, Sorenson B, Whaley PA. Stability of captopril in SyrSpend SF. IJPC 2013; 17(4): 336–338.
9. Sorenson B, Voudrie MA II, Gehrig D. Stability of gabapentin in SyrSpend SF. IJPC 2012; 16(4): 347–349.
10. Vu NT, Aloumanis V, Ben M et al. Stability of metronidazole benzoate in SyrSpend SF One-step Suspension System. IJPC 2008; 12(6): 558–564.
11. Geiger CM, Sorenson B, Whaley PA. Stability of midazolam in SyrSpend SF and SyrSpend SF Cherry. IJPC 2013; 17(4): 344–346.
12. Whaley PA, Voudrie MA, Sorenson B. Stability of omeprazole in SyrSpend SF Alka (reconstituted). IJPC 2012; 16(2): 164–166.
13. Voudrie MA, Allen DB. Stability of oseltamivir phosphate in SyrSpend SF, Cherry Syrup and SyrSpend SF (for reconstitu-tion). IJPC 2010; 14(1): 82.
14. Geiger CM, Voudrie MA, Sorensen B. Stability of propranolol hydrochloride in SyrSpend SF. IJPC 2012; 16(6): 513–514.
15. Sorenson B, Whaley P. Stability of Rifampin in SyrSpend SF. IJPC 2013; 17(2): 162–164.
16. Geiger CM, Voudrie MA II, Sorenson B. Stability of ursodiol in SyrSpend SF Cherry Flavored. IJPC 2012; 16(6): 510–512.
17. Whaley PA, Voudrie MA II. Stability of vancomycin in SyrSpend SF. IJPC 2012; 16(2): 167–169.
18. Voudrie MA, Alexander B, Allen DB. Stability of verapamil hydrochloride in SyrSpend SF compared to sorbitol containing syrup and suspending vehicles. IJPC 2011; 15(3): 255–258.
19. United States Pharmacopeial Convention, Inc. United States Pharmacopeia –National Formulary. Rockville, MD: US Phar-macopeial Convention, Inc.; Current Edition.
20. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: International Conference on Harmonisa-tion of Technical Requirements for Registration of Pharmaceu-ticals for Human Use. Validation of Analytical Procedures: Text and Methodology Q2(R1). November 2005.
21. British Pharmacopoeia. British Pharmacopoeia. London, UK: British Pharmacopoeia Commission Office: The Stationery Of-fice; 2015.
22. Council of Europe. European Pharmacopoeia 8.0. Strasbourg, France: Council of Europe; 2015.
23. Alexander KS, Haribhakti RP, Parker GA. Stability of acetazol-amide in suspension compounded from tablets. Am J Hosp Pharm 1991; 48(6): 1241–1244.
24. Allen LV Jr., Erickson MA III. Stability of acetazolamide, allopu-rinol, azathioprine, clonazepam, and flucytosine in extempora-neously compounded oral liquids. Am J Health Syst Pharm 1996; 53(16): 1944–1949.
25. Allen LV, Erickson MA III. Stability of baclofen, captopril, diltiazem hydrochloride, dipyridamole, and flecainide acetate in
extemporaneously compounded oral liquids. Am J Health Syst Pharm 1996; 53(18): 2179–2184.
26. Nahata MC, Morosco RS, Trowbridge JM. Stability of propyl-thiouracil in extemporaneously prepared oral suspensions at 4 and 25 degrees C. Am J Health Syst Pharm 2000; 57(12): 1141–1143.
27. Alexander KS, Mitra P. Stability of an extemporaneously com-pounded propylthiouracil suspension. IJPC 2005; 9(1): 82–86.
28. Allen LV Jr., Erickson MA. Stability of bethanechol chloride, pyrazinamide, quinidine sulfate, rifampin, and tetracycline hydrochloride in extemporaneously compounded oral liquids. Am J Health Syst Pharm 1998; 55(17): 1804–1809.
Address correspondence to Anderson O. Ferreira, Ortofarma – Qual-ity Control Laboratories BR 040, n. 39, Empresarial Park Sul, 36120-000, Matias Barbosa – MG. Brazil. E-mail: [email protected]
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Anderson de Oliveira Ferreira, Bpharm, MSc, PhD Candidate Hudson C. Polonini, BPharm, MSc, PhDSharlene Loures da Silva, BBiomedVictor Augusto Cerqueira de Melo, BPharm CandidateLaura de Andrade, BPharm, MSc CandidateMarcos Antônio Fernandes Brandão, BPharm, PhD
Stability of Alprazolam, Atropine Sulfate, Glutamine, Levofloxacin, Metoprolol Tartrate, Nitrofurantoin, Ondansetron Hydrochloride, Oxandrolone, Pregabaline, and Riboflavin in SyrSpend SF PH4 Oral Suspensions
ABSTRACT The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): alprazolam 1.0 mg/mL, atropine sulfate 0.1 mg/mL, glutamine 250.0 mg/mL, levofloxacin 50.0 mg/mL, metoprolol tartrate 10.0 mg/mL, nitrofurantoin 2.0 mg/mL, ondansetron hydrochloride 0.8 mg/mL, oxandrolone 3.0 mg/mL, pregabaline 20.0 mg/mL, riboflavin 10.0 mg/mL. All suspensions were stored at both controlled refrigeration (2°C to 8°C) and controlled room temperature (20°C to 25°C). Stability was assessed by measuring the percent recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions with regard to both temperatures. This suggests that the vehicle is stable for compounding active pharmaceutical ingredients from different pharmacological classes.
The authors’ affiliations are as follows: Anderson de Oliveira Ferreira, Hudson C. Polonini , Sharlene Loures da Silva, and Victor Augusto Cerqueira de Melo, Ortofarma–Quality Control Laboratories, Matias Barbosa, MG, Brazil; Laura de Andrade, Marcos Antônio Fernandes Brandão, and Anderson de Oliveira Ferreira, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil. Hudson Polonini and Victor Augusto Cerqueira de Melo also are affiliated with Universidade Presidente Antônio Carlos (Unipac-JF), Juiz de Fora, MG, Brazil.
INTRODUCTION Swallowing is a complex process, involving both the muscles of the throat as well as the lips, tongue and cheeks.1 A healthy person unconsciously swallows approximately two times per minute.2 Nevertheless, dysphagia or swallowing difficulty is common among various types of patients. Studies have shown that 25% to 45% of the pediatric patients, 50% to 75% of the elderly, and almost 23% of the general population suffer from dysphagia.3-5 Dysphagia may be caused by physical changes of the mouth, throat, and/or larynx. In addition, with age, due to medication side effects or local nerve damage, problems may also arise in the control of the muscles. Dys-phagia may subsequently lead to malnutrition, exsiccosis, aspira-tion pneumonia, and respiratory failure.6
In practice, dysphagia is infrequently acknowledged and con-sidered when prescribing medication. An important factor is that
PEER REVIEWED
patients or their caretakers do not address the problem or are not aware of it. Dysphagia, however, has a great impact on medication intake. Common solutions to allow patients to take their medica-tion are the crushing of tablets, the filling of capsules, or, if possible, the abandonment of medication. These modifications will affect both safety, efficacy, and quality of life.7 Crushing enteric-coated or controlled-release tablets might result in degradation of the active or dose dumping, respectively, which can result in decreased ef-ficacy or an increased risk of side effects.8
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For patients with dysphagia, oral liquids are often a more convenient, better adhered, and safer alterna-tive. Because the majority of medicines are not readily available as a liquid, pharmacists frequently need to compound the oral medication. In order to obtain sufficient physical, chemical, and microbiological stability as well as an acceptable taste, suspensions are often a better option than solutions, or even the only possible option.9
Since many people suffer from dysphagia, it is important to determine the feasibility of using SyrSpend SF for the compounding of many different active pharmaceutical ingredients (APIs), so it can be a better alternative to crushed tablets or capsules. During this study, we investigated the stability of 10 APIs representing different pharmacological classes, including alprazolam, atropine sulfate, glutamine, levofloxacin, metoprolol tartrate, nitrofurantoin, ondansetron hydrochloride (HCl), oxandrolone, pregabaline, and riboflavin. SyrSpend SF is designed to help optimize the compounding of suspensions. The patented “Active Suspending Technology” assists in administering the right dose throughout the therapy. The use of starch instead of methylcellulose makes SyrSpend SF highly compatible with a wide range of APIs.10-25 A single concentration of the APIs (Table 1) was selected based on commonly prescribed medications, and the sus-pensions were stored both at refrigerated and at room temperature throughout the study.
MATERIALS AND METHODSREAGENTS, REFERENCE STANDARDS, AND MATERIALS All API raw materials and SyrSpend SF PH4 (liquid) (Lot 14F02-U59-019404) were obtained from Fagron (St. Paul, Minnesota). High-performance liquid chromatography (HPLC)-grade reagents (Panreac, Barcelona, Spain) were used. Ultrapure water obtained with an AquaMax-Ultra 370 Series (Young Lin, Anyang, Korea) (18.2 MΩ·cm resistivity at 25°C and <10 ppb total organic carbon) was used throughout the experiments. The reference standards used were all work standards obtained using primary United States Pharmacopeia (USP) (Rockville, Maryland) reference materials. All the mobile phases and receptor media were filtered through a 0.45-µm filter membrane (RC-45/15 MS; Chromafil, Düren, Germany) and degassed using an ultrasonic apparatus (Model 1600A; Unique, Indaiatuba, Brazil) for 30 minutes, immediately before use. All volu-metric glassware and analytical balances used were calibrated.
EQUIPMENT HPLC analyses were performed on a qualified and calibrated chromatography system (Young Lin, Anyang, Korea) composed of a quaternary gradient pump (YL 9110), a photodiode array detector (PDA) (YL 9160), a 96-vial programmable autosampler (YL 9150), a
column oven compartment (YL 9130), a variable sample loop up to 200 µL, and a software controller (Clarity).
CHROMATOGRAPHIC CONDITIONS
The chromatographic determinations were based upon USP methods for the APIs or their final products, with minor modifica-tions when necessary. The exact chromatographic conditions used for each API are stated in Table 2. The columns were connected with a pre-column with the same packing (4.0 × 3.0 mm, 5 µm) from the same vendor of the columns.
VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD
The validation protocol and the acceptance criteria were estab-lished based upon USP (2015) and International Conference on Harmonization (ICH) (2005) guidelines.26,27 Specificity of the method was determined by running HPLC analyses of a standard solution, a SyrSpend SF PH4 (liquid) blank solution, and a mobile phase/diluents blank solution. The accep-tance criterion was defined as a percentage of discrepancy [(stan-dard area – sample area)/standard area] × 100 between the peak areas of less than 2%. In addition, the specificity of the method was obtained through comparison of standard chromatograms with and without the SyrSpend SF PH4 (liquid) matrix. All analyses were run in triplicate. Precision was evaluated as repeatability and intermediate preci-sion. Repeatability was determined by consecutively analyzing six replicates by a single analyst in a single day. Intermediate precision was also performed in six replicates, but over two days, by different analysts. An injection precision of more than 95% (coefficient of variation [CV]) was considered acceptable. The accuracy of the method was determined through spike-recovery of the SyrSpend SF PH4 (liquid) matrix, diluted within the range used for final sample measurements (to the calibration
T A B L E 1 . CONCENTRATIONS OF THE SUSPENSIONS USED IN THE STUDY.
ACTIVE PHARMACEUTICAL CONCENTRATION INGREDIENTS IN SUSPENSION ACTION AND USEAlprazolam 1.0 mg/mL Benzodiazepine
Atropine sulfate 0.1 mg/mL Anticholinergic
Glutamine 250.0 mg/mL Aminoacid
Levofloxacin 50.0 mg/mL Antibacterial
Metoprolol tartrate 10.0 mg/mL Beta-adrenoceptor agonist
Nitrofurantoin 2.0 mg/mL Antibacterial
Ondansetron hydrochloride 0.8 mg/mL Serotonin 5HT3 antagonist
Oxandrolone 3.0 mg/mL Anabolic steroid
Pregabaline 20.0 mg/mL Antiepileptic
Riboflavin 10.0 mg/mL Vitamin B2
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T A B L E 2 . CHROMATOGRAPHIC CONDITIONS USED IN THE COMPATIBILITY STUDY.
ACTIVE WORK UV DETECTIONPHARMACEUTICAL MOBILE PHASE CONCENTRATION FLOW WAVELENGTHINGREDIENT COMPOSITION (µG/ML)* COLUMN (ML/MIN) (NM)
Acetonitrile and water (75:25),
with pH adjusted to 2.75 with 20.0; 20 µL L1, 4.6-mm ×
Alprazolam hydrochloric acid injection 25-cm; at 25°C1 1.0 254
5.1 g of tetrabutylammonium
hydrogen sulfate with 50 mL of
acetonitrile and qs of buffer (4.1 g
of sodium acetate and 2.9 mL of
glacial acetic acid in 1 L of water)
to 1 L. This solution was adjusted
with 5 N sodium hydroxide to a L1, 3.9-mm ×
Atropine sulfate pH of 5.5. 80.0; 20 µL injection 30-cm; at 25°C2 2.0 254
500.0, in a
mixture of
acetonitrile and
Acetonitrile and ammonium water (75:25); L8, 4.6-mm ×
Glutamine hydroxide buffer pH 7.5 (75:25) 20 µL injection 15-cm; at 35°C3 1.0 195
15, in a mixture
of acetonitrile
Acetonitrile and water (18:82), and water
containing 1 mL of trifluoroacetic (18:82); 20 µL L11, 4.6-mm ×
Levofloxacin acid in each 1000 mL of solution injection 15-cm; at 30°C4 1.5 294
961 mg of 1-pentanesulfonic acid
sodium salt (monohydrate) and
82 mg of anhydrous sodium acetate
in a mixture of 550 mL of methanol
and 470 mL of water, with 0.57 mL L1, 4.6-mm ×
Metoprolol tartrate of glacial acetic acid 100.0; 20 µL injection 25-cm; at 25°C5 1.0 254
Nitrofurantoin 5 mM potassium phosphate and
acetonitrile (80:20), with pH 2,500.0 in
adjusted to 3.0 with phosphoric acetonitrile; L1, 4.6-mm ×
acid 20 µL injection 15-cm; at 30°C6 1.0 370
43 mM monobasic potassium
phosphate buffer adjusted with a
mixture of 1 N sodium hydroxide
Ondansetron and acetonitrile (85:15) to a pH of 4.0; 50 µL L10, 4.6-mm ×
hydrochloride 5.4 injection 25-cm; at 30°C7 1.5 216
1,200.0, in
acetonitrile; L1, 4.6-mm ×
Oxandrolone Water and acetonitrile (50:50) 20 µL injection 25-cm; at 25°C8 1.0 210
0.05 M phosphate buffer pH 6.9 800.0; 20 µL L1, 4.6-mm ×
Pregabaline and acetonitrile (35:5) injection 25-cm; at 25°C9 1.0 200
Methanol, glacial acetic acid, and
water (27:1:73), containing 1.40 mg/mL 10.0; 20 µL L1, 4.6-mm ×
Riboflavin of sodium 1-hexanesulfonate injection 15-cm; at 25°C10 1.0 280
*Diluted with mobile phase, unless specified otherwise.1Zorbax Eclipse XDB 5µ (Agilent); 2Zorbax Eclipse XDB 5µ (Agilent); 3Microsorb-MV 100-5 (Varian); 4Zorbax Eclipse XDB 5µ (Agilent); 5Zorbax Eclipse XDB 5µ (Agilent); 6Zorbax Eclipse XDB 5µ (Agilent); 7Kromasil 60 (Kromasil); 8Zorbax Eclipse XDB 5µ (Agilent); 9Luna 5µ 100A (Phenomenex); 10Zorbax Eclipse XDB 5µ (Agilent)
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curves). Percent recovery was calculated from the concentration measured relative to the theoretical concentration spiked. For linearity, concentrations from 70% to 130% of the work-ing concentration of the API in SyrSpend SF PH4 (liquid) were prepared and analyzed. The data from each experiment was fitted by ordinary least squares method and was evaluated by analysis of variance (ANOVA). The limit of detection (LOD) and limit of quantification (LOQ) were determined from three standard calibration curves of the APIs in the presence of the SyrSpend SF PH4 (liquid) matrix and were calculated as shown in equations (1) and (2), respectively:
LOD = s 3 (1) a
LOQ = s 10 (2) a
where a is the slope of the calibration curve, and s is the standard deviation of the y-intercept. The LOD and LOQ were confirmed by the analysis of chromatograms generated by injecting solutions in their respective limit concentrations.
PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS SUSPENSION SAMPLES
The API suspensions were prepared using the following general protocol:
1. The required quantity of each ingredient for the total amount to be prepared was calculated.
2. Each ingredient was accurately weighed.3. The API was placed in a mortar and triturated until a fine powder
was obtained.4. A small amount of the SyrSpend SF PH4 (liquid) was added to the
powder and mixed to form a uniform paste.5. The SyrSpend SF PH4 (liquid) was further added in approximately
geometric portions almost to volume, mixing thoroughly after each addition.
6. Sufficient SyrSpend SF PH4 (liquid) was added to bring the volume to 300 mL, and then mixed well.
7. The final product was packaged in low-actinic, light-resistant pre-scription bottles and labeled.
The final concentrations in the bottles are summarized in Table 1. The suspensions were then immediately assayed at T = 0, and then separated into two different 150-mL bottles: one sample was stored at controlled refrigerated (2ºC to 8ºC) and the other sample at room temperature (20ºC to 25ºC), for the duration of the study (temperature and humidity were checked in real time throughout the whole experiment, using a calibrated, digital thermo-hygrome-ter [Incoterm]).
FORCED-DEGRADATION STUDIES: STABILITY-INDICATING CHARACTERISTICS API samples were subjected to the following stressing condi-tions to determine the capacity of the HPLC method to detect any possible degradation products that may arise during storage of the oral suspension:
1. Dilution in acid (0.1M HCl, at 25°C)2. Dilution in base (0.1M NaOH, at 25°C)3. Exposure to ultraviolet (UV) light at 365 nm (at 25°C)4. Heating at 70°C5. Dilution in H2O2 35% (v/v) (at 25°C).
These solutions were prepared for each API at its respective work concentration by means of serial dilution from a stock-solu-tion and using suitable diluents (see Table 2). The stock-solutions were sonically dispersed for 10 minutes, and the final solutions were filtered (15-mm regenerated cellulose syringe filters, with 0.45-µm pore size) before injection onto the HPLC system. Any extraneous peaks found in the chromatograms were labeled. A resolution of 1.5 between the peaks of the degradation products and the API was considered full separation. Also, a discrep-ancy greater than 2% between the stressed sample peak and the standard, non-stressed sample peak was considered indicative of API decomposition.
STABILITY STUDY The API samples were assayed by HPLC at pre-determined time points to verify the stability of the API in SyrSpend SF PH4 (liq-uid). Before analyses, the bottles were shaken until the API was uniformly dispersed by visual inspection. Aliquots for quantifica-tion (variable for each API) were withdrawn from the middle of the bottles, without contact with the inner surface of the bottle, and diluted in order to obtain work solutions in the concentration described in Table 2. Sampling times were:
• Initial (T = 0)• 7 days (T = 7)• 14 days (T = 14)• 30 days (T = 30)• 60 days (T = 60)• 90 days (T = 90)
All suspensions were immediately assayed six times (6 ali-quots) at each time point (samples were diluted, sonicated for 10 minutes, and then filtered in 15-mm regenerated cellulose syringe filters with a 0.45-µm pore size before injection onto the HPLC system). The evaluation parameter was the percent recovery with respect to T = 0, using the HPLC method (results given as average percentage from six independent measurements ± standard deviation).
ESTUDO 25
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Peer Reviewed
RESULTS AND DISCUSSION Validation studies of all methods of analysis (see the chromato-graphic conditions described in Table 2) were performed and all results (Table 3) met the respective acceptance criteria, confirm-ing the suitability of the methods for the objectives of this work. Stability-indicating studies were also conducted, and the results are summarized in Table 4. These types of studies are important to determine if the used methods are fully validated and adequate to identify decomposition of the APIs by chromatographic analysis. The decomposition profile of the APIs notably varied for different stressing conditions. Acidic stress affected all APIs except for levo-
floxacin; alkaline stress affected all APIs but alprazolam; UV-light exposure did not decompose levofloxacin, nitrofurantoin, oxandro-lone, and pregabaline; heat exposure did not lead to decomposition of alprazolam, atropine, glutamine, and nitrofurantoin; and oxida-tive stress did not affect atropine sulfate. Once the forced-degrada-tion profiles of the APIs were determined, the stability of the APIs in SyrSpend SF PH4 (liquid) was assessed. For the stability study, the suspensions were first visually in-spected at each sampling time to verify their physical homogeneity and stability. Color, odor, and pH did not change appreciably. None of the following phenomena were observed throughout the study:
Acceptance criteria were: R2 >0.99; F (significance of regression) >>4.67; F (lack of fit) <3.71; discrepancy <2%; repeatability and intermediate precision <5%; recovery = 100% ± 2%. All analytical ranges(µg/mL) were adequate to quantify the APIs in the concentrations used in the suspensions (mg/mL).API = active pharmaceutical ingredient; LOD = Limit of Detection; LOQ = Limit of Quantification (20 µL injections); CV = coefficient of variation
T A B L E 3 . SUMMARY OF LINEARITY’S STUDY FOR THE VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD.
API
Alprazolam
Atropine sulfate
Glutamine
Levofloxacin
Metoprolol tartrate
Nitrofurantoin
Ondansetron HCl
Oxandrolone
Pregabaline
Riboflavin
Range (µg/mL)
14.28 – 26.52
56.07– 104.13
351.96 – 653.64
84.14 – 156.26
70.07 – 120.12
350.14 – 650.26
2.88 – 5.35
840.56 –1561.04
701.68 –1303.12
7.14 – 13.26
Analytical Curve
y = 130.78x – 95.91
y = 1.24x + 6.61
y = 14.02x + 22.87
y = 62.63x – 172.63
y = 1.09x – 0.81
y = 71.14x + 1443.85
y = 140.34x + 27.45
y = 0.19x – 8.16
y = 1.57x – 57.68
y = 44.95x – 1.65
R2
0.9993
0.9951
0.9991
0.9987
0.9952
0.9961
0.9976
0.9908
0.9993
0.9970
ANOVA’s Significance of Regression (F)
18409.20
2621.65
14178.93
10386.85
2687.89
3336.62
5480.33
1399.47
1939.78
4313.08
ANOVA’s Lack of Fit (F)
2.26
2.53
0.98
0.94
3.26
3.26
2.05
0.36
3.70
1.75
LOD (µg/mL)
0.07
0.01
5.07
0.004
0.02
0.004
0.30
0.005
0.003
0.33
LOQ (µg/mL)
0.25
0.04
16.89
0.02
0.08
0.01
1.00
0.02
0.01
1.10
SPECIFICITY
Discrepancy (%)
|1.61|
|1.79|
|0.07|
|1.50|
|0.16|
|1.97|
|0.08|
|1.90|
|1.62|
|1.48|
Repeatability (CV, %)
1.00
0.39
0.41
0.22
0.58
0.35
0.48
0.99
0.82
0.56
IntermediatePrecision (CV, %)
0.67
1.06
0.54
0.49
3.70
0.64
1.08
0.85
1.17
0.92
ACCURACY
Recovery (%)
100.15
99.95
100.06
99.79
99.46
99.33
100.13
100.15
100.73
99.36
T A B L E 4 . SUMMARY OF THE STABILITY-INDICATING STUDY FOR THE ACTIVE PHARMACEUTICAL INGREDIENTS.
Note: The results are presented as the average of 3 replicates, at the work concentration.*%d = Percentage of discrepancy between the API peak without submission to stressing factors (negative control) and the peak of a sample subjected to one of the cited accelerated-degradation factors. Areas given as mV. Maximum acceptable = 2% (values higher than this are in bold).API = active pharmaceutical ingredient; HCl = hydrochloride; UV = ultraviolet
%d*
|-2.41| |-0.11|
|-100.00| |-2.61||5.05||-9.54||2.51||-5.01||-13.46||-84.83|
APIAlprazolam
Atropine sulfate
Glutamine
Levofloxacin
Metoprolol tartrate
Nitrofurantoin
Ondansetron HCl
Oxandrolone
Pregabaline
Riboflavin
Area
171.29
27.40
0.00
7389.23
108.84
9658.69
558.17
0.00
1504.91
415.66
%d*
|-93.09||-73.68||-100.00||0.47|
|6.35||-73.56||4.65||-100.00||-4.88||-5.03|
Area
2481.95
0.00
16989.88
7171.50
109.19
0.00
279.62
213.00
1530.00
19567.98
%d*
|0.18|
|-100.00||93.52||-2.49||6.70||-100.00||-47.57||2.38||-3.30||4371.43|
Area
2553.00
108.69
10031.24
7217.75
105.95
36895.64
561.78
215.67
1574.19
376.44
%d*
|3.05||4.41||14.26||-1.86|
|3.53||1.02|
|5.33||-1.15|
|-0.50|
|-13.99|
Area
2473.66
105.77
8830.02
7127.73
104.76
36824.46
587.55
213.12
1531.12
421.18
%d*
|-0.15|
|1.61|
|0.58|
|-3.09||-2.38||0.82|
|10.16||-2.32||-3.23||-3.76|
Area
2417.72
103.98
0.00
7162.61
107.50
33041.45
546.76
207.25
1369.27
66.37
LINEARITY PRECISION
HCl NaOH UV HEAT H2O2
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Peer Reviewed
% RECOVERY
Controlled Room Refrigerated Temperature TemperatureElapsed Time (Days) (2OC to 8OC) (20OC to 25OC)
ALPRAZOLAM 1.0 MG/ML
T = 0 100 ± 0.16 100 ± 0.16
T = 7 97.15 ± 0.56 97.42 ± 0.54
T = 14 98.30 ± 0.48 98.35 ± 0.47
T = 30 97.35 ± 0.68 99.12 ± 0.51
T = 60 95.83 ± 0.43 97.74 ± 0.79
T = 90 96.52 ± 0.55 96.55 ± 0.41
ATROPINE SULFATE 0.1 MG/ML
T = 0 100 ± 0.39 100 ± 0.39
T = 7 99.28 ± 0.80 98.77 ± 0.42
T = 14 94.88 ± 0.80 97.94 ± 0.74
T = 30 94.97 ± 0.72 94.35 ± 0.96
T = 60 94.36 ± 0.35 96.30 ± 0.79
T = 90 95.44 ± 0.66 94.64 ± 0.65
GLUTAMINE 250 MG/ML
T = 0 100 ± 0.53 100 ± 0.53
T = 7 99.22 ± 0.78 101.39 ± 0.64
T = 14 100.80 ± 0.35 100.78 ± 0.42
T = 30 101.25 ± 0.27 101.85 ± 0.23
T = 60 99.13 ± 0.36 98.96 ± 0.51
T = 90 99.53 ± 0.52 99.45 ± 0.56
LEVOFLOXACIN 50 MG/ML
T = 0 100 ± 0.24 100 ± 0.24
T = 7 99.25 ± 0.71 101.26 ± 0.36
T = 14 101.60 ± 0.25 101.18 ± 0.25
T = 30 102.34 ± 0.48 99.63 ± 0.30
T = 60 99.51 ± 0.37 99.37 ± 0.85
T = 90 100.13 ± 0.16 99.64 ± 0.40
METOPROLOL TARTRATE 10 MG/ML
T = 0 100 ± 0.61 100 ± 0.61
T = 7 96.03 ± 0.32 100.46 ± 0.64
T = 14 97.88 ± 0.90 99.92 ± 0.58
T = 30 102.03 ± 0.99 101.49 ± 1.70
T = 60 96.37 ± 0.24 97.23 ± 1.20
T = 90 100.69 ± 0.19 100.81 ± 0.16
T A B L E 5 . STABILITY OF THE ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID).
% RECOVERY
Controlled Room Refrigerated Temperature Temperature Elapsed Time (Days) (2OC to 8OC) (20OC to 25OC)
NITROFURANTOIN 2 MG/ML
T = 0 100 ± 0.19 100 ± 0.19
T = 7 99.04 ± 0.28 99.82 ± 0.42
T = 14 100.18 ± 0.18 99.95 ± 0.25
T = 30 100.32 ± 0.55 100.34 ± 0.65
T = 60 99.72 ± 0.65 99.78 ± 0.36
T = 90 100.55 ± 0.65 98.79 ± 0.30
ONDANSETRON HYDROCHLORIDE 0.8 MG/ML
T = 0 100 ± 0.65 100 ± 0.65
T = 7 99.88 ± 0.55 100.60 ± 0.51
T = 14 100.97 ± 0.50 100.22 ± 0.45
T = 30 100.38 ± 0.18 100.41 ± 0.28
T = 60 99.18 ± 1.53 99.29 ± 0.63
T = 90 99.59 ± 0.21 99.74 ± 0.20
OXANDROLONE 3 MG/ML
T = 0 100 ± 0.73 100 ± 0.73
T = 7 99.24 ± 0.59 97.12 ± 0.77
T = 14 99.60 ± 0.34 99.87 ± 0.44
T = 30 98.28 ± 0.48 96.79 ± 0.87
T = 60 93.38 ± 2.14 99.96 ± 1.02
T = 90 98.59 ± 0.43 98.84 ± 0.41
PREGABALINE 20 MG/ML
T = 0 100 ± 0.32 100 ± 0.32
T = 7 99.05 ± 0.32 100.44 ± 0.16
T = 14 99.16 ± 0.59 99.75 ± 0.33
T = 30 98.13 ± 0.37 100.27 ± 1.34
T = 60 100.67 ± 0.37 100.96 ± 0.28
T = 90 98.73 ± 0.54 100.33 ± 0.28
RIBOFLAVIN 10 MG/ML
T = 0 100 ± 0.68 100 ± 0.68
T = 7 102.92 ± 0.80 98.99 ± 0.61
T = 14 101.37 ± 0.63 98.92 ± 0.49
T = 30 102.05 ± 0.38 99.85 ± 0.36
T = 60 102.38 ± 0.61 99.73 ± 0.66
T = 90 101.77 ± 0.33 99.99 ± 0.33
• Caking
• Floculation
• Macroscopically visible crystal growth
• Phase separation
• Precipitation
• Turbidity
The stability results are shown in Table 5 and are expressed as relative percent of recovery (initial sampling time = 100%). For
the suspensions to be considered stable, the relative percentage recovery should lie within 90% to 110%.26,28,29 Figure 1 graphically represents the stability of the APIs in SyrSpend SF PH4 (liquid) in terms of absolute nominal concentration.
Alprazolam Oral Suspension
Allen and Erickson30 evaluated 1-mg/mL alprazolam oral suspen-sions compounded with Ora-Sweet and Ora-Plus (Perrigo) (50:50, v/v) or cherry syrup (Robinson Laboratories) mixed with 1:4 with
ESTUDO 25
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simple syrup, prepared from tablets. They found out that all suspen-sions remained stable for up to 60 days of storage, both at 5°C and 25°C (losses of 7% to 9% for cherry syrup and less than 5% for Ora-Plus-containing suspensions), which is a lower storage period than the one found in our study (90 days).
Levofloxacin Oral Suspension
For levofloxacin, VandenBussche et al31 evaluated 50-mg/mL oral suspensions prepared from tablets in Ora-Plus and strawberry syrup (50:50, v/v/). HPLC analysis demonstrated that the suspen-sions remained stable for 57 days when packaged in amber, plastic prescription bottles and stored at 3°C to 5°C or 23°C to 25°C, in contrast with the 90-day period of stability found here.
Metoprolol Tartrate Oral Suspension
Allen and Erickson32 evaluated 10-mg/mL metoprolol tartrate oral suspensions compounded with Ora-Sweet and Ora-Plus (50:50, v/v) or cherry syrup mixed with 1:4 with simple syrup, prepared from tablets. They found out that all suspensions presented losses in API content lower than 3% after 60 days of storage in the dark, both at 5°C and 25°C. Gupta and Maswoswe33 reported that 5-mg/mL aque-ous mixtures prepared from metoprolol tartrate tablets were stable for 16 days at 25°C. Peterson et al34 evaluated metoprolol tartrate 10-mg/mL suspensions (compound tragacanth powder–3g; concen-trated chloroform water–1.25 mL; syrup–12.5 mL; distilled water–qs 100 mL). The suspensions were packaged in amber glass bottles and stored at 5°C to 7°C or 21°C to 25°C. The HPLC analyses revealed no loss in API content at 60 days refrigerated and a 10% loss in 28 days at room temperature. All these metoprolol studies reported a shorter period of stability during storage compared to our results, showing that the formulation used here possesses a higher storage capacity for this API, comparatively.
Ondansetron Hydrochloride Oral Suspension
The same improved stability was observed for ondansetron HCl. Williams et al35 assayed four 0.8-mg/mL ondansetron HCl suspen-sions, compounded with: Cherry Syrup USP; Syrpalta (HUMCO); Ora-Sweet (Perrigo); and Ora-Sweet Sugar-Free (Perrigo). All suspensions remained stable for 42 days, when stored at 4°C, lower than what was found in this study.
Oxandrolone Oral Suspension
As for the oxandrolone oral suspension, data from literature shows that the stability of the vehicle used in this study is compa-rable with other vehicles. For instance, Johnson et al36 evaluated oxandrolone oral suspension (1 mg/mL) prepared using oxandro-lone tablets in 1:1 mixtures of Ora-Plus and either Ora-Sweet or Ora-Sweet SF, stored in 2-oz amber, plastic bottles, and at room temperature (23°C to 25°C). They reported that at least 98% of the original oxandrolone concentration remained in both formulations
at the end of the 90-day study period (a slightly higher loss than the one from the present study).
Atropine Sulfate, Glutamine, Nitrofurantoin, Pregabalin, Riboflavin Oral Suspensions
Lastly, to the best of the authors’ knowledge, no study concerning the stability of atropine sulfate, glutamine, nitrofurantoin, prega-balin, and riboflavin in oral suspensions was performed until the submission of this study for publication.
CONCLUSION As the results showed, oral suspensions of alprazolam, atropine sulfate, glutamine, levofloxacin, metoprolol tartrate, nitrofurantoin, ondansetron HCl, oxandrolone, pregabaline, and riboflavin prepared with SyrSpend SF PH4 are stable for at least 90 days when stored both at refrigerated and at room temperatures. This indicates the probable success of validating the APIs evaluated in this study for the multiple dosages likely to be used in clinical applications by pharmacists or drug manufacturers interested in using oral suspen-sions for drug administration.
REFERENCES1. Matsuo K, Palmer JB. Anatomy and physiology of feeding and
swallowing: Normal and abnormal. Phys Med Rehabil Clin N Am 2008; 19(4): 691–707.
2. Rouse MH. Neuroanatomy for Speech Language Pathology and Au-diology. Burlington, MA: Jones and Bartlett Learning; 2016: 200.
3. Gosa M, Schooling T, Coleman J. Thickened liquids as a treat-ment for children with dysphagia and associated adverse effects: A systematic review. Sage Journals (Infant, Child & Adolescent Nutrition) 2011; 3(6): 344–350.
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Peer ReviewedESTUDO 25
262International Journal of Pharmaceutical CompoundingVol. 21 No. 3 | May | June | 2017
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Formulations
F I G U R E 1 . PLOT OF ACTIVE PHARMACEUTICAL INGREDIENTS IN SYRSPEND SF PH4 (LIQUID) THROUGHOUT THE COMPATIBILITY STUDY.
Dashed lines represent the lower and upper limits, corresponding to 90% and 110% of labeled concentration. Values represent mean ± SD (n=6).
1.2
1.1
1.0
0.9
0.8 Time (Days)
[Alp
razo
lam
] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
300
275
250
225
200 Time (Days)
[Glu
tam
ine]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)
[Met
opro
lol]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
0.96
0.88
0.80
0.72
0.64 Time (Days)[Ond
anse
tron
HCl
] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)
[Pre
gaba
line]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
0.12
0.11
0.10
0.09
0.08 Time (Days)[Atr
opin
e su
lpha
te]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
60
55
50
45
40 Time (Days)
[Lev
oflox
acin
] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
2.4
2.2
2.0
1.8
1.6 Time (Days)[Nitr
ofur
anto
in]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
3.6
3.3
3.0
2.7
2.4 Time (Days)
[Oxa
ndro
lone
] m
g/m
L
0 30 60 90
RefrigeratedRoom Temperature
12
11
10
9
8 Time (Days)
[Rib
oflav
in]
mg/
mL
0 30 60 90
RefrigeratedRoom Temperature
A – Alprazolam 1.0 mg/mL B – Atropine sulfate 0.1 mg/mL
C – Glutamine 250.0 mg/mL D – Levofloxacin 50.0 mg/mL
E – Metoprolol tartrate 10.0 mg/mL F – Nitrofurantoin 2.0 mg/mL
G – Ondansetron HCl 0.8 mg/mL H – Oxandrolone 3.0 mg/mL
I – Pregabaline 20.0 mg/mL J – Riboflavin 10.0 mg/mL
ESTUDO 25
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Formulations
11. Ferreira AO, Polonini HC, Silva SL et al. Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydro-chloride, trimethoprim and zonisamide in SyrSpend SF PH4 oral suspensions. J Pharm Biomed Anal 2016; 118: 105–112.
12. Vu NT, Aloumanis V, Ben MJ et al. Stability of metronidazole benzoate in SyrSpend SF One-Step Suspension System. IJPC 2008; 12(6); 558–564.
13. Geiger CM, Voudrie MA II, Sorenson B. Stability of ursodiol in SyrSpend SF Cherry Flavored. IJPC 2012; 16(6): 510–512.
14. Sorenson B, Whaley P. Stability of rifampin in SyrSpend SF. IJPC 2013; 17(2): 162–164.
15. Geiger CM, Sorenson B, Whaley PA. Stability of captopril in SyrSpend SF. IJPC 2013; 17(4): 336–338.
16. Sorenson B, Voudrie MA II, Gehrig D. Stability of gabapentin in SyrSpend SF. IJPC 2012; 16(4): 347–349.
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20. Whaley PA, Voudrie MA II. Stability of vancomycin in SyrSpend SF. IJPC 2012; 16(2): 167–169.
21. Voudrie MA II, Alexander B, Allen DB. Stability of verapamil hydrochloride in SyrSpend SF compared to Sorbitol containing syrup and suspending vehicles. IJPC 2011; 15(3): 255–258.
22. Geiger CM, Voudrie MA II, Sorenson B. Stability of propranolol hydrochloride in SyrSpend SF. IJPC 2012; 16(6): 513–515.
23. Polonini HC, Silva SL, Cunha CN et al. Compatibility of chole-calciferol, haloperidol, imipramine hydrochloride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacrolimus monohydrate, terbinafine, tramadol hydrochloride and valsartan in SyrSpend SF PH4 oral suspensions. Pharmazie 2015; 71(4): 185–191.
24. Polonini HC, Silva SL, de Almeida TR et al. Compatibility of caf-feine, carvedilol, clomipramine hydrochloride, folic acid, hydro-chlorothiazide, loperamide hydrochloride, methotrexate, nado-lol, naltrexone hydrochloride and pentoxifylline in SyrSpend SF PH4 oral suspensions. Eur J Hosp Pharm 2016; 23(6).
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30. Allen LA Jr, Erickson MA 3rd. Stability of alprazolam, chloro-quine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids. Am J Health Syst Pharm 1998; 55(18): 1915–1920.
31. VandenBussche HL, Johnson CE, Fontana EM et al. Stability of levofloxacin in an extemporaneously compounded oral liquid. Am J Health Syst Pharm 1999; 56(22): 2316–2318.
32. Allen LV Jr, Erickson MA 3rd. Stability of labetalol hydro-chloride, metoprolol tartrate, verapamil hydrochloride, and spironolactone with hydrochlorothiazide in extemporaneously compounded oral liquids. Am J Health Syst Pharm 1996; 53(19): 2304–2309.
33. Gupta VD, Maswoswe J. Quantitation of metoprolol tartrate and propranolol hydrochloride in pharmaceutical dosage forms: Sta-bility of metoprolol in aqueous mixture. IJPC 1997; 1(2): 125–127.
34. Peterson GM, Meaney MF, Reid CA et al. Stability of extempo-raneously prepared mixtures of metoprolol and spironolactone. Aust J Hosp Pharm 1989; 19: 344–346.
35. Williams CL, Sanders PL, Laizure SC et al. Stability of ondan-setron hydrochloride in syrups compounded from tablets. Am J Hosp Pharm 1994; 51(6): 806–809.
36. Johnson CE, Cober MP, Hawkins KA et al. Stability of extempo-raneously prepared oxandrolone oral suspensions. Am J Health Syst Pharm 2011; 68(6): 519–521.
Address correspondence to Anderson O. Ferreira. Ortofarma–Quality Control Laboratories, BR 040, n. 39, Empresarial Park Sul. 36120-000, Matias Barbosa – MG. Brazil. E-mail: [email protected]
ESTUDO 25
240International Journal of Pharmaceutical CompoundingVol. 21 No. 3 | May | June | 2017
www.IJPC.com
PEER REVIEWED
FUNDING The original stability study and this up-dated stability study were performed under the sponsorship of Fagron.
UPDATED STABILITY STUDY DATA Stability data for three different active pharmaceutical ingredients (midazolam, oseltamivir phosphate, propranolol hydro-chloride) in SyrSpend SF and minoxidil in Espumil were previously published in the International Journal of Pharmaceutical Compounding.1-4 At the time, there was an urgent need to publish the data. Therefore, studies were published at an intermediate time-point. Since publication of those stud-ies, the sample preparations have reached their final beyond-use date.
Studies were performed at 2°C to 8°C (controlled refrigerated temperature) or at room temperature (RT). Data marked by an * were not previously published.
Studies were performed at 2°C to 8°C (controlled refrigerated temperature). Data marked by an * were not previously published.
T A B L E 2 . SUMMARY OF ANALYTICAL DATA FOR OSELTAMIVIR PHOSPHATE IN SYRSPEND SF.
T I M E O S E L T A M I V I R P H O S P H A T E I N S Y R S P E N D( D A Y S ) S F ( 2 ° C T O 8 ° C )0 100.0
3 100.4
7 103.0
14 103.5
31 100.7
45* 103.4
60* 106.7
90* 102.6
T A B L E 1 . SUMMARY OF ANALYTICAL DATA FOR MIDAZOLAM IN SYRSPEND SF NEUTRAL AND MIDAZOLAM IN SYRSPEND SF CHERRY.
M I D A Z O L A M I N M I D A Z O L A M I N M I D A Z O L A M I N M I D A Z O L A M I NT I M E S Y R S P E N D S F N E U T R A L S Y R S P E N D S F N E U T R A L S Y R S P E N D S F C H E R R Y S Y R S P E N D S F C H E R R Y( D A Y S ) ( 2 ° C T O 8 ° C ) ( R T ) ( 2 ° C T O 8 ° C ) ( R T )
0 100.0 100.0 100.0 100.0
7 99.4 100.3 100.9 99.8
14 97.7 93.8 98.5 93.8
30 99.1 98.9 99.2 99.5
42 99.8 100.1 98.5 99.1
60* 99.1 99.3 99.9 99.6
Updated Stability Data of Midazolam, Oseltamivir Phosphate, and Propranolol Hydrochloride in SyrSpend SF and Minoxidil in Espumil
The authors are affiliated with Fagron BV, The Netherlands, in the following capacities: Eli Dijkers, Global Compounding Knowledge Manager; Valerie Nanhekhan, Global Project Manager Compounding; Astrid Thorissen, Global Quality Innovation Officer.
Eli Dijkers, PharmD, PhDValerie Nanhekhan, MScAstrid Thorissen, PharmD
The analytical methods by which the studies were performed were described in each of the separate manuscripts.1-4 A summary of the results of those previously published manuscripts can be found in Tables 1 through 4. Also included in the Tables are the updated stability data [not published previously], which have been indicated with an asterisk (*). Summarizing, the final study results show that midazolam, osel-tamivir phosphate, and propranolol hydrochloride in SyrSpend SF and minoxidil in Espumil have an even more favorable beyond-use date compared to results that have been previously published.
ESTUDO 24
241International Journal of Pharmaceutical Compounding
Vol. 21 No. 3 | May | June | 2017www.IJPC.com
Peer Reviewed
T A B L E 4 . SUMMARY OF ANALYTICAL DATA FOR MINOXIDIL IN ESPUMIL FOAM BASE.
T I M E( D A Y S ) M I N O X I D I L I N E S P U M I L F O A M B A S E ( R T )
0 100.0
7 100.9
15 98.9
35 99.3
45 100.9
64 98.5
92 101.5
183* 98.2
Studies were performed at room temperature (RT). Data marked by an * were not previously published.
T A B L E 3 . SUMMARY OF ANALYTICAL DATA FOR PROPRANOLOL HYDROCHLORIDE IN SYRSPEND SF.
T I M E P R O P R A N O L O L H Y D R O C H L O R I D E I N ( D A Y S ) S Y R S P E N D S F ( R T )0 100.0
20 100.9
32 102.1
90 97.7
146* 100.4
Studies were performed at room temperature (RT). Data marked by an * were not previously published.
REFERENCES1. Geiger CM, Sorenson B, Whaley PA. Stability of midazolam
in SyrSpend SF and SyrSpend SF Cherry. IJPC 2013; 17(4): 344–346.
2. Voudrie MA II, Allen B. Stability of oseltamivir phosphate in SyrSpend SF, Cherry Syrup, and SyrSpend SF (For Reconstitu-tion). IJPC 2010; 14(1): 82–85.
3. Geiger CM, Voudrie MA II, Sorensen B. Stability of propranolol hydrochloride in SyrSpend SF. IJPC 2012; 16(6): 513–515.
4. Geiger CM, Sorenson B, Whaley PA. Stability of minoxidil in Espumil foam base. IJPC 2013; 17(2): 165–167.
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ESTUDO 24
The formulation was tolerated well without any adverseeects.Conclusion Amphotericin formulated as a mouthwash is anattractive alternative for oropharyngeal candidiasis in pregnantwomen.
No conict onterest
PP-028 STABILITY STUDY OF 1 MG/ML PAEDIATRIC WARFARINORAL SUSPENSION IN SYRSPEND
G Guillois*, L Fetique, I Perovic, PN Boivin, MA Lester.CHU Rennes, Pharmacie, Rennes,France
10.1136/ejhpharm-2017-000640.475
Background Warfarin (Coumadin) is the most commonly usedvitamin K antagonist, a drug with a narrow therapeutic range.One suspension exists but is available for adults only and withspecial authorisation in some countries. The absence of apaediatric formulation means the pharmacist has to produce amagistral preparation.Purpose The aim of this study was to determine the stabilityof warfarin oral suspension in Syrspend in order to establish ashelf-life for the preparation after manufacturing.Material and methods 6 oral suspensions were prepared, usingcoumadine 5 mg tablets and Syrspend SF-PH4, packaged inamber vials, to protect from light, and stored at room temper-ature (3 batches) or at +2 °C and +8 °C (3 batches). Severalparameters were studied on dierent days (0, 1, 3, 6, 10, 14,23 and 44 (n=7)): physical stability (visual inspection, osmo-lality measurements) and chemical stability (pH measurement,concentrations were analysed by liquid chromatography-highresolution-UV detection (HPLC-UV) with an AT3 column, 5mm, 4.6×150 mm). Degradation products were revealed withacid and alcalin hydrolysis (degradation over 1 hour and 16hours). Microbiological stability was tested using colony countson media platings.Results After 44 days, no variation in pH or osmolality wasobserved. Once again, the microbiological cultures were nega-tive. Visual inspection showed viscosity increased after 10days. Also, concentrations were the same until 44 days andno degradation products were observed in the 6 batches.Conclusion This study showed that 1 mg/mL warfarin oralsuspension in Syrspend at room temperature, was stable for atleast 44 days, so we can x the shelf-life at 44 days. A studyis in progress to determine stability at 60 days.
No conict onterest
PP-029 STABILITY OF FROZEN 1% VORICONAZOLE EYE DROPSIN GLASS AND IN INNOVATIVE CONTAINERS
1M Roche*, 1D Lannoy,1F Bourdon,1C D’Horne, 1C Berneron,2C Danel, 2MJGarcia Fernandez,1N Simon, 1P Odou. 1Centre Hospitalier Régional Universitaire,Pharmacie, Lille, France; 2Univ Lille, EA 7365-GRITA-Groupe de Recherche sur les formesInjectables et les Technologies Associées, Lille, France
10.1136/ejhpharm-2017-000640.476
Background Voriconazole is an antifungal agent eective onmost keratitis causative fungi with an excellent transcornealpenetration. Voriconazole eyedrops (VED) are unavailable inEurope and are usually compounded in hospital pharmacies.New eyedrop containers emerged on the hospital market (eg,
high density polyethylene bottles available in trays (CAT)) forwhich few stability data are available, or Novelia bottles whichinnovative insert maintains sterility after opening (no stabilitydata available).Purpose To collect data on VED stability in 3 dierent con-tainers in order to switch if necessary: amber glass, HPDEbottles and Novelia bottles stored frozen ( 20°C) and refri-gerated once thawed.Material and methods 3 batches of 1% VED (10 mL) wereaseptically compounded under a laminar ow hood frominjectable Vfend (Pzer) and sterile water for injection(Baxter), and stored at 20°C in amber glass (n=32; Gravis),HDPE (n=32; CAT) or Novelia (n=31; Nemera) bottles. Thestability study was done according to the GERPAC-SFPCstability study guidelines. At each time point, the visual aspectwas checked and voriconazole concentration (using a stabilityindicating HPLC-UV-diode array detector method), pH andosmolality were measured. Non-visible particle counts (by lightobscuration particle count test), sterility and absence of race-misation (impurity D –(2S,3R)-voriconazole –detected by chiralHPLC) were assessed at the beginning and end of the study.Parameters were measured: when stored for 3 months at
20°C; then thawed, after 15 days at +2 to +8 °C, withcomparison of two thawing methods (+2 to +8 °C for 6hours or 25 °C for 2 hours). Statistical analysis were per-formed using non-parametric tests (a < 5%) to comparecontainers.Results During storage, the concentration was between 95.2±1.4% and 103.6±1.3% of the initial concentration (Co)(NS); 15 days after thawing, the concentration was between97.1±1.6% and 98.6±0.8% of Co (NS). pH remained stable(NS). Osmolality was slightly higher in glass than in plasticcontainers (p=0.003). Sterility was preserved. Count of $ 10mm particles remained <80/mL. Degradation product areasincreased by a maximum of 1.45 and remained unquantiable.No impact of the thawing method was evidenced. Impurity Dwas not detected.Conclusion VED remained stable for up to 3 months at
20°C and for 15 days after thawing, with no notable dier-ence between the three containers, allowing us to choose themost suitable.
No conict onterest
PP-030 THE INFLUENCE OF THE DEAD VOLUME OF THE CLOSEDSYSTEM (SPIKE–CONNECTOR–SYRINGE) ON THERECONSTITUTION OF INJECTABLE DRUGS
1A Cheikh*,2Y Rhali,3H Mefetah,4I Sbai,5B Mojemmi,5M Draoui,5M Bouatia.1AbulcasisUniversity-Faculty of Pharmacy, Rabat, Morocco; 2Mohammed V University, GalenicPharmacy, Rabat, Morocco; 3Paediatrics Hospital, Pharmacy, Rabat, Morocco; 4Hassan IIUniversity, Analytical Chemistry, Casablanca, Morocco; 5Mohammed V University, AnalyticalChemistry, Rabat, Morocco
10.1136/ejhpharm-2017-000640.477
Background The closed system is designed, rst, to protectpatients and clinicians against exposure to hazardous drugsduring the preparation of cytotoxic drugs and secondly, toprotect the drugs against any exposure to external microbio-logical and physical contaminants.Purpose The aim of this study was to determine the dead vol-ume of spike–connector–syringe system used for the
Abstracts
A214 Eur J Hosp Pharm2017;24(Suppl 1):A1–A288
ESTUDO 23
Compounded
formulation
Lidollanten
1%
2 3 4 5
Components - Llanten
leaves
- Lidocaine
- Sodium
borate
- Potassium
chlorate
- Pink
honey
extract
- Syrup
- Chlorhexidine 5%
-
Methylprednisolone
- Mepivacaine 2%
- Sodium
bicarbonate
- Sodium chloride
- Sterile water
-
Mepivacaine
2%
- Aluminium
hydroxide
- Magnesium
hydroxide
- Sorbitol
70%
- Guar gum
1%
- Nipagin
- Citric acid
- Peppermint
oil- Sterile
water
- Gentamicine
-
Hydrocortisone
- Nystatin
- Lidocaine
- Sodium
bicarbonate
- Cremophor
RH 40
- Xanthan
gum
- Sorbitol 70%
- Peppermint
oil- Sterile
water
- Sucralfate
- Lidocaine
-
Cremophor
RH 40
- Sorbitol
70%-
Sterile
water
Complexity High Low High Medium Medium
Preparation
time
5 hours 30 min 30 min 2 hours 30 min
Storage Fridge Ambient
temperature
Ambient
temperature
Fridge Fridge
Expiry time
(days)
30 days 30 days 60 days 15 days 15 days
Cost (100
mL) (C¼ )
1.55 1.36 4.27 6.51 2.53
Conclusion According to our data, the least expensive formu-lation (from the point of view of acquisition cost) was No 2,which also happened to be that requiring the least processingtime; it can be stored at room temperature, with an expirytime of 1 month. For these reasons, we believe it is the mostecient. Future studies will determine whether there are dif-ferences in eectiveness between the dierent formulations.
REFERENCES AND/OR ACKNOWLEDGEMENTS1. Lalla RV, Bowen J, Barasch A,et al. MASCC/ISOO clinical practice guidelines for
the management of mucositis secondary to cancer therapy.Cancer2014;120:1453–61.
No conict onterest
PP-054 STABILITY STUDY OF 100 MG/ML PAEDIATRICPYRAZINAMIDE ORAL SUSPENSION IN SYRSPEND
1PN Boivin*,2C Geroy,3C Tron,1C Luans,1MA Lester.1CHU Rennes, Pharmacy, Rennes,France; 2CH Vitre, Pharmacy, Vitre, France; 3CHU Rennes, Pharmacology, Rennes, France
10.1136/ejhpharm-2017-000640.501
Background Pyrazinamide is an antituberculosis agent used inadjunctive treatment of tuberculosis infection in combinationwith other antituberculosis agents, such as isoniazid, rifampicinand ethambutol. The tablet form is unsuitable for paediatricpatients and the pharmacist needs to produce an oral suspen-sion. Data on pyrazinamide stability in an oral suspension arescarce and were produced several decades ago. Thus newstability information is needed.Purpose The aim of this study was to determine the stabilityof 100 mg/mL pyrazinamide oral suspension in commercialcompounding excipient Syrspend SF PH4 (FAGRON).
Material and methods 3 batches of oral suspensions were pre-pared, using pyrazinamide tablets and Syrspend SF-PH4, pack-aged in amber vials to protect from light, and stored at roomtemperature. Several parameters were studied on days 0, 3, 5,8, 15, 30, 60 and 90 (n=3): physical stability (visual inspec-tion, osmolality measurements) and chemical stability (pHmeasurement, residual concentrations of pyrazinamide, degra-dation products identication). Pyrazinamide concentrationswere determined using a validated analytical method based onhigh performance liquid chromatography with UV detection at280 nm. Chromatographic separation of the analytes was per-formed with a WATERS C18 ATLANTIS T3 column(150×4.6 mm, 5 mm). The mobile phase was composed ofacetonitrile/phosphate buer at pH 3 (40:60 v/v) and owrate was adjusted at 1 mL/min. Data were acquired and proc-essed with EMPOWER Software. Microbiological stability waschecked according to the test using colony counts on mediaplatings.Results No change in physical properties was observed duringthe study period. Drug concentration remained within ±5%of nominal values over 90 days and no degradation productsappeared on the chromatograms. Microbiological media platesremained free from any bacterial or fungal colony.Conclusion This study showed that 100 mg/mL pyrazinamideoral suspension in Syrspend SF PH4 was stable for at least 90days at room temperature, so we determined a shelife of90 days for this preparation. Further study, using a mass spec-trometer method, will be conducted to conrm this shelf-life.
REFERENCES AND/OR ACKNOWLEDGEMENTSMethodological guidelines for stability studies of hospital pharmaceutical preparations.ICH Guidelines
.
No conict onterest
PP-055 CONGENITAL CHAGAS DISEASE. A CASE REPORT1C Marti-Gil, 1I Martin-Niño,1L Recuero-Galve,2E Cueto-Calvo,1J Sanchez-Gundin,1D Barreda-Hernandez*.1Virgen de la Luz Hospital, Pharmacy, Cuenca, Spain; 2Virgen de laLuz Hospital, Paediatrics, Cuenca, Spain
10.1136/ejhpharm-2017-000640.502
Background Congenital infection with Trypanosoma cruzioccurs in an average of 5% of children born of mothers withchronic infection.Purpose To describe a case report of a newborn with Chagasdisease (CD) acquired by vertical transmission in a non=en-demic zone.Material and methods Medical history review and literatureresearch.Results The case was a 10-day-old girl, born after spontaneousgestation of normal evolution and eutocic birth (Apgar test 8/10, 3100 g, 49 cm), whose mother (40-year-old South-Ameri-can) had negative serologies and SBAgalactiae test, immunerubella and toxoplasma, but had IgG+ for CD. After the new-born had positive PCR for T cruzi and IgG+ antibodies toCD, the paediatrics service consulted the pharmacy serviceregarding the possibility of a pharmaceutical compoundingpreparation (PCP) for paediatric dosing of benznidazole. Thedosage regimen, according to WHO criteria, was 5 –10 mg/kg/day of benznidazole for 60 days, divided into two daily doses.4 PCP were found from available benznidazole tablets(Abarax): 2 oral suspensions (PCP1, PCP2), capsules and
Abstracts
Eur J Hosp Pharm2017;24(Suppl 1):A1–A288 A225
ESTUDO 22
Compatibility of proton pump inhibitorsin a preservative-free suspending vehicleHudson C Polonini,1 Sharlene L Silva,1 Shirley Loures,1 Rachel Almy,2
Antoine Balland,2 Marcos Antônio F Brandão,1 Anderson O Ferreira1
Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/ejhpharm-2016-001034).1Ortofarma—Quality ControlLaboratories, Matias Barbosa,MG, Brazil2Eurofins—Pharma QualityControl, Sainte Croix en Plaine,France
Correspondence toAnderson Ferreira, OrtofarmaLaboratório de Controle daQualidade, Empresarial ParkSul, n. 39, Matias Barbosa,MG 36120-000, Brazil;[email protected]
Received 28 June 2016Revised 3 November 2016Accepted 8 November 2016
EAHP Statement 3:Production andCompounding
To cite: Polonini HC,Silva SL, Loures S, et al. EurJ Hosp Pharm PublishedOnline First: [please includeDay Month Year]doi:10.1136/ejhpharm-2016-001034
ABSTRACTObjectives To evaluate the microbiological andphysicochemical compatibility of commonly used protonpump inhibitors (PPIs) esomeprazole, lansoprazole,omeprazole and pantoprazole compounded at a singleconcentration using SyrSpend SF Alka and stored atrefrigerated temperatures (omeprazole was also stored atroom temperature because it has the mostwidespread use).Methods Compatibility was assessed by measuring theper cent recovery at varying time points throughout a90-day period. Quantification of the APIs was performedby a validated high performance liquid chromatography(HPLC-UV) method. This same assay was also used todetermine the dosage content uniformity of thesuspensions. Microbiological stability (‘test in use’) wasassessed during 60 days and total aerobic microbialcount (TAMC), total combined yeasts and moulds count(TYMC), detection of Escherichia coli and pHdetermination were performed. Antimicrobialeffectiveness testing was determined following EuropeanPharmacopoeia guidelines.Results Beyond-use dates of maximum 60 days foromeprazole (5 mg/mL), pantoprazole (3 mg/mL) andesomeprazole (3 mg/mL) were established. Allsuspensions that met the physicochemical criteria forstability also met the content uniformity criteria. Thesuspensions showed no antimicrobial efficiency againstbacteria, yeasts and moulds as SyrSpend SF Alka is anunpreserved vehicle, but the ‘test in use’ showed thatthe suspensions can remain microbiologically stable forup to 60 days.Conclusions SyrSpend SF Alka can be used tocompound palatable (taste-masking properties)preservative-free oral suspensions with almost allcommonly used PPIs.
INTRODUCTIONProton pump inhibitors (PPIs) esomeprazole, lanso-prazole, omeprazole, pantoprazole and rabeprazole,known to be highly effective for treatment ofgastro-oesophageal reflux disease, ulcers and gastro-intestinal bleeding,1 are also commonly used forpaediatric patients2–5 and patients with enteralfeeding tubes.1 6–8 A recent study found the inci-dence of gastro-oesophageal reflux disease to behighest among young children,9 and stress ulcer-ation has been reported to be present in 70–100%of all critically ill patients.10
Paediatric patients are often unable to swallowPPIs in a solid dosage form (tablets or capsules)and critically ill patients frequently rely on enteralnutrition. Intravenous administration of PPIs is
preferably avoided due to possible complications,cost restrictions and patient discomfort.1
Therefore, PPIs (crushed or as raw powder) areusually administered in the form of an oral suspen-sion for these patient groups.Preparation of PPI suspensions from the (intact)
granules out of commercial capsules or granulatesfor suspension may be complicated by the instabil-ity of the medication at acidic pH and by the time-consuming compounding procedures.1 These PPIsuspensions also figure among the formulationsthat most frequently obstruct enteral feedingtubes.11 Therefore, pharmacists frequently turn toextemporaneously preparing liquid formulationsfor the PPIs, demonstrated by the fact that omepra-zole and lansoprazole are reported to be the mostcommonly compounded formulations in the hos-pital setting.12 13
Traditionally, simplified 8.4% sodium bicarbon-ate suspension has been used for compoundingomeprazole and lansoprazole oral liquids becauseits high pH protects the PPI against degradation.6 14
However, preparing these sodium bicarbonate for-mulations can be time-consuming,1 can be trouble-some due to their high sodium content15 and doesnot result in a palatable formulation, which isimportant for compliance in paediatric therapy.16
In this sense, use of ready-to-use suspendingvehicles can be of great value to the healthcareteam. One of these vehicles is SyrSpend SF Alka, astarch-based powder that can be reconstituted tomake a taste-masking oral liquid vehicle whosecomposition is detailed in table 1. It includescalcium carbonate to adjust the pH to >7 toprevent PPIs from degradation.17 18 It does notcontain traditionally used suspension excipientsthat can have toxicological effects, induce allergicreactions or cause irritation, such as sugar,19 20
ethanol,21 22 propylene glycol,23 24 sorbitol,25 26
benzyl alcohol27–29 and common food aller-gens.30 31 It is also a preservative-free vehicle tofacilitate administration to neonates.32 Although itseems to be an adequate vehicle to be used incommon pharmaceutical practice, its compatibilitywith PPIs has not yet been demonstrated, exceptfor omeprazole at 2 mg/mL.18
Within this context, this study was designed toevaluate the compatibility of commonly used PPIs(esomeprazole, lansoprazole, omeprazole and pan-toprazole) compounded with SyrSpend SF Alka inorder to determine their beyond-use dates. For thatpurpose, we evaluated the microbiological andphysicochemical stabilities as well as the contentuniformity of the suspensions stored at refrigeratedtemperature (omeprazole was also stored at room
Polonini HC, et al. Eur J Hosp Pharm 2016;0:1–7. doi:10.1136/ejhpharm-2016-001034 1
Original article
group.bmj.com on November 26, 2016 - Published by http://ejhp.bmj.com/Downloaded from ESTUDO 21
temperature because it has the most widespread use).Rabeprazole was not included in this study since the safety andefficacy of a rabeprazole suspension has never been demon-strated in the literature and rabeprazole is far less frequently pre-scribed than the other PPIs.33 To the best of the authors’knowledge, there is no previous study in the literature dealingwith the individual stability of these four PPIs in the referredconcentrations, compounded in a single taste-masking, alkaline,oral liquid vehicle.
MATERIALS AND METHODSReagents, reference standards and materialsAll PPI raw materials and SyrSpend SF Alka (powder for recon-stitution) were obtained from Fagron (batch number12F19-U01-005190; St Paul, Minnesota, USA) and HPLC-gradereagents (Carvalhaes, Spain) were used. Ultrapure waterobtained with an AquaMax-Ultra 370 Series (Young Lin,Anyang, Korea; 18.2 MΩ cm resistivity at 25°C and totalorganic carbon content of <10 ppb) was also used throughoutthe experiments. The reference standards were work standardsobtained using primary USA Pharmacopeia (USP, Rockville,Maryland, USA) reference materials. All of the mobile phasesand receptor media were filtered through a 0.45 μm filter mem-brane (RC-45/15 MS; Chromafil, Düren, Germany) anddegassed using an ultrasonic apparatus (model 1600A, Unique,Indaiatuba, Brazil) for 30 min immediately before use. All volu-metric glassware and analytical balances were previouslycalibrated.
Preparation of PPI suspension samplesThe PPI suspensions were prepared using the following generalprotocol: (1) the required quantity of each ingredient for thetotal amount to be prepared was calculated; (2) each ingredientwas accurately weighed; (3) the PPI was placed in a mortar andtriturated until a fine powder was obtained; (4) the trituratedPPI was added to the SyrSpend SF Alka and mixed; (5) about80 mL of purified water was added, mixing thoroughly; (6) suf-ficient water was added to bring the volume to 100 mL andthen mixed well; (7) the final product was packaged in low-actinic plastic prescription bottles and labelled.
For lansoprazole, 8.5% pellets were used. The pellets wereplaced in a glass mortar and 5 mL absolute ethanol was added.The pellets were allowed to rest for 5 min to soften the coating,and then they were triturated to form a fine powder. Theethanol was left to evaporate completely. After that, the proto-col continued from step (4) above.
The final concentrations in the suspensions were: esomepra-zole magnesium trihydrate 3.0 mg/mL, lansoprazole 3.0 mg/mL,omeprazole 5.0 mg/mL and pantoprazole (as sodium sequihy-drate salt) 3.0 mg/mL. The suspensions were immediatelyassayed at T=0. The omeprazole suspensions were separatedinto two different bottles; one sample was stored at controlledrefrigeration (2–8°C) and the other at controlled room
temperature (20–25°C) during the study, as these are the officialtemperature ranges for storage according to the USP (tempera-ture and humidity were checked in real time throughout theexperiment using a calibrated digital thermo-hygrometer;Incoterm, Brazil). The other suspensions were stored only refri-gerated, which is the recommended storage condition for anypreservative-free suspension.34 All samples were protected fromlight.
Chromatographic conditionsHPLC analyses were performed on a qualified and calibratedchromatography system (Young Lin) comprising a quaternarygradient pump (YL 9110), a photodiode array (PDA) detector(YL 9160), a 96-vial programmable autosampler (YL 9150), acolumn oven compartment (YL 9130), a variable sample loopup to 200 μL and a software controller (Clarity).
The chromatographic determinations were based upon USPmethods for PPIs or their final products, with modificationswhen necessary. The standards were diluted in the mobilephase. Samples were prepared as follows: (1) appropriate ali-quots of each suspension were pipetted and transferred to a suit-able volumetric flask to achieve the work concentrationsdescribed below; (2) two-thirds of the flask capacity were filledwith mobile phase and then agitated by sonication for 20 min;(3) mobile phase was added to the flask volume; (4) this solu-tion was filtered in filter paper and then in cellulose membranefilters (0.45 mm) and transferred to HPLC vials for automaticinjection. For all analyses, the columns were connected with apre-column with the same packing (4.0 × 3.0 mm; 5 μm) fromthe same vendor and the injection volume was 20 μL.
For esomeprazole magnesium trihydrate (work concentration50 μg/mL), the mobile phase consisted of a mixture of aceto-nitrile and Solution A (0.725 g monobasic sodium phosphateand 4.472 g dibasic sodium phosphate in 1000 mL; a 250 mLof this solution diluted to 1000 mL with water, with pHadjusted to 7.6) (35:65) at a flow rate 1.0 mL/min. Separationwas achieved in a L7, 4.0 mm×15 cm column (Kromasil) at 25°C; detection was performed at 280 nm.
For lansoprazole (work concentration 100 μg/mL), the mobilephase consisted of a mixture of acetronitrile, water and triethy-lamine (40:60:1), with pH adjusted to 10 with phosphoric acid,at a flow rate of 1.0 mL/min. Separation was achieved in a L1,4.6 mm×25 cm column (Agilent) at 25°C; detection was per-formed at 280 nm.
For omeprazole (work concentration 50 μg/mL), the mobilephase consisted of a mixture of acetronitrile and 50 mM sodiumphosphate pH 8.5 solution (25:75) at a flow rate of 1.0 mL/min. Separation was achieved in a L1, 3.9 mm×15 cm column(Agilent) at 35°C; detection was performed at 302 nm.
For pantoprazole sodium (work concentration 50 μg/mL inwater), the mobile phase consisted of a mixture of acetonitrileand 50 mM dibasic sodium phosphate (4:6), with pH adjustedto 7.0, at a flow rate of 2.0 mL/min. Separation was achieved ina L1, 4.6 mm×25 cm column (Phenomenex) at 25°C; detectionwas performed at 280 nm.
Validation of the HPLC method and stability-indicatingcharacteristics (extended specificity)The methods and their acceptance criteria were established onthe basis of the USP34 and ICH International Conference onHarmonization (ICH) guidelines.35 Specificity, precision, accur-acy, linearity and limits of detection and quantification weredetermined following a protocol described in a previous study.36
In this protocol, during specificity determination a stressing test
Table 1 SyrSpend SF Alka composition
Ingredient Function Safety references
Modified food starch Suspending agent FDA 21CFR 172.89259
Calcium carbonate pH adjustment FDA GRAS listed60
Sucralose Sweetener FDA, EC Scientific Committee onFood61 62
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was also conducted (acid, alkaline, ultraviolet light, heat andoxidising stresses).
Physical and chemical stabilitiesThe PPI samples were assayed by HPLC at predetermined timepoints to verify the compatibility of the PPI in SyrSpend SFAlka. The samples were shaken manually for 1 min to simulatepatient shaking during dosing. Occurrence of physical phenom-ena (precipitation, turbidity, macroscopically visible crystalgrowth, odour generation, phase separation, flocculation orcaking) was checked. A detailed protocol is described byFerreira et al.36 Samples were withdrawn at 0 (baseline), 7, 14,30, 60 and 90 days (T=0, 7, 14, 30, 60 or 90) and assayed sixtimes at each time point.
Uniformity of dosage units/content uniformityTo ensure dosing accuracy of the suspensions over time, the uni-formity of dosage units from the suspensions was determined byapplying an adaptation of the British and EuropeanPharmacopoeias content uniformity for liquid dosage forms cal-culation.37 38 Smeets et al have provided a smaller set-up (n=6instead of n=10) with the same statistical confidence to calcu-late the acceptance value (AV) for small-scale preparations asused in compounding pharmacies.39
Microbiological stabilityA ‘test in use’ was conducted to evaluate if normal utilisation ofthe unpreserved PPI suspensions would result in microbiologicalcontamination.40 SyrSpend SF Alka was prepared with 100 mLwater and stored at refrigerated temperature (2–8°C) for60 days. The bottle was opened every day for a few seconds atregular room temperature (15–25°C) with no product with-drawal. At T=0, total aerobic microbial count (TAMC), totalcombined yeasts and moulds count (TYMC), detection ofEscherichia coli and pH determination were performed. AtT=15, T=30 and T=60, TAMC, TYMC and pH determinationwere repeated.
Antimicrobial effectiveness testing was also performed follow-ing European Pharmacopoeia 2015 guidelines.38 Briefly, a seriesof containers of the product to be examined (SyrSpend SF Alka)was inoculated, each with a suspension of one of the test organ-isms to give an inoculum of 105–106 micro-organisms per mLof the preparation. The volume of the suspension of inoculumdid not exceed 1% of the volume of the product. The inocu-lated product was maintained at 20–25°C and protected fromlight. A suitable sample from each container was removed at 0hours and at appropriate intervals (2, 7, 14 and 28 days) todetermine the number of viable micro-organisms by plate count.The results were given as the log10 reduction in the number ofviable micro-organisms against the value obtained for theinoculum.
RESULTS AND DISCUSSIONValidation and forced degradation testAll the results of the validation studies of all methods of ana-lyses (table 2) met the respective acceptance criteria, proving themethods to be adequate for the study.
The results of the stability-indicating studies are summarisedin online supplementary table S1. The decomposition profile ofthe PPIs was notably similar (see online supplementary figure S1for chromatograms and additional information on typical HPLCresponses for the PPIs). Acidic stress led to total destruction ofthe PPIs, and oxidising stress led to the same result for lansopra-zole and esomeprazole magnesium trihydrate. UV exposure led
Table2
Summaryof
validationof
HPLC
methods
Line
arity
Specificity
Precision
Accuracy
PPI
Rang
e(μg/mL)
Ana
lytic
alcurve
R2ANOVA
sign
ificance
ofregression
(F)
ANOVA
lack
offit
(F)
LOD
(μg/mL)
LOQ
(μg/mL)
Discrep
ancy
(%)
Repe
atab
ility
(CV,
%)
Interm
ediate
precision(CV,
%)
recovery
(%)
Esom
eprazolemagnesiu
mtrihydrate
37.07–65.13
y=25.38×−77.04
0.9956
2926.96
2.73
2.01
6.71
|1.33|
1.27
1.27
99.45
Lansoprazole
70.07–130.13
y=3.57
×−12.47
0.9967
3966.78
3.57
0.02
0.06
|0.11|
0.53
0.59
100.37
Omeprazole
35.70–66.30
y=37.85×+22.42
0.9974
5084.23
0.05
0.04
0.14
|1.75|
0.55
0.98
100.05
Pantoprazolesodium
10.50–19.50
y=48.10−27.11
0.9960
3213.12
3.32
1.91
6.35
|0.79|
0.36
1.17
99.18
Acceptance
criteria
were:R2
>0.99,F
(significance
ofregressio
n)>4.67,F
(lack
offit)<
3.71,d
iscrepancy<2%
,repeatabilityandinterm
ediate
precision
<5%
,and
recovery=100%
±2%
.Allanalyticalranges
(μg/mL)wereadequate
toquantifythePPIsin
theconcentra
tions
used
inthesuspensio
ns(mg/mL).
CV,coefficientof
variation;
LOD,
limitof
detection;
LOQ,limitof
quantification;
PPI,proton
pumpinhibitor.
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to fewer discrepancies between the various PPIs with or withoutexposure to stress conditions, but it also achieved up to 22% ofthe difference among the analytical peaks. Only heat exposuredid not lead to degradation (except for lansoprazole), confirm-ing the susceptibility of these molecules to degradation, and thatthe method is stability-indicating in being able to detect thedecomposition of the PPIs.
Physicochemical stability and content uniformityChemical stability results of each suspension are depicted infigure 1, which graphically represents the stability of the PPIs inSyrSpend SF Alka in terms of absolute nominal concentration.Detailed results expressed as the relative per cent of recovery(initial sampling time=100%) are shown in onlinesupplementary table S2. For the suspensions to be consideredstable, the relative per cent of recovery should lie within 90–110%, according to the USP, British Pharmacopoeia andEuropean Pharmacopoeia.34 37 38 At each sampling time the sus-pensions were visually inspected to evaluate their homogeneity/physical stability. Throughout the whole study, no precipitation,turbidity, macroscopically visible crystal growth, odour gener-ation, phase separation, flocculation or caking was observed. Acolour change was observed only for the omeprazole suspensionand will be discussed below.
Esomeprazole magnesium trihydrate was chemically and phys-ically stable for up to 90 days when stored at refrigerated tem-perature. Few studies are available dealing with thecompatibility of esomeprazole in liquid formulations. Kupiecet al41 found esomeprazole 0.4 and 0.8 mg/mL as the sodiumsalt in infusion solutions (5% dextrose, 0.9% sodium chloride,and lactated Ringer’s injection) to be chemically and physically
stable for at least 2 days at room temperature and 5 days underrefrigeration. SyrSpend SF Alka is thus a substantially morestable vehicle for this PPI in comparison to this previous work.
Lansoprazole was found not to be stable for the minimumperiod studied (ie, 7 days). This is not in accordance with thestudy by DiGiacinto et al42 who evaluated the stability of lanso-prazole 3 mg/mL suspension prepared from capsules and mixedwith sodium bicarbonate 8.4% injection. At room temperature10% lansoprazole loss occurred in 8 hours; while refrigeratedthe sample showed 4% loss in 14 days and 12% loss after21 days. Melkoumov et al43 also evaluated a liquid formulationof lansoprazole and found a maximum stability of 7 days whenstored at 4.5–5.5°C, but an extemporaneous formulation
Figure 1 Plot of proton pump inhibitors (PPIs) in SyrSpend SF Alka throughout the compatibility study (dashed lines represent the lower and upperlimits corresponding to 90% and 110% of labelled concentration). Values represent mean±SD (n=6). (A) Esomeprazole magnesium trihydrate3.0 mg/mL. (B) Lansoprazole 3.0 mg/mL. (C) Omeprazole 5.0 mg/mL. (D) Pantoprazole sodium 3.0 mg/mL.
Figure 2 Indicative colour chart of omeprazole stability in SyrSpendSF Alka. Section 1 represents acceptable colour changes while Section2 represents unacceptable colouring of the suspension.
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consisting of lansoprazole microgranules in Ora-Blend main-tained acceptable quality attributes when stored for only 3 daysat 4.5–5.5°C. However, in both studies the sample preparationswere significantly different from our work as they did not usecrushed pellets for sample preparation; we used this form ofraw material as it is more representative of common compound-ing practice.
As for omeprazole, the suspensions remained stable for up to30 days at room temperature and at least 90 days refrigerated.This is in line with the findings of others for the stability ofomeprazole suspensions. Whaley et al44 studied omeprazole inthe same vehicle but with a 2 mg/mL concentration and foundthat the product was stable for 92 days when stored under refri-gerated conditions (2–8°C). This confirms that SyrSpend SFAlka could be a viable alternative to commercially available cap-sules when that dosage form is found to be inappropriate.Quercia et al45 evaluated omeprazole 8.4% sodium bicarbonatemixtures. In this study omeprazole was stable for 30 days at−20°C and 4°C while the samples stored at room temperaturehad 8% loss in 14 days and 14% loss in 18 days. Phillips et al46
evaluated a 2 mg/mL suspension compounded with 8.4%sodium bicarbonate. Refrigerated samples remained stable whenstored for 24 weeks but room temperature samples had a 13%loss in 2 weeks and 25% in 4 weeks. Johnson et al47 evaluatedthe stability of a reconstituted commercial omeprazole–sodiumbicarbonate 2 mg/mL oral suspension stored at 3–5°C. A loss ofonly 2% in concentration throughout the 45 days of the studywas observed. It is also important to note that the addition ofbicarbonate to omeprazole suspensions can generate an
unpleasant taste, which could possibly lead to a low compliancerate for paediatric patients.48 49
Although the omeprazole suspension in SyrSpend SF Alkastored at refrigerated temperature showed no chemical degrad-ation of omeprazole, a slight grey/purple discolourationappeared and became more apparent with time. This discolour-ation was largely prevented at 2–8°C but, when left at roomtemperature for prolonged periods, the suspensions becamedark purple. There are reports in the literature that confirm thatthe decomposition of omeprazole can be macroscopically seento go through dark yellow, orange, purple, brown or black dis-colouration in aqueous media.41 50–54 The discolouration ofomeprazole has been reported to be not harmful.55 Based uponour results, figure 2 was designed and presents an indicativecolour chart of omeprazole in SyrSpend SF Alka. The colourrange presented in Section 1 shows acceptable colours of theomeprazole suspension while Section 2 shows the colour of sus-pensions where unacceptable omeprazole decomposition hasoccurred (ie, <90% omeprazole left).
Pantoprazole was also chemically and physically stable for atleast 90 days at refrigerated temperature. This was superior tothe findings of Dentinger et al56 who studied pantoprazole2 mg/mL oral suspensions extemporaneously prepared fromtablets, sterile water and sodium bicarbonate.
Finally, all suspensions that met the physicochemical criteriafor stability also met the content uniformity criteria (AV<15)37 38 (figure 3). In fact, the AV found in this study at alltime points and storage temperatures is similar to—if not betterthan—those found in commercial solid dosage forms whereKatori et al57 report an AV of ≥3 for 279 evaluated lots of plaintablets and 168 lots of film-coated tablets sold in Japan. Thisindicates homogeneity and good resuspendability of the suspen-sion and confirms that dose accuracy can be obtained withSyrSpend SF Alka suspensions, especially when used in combin-ation with an oral syringe.58
Microbiological stabilityIn addition to the physicochemical stability tests, antimicrobialeffectiveness testing was performed on SyrSpend SF Alka afterreconstitution. As expected, this preservative-free formulationshowed no antimicrobial efficiency against bacteria, yeasts andmoulds (table 3). However, when patient use was simulatedduring the ‘test in use’, the reconstituted suspension remainedmicrobiologically stable to pH for up to 60 days (table 4).Intermediates and final microbial results complied with the
Figure 3 Results of content uniformity test. Acceptance value (AV)must be <15.
Table 3 Antimicrobial effectiveness testing of reconstituted SyrSpend SF Alka
Test bacterialsuspension(CFU/mL)
SyrSpend SF Alka reconstituted with 200 mL water
D0 D2 D7 D14 D28
GermsResult(log red)
Result(CFU/mL)
Result(log red)
Result(CFU/mL)
Result(log red)
Result(CFU/mL)
Result(log red)
Result(CFU/mL)
Result(log red)
Result(CFU/mL)
Staphylococcus aureusATCC 6538
4.2×105 NR 3.8×105 <1.2 >2.5104 <0.2 >2.5×105 <0.2 >2.5×105 <0.2 >2.5×105
Pseudomonasaeruginosa ATCC 9027
5.4×105 NR 2.8×105 <1.3 >2.5×104 <0.3 >2.5×105 <0.3 >2.5×105 <0.3 >2.5×105
Candida albicans ATCC10231
1.0×104 NR 1.5×105 NR NR NR NR 0 >5×104 0 >5×104
Aspergillus brasiliensisATCC 16404
1.1×105 NR 1.0×105 NR NR NR NR 0 >5×104 0 >5×104
Acceptance criteria: Bacteria (D2=2, D7=3, D14=−, D28=no increase); Fungi (D2=−, D7=−, D14=2, D28=no increase).CFU, colony-forming unit; D, day; log red, log reduction; NR, not required.
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specifications for the suspension and the pH values were similarfor the suspension at every time point. This test shows that theproduct is physically and microbiologically stable when preparedand stored at a temperature of 2–8°C. When not actively con-taminated and exposed to opening once every day at room tem-perature, the suspension also remains stable. These resultsdemonstrate that regular use of these suspensions by patients isnot expected to generate microbial contamination or a fluctu-ation in the pH.
CONCLUSIONSSyrSpend SF Alka showed different compatibility profiles forthe PPIs studied and, based on the physicochemical and micro-biological results, beyond-use dates of a maximum of 60 daysfor omeprazole (5 mg/mL), pantoprazole (3 mg/mL) andesomeprazole (3 mg/mL) have been determined. These resultsdemonstrate that it is appropriate to use this suspendingvehicle for PPIs in hospital and compounding centresworldwide.
What this paper adds
What is already known on this subject Oral liquids are appropriate alternatives to solid dosage
forms, particularly for elderly and paediatric patients. Ready-to-use suspending vehicles are a useful resource for
pharmacists as they constitute a safe, time-saving and betterstudied option.
The stability of omeprazole at 2 mg/mL in SyrSpend SF Alkahas already been shown, but it is important to determinethe compatibility of each proton pump inhibitor (PPI) withthe suspending vehicle as stability is a result of individualbehaviour within the vehicle.
What this study adds We focused on four PPIs at refrigerated temperatures:
esomeprazole (3 mg/mL), lansoprazole (3 mg/L), omeprazole(5 mg/mL, also at room temperature) and pantoprazole(3 mg/mL).
For the first time, physicochemical stability throughout a60-day period was determined for these PPIs in SyrSpend SFAlka.
Also for the first time, microbiological stability wasdetermined for these suspensions and antimicrobialeffectiveness testing was performed for the vehicle.
Beyond-use dates of 60 days for omeprazole (5 mg/mL),pantoprazole (3 mg/mL) and esomeprazole (3 mg/mL) wereestablished.
Contributors HCP created the protocol, supervised the work and wrote the paper.SLS, SL, RA and AB performed the experiments and helped to write the manuscript.MAFB and AOF coordinated the entire work and revised/approved the final version.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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Table 4 Microbiological ‘test in use’ of reconstituted SyrSpend SF Alka
Results
Parameter D0 D15 D30 D60
Total aerobic microbial count (TAMC) <10 CFU/mL <10 CFU/ mL <10 CFU/ mL <10 CFU/ mLTotal combined yeasts and moulds count (TYMC) <10 CFU/ mL <10 CFU/ mL <10 CFU/ mL <10 CFU/ mLEscherichia coli Absent NP NP NPpH 9.92 9.85 10.09 10.06
Acceptance criteria: TAMC=102 CFU/mL, TYMC=101, E. coli=absence.CFU, colony-forming unit; NP, not performed.
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54 Burnett JE, Balkin ER. Stability and viscosity of a flavouredomeprazole oral suspension for pediatric use. Am J Health Syst Harm2006;63:2240–7.
55 Nederlands Bijwerkingen Centrum Lareb. Omeprazole and discolouration of thegastric content. http://databankws.lareb.nl/Downloads/KWB_2013_4_omepr.pdf
56 Dentinger PJ, Swenson CF, Anaizi NH. Stability of pantoprazole in anextemporaneously compounded oral liquid. Am J Health Syst Pharm2002;59:953–6.
57 Katori N, Aoyagi N, Kojima S. The study of the applicability of content uniformityand weight variation test—the state of commercial tablets and capsules in Japan.Chem Pharm Bull 2001;49:1412–19.
58 Neville K, Galinkin JL, Green TP, et al. Metric units and the preferred dosing oforally administered liquid medications. Pediatrics 2015;135:784–7.
59 US Food and Drug Administration. Title 21 Food and Drugs—Part 172 FoodAdditives Permitted for Direct Addition to Food for Human Consumption: Subpart172.892 Food starch-modified. 28 December 2015. Electronic Code of FederalRegulations. 2015. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=172.892 (accessed Oct 2016).
60 US Food and Drug Administration. Select Committee on GRAS Substances (SCOGS)Opinion: Carbonate Salts. Calcium carbonate, potassium bicarbonate, potassiumcarbonate, sodium bicarbonate, sodium carbonate, sodium sesquicarbonate. http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm260878.htm(accessed Oct 2016).
61 US Food and Drug Administration. Title 21 Food and Drugs—Part 172 FoodAdditives Permitted for Direct Addition to Food for Human Consumption: Subpart172.831 Sucralose. 28 December 2015. Electronic Code of Federal Regulations.2015. http://www.ecfr.gov/cgi-bin/text-idx?SID=7378bd8e596fbeb60037469349cdb40c&mc=true&node=se21.3.172_1831&rgn=div8 (accessed Oct 2016).
62 EU (European Union). Directive 2003/115/EC of the European Parliament and ofthe Council of 22 December 2003 amending Directive 94/35/EC on sweeteners foruse in foodstuffs. 22 December 2003. Official Journal L 024. 20 12 2015. http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32003L0115 (accessedOct 2016).
Polonini HC, et al. Eur J Hosp Pharm 2016;0:1–7. doi:10.1136/ejhpharm-2016-001034 7
Original article
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preservative-free suspending vehicleCompatibility of proton pump inhibitors in a
Antoine Balland, Marcos Antônio F Brandão and Anderson O FerreiraHudson C Polonini, Sharlene L Silva, Shirley Loures, Rachel Almy,
published online November 25, 2016Eur J Hosp Pharm
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426International Journal of Pharmaceutical CompoundingVol. 20 No. 5 | September | October | 2016
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PEER REVIEWED
INTRODUCTION Oral medications administered as liquids, whether solutions or suspensions, remain the standard pharmaceutical dosage form for a range of patients, notably pediatric and elderly.1 Solutions or suspensions are also known to help treatment adherence and potentially reduce dosage/medication errors2 as long as their physicochemical stability is established.3 Therefore, commercially available suspending vehicles are a beseeming resource for phar-macists, as they are an efficient and safe alternative to the compounding of individualized oral suspensions.4
Based on United States Pharmacopeia (USP) Chapter <795>, in the absence of stability data, when stored in a refrigerator (2°C to 8°C), aqueous oral preparations should be as-signed a 14-day beyond-use date (BUD).5 In order for pharmacists to assign their com-
Stability of Allopurinol, Amitriptyline Hydrochloride, Carbamazepine, Domperidone, Isoniazid, Ketoconazole, Lisinopril, Naproxen, Paracetamol (Acetaminophen), and Sertraline Hydrochloride in SyrSpend SF PH4 Oral Suspensions
ABSTRACTOral liquids are safe alternatives to solid dosage forms, notably for elderly and pediatric patients that present dys-phagia. The use of ready-to-use suspending vehicles such as SyrSpend SF PH4 is a suitable resource for pharmacists as they constitute a safe and timesaving option that has been studied often. The objective of this study was to evaluate the stability of 10 commonly used active pharma-ceutical ingredients (allopurinol 20 mg/mL; amitriptyline hydrochloride 10 mg/mL; carbamazepine 25 mg/mL; dom-peridone 5 mg/mL; isoniazid 10 mg/mL; ketoconazole 20 mg/mL; lisinopril 1 mg/mL; naproxen 25 mg/mL; paracetamol [acetaminophen] 50 mg/mL; and sertraline hydrochloride 10 mg/mL) compounded in oral suspen-sions using SyrSpend SF PH4 as the vehicle throughout the study period and stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stabil-ity was assessed by means of measuring the percent recovery at varying time points throughout a 90-day
The authors are affiliated with Ortofarma – Quality Control Laboratories, located in Minas Gerais State, Brazil.
Hudson C. Polonini, BPharm, PhDSharlene Loures, BBiomedEdson Peter de Araujo, BS ChemMarcos Antônio F. Brandão, BPharm, PhDAnderson O. Ferreira, BPharm, MSc
period. The quantification of the active pharmaceutical ingredients was performed by high-performance liquid chromatography through a stability-indicating method. Methods were adequately validated. Forced-degradation studies showed that at least one parameter influenced the stability of the active pharmaceutical ingredients. All sus-pensions were assayed and showed active pharmaceutical ingredient contents between 90% and 110% during the 90-day study period. Although the forced-degradation experiments led to visible fluctuations in the chromato-graphic responses, the final preparations were stable in the storage conditions. The beyond-use dates of the prep-arations were found to be at least 90 days for all suspen-sions, both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable suspending vehicle for compounding with a broad range of different active pharmaceutical ingredients for different medical usages.
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pounded medication a longer BUD, physical-chemical stabil-ity testing has to be performed to investigate possible interac-tions among the vehicle’s excip-ients and the active pharma-ceutical ingredients (APIs). In this study, we focused on stability studies for SyrSpend SF PH4, a practical, ready-to-use suspending vehicle that has been gaining momentum in compounding pharmacies worldwide. The objective of this study was to evaluate the stability of 10 different commonly used APIs (allopurinol, amitriptyline hydrochloride [HCl], carbam-azepine, domperidone, iso-niazid, ketoconazole, lisinopril, naproxen, paracetamol [acet-aminophen], and sertraline HCl) compounded using SyrSpend SF PH4 as the vehicle throughout the study period and stored both at controlled refrigerated and at room temperature.
METHODSREAGENTS, REFERENCE STANDARDS AND MATERIALS The 10 API SyrSpend SF PH4 combinations studied in this article and their corresponding concentration and the vehicle composition are listed in Table 1. SyrSpend SF PH4 (Lot 14F02-U59019404) and Transcutol (Lot 14217-U09-023117) were obtained from Fagron (St. Paul, Minnesota). Allopurinol (Lot 13125096A), amitriptyline HCl (Lot 1362118B), ketoconazole (Lot 14084115C), and lisinopril (Lot 140410871A) were obtained from Pharmanostra (Anápolis, GO, Brazil). Carbamazepine (Lot 15084816), domperi-
done (Lot 14031360), naproxen (Lot 14021192), paracetamol/acetaminophen (Lot 14084239), and sertraline HCl (Lot 15095260B) were obtained from Fagron (Anápolis, GO, Brazil). Isoniazid (Lot INH-144/14*032439/14-31123) was obtained from Hen-rifarma (São Paulo, SP, Brazil). High-performance liquid chromatographic (HPLC)-grade reagents (Vetec, Rio de Janeiro, Brazil) were used. Ultrapure water obtained with an AquaMax-Ultra 370 Series (Young Lin, Anyang, South Korea) (18.2 MΩ cm resistivity at 25°C and <10 ppb total organic carbon) was used throughout the experiments. The reference standards used were all work standards obtained us-ing certified reference materials from United States Pharmacopeia (Rockville, Maryland) reference materials. All the mobile phases and receptor media were filtered through a 0.45-µm filter membrane (RC-45/15 MS; Chromafil, Düren, Germany) and de-gassed using an ultrasonic apparatus (Model 1600A; Unique, Indaiatuba, Brazil) for 30 minutes im-mediately before use. All volumetric glassware and analytical balances used were previously calibrated.
EQUIPMENT HPLC analyses were performed on a qualified and calibrated chromatography system (Young Lin) composed of a quaternary gradient pump (Model YL 9110), a photodiode array (PDA) detector (Model YL 9160), a 96-vial program-mable auto sampler (Model YL 9150), a column oven compartment (Model YL 9130), a variable sample loop up to 200 µL, and a software con-troller (Clarity).
CHROMATOGRAPHIC CONDITIONS The chromatographic determinations were performed according to the official USP method for each API, with minor modifications when necessary. The mobile phase used for each API is stated in Table 2. The standards were diluted in the mobile phase unless stated otherwise. All columns were from Phenomenex (Torrance, California), unless stated otherwise. The col-umns were connected with a pre-column with the same packing (4.0 × 3.0 mm, 5 µm) from the same manufacturer as the particle column. The injection volume was 20 µL for every chromato-graphic analysis.
FORCED-DEGRADATION STUDIES: STABILITY-INDICATING CHARACTERISTICS AND VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD The following methods and their accep-tance criteria were established based upon the protocols defined by the United States Phar-macopeial Convention5 and the International Conference on Harmonisation.6
API samples were subjected to the following stressed conditions to determine the capacity of the HPLC method to detect any possible deg-radation product produced during storage of the oral suspension: (1) dilution in acid (0.1M HCl); (2) dilution in base (0.1M NaOH); (3) exposure to ultraviolet (UV) light at 365 nm during 24 hours; and (4) heating at 70°C during 24 hours. These solutions were prepared at their respec-tive work concentrations for each API and then assayed by HPLC. Any extraneous peaks found in the chromatograms were labeled. Also the resolution and peak purity were determined between the degradation products and the API
TABLE 1. Concentrations of the Suspensions Used in the Study and Formulation of the Vehicle Used.A C T I V E P H A R M A C E U T I C A L C O N C E N T R A T I O NI N G R E D I E N T I N S U S P E N S I O N
Allopurinol 20.0
Amitriptyline hydrochloride 10.0
Carbamazepine 25.0
Domperidone 5.0
Isoniazid 10.0
Ketoconazole 20.0
Lisinopril 1.0
Naproxen 25.0
Paracetamol (acetaminophen) 50.0
Sertraline hydrochloride 10.0
V E H I C L E I N G R E D I E N T F U N C T I O N
Purified water Liquid phase
Modified food starch Suspending agent
Sodium citrate Buffering agent
Citric acid Buffering agent
Sucralose Sweetener
Sodium benzoate Preservative
Malic acid Buffering agent
Simethicone Anti-foaming agent
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U L T R A V I O L E T D E T E C T I O N W A V E L E N G T H ( N M )
254
254
310
280
254
223
215
254
243
220
TABLE 2. Chromatographic Conditions Used in the Stability study.
A C T I V E P H A R M A C E U T I C A L I N G R E D I E N T
Allopurinol
Amitriptyline hydrochloride
Carbamazepine
Domperidone
Isoniazid
Ketoconazole
Lisinopril
Naproxen
Paracetamol (acetaminophen)
Sertraline hydrochloride
M O B I L E P H A S E C O M P O S I T I O N
0.05 M solution of monobasic ammonium
phosphate
Acetonitrile and buffer (11.04 g of monobasic
sodium phosphate in 900 mL of water, adjusted
with phosphoric acid to a pH of 2.5 ± 0.5, and
diluted with water to 1000 mL) (42:58)
Methanol, acetic acid, and water (24:1:75)
5 g/L ammonium acetate solution and methanol
(40:60)
4.4 g/L of docusate sodium in a mixture of
methanol and water (600:400), adjusted with 2
N sulfuric acid to a pH of 2.5
Acetonitrile and 0.01 M tetrabutylammonium
hydrogen sulfate (25:75)
1.0 g/L of sodium 1-hexanesulfonate in
acetonitrile and Solution A (4.1 g/L of monobasic
potassium phosphate, adjusted with phosphoric
acid to a pH of 2.0) (18:82).
500 mL of methanol, 500 mL of water, and
2.46 g of anhydrous sodium acetate, adjusted
with glacial acetic acid to a pH of 5.8
0.01M sodium butanesulfonate solution in a
mixture of 0.4 volumes of formic acid, 15 volumes
of methanol and 85 volumes of water
Acetonitrile and buffer (0.8 g/L of ammonium
acetate in water – to each L of this solution,
10 mL of triethylamine and the final buffer were
adjusted with phosphoric acid to a pH of 5.0)
(30:70).
W O R K C O N C E N -T R A T I O N (µG / M L ) *
20 (in acetonitrile)
200 (in water)
700
100 (in 0.1 N
hydrochloric acid)
320
400 (in methanol
and water [50:50])
200 (in methanol
and water [20:80])
50
120
100 (in methanol
and water [50:50])
C O L U M N
Luna L1, 4.0-mm ×
3.0-cm, 5-µm particle
column
(Phenomenex,
Torrance, California)
Luna L1, 4.0-mm ×
30-cm, 5-µm particle
colum (Phenomenex)
Zorbax Eclipse
XDB-CN L10, 4.6-mm
× 25-cm, 5-µm
particle column
(Agilent, Santa Clara,
California). At 30°C.
Zorbax Eclipse
XDB-C8 L7, 4.6-mm ×
25-cm, 3.5-µm
particle column
(Agilent)
Synergi Fusion L1,
4.6-mm × 15-cm,
4-µm particle column
(Phenomenex)
Synergi Fusion L1,
4.6-mm × 25-cm,
5-µm particle column
(Phenomenex). At
30°C.
Zorbax Eclipse
XDB-C8
L7, 4.6-mm × 25-cm,
5-µm particle column
(Agilent). At 40°C.
L1, 4.6-mm × 25-cm,
10-µm particle
column (Kromasil,
Bohus, Sweden)
L1, 4.6-mm × 25-cm,
10-µm particle
column (Kromasil)
Synergi Fusion L1,
4.6-mm × 15-cm,
5-µm particle column.
(Phenomenex) At
50°C.
F L O W ( M L /M I N )
1.5
2.0
1.5
1.0
1.5
1.0
1.0
2.0
2.0
2.0
*Diluted with mobile phase, unless specified otherwise.
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peaks. A resolution of 1.5 between the peaks was considered full separation. Specificity of the method was determined using the above mentioned solutions and also running HPLC analyses of standard so-lutions; a SyrSpend SF PH4 blank solution, and a mobile phase/diluents blank solution. The acceptance criterion was defined as a percentage of discrepancy between the peak areas lower than 2%. In addition, the speci-ficity of the method was obtained through comparison of standard chromatograms with and without the matrix. All analyses were run in triplicate. Precision was tested by assessing the de-gree of dispersion among the series of mea-surements obtained by the same analyst (repeatability) and between two analysts and two days (within-lab variations, inter-mediate precision) for solutions of the API at work concentration. Repeatability was determined by consecutively analyzing six replicates by a single analyst in a single day. Intermediate precision was also performed in six replicates, but in two days, by differ-ent analysts. An injection precision of <5 % relative to the coefficient of variation (CV) was considered acceptable. Accuracy measurements were performed by the same analyst by injecting the chro-matographic samples to which the matrix was added (at the same concentration levels performed for the linearity test [n=3 for each concentration level]). The result was expressed as a percentage of recov-ery, compared with the analytical curve obtained from linearity. For linearity, the test was conducted by the plotting of three standard curves, each constructed from the API concentrations of 70% to 130% of work concentrations in order to assess the linear relationship between the concentration of the analyte and the obtained areas. For this purpose, the data for each concentration range of the curve after fitting by ordinary least squares method were evaluated by analysis of variance (ANOVA) and subject-ed to the least squares method to determine the correlation coefficient of the calibra-tion curve. The limit of detection (LOD) and limit of quantification (LOQ) were determined from
three standard calibration curves and were calculated as shown in Equations 1 and 2, respectively:
LOD = s 3 (1)
a
LOQ = s 10 (2) a
where a is the slope of the calibration curve, and s is the standard deviation of the y-intercept. The LOD and LOQ were confirmed by the analysis of chromatograms generated by injecting solutions in their respective limit concentrations.
PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENT SUSPENSION SAMPLES The suspensions were compounded at Ortofarma’s Galenic Laboratory. The API suspensions were pre-pared per API by adding the required quantity of API to each of a low-actinic prescription bottle. SyrSpend SF PH4 was added using a volumetric pipette to achieve a final volume of 300 mL. The final concentrations in the bottles are summarized in Table 1 (two bottles per API). The suspensions were then assayed at time-zero, and subsequently separated into two different bottles: one sample was stored at USP-controlled5 refrigerated temperature (2ºC to 8ºC), the other at room tempera-ture (20ºC to 25ºC), for the duration of the study. Tem-perature and humidity (maximum 60%) were checked in real time throughout the whole experiment, using a calibrated, digital thermo-hygrometer from Incoterm (Porto Alegre, Brazil). Both samples were protected from light. Before analyses, the bottles were shaken until the API was optically uniformly dispersed.
STABILITY STUDY The API samples were HPLC assayed in pre-deter-mined time points to verify the stability of the API in SyrSpend SF PH4. The samples were shaken manually for 1 minute and then adequate volumetric aliquots for quantification (variable for each API) were withdrawn from the middle of the bottles, without contact with the inner surface of the bottle, and diluted properly in order to obtain work solutions in the concentration described in Chromatographic Conditions. Sampling times were: initial (T = 0), 7 days (T = 7), 14 days (T = 14), 30 days (T = 30), 60 days (T = 60), and 90 days (T = 90). All suspen-sions were assayed six times at each time point. The evaluation parameter was the percent recovery with respect to T = 0 using the HPLC method (results given as percentage ± standard deviation).
RESULTS For the methods’ validation, the results of specificity, preci-sion, accuracy, and linearity are listed in Table 3. All analysis methods met the respective acceptance criteria. Data from the stability-indi-cating studies are summarized in Table 4. The majority of the parameters evaluated led to alteration in the chromato-graphic peak of the APIs, with a few exceptions. Allopurinol was stable under alkaline stress and heat exposure; carbamazepine was heat stable; domperidone was stable to UV and heat exposure; lisinopril was UV stable; and naproxen did not present any intercurrence within the analytical peaks under any condition. When there was chemical degradation in the suspensions, the assay would give variable results, higher or lower than expected. Thus, these fluctuations in the chromatograms were carefully followed up, as they indicated when degradation could occur within the suspensions. For the stability studies, concentrations for studies were selected based on commonly prescribed concentrations so that expected dosages (from children up to adults) can easily be measured. The results of the stability studies are shown in Table 5 and are expressed as relative percent of recovery (initial sampling time = 100%). For the suspensions to be considered stable/compatible, the relative percentage recovery should be within 90% to 110%, according to the international pharmaco-peias used (i.e., USP,5 British Pharmacopoeia,7 European
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TABLE 4. Summary of the Stability-indicating Study for the Active Pharmaceutical Ingredients.
H C L N A O H U V H E A T A P I A R E A % D * A R E A % D * A R E A % D * A R E A % D *
Allopurinol 709.42 |5.42| 735.65 |1.92| 722.20 |3.72| 746.39 |0.49|
Amitriptyline 3267.92 |36.65| 104.78 |95.62| 2572.98 |7.59| 2550.55 |6.65|HCl
Carbamazepine 8021.42 |3.76| 8010.89 |3.62| 7904.09 |2.24| 7828.24 |1.26|
Domperidone 2678.34 |6.06| 2621.19 |8.07| 2864.76 |0.48| 2892.64 |1.46|
Isoniazid 7253.38 |6.91| 6470.33 |4.63| 6469.75 |4.64| 7118.02 |4.92|
Ketoconazole 20549.64 |2.57| 3302.90 |83.51| 18465.17 |7.83| 19622.17 |2.05|
Lisinopril 5747.58 |11.17| 5175.11 |20.01| 6349.55 |1.86| 6312.49 |2.44|
Naproxen 902.61 |0.48| 898.81 |0.06| 902.32 |0.45| 889.62 |0.96|
Paracetamol 2030.81 |32.01| 1591.68 |3.46| 1967.85 |27.92| 1652.74 |7.43|
(Acetominophen)
Sertraline HCl 3244.25 |27.87| 3137.95 |23.67| 2043.91 |19.45| 2180.10 |14.08|
API = active pharmaceutical ingredient; HCl = hydrochloride; UV = ultraviolet*%d = percentage of discrepancy between the API peak without degradation (negative control) and the peak of a sample subjected to one of the cited accelerated-degradation factors.Areas given as mV. Maximum acceptable = 2%.Bold numbers indicate factors that led to high interference with the analytical peak of the API.Note: Results presented as average of 3 replicates at the work concentration.
Pharmacopoeia8). Figures 1A through Figure 1J graphically represent the stability of the APIs in SyrSpend SF PH4 in terms of absolute nominal con-centration. At each sampling time, the visual aspect (color, odor, creaming, deflocculation/caking) of the suspensions was evaluated to verify the physical stability.
DISCUSSION Oral suspensions are a valuable resource for pharmacological treatments. For instance, pedi-atric patients can benefit from these formulations because they consist of an easy and accurate form to measure the non-stan-
dard doses normally required by them. In addition to these cases, elderly patients and adults that suffer from dysphagia (as a consequence of an underlying pathology or related to the ageing process) can benefit from liquid dosing as well.1
APIs administered in suspended dosage forms, although common in pharmaceutical compounding practice, can be challeng-ing for the pharmacist if he does not have a
99.93
100.38
100.81
99.51
99.48
100.07
99.83
100.38
100.44
100.21
TABLE 3. Summary of Linearity’s Study for the Validation of the High-performance Liquid Chromatographic Method.
Allopurinol
Amitriptyline
HCl
Carbamazepine
Domperidone
Isoniazid
Ketoconazole
Lisinopril
Naproxen
Paracetamol
Sertraline HCl
LOD = Limit of detection; LOQ = Limit of quantification; CV = coefficient of variation
Acceptance criteria: R2 >0.99; F (significance of regression) >>4.67; F (lack of fit) <3.71; dis-crepancy <2%; repeatability and intermediate precision <5%; and recovery = 100% ± 2%. All analytical ranges (µg/mL) were adequate to quantify the active pharmaceutical ingredients in the concentrations used in the suspensions (mg/mL).
14.07 to 26.13
140.14 to 260.26
140.14 to 260.26
70.42 to 130.78
224 to 416
280.28 to 520.52
140.56 to 261.04
35.14 to 65.26
84.07 to 156.13
70.0 to 130.0
y = 36.31x + 13.78
y = 14.64x – 438.86
y = 36.37x + 527.37
y = 14.71x - 69.76
y = 26.74x - 35.44
y = 36.37x + 527.37
y = 20.92x- 149.11
y = 17.23x - 0.80
y = 14.71x - 69.76
y = 14.71x - 69.76
0.9991
0.9907
0.9954
0.9985
0.9914
0.9930
0.9929
0.9944
0.9980
0.9944
14301.54
1385.64
2852.00
8809.70
1504.65
1840.92
1810.19
2325.15
6532.29
2297.47
0.69
3.18
2.88
3.16
3.38
2.90
3.54
2.32
2.05
1.69
0.15
0.01
0.003
0.01
0.01
0.003
0.03
0.10
0.02
0.0004
0.50
0.02
0.009
0.02
0.04
0.01
0.09
0.34
0.06
0.001
|0.10|
|1.73|
|0.07|
|1.92|
|1.49|
|0.23|
|1.60|
|0.62|
|0.88|
|1.18|
0.89
0.78
0.33
0.62
0.28
0.29
0.13
0.26
0.85
0.53
0.75
4.74
3.61
2.39
1.10
2.94
0.40
1.09
2.54
4.33
ACTIVE
P
HARM
ACEUTICAL
IN
GREDIENT
LINEARITY
R
ANG
E (µG
/ML)
ANALYTICAL
C
URVE
R2
ANOVA’S
S
IGN
IFICANCE O
F
REG
RESSION (F)
ANOVA’S
LACK
OF
F
IT (F)
LODLOQ
SPECIFICITY
D
ISCREPANCY (%
)
PRECISION
R
EPEATABILITY (CV, %)
INTERM
EDIATE
P
RECISION (CV, %
)
ACCURACY
R
ECOVERY
(%
)
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TABLE 5. Stability of the Active Pharmaceutical Ingredients in SyrSpend SF PH4.
% R E C O V E R Y C O N T R O L L E DE L A P S E D R E F R I G E R A T E D R O O MT I M E T E M P E R A T U R E T E M P E R A T U R E( D A Y S ) ( 2 º C - 8 º C ) ( 2 0 º C - 2 5 º C )
Allopurinol 20 mg/mL
T = 0 100 ± 0.31 100 ± 0.31
T = 7 100.59 ± 0.13 99.70 ± 0.32
T = 14 99.75 ± 0.19 100.09 ± 0.32
T = 30 97.32 ± 0.42 98.31 ± 0.32
T = 60 98.12 ± 0.36 98.58 ± 0.67
T = 90 98.03 ± 0.24 98.02 ± 0.23
Amitriptyline Hydrochloride 10 mg/mL
T = 0 100 ± 1.24 100 ± 1.24
T = 7 97.38 ± 0.96 96.60 ± 0.49
T = 14 97.08 ± 0.92 97.19 ± 1.04
T = 30 97.57 ± 0.85 97.45 ± 0.74
T = 60 97.16 ± 0.35 104.68 ± 0.23
T = 90 98.18 ± 0.38 97.55 ± 0.40
Carbamazepine 25 mg/mL
T = 0 100 ± 0.79 100 ± 0.79
T = 7 100.31 ± 0.53 99.92 ± 0.55
T = 14 99.93 ± 1.21 99.93 ± 1.13
T = 30 99.99 ± 0.17 100.81 ± 1.60
T = 60 100.23 ± 0.28 100.08 ± 0.34
T = 90 99.10 ± 0.44 99.95 ± 0.44
Domperidone 5 mg/mL
T = 0 100 ± 0.28 100 ± 0.28
T = 7 100.24 ± 0.24 103.42 ± 0.20
T = 14 98.07 ± 0.15 107.44 ± 2.20
T = 30 102.13 ± 1.29 104.91 ± 0.53
T = 60 105.03 ± 0.78 104.69 ± 0.64
T = 90 105.97 ± 0.56 106.96 ± 1.31
Isoniazid 10 mg/mL
T = 0 100 ± 0.39 100 ± 0.39
T = 7 95.02 ± 0.37 99.37 ± 0.35
T = 14 93.49 ± 0.23 96.11 ± 0.30
T = 30 93.36 ± 0.27 93.68 ± 0.41
T = 60 94.02 ± 0.27 94.76 ± 0.81
T = 90 94.06 ± 0.45 93.89 ± 0.46
% R E C O V E R Y C O N T R O L L E DE L A P S E D R E F R I G E R A T E D R O O MT I M E T E M P E R A T U R E T E M P E R A T U R E( D A Y S ) ( 2 º C - 8 º C ) ( 2 0 º C - 2 5 º C )
Ketoconazole 20 mg/mL
T = 0 100 ± 0.69 100 ± 0.69
T = 7 99.86 ± 0.75 100.07 ± 0.57
T = 14 98.79 ± 0.76 98.38 ± 0.47
T = 30 100.32 ± 0.85 99.20 ± 0.69
T = 60 100.51 ± 0.89 97.50 ± 0.16
T = 90 99.59 ± 0.41 98.96 ± 1.21
Lisinopril 1 mg/mL
T = 0 100 ± 0.40 100 ± 0.40
T = 7 97.57 ± 0.33 99.63 ± 0.19
T = 14 99.99 ± 0.45 100.85 ± 0.38
T = 30 97.43 ± 0.18 103.71 ± 0.22
T = 60 103.30 ± 1.15 104.20 ± 0.35
T = 90 103.19 ± 0.43 103.39 ± 0.36
Naproxen 25 mg/mL
T = 0 100 ± 0.88 100 ± 0.88
T = 7 100.79 ± 0.67 101.10 ± 1.93
T = 14 95.83 ± 0.70 100.35 ± 1.20
T = 30 97.19 ± 0.32 97.07 ± 0.54
T = 60 94.70 ± 1.02 98.82 ± 0.98
T = 90 98.45 ± 0.34 98.38 ± 0.40
Paracetamol (Acetaminophen) 50 mg/mL
T = 0 100 ± 0.35 100 ± 0.35
T = 7 103.17 ± 0.70 97.32 ± 1.50
T = 14 98.80 ± 1.36 96.60 ± 0.26
T = 30 101.33 ± 0.65 99.29 ± 0.45
T = 60 96.37 ± 0.21 97.16 ± 0.28
T = 90 96.40 ± 0.45 99.85 ± 0.58
Sertraline Hydrochloride 10 mg/mL
T = 0 100 ± 0.91 100 ± 0.91
T = 7 101.74 ± 0.37 100.86 ± 0.66
T = 14 102.34 ± 1.02 101.31 ± 0.49
T = 30 104.01 ± 0.69 102.51 ± 0.58
T = 60 103.62 ± 0.44 102.89 ± 0.89
T = 90 103.17 ± 0.79 103.15 ± 0.82
ready-to-use vehicle. Furthermore, the majority of the oral suspen-sions’ stability studies are conducted with such vehicles.9
In this study, we checked the stability of 10 different APIs compounded with a commonly used vehicle, SyrSpend SF PH4.
SyrSpend SF PH4 is an alcohol- and sorbitol-free agent that helps mask unpleasant taste, and it is formulated with starch. The results showed that none of the APIs presented any significant degradation up to the 90 days of the study, which is in accordance with previous
Peer Reviewed
ESTUDO 20
432International Journal of Pharmaceutical CompoundingVol. 20 No. 5 | September | October | 2016
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0 30 60 90
24
22
20
18
16
Time (days)
[Allo
purin
o] m
g/m
L
[Allopurinol] mg/mL (refrigerated)[Allopurinol] mg/mL (room temperature)
0 30 60 90
12
11
10
9
8
Time (days)
[Am
itryp
tilin
e H
Cl]
mg/
mL
[Amitriptyline HCl] mg/mL (refrigerated)[Amitriptyline HCl] mg/mL (room temperature)
0 30 60 90
30.0
27.5
25.0
22.5
20.0
Time (days)
[Car
bam
azep
ine]
mg/
mL
[Carbamazepine] mg/mL (refrigerated)[Carbamazepine] mg/mL (room temperature)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
Time (days)
[Dom
perid
one]
mg/
mL
[Domperidone] mg/mL (refrigerated)[Domperidone] mg/mL (room temperature)
0 30 60 90
12
11
10
9
8
Time (days)
[Iso
niaz
id]
mg/
mL
[Isoniazid] mg/mL (refrigerated)[Isoniazid] mg/mL (room temperature)
24
22
20
18
16
Time (days)
[Ket
ocon
azol
e] m
g/m
L
[Ketoconazole] mg/mL (refrigerated)[Ketoconazole] mg/mL (room temperature)
0 20 40 60 80 100
0 30 60 90
24
22
20
18
16
Time (days)
[Allo
purin
o] m
g/m
L
[Allopurinol] mg/mL (refrigerated)[Allopurinol] mg/mL (room temperature)
0 30 60 90
12
11
10
9
8
Time (days)
[Am
itryp
tilin
e H
Cl]
mg/
mL
[Amitriptyline HCl] mg/mL (refrigerated)[Amitriptyline HCl] mg/mL (room temperature)
0 30 60 90
30.0
27.5
25.0
22.5
20.0
Time (days)
[Car
bam
azep
ine]
mg/
mL
[Carbamazepine] mg/mL (refrigerated)[Carbamazepine] mg/mL (room temperature)
0 30 60 90
6.0
5.5
5.0
4.5
4.0
Time (days)
[Dom
perid
one]
mg/
mL
[Domperidone] mg/mL (refrigerated)[Domperidone] mg/mL (room temperature)
0 30 60 90
12
11
10
9
8
Time (days)
[Iso
niaz
id]
mg/
mL
[Isoniazid] mg/mL (refrigerated)[Isoniazid] mg/mL (room temperature)
24
22
20
18
16
Time (days)
[Ket
ocon
azol
e] m
g/m
L
[Ketoconazole] mg/mL (refrigerated)[Ketoconazole] mg/mL (room temperature)
0 20 40 60 80 100
FIGURE 1A THROUGH FIGURE 1J. Graphic representation of the stability of the active pharmaceutical ingredients in SyrSpend SF PH4 in terms of absolute nominal concentration.
FIGURE 1A
FIGURE 1B
FIGURE 1C
FIGURE 1D
FIGURE 1E
FIGURE 1F
ESTUDO 20
433International Journal of Pharmaceutical Compounding
Vol. 20 No. 5 | September | October | 2016www.IJPC.com
Peer Reviewed
studies, as the stability of SyrSpend SF PH4 with various APIs has already been shown.10-19
The final safe, stable suspension is a product of multiple factors, including chemical, physical, and microbiological stability of the API itself and also of its interaction with the vehicle and the packaging.9
We evaluated the stability of the APIs in SyrSpend SF as a factor of degradation of the API with time. The results of the validations prove that the methods were suitable for the studies: the method provided a tool for monitoring extraneous peaks in the chromato-gram and as well as the API content within the vehicle throughout the study period. The degradation pathways monitored (i.e., acid or basic hydrolysis, photolysis, thermolysis, oxidation) altogether provided data to understand and to monitor the behavior of the API within the vehicle throughout the study (Table 4).
0 30 60 90
60
55
50
45
40
Time (days)
[Par
acet
amol
] m
g/m
L
[Paracetamol] mg/mL (refrigerated)[Paracetamol] mg/mL (room temperature)
0 30 60 90
12
11
10
9
8
Time (days)
[Ser
tral
ine
HCl
] m
g/m
L
[Sertraline HCl] mg/mL (refrigerated)[Sertraline HCl] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
Time (days)
[Lis
inop
ril]
mg/
mL
[Lisinopril] mg/mL (refrigerated)[Lisinopril] mg/mL (room temperature)
0 30 60 90
30.0
27.5
25.0
22.5
20.0
Time (days)
[Nap
roxe
n] m
g/m
L
[Naproxen] mg/mL (refrigerated)[Naproxen] mg/mL (room temperature)
0 30 60 90
0 30 60 90
60
55
50
45
40
Time (days)
[Par
acet
amol
] m
g/m
L
[Paracetamol] mg/mL (refrigerated)[Paracetamol] mg/mL (room temperature)
0 30 60 90
12
11
10
9
8
Time (days)
[Ser
tral
ine
HCl
] m
g/m
L
[Sertraline HCl] mg/mL (refrigerated)[Sertraline HCl] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
Time (days)
[Lis
inop
ril]
mg/
mL
[Lisinopril] mg/mL (refrigerated)[Lisinopril] mg/mL (room temperature)
0 30 60 90
30.0
27.5
25.0
22.5
20.0
Time (days)
[Nap
roxe
n] m
g/m
L
[Naproxen] mg/mL (refrigerated)[Naproxen] mg/mL (room temperature)
0 30 60 90
Although the forced-degradation experiments led to visible fluctuations in the chromatographic responses, the final prepara-tions were stable in the storage conditions (Table 5 and Figure 1). There was no interaction between the API and the excipients of the vehicle for up to 90 days beyond preparation, in both controlled refrigerated and room temperature.
CONCLUSION In summary, all the APIs evaluated were stable with SyrSpend SF PH4 throughout the duration of the study (90 days after prepara-tion), when stored both at controlled refrigerated temperature (2ºC to 8ºC) conditions and at room temperature (20ºC to 25ºC) condi-tions. As the results show, SyrSpend SF PH4 is stable with a wide
Note: At each sampling time, the visual aspect (color, odor, creaming, deflocculation/caking) of the suspensions was evaluated to verify the physical stability.
FIGURE 1G
FIGURE 1H
FIGURE 1I
FIGURE 1J
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434International Journal of Pharmaceutical CompoundingVol. 20 No. 5 | September | October | 2016
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range of APIs and, therefore, represents a safe, stable, and high-quality suspending vehicle.
REFERENCES1. Bauters T, Claus B, Willems E et al. What's in a drop? Optimizing
strategies for administration of drugs in pediatrics. Int J Clin Pharm 2012; 34(5): 679–681.
2. Allen LV Jr. Dosage form design and development. Clin Ther 2008; 30(11): 2102–2111.
3. Provenza N, Calpena AC, Mallandrich M et al. Design and physi-cochemical stability studies of paediatric oral formulations of sildenafil. Int J Pharm 2014; 460(1–2): 234–239.
4. Patel VP, Desai TR, Chavda BG et al. Extemporaneous dosage form for oral liquids. Pharmacopore 2011; 2: 86–103.
5. United States Pharmacopeial Convention, Inc. United States Phar-macopeia–National Formulary. Rockville, MD: US Pharmacopeial Convention, Inc.; Current Edition.
6. International Conference on Harmonisation. International Confer-ence on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Q2(R1) Validation of Analytical Procedures: Text and Methodology; 2005.
7. British Pharmacopoeia Commission Office. British Pharmacopoeia 2015. London, UK: The Stationery Office; 2015.
8. Council of Europe. European Pharmacopoeia 8.0. Germany: Druck-erei C. H. Beck; 2015.
9. Haywood A, Glass BD. Liquid dosage forms extemporaneously prepared from commercially available products – considering new evidence on stability. J Pharm Pharm Sci 2013; 16(3): 441–455.
10. Vu NT, Aloumanis V, Ben M et al. Stability of metronidazole benzo-ate in SyrSpend SF One-Step Suspension System. IJPC 2008; 12(6): 558–564.
11. Geiger CM, Voudrie MA, Sorenson B. Stability of ursodiol in SyrSpend SF Cherry Flavored. IJPC 2012; 16(6): 510–512. Erratum in IJPC 2013; 17(1): 86.
12. Sorenson B, Whaley P. Stability of rifampin in SyrSpend SF. IJPC 2013; 17(2): 162–164.
13. Geiger CM, Sorenson B, Whaley PA. Stability of Captopril in SyrSpend SF. IJPC 2013; 17(4): 336–338.
14. Sorenson B, Voudrie MA, Gehrig D. Stability of Gabapentin in SyrSpend SF. IJPC 2012; 16(4): 347–379.
15. Geiger CM, Sorenson B, Whaley PA. Stability of midazolam in SyrSpend SF and SyrSpend SF Cherry. IJPC 2013; 17(4): 344–346.
16. Whaley PA, Voudrie MA II, Sorenson B. Stability of omeprazole in SyrSpend SF Alka (reconstituted). IJPC 2012; 16(2): 164–166.
17. Voudrie MA, Allen DB. Stability of oseltamivir phosphate in SyrSpend SF, Cherry Syrup, and SyrSpend SF (for reconstitution). IJPC 2010; 14(1): 82–85.
18. Whaley PA, Voudrie MA, Sorenson B. Stability of vancomycin in SyrSpend SF. IJPC 2012; 16(2): 167–169. Erratum in IJPC 2013; 17(1): 86.
19. Voudrie MA, Alexander B, Allen DB. Stability of verapamil hydro-chloride compared to sorbitol containing syrup and suspending vehicles. IJPC 2011; 15(3): 255–258.
Address correspondence to Ortofarma Laboratório de Controle de qualidade, BR 040, Empresarial Park Sul, n. 39 – CEP 36120-000 – Matias Barbosa – MG, Brazil.
ESTUDO 20
RESULTATS
• Stabilité microbiologique Test de ferlité : pas d’inhibion de croissance des micro-organismes par le véhicule de suspension Aucune croissance microbienne jusqu’à J60
• Stabilité physico-chimique Aucune variation de l’aspect macroscopique Stabilité chimique : Osmolalité [38-49 mOsm/kg]; pH [4,26-4,36]
AU
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0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
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72
STABILITÉ D’UNE SUSPENSION BUVABLE DE NITRENDIPINE 5 MG/ML R. BELLAY 1, F. LESOURD 1, C. QUILLIEC 1, T. GICQUEL 2, P-N BOIVIN 1, M-A LESTER 1
1 : Pharmacie, CHU de Rennes, 2 Rue Henri Le Guilloux, 35000 Rennes 2 : Laboratoire de Toxicologie, CHU de Rennes, 2 Rue Henri Le Guilloux, 35000 Rennes
INTRODUCTION
La Nitrendipine (NTD), ulisée en pédiatrie dans certains cas d’hypertension artérielle, est uniquement commercialisée en France sous forme de comprimés. Cette forme galénique, inadaptée à l’usage pédiatrique, ne permet pas d’obtenir des prises précises au regard des posologies pédiatriques . La préparation d’une suspension buvable de NTD dosée à 5 mg/ml a donc été validée et une étude de stabilité a été menée.
MATERIELS ET METHODE
• 3 lots de suspensions buvables de NTD à 5 mg/ml ont été préparés à parr de comprimés de Nidrel® 20 mg et d’un véhicule de suspension Syrspend® SF-PH4, puis condionnés en flacons en verre brun (photosensibilité de la NTD) et conservés à température ambiante
• Temps de prélèvements : J0, J3, J5, J8, J10, J15, J30, J60 • Paramètres étudiés :
• Stabilité microbiologique : test de ferlité du véhicule de suspension, ensemencement direct sur gélose et dénombrement des germes (selon Pharmacopée Européenne)
• Stabilité physico-chimique : aspect macroscopique , pH, osmolalité Mesure de la concentraon de NTD: HPLC en phase inverse avec détecon UV (235 nm); Phase mobile : mélange méthanol/eau/acétonitrile (45/45/10); Colonne Atlans C18 T3 5 μm (4.6 x 150 mm)
Validaon de la méthode de dosage : linéarité, fidélité, exactude Spécificité de la méthode : mise en évidence des produits de dégradaon
CONCLUSION
Stabilité physico-chimique et microbiologique de la suspension buvable de NTD 5 mg/ml jusqu’à 60 jours. Déterminaon d’une durée de conservation de 60 jours avant ouverture, à température ambiante à l’abri de la lumière.
11èmes Rencontres Convergences Santé Hôpital, 28-30 septembre 2016 – Avignon, France
• Concentration en principe actif Variation de concentrations par rapport à la concentraon
iniale (C0) dans les limites acceptables [98%;103%]
OBJECTIFS
L’objecf de cee étude est d’évaluer la stabilité physico-chimique et microbiologique de la suspension buvable de NTD 5 mg/mL afin de déterminer une durée de conservaon.
0,0
2,0
4,0
6,0
8,0
10,0
12,0
14,0
0
10
20
30
40
50
60
70
80
0 10 20 30 40 50 60 70
pH
Osm
olal
lité
en m
Osm
/kg
Jours
Evolution de l’osmolalité et du pH d'une suspension buvable de NTD 5 mg/ml
Osmolalité pH
Absence de produits de dégradation
PT 136
Chromatogramme de la NTD (235 nm)
70,00%
75,00%
80,00%
85,00%
90,00%
95,00%
100,00%
105,00%
110,00%
0 5 10 15 20 25 30 35 40 45 50 55 60 65
Jours
Pour
cent
age
de c
once
ntra
tion
(Ci/C
0)
Variation de la concentration de NTD par rapport à C0 en fonction du temps
ESTUDO 19
Introduction
Matériels et méthode
Conclusion
Résultats
Stabilité physico-chimique : • Examen macroscopique • Evoluon du pH : pHenomenal VWR® • Evoluon de l’osmolalité : Advanced Instruments Model 3250 • Mise en évidence des produits de dégradaon : chauffage, HCl, NaOH • Mesure de la concentraon en cloxacilline
- colonne Atlans C18 T3 5 μm (4.6 x 150 mm) - phase mobile : mélange (50:50) CH3CN/Tampon pH 2 - débit: 1 ml/min, run de 9 minutes, volume d’injecon : 20 μl - détecon UV : 210 nm
Cee étude montre que la suspension buvable de CLX à 50 mg/ml dans le Syrspend® a une durée de conservaon limitée à 5 jours entre +2°C et +8°C ce qui limite son développement en tant que préparaon hospitalière. Cependant, une ulisaon ponctuelle de cee suspension sous le statut de préparation magistrale est possible.
Recherche de micro-organismes : négave jusqu’à la fin de l’étude. Examen macroscopique : apparion d’une coloration jaune-beige à J28 traduisant une dégradaon de la suspension.
La cloxacilline (CLX) est une bêta-lactamine ulisée pour traiter certains types d’infecons à germes sensibles aux Péni-M. Actuellement, une seule spécialité orale de CLX est commercialisée en France (Orbénine®). Celle-ci se présente sous formes de gélules dosées à 500 mg empêchant une ulisaon opmale en pédiatrie.
La pharmacie à usage intérieur a été sollicitée pour développer une préparation orale de CLX. Une suspension buvable de CLX à 50 mg/ml dans du Syrspend® a été proposée et, en l’absence de données bibliographiques, une étude de stabilité a été menée pour déterminer une durée de conservaon.
• 3 lots de suspension buvable de CLX 50 mg/ml à parr de gélules d’Orbénine® 500 mg et de Syrspend® SF PH4
• Condionnement : flacon verre brun • Conservaon : entre +2°C et +8 °C • Durée de l’étude: 36 jours • Temps de prélèvement: J0, J3, J5, J7, J12, J20, J28, J36 • Stabilité microbiologique et physico-chimique
Stabilité microbiologique : Ensemencement de gélose TSA et incubaon 14 jours à 36°C
La concentraon en CLX dans la suspension est acceptable jusqu’au J5 (- 8,7 %) mais diminue ensuite de manière significave avec apparion nee d’un pic de dégradation.
0
2
4
6
8
10
12
14
100
120
140
160
180
200
220
240
0 5 10 15 20 25 30 35 40
pH
Osm
olal
lité
en m
Osm
/kg
Durée en jours (J)
Evoluon du pH et de l'osmolalité en foncon du temps
Osmolalité pH
C. Barbazan1 , B. Le Daré1, M-A Lester1, P-N Boivin1 1Service de pharmacie - CHU Rennes, 2 Rue Henri Le Guilloux, 35000 Rennes
0
20
40
60
80
100
120
0 3 5 7 12 20 28 36
Pour
cent
age
de C
LX re
stan
t pa
r rap
port
au
J0 [%
]
Durée en jours [J]
Evoluon de la concentraon de CLX par rapport à la concentraon iniale en foncon du temps
Etude de stabilité d’une suspension buvable de cloxacilline à usage pédiatrique
Apparion de produits de dégradaon dans la suspension au cours du temps
11èmes Rencontres Convergences Santé Hôpital, 28-30 septembre 2016 – Avignon, France
PT135
J0 Cloxacilline
Produit de dégradaon
J36
Cloxacilline
90%
Tr= 5,5 minutes
ESTUDO 18
31OR
CONFLICT OF INTEREST
This work has been conducted under the sponsorship of Fagron.
INTRODUCTION
Sildenal citrate is used to treat erectile dysfunction (ED) in adult males and pulmonary arterial hypertension (PAH) in both children and adults. National Institute of Health (NIH) has dened ED as the permanent inability of a man to attain and/or maintain penile erection sucient to permit satisfactory sexual intercourse (NIH, 1993). Abdo et al. (2006) dened it as a condition clearly compromising the quality of life. The main treatment for ED is the use of oral phosphodiesterase type 5 (IF5) inhibitors, amongst which sildenal citrate is best known
and most widely used (Toledo, 2013; Af-Abdo, 2007). IF5 inhibitors increase relaxation of smooth muscle and dilation of the sinusoids body, resulting in an increased blood ow, allowing penile erection (Porst et al., 2012; Montorsi et al., 2010). PAH is characterised by progressive destruction of the pulmonary vasculature and associated with high morbidity and mortality, especially in children (Tissot & Beghetti, 2009). Sildenal is most widely used in PAH by relaxing the blood vessels in the lungs and reducing blood pressure and has contributed to improved survival in this group, from a historical less-than-1-year survival in untreated children with severe PAH in the 1980s to a 97% 5-year survival rate (Tissot & Beghetti, 2009; Martínez et al., 2003; Humpl et al., 2005; Keller et al., 2004; Kothari & Duggal, 2002; Ladha et al., 2005; Leibovitch et al., 2007; Namachivayam et al., 2006; Barnett & Machado, 2006). However, it must be conceded that most of the agents mentioned are used o-label in children
Stability Of Sildenal Citrate Oral Suspension With Syrspend® Sf
Geiger Ch. M.,1 , Sorenson B.,2, Whaley P.,3
Aim: Sildenal citrate is a drug used to treat erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). As for both clinical applications, the only available dosage form is tablets; there is a clear need for a safe oral liquid, especially for children. The objective of this study was to determine the stability of sildenal citrate in SyrSpend® SF PH4, a suspending agent containing neither sorbitol nor alcohol.Material/Methods: The studied sample was compounded into a 2.5-mg/mL suspension and stored in low-actinic plastic bottles at temperatures between 2 and 8°C and at room temperature conditions. Six samples were assayed at each time point out to 92 days by a high-performance liquid chromatography (HPLC) method. The method was validated for its specicity through forced-degradation studies.Results: The samples remained within 90–110% of the initial concentration throughout the course of the study.Conclusions: On the basis of the data collected, the beyond-use date of this product is at least 92 days when protected from light at both refrigerated and room temperature storage conditions.
Compatibility – Stability – Compounding – Oral suspension – SyrSpend – SildenalKeywords
© European Pharmaceutical Journal
EUROPEAN PHARMACEUTICAL JOURNAL
Abstract
Eur. Pharm. J. 2018, 65 (1): 31-35. ISSN 1338-6786 (online) and ISSN 2453-6725 (print version),
DOI: 10.2478/afpuc-2018-0007
Received 22 June, 2016, accepted 19 July, 2016
Original Paper
* E-mail: cgeiger@ dynalabs.us
1Lab Technician III, Dynalabs, LLC, Saint Louis, Missouri
2Project Manager, Sigma Aldrich, Saint Louis, Missouri
3Laboratory Manager, Advanced Pain Center, Festus, Missouri
UnauthenticatedDownload Date | 7/22/18 2:32 AM
ESTUDO 17
Geiger Ch. M., Sorenson B., Whaley P.
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and the use is based mainly on experience in adults with PAH (Dodgen & Hill, 2015). For both ED and PAH, the only commercially available dosage form of sildenal citrate is tablets. Sildenal is available as a tablet only and the dosage in newborns ranges from 0.3 to 8 mg/kg/day (Huddleston et al., 2009). In addition, up to 22.4% of the adult population have swallowing diculties, which highlights the importance of liquid formulations with adequate quality and stability for both paediatric patients and adults (Lau et al., 2003; Schirm et al., 2003).The objective of this study was to determine the stability of sildenal citrate in SyrSpend® SF, a suspending agent containing neither sorbitol nor alcohol or other excipients to be avoided in children (Gershanik et al., 1982). Currently, the stability of a large number of other active pharmaceutical ingredients (APIs) has already been shown in SyrSpend® SF (Vu et al., 2008; Geiger et al., 2012a, 2012b; Sorenson & Whaley, 2013; Geiger et al., 2013a, 2013b; Sorenson et al., 2012; Whaley et al., 2012a, 2012b; Voudrie & Allen, 2010; Voudrie et al., 2011; Geiger et al., 2015; Ferreira et al., 2016; Polonini et al., 2015; Polonini et al., 2016a, 2016b, 2016c). Sildenal stability in SyrSpend® SF (2.5 mg/mL) was assessed throughout a 92-day period at both controlled refrigerated (2–8°C) and room temperature.
METHODS
Chemical Reagents
Sildenal citrate raw powder was received from Fagron US (Lot 0911227111; St. Paul, Minnesota). SyrSpend® SF PH4 (liquid) was received from Fagron US – formally Gallipot (Lot 1110358V14; St. Paul, Minnesota). High-performance liquid chromatographic (HPLC) grade acetonitrile (Lot DG353; Honeywell Burdick and Jackson, Muskegon, Michigan), dibasic sodium phosphate heptahydrate (Lot 115824; Fisher, Fairlawn, NJ) and phosphoric acid (Lot 40350080404; CCI, Columbus, Wisconsin) were used in this study. HPLC-grade water was supplied by ltering deionised water from a Millipore Elix through a Millipore Simplicity (Billerica, Massachusetts).
Equipment and Chromatographic Conditions
Two dierent types of HPLCs were used. The rst, used for validation and the stability study, was a Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quaternary gradient solvent delivery system, a dual wavelength UV/VIS detector, a 100-vial programmable autosampler with a Peltier tray, 200-µL sample loop and a 250-µL syringe. The second HPLC system, used for forced degradation studies, was a Varian Prostar (Palo Alto, California) equipped with a tertiary gradient solvent delivery system, a photodiode array detector (PDA), an 84-vial programmable autosampler with a 100-µL sample loop and a 250-µL syringe. The Perkin Elmer HPLC was operated and the data was collected using Perkin Elmer
Totalchrom chromatography software, whilst the Varian HPLC used Galaxie chromatography software. The mobile phase for the HPLC method was prepared by adding 5.3 g of dibasic sodium phosphate heptahydrate to 650 mL of HPLC-grade water and 350 mL of HPLC-grade acetonitrile. The mobile phase was adjusted to pH 6.5 with 85% phosphoric acid and delivered at 1.5 mL/min. Chromatographic separation was achieved using a 150 mm × 4.6 mm Phenomenex (Torrance, California) Gemini C8 column with 5-µL particle packing. The mobile phase was used as solvent to dilute the standard and assay preparations to 25 µg/mL sildenal citrate. The assay was monitored following a 100-µL injection.
Validation of Forced-Degradation Studies to Determine the Characteristics of the HPLC Method
Sildenal citrate samples were stressed and assayed at 293 nm to determine the specicity of the HPLC method to any possible degradation product produced during the storage of an oral suspension. Sildenal citrate was diluted to 25 µg/mL in solutions of acid (0.1M HCl), base (0.1M NaOH) and hydrogen peroxide (3.5%), in addition to exposure to ultraviolet light at 365 nm and heat at 70°C for 3 h. Any extraneous peaks found in the chromatogram were labelled and the resolution was determined between the degradant and the sildenal citrate. Purity calculations were performed in Galaxie on the sildenal citrate peak using the controlled unstressed standard as a reference.For determining the linearity of the method, the test was conducted by the plotting three standard curves in the range of 2.49–99.55 µg/mL and a determination coecient higher than 0.99 was considered adequate. Precision of the method was assessed through repeatability: it was determined by consecutively analysing six replicates by a single analyst in a single day. An injection precision of <5% relative to the coecient of variation (CV) was considered acceptable. Accuracy measurements were performed by the same analyst by injecting the chromatographic samples to which the matrix was added (at the same concentration levels performed for the linearity test (n = 3 for each concentration level)). The result was expressed as a percentage of recovery and compared with the analytical curve obtained from linearity.
Preparation of Sildenal Citrate Suspension Samples
The sildenal citrate suspension was prepared by adding 250 mg of sildenal citrate to a low actinic prescription bottle. An aliquot of SyrSpend® SF PH4 (liquid) was added to the bottle to achieve a nal volume of 100 mL. The nal concentration was 2.5 mg/mL sildenal citrate. The suspensions were stored at temperatures between 2 and 8°C and at room temperature storage conditions for the duration of the study.
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Stability Study
The sample of sildenal citrate suspended in SyrSpend® SF PH4 (liquid) at a concentration of 2.5 mg/mL was submitted for stability. The initial submitted sample was assayed and then split into two containers. The sample was packaged in low actinic plastic prescription bottles and stored at refrigerated storage conditions between 2 and 8°C and at room temperature storage conditions. Time points for the study were initial (T = 0), 7 days (T = 7), 14 days (T = 14), 30 days (T = 30), 61 days (T = 61) and 92 days (T = 92). The evaluation parameter was percent recovery assay and also appearance, taste, odour and pH. The stability of the sildenal citrate in suspension was dened by the percent recovery with respect to T = 0 using the validated HPLC method. The sample stock was prepared six times by adding 100 µL of suspension to a 10-mL volumetric ask and diluting to volume with mobile phase. The average and coecient of variation of all replicate injections (n = 3) at each time point were used to calculate the percent recovery.
RESULTS AND DISCUSSIONS
As a rst step of our work, the HPLC method was monitored in order to verify its applicability to the main objective of this study, which is the inference for the stability of sildenal citrate in SyrSpend® SF PH4 (liquid). A summary of the HPLC method parameters can be found in Table 1, which provides the data for peak tailing, range of the analytical curve, its coecient of determination (linearity), precision and accuracy (in terms of percentage of recovery). All data are within international guidelines acceptance criteria (Council of Europe, 2015; ICH, 2005), which are coecient of determination higher than 0.99 for linearity, coecient of variation lower than 5% for precision (in terms of repeatability, intra-assay variation) and percentage of recovery within 98.0% and 102.0% of the target value for accuracy. Figure 1 depicts typical chromatograms of standard and simple, conrming specicity of the method. With a peak tailing lower than 2.0 and a theoretical plate number over 4,000, good separation capacity for the HPLC column was demonstrated.Evaluation of possible degradation was also conducted to identify the decomposition of the APIs and assure sucient separation by chromatographic analysis. The decomposition prole of the API varied for dierent stressing conditions. Sildenal citrate was stable to acid, base, light and heat, but oxidiser created signicant degradation. The degradants present were all completely separated from the analyte with acceptable resolution (>1.5).The suspension compounded with SyrSpend® SF PH4 (liquid) was prepared and its stability prole was traced. The initial concentration of the suspension was 2.59 mg/mL, which was set as the baseline for all other time points tested. The results were expressed in terms of percentage of recovery (Table 2). The assay results varied between 2.57 (T = 30) and 2.59
mg/mL (T = 0) for the room temperature storage condition and between 2.56 (T = 7) and 2.61 mg/mL (T = 61) for the refrigerated storage condition. All sample preparations at each time point were within specication, with a maximum variability in the assays of CV = 4.21% (T = 30) for room temperature conditions and 4.91% (T = 92) for refrigerated conditions. All time points showed a similar chromatographic prole and clear degradant separation. In addition to the assay, appearance, taste and odour were evaluated and remained exactly the same as T = 0 throughout the whole study. Initial pH was measured as 4.21 and also remained constant during the study.By the exposed, the sildenal citrate suspension compounded with SyrSpend® SF PH4 (liquid) presented equal to or better physicochemical stability than other vehicles. Roque et al. (2013) developed two dierent oral liquid formulations of
Table 1. Summary of the HPLC parameters used in the stability study of sildenal citrate in SyrSpend® SF PH4 (liquid).
Parameter Result
Peak tailing 1.31 (CV = 0.23)
Theoretical plates 4126.82 (CV = 0.59)
Linearity
Range 2.49–99.55 mcg/mL
Determination coecient 0.9996
Precision (repeatability, n = 6) CV = 1.06%
Accuracy Recovery = 99.74%
CV, coecient of variation.
Figure 1. Typical chromatograms of sildenal oral suspension in SyrSpend® SF PH4 obtained with the HPLC-validated method: (a) sildenal standard; (b) oral suspension sample. Retention times of the chromatographic peaks show suitability of the method.
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sildenal citrate for paediatric use without preservatives, and the shelf-life of both formulations was three months (91 days); however, upon opening, aqueous solutions should be used within 10 days and kept refrigerated, and syrup solutions should be used within 14 days – which are signicantly lower than what was obtained with our study.A study by Nahata et al. (2006), for their turn, veried stability of two dierent extemporaneously prepared sildenal formulations, prepared from crushed tablets and using two dierent suspending agents (1:1 mixture of Ora-Sweet® and Ora-Plus® and a 1:1 mixture of methylcellulose 1% and Simple Syrup NF). Both formulations were evaluated for physicochemical stability over a three-month period (91 days) under refrigerated conditions (4 and 8°C). No changes in pH, odour or physical appearance were observed throughout the study period, and the products remained stable after 91 days of preparation. Ora-Sweet® and Ora-Plus®, however, contain ingredients to be generally avoided in children, including glucose (Hill EM, Jijo A), carrageenan (Bhattacharyya S),
glycerin (Maclaren NK), parabens (Rowe RC, European Commission, Weil, E) and sorbitol (Johnston KR, Payne ML, Pawar S and Pecar A). In addition, theses suspensions needed to be kept in refrigerator and were prepared from commercial tablets, not high-quality pharmaceutical raw materials (Jooste, 2011). Lastly, Provenza et al. (2014) developed two oral liquid formulations of sildenal citrate for paediatric use from pure powder: a suspension (containing citrate buered solution, ‘excipient for syrup’ and distilled water) and a solution (containing citrate buered solution, ‘excipient for syrup sugar free’ and distilled water). They showed that the suspensions presented better stability (90 days at 4 and 25 °C, whilst the solution was stable for 30 days when stored at 25 and 40 °C and 15 days at 4 °C, because of the formation of non re-dispersible sediment).All these studies conrm that the sildenal citrate suspension compounded with SyrSpend® SF PH4 (liquid) posses better physicochemical stability than other vehicles reported on the literature and ingredients that are safe for use in children.
CONCLUSION
When compounded from the raw powder, sildenal citrate was stable in SyrSpend® SF PH4 (liquid) for 92 days at both room temperature and refrigerated conditions. The samples were still within specication at day 92 so the beyond-use date is concluded to be 92 days. The ndings of this study show that SyrSpend® SF PH4 (liquid) is an acceptable oral syrup and suspending vehicle for preparing individually compounded sildenal citrate suspensions. The formulations would be viable alternatives to commercially available tablets when that dosage form is found to be inappropriate whilst remaining alcohol-, sorbitol- and sugar-free.
Table 2. Stability of sildenal citrate in SyrSpend® SF PH4 (liquid).
Elapsed Time
(days)
% Recovery
Room Temperature
Refrigerated Temperature (2–8 ºC)
T = 0 100.00 100.00
T = 7 99.94 ± 3.14 98.82 ± 1.45
T = 14 99.41 ± 2.10 99.41 ± 2.47
T = 30 99.13 ± 4.21 99.55 ± 1.36
T = 61 99.38 ± 2.85 100.72 ± 3.19
T = 92 99.57 ± 1.28 100.52 ± 4.91
Values expressed as the average of three replicates ± relative standard deviation (= coecient of variation)
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[14] Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Benecial eect of oral sildenal therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation 2005;111(24):3274-3280.
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[27] Polonini HC, Loures S, Lima LC, Ferreira AO, Brandão MAF. Stability of Atenolol, Clonazepam, Dexamethasone, Diclofenac Sodium, Diltiazem, Enalapril Maleate, Ketoprofen, Lamotrigine, Penicillamine-D, and Thiamine in SyrSpend SF PH4 Oral Suspensions. Int. J. Pharm. Compd. 2016a;20(2):167.
[28] Polonini HC, Silva SL, Cunha CN, Brandão MAF, Ferreira AO. Compatibility of cholecalciferol, haloperidol, imipramine hydrochloride, levodopa/carbidopa, lorazepam, minocycline
hydrochloride, tacrolimus monohydrate, terbinane, tramadol hydrochloride and valsartan in SyrSpend® SF PH4 oral suspensions. Die Pharmazie 2015;71(4):185-191.
[29] Polonini HC, Loures S, Araujo EP, Brandão MAF, Ferreira AO. Compatibility of allopurinol, amitriptyline HCl, carbamazepine, domperidone, isoniazid, ketoconazole, Lisinopril, naproxen, paracetamol (acetaminophen) and sertraline HCl in SyrSpend SF PH4 oral suspensions. Int. J. Pharm. Compd. 2016b. In press.
[30] Polonini HC, Silva SL, de Almeida TR, Brandão MAF, Ferreira AO. Compatibility of caeine, carvedilol, clomipramine hydrochloride, folic acid, hydrochlorothiazide, loperamide hydrochloride, methotrexate, nadolol, naltrexone hydrochloride and pentoxifylline in SyrSpend SF PH4 oral suspensions. Eur. J. Hosp. Pharm. 2016c. In press.
[31] Porst H, Hell-Momeni K, Büttner H. Chronic PDE-5 inhibition in patients with erectile dysfunction -- a treatment approach using tadalal once-daily. Expert Op. Pharmacother. 2012;13(10):1481-1494.
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[33] Roque F, Rama AC, Sousa JJ, Pina ME. Development and stability assessment of liquid paediatric formulations containing sildenal citrate. Braz. J. Pharm. Sci. 2013;49(2):381-388.
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[35] Sorenson B, Whaley P. Stability of rifampin in SyrSpend SF. Int. J. Pharm. Compd. 2013;17:162-164.
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[37] Toledo ACT. Efeito da tadalala na prevenção de alterações do corpo cavernoso após lesão vasculho-nervosa do feixe periprestático. Estudo experimental em ratos. PhD Thesis, Universidade Estadual de São Paulo: São Paulo, 2013.
[38] Tissot C, Beghetti M. Advances in therapies for pediatric pulmonary arterial hypertension. Expert Rev. Respir. Med. 2009;3(3):265-282.
[39] Voudrie MA, Allen DB. Stability of oseltamivir phosphate in SyrSpend SF, Cherry Syrup, and SyrSpend SF (For Reconstitution). Int. J. Pharm. Compd. 2010;14:82-85.
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167International Journal of Pharmaceutical Compounding
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INTRODUCTION SyrSpend SF PH4 is a ready-to-use suspending vehicle that has been gaining momentum in compounding pharmacies worldwide. It is a unique suspending vehicle, as it is an alcohol- and sorbitol-free agent that helps mask unpleasant taste, and it is formulated with starch, making it less reactive. The stability of SyrSpend SF PH4 with various active pharmaceutical ingredients (APIs) has already been shown.1-11
In addition, it has been shown that SyrSpend SF is safe for vulnerable patients.12 It is important to determine the stability of different APIs within the suspending vehicle because final correct patient dosing is the result of multiple factors, from which combined physical and chemical suspension stability play a key role. Physical instability will bring inhomogeneity to the suspension and, consequently, lead to different dosing throughout treatment. Chemical instability can result in API concentrations out of the therapeutic range, or result in consumption of toxic degradation products. In both cases, the dosing can be unreliable and/or hazardous. In order to further underline the low reactivity of starch in SyrSpend SF PH4 and thus its broad stability, we performed
Stability of Atenolol, Clonazepam, Dexamethasone, Diclofenac Sodium, Diltiazem, Enalapril Maleate, Ketoprofen, Lamotrigine, Penicillamine-D, and Thiamine in SyrSpend SF PH4 Oral Suspensions
Hudson C. Polonini, BPharm, PhDSharlene Loures, BBiomedLuis Claudio Lima, BPharmAnderson O. Ferreira, BPharm, PhD CandidateMarcos Antônio F. Brandão, BPharm, PhD
The authors are affiliated with Ortofarma – Quality Control Laboratories, located in Minas Gerais State, Brazil.
ABSTRACTThe objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients compounded in oral suspensions using SyrSpend SF PH4 (atenolol 1.0 and 5.0 mg/mL, clonazepam 0.2 mg/mL, dexa-methasone 1.0 mg/mL, diclofenac sodium 5.0 mg/mL, diltiazem 12.0 mg/mL, enalapril maleate 1.0 mg/mL, ketoprofen 20.0 mg/mL, lamotrigine 1.0 mg/mL, penicillamine-D 50.0 mg/mL, thiamine 100 mg/mL) and stored both at con-trolled refrigerated (2OC to 8OC) and room temperature (20OC to 25OC). Stabil-ity was assessed by means of measuring percent recovery at varying time points throughout a 90-day period. The quantification of the active pharma-ceutical ingredients was performed by a stability-indicating, high-performance liquid chromatographic method. The beyond-use date of the products was found to be at least 90 days for all suspensions (except atenolol 1 mg/mL, which was stable up to 60 days), both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable sus-pending vehicle for compounding with a broad range of different active phar-maceutical ingredients.
stability studies with 10 different APIs not reported yet. The objective of this study was to evaluate the stability of the oral suspensions listed in Table 1, compounded using liquid SyrSpend SF PH4 and stored both at refrigerated and at room temperature.
MATERIAL AND METHODSREAGENTS, REFERENCE STANDARDS, AND MATERIALS All API raw materials and SyrSpend SF were obtained from Fagron ([atenolol] Lot 1402095C; [clonazepam] Lot 110222-1 #2; [dexamethasone] Lot 14010102 E; [diclofenac sodium] Lot 14073567; [diltiazem] Lot 14062857; [enalapril maleate] Lot 14083885; [ketoprofen] Lot 14020780; [lamotrigine] Lot 14041884 A; [penicillamine-D] Lot STBD8962V; [thiamine] Lot 14031443; [SyrSpend SF PH4] Lot 14F02-U59-019404). HPLC-grade reagents (Vetec, Rio de Janeiro, RJ, Brazil) were used. Ultrapure water obtained with an AquaMax-Ultra 370 Series (Young Lin, Anyang, Korea) (18.2 MΩ cm resistivity at 25°C and <10 ppb total organic carbon) was used throughout the experiments. The used reference standards were all work standards obtained using primary United
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States Pharmacopeia (USP) (Rockville, MD, USA) reference materials. All the mobile phases and receptor media were filtered through a 0.45-mcm filter membrane (RC-45/15 MS, Chromafil, Düren, Germany) and degassed for 30 minutes, immediately before use, using an ultrasonic apparatus (Model 1600A; Unique, Indaiatuba, SP, Brazil). All volumetric glassware and analytical balance used were previously calibrated.
EQUIPMENT High-performance liquid chromatographic (HPLC) analyses were performed on a qualified and calibrated chromatography system (Young Lin, Anyang, Korea) composed of a quaternary gradient pump (YL 9110), a photodiode array (PDA) detector (YL 9160), a 96-vial programmable autosampler (YL 9150), a column oven compartment (YL 9130), a variable sample loop up to 200 µL, and a software controller (Clarity).
CHROMATOGRAPHIC CONDITIONS The chromatographic determinations were performed according to the official USP method for each API, with minor modifications when necessary. The mobile phase used for each API is stated in Table 2. The standards were diluted in the mobile phase unless stated otherwise. All columns were from Phenomenex (Torrance, California), unless stated otherwise. The columns were connected to a pre-column with the same packing (4.0 × 3.0 mm, 5 µm) from the same manufacturer as the particle column. The injection volume was 20 µL for every chromatographic analysis.
FORCED-DEGRADATION STUDIES: STABILITY-INDICATING CHARACTERISTICS AND VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD API samples were subjected to the following stress conditions to determine the capacity of the HPLC method to detect any possible degradation product produced during storage of the oral suspension the API samples were subjected to the following stress conditions: (1) dilution in acid (0.1M HCl); (2) dilution in base (0.1M NaOH); (3) exposure to ultraviolet (UV) light at 365 nm; and (4) heating at 70°C. These solutions were prepared at their respective work concentrations for each API and then assayed by HPLC. Any extraneous peaks found in the chromatograms were labeled. Also the resolution and peak purity were determined between the degradant and the API peaks. A resolution of 1.5 was considered full separation.
TABLE 1. Concentrations of the Suspensions Used in the Study.
A C T I V E C O N C E N T R A T I O NP H A R M A C E U T I C A L I N S U S P E N S I O NI N G R E D I E N T ( M G / M L )
Atenolol 1.0
Atenolol 5.0
Clonazepam 0.2
Dexamethasone 1.0
Diclofenac sodium 5.0
Diltiazem 12.0
Enalapril maleate 1.0
Ketoprofen 20.0
Lamotrigine 1.0
Penicillamine-D 50.0
Thiamine 100.0
Specificity of the method was determined using the above-mentioned solutions and also running HPLC analyses of a standard solution, a SyrSpend SF PH4 blank solution, and a mobile phase/diluents blank solution. The acceptance criterion was defined as a percentage of discrepancy between the peak areas lower than 2%. In addition, the specificity of the method was obtained through comparison of standard chromatograms with and without the matrix. All analyses were run in triplicate. To determine the precision, the test was designed to assess the degree of dispersion
among the series of measurements obtained by the same analyst (repeatability), and between two analysts and two days (within-lab variations, intermediate precision) for solutions of the API at work concentration. Repeatability was determined by consecutively analyzing six replicates by a single analyst in a single day. Intermediate precision was also performed in six replicates, but in two days, by different analysts. An injection precision of <5% relative to the coefficient of variation (CV) was considered acceptable. Accuracy measurements were performed by the same analyst by injecting the chromatographic samples to which the matrix was added (at the same concentration levels performed for the linearity test [n=3 for each concentration level]). The result was expressed as a percentage of recovery, compared with the analytical curve obtained from linearity. To define linearity, three standard curves were plotted, each constructed from the API concentrations of 70% to 130% of work concentrations in order to assess the linear relationship between the concentration of the analyte and the obtained areas. For this purpose, the data for each concentration range of the curve after fitting by ordinary least squares method were evaluated by analysis of variance (ANOVA) and subjected to the least squares method to determine the correlation coefficient of the calibration curve. The limit of detection (LOD) and limit of quantification (LOQ) were determined from three standard calibration curves and were calculated as shown in Equations (1) and (2), respectively:
LOD = s 3
Equation (1)
a
LOQ = s
10 Equation (2)
a
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A C T I V E PHARMACEUTICAL I N G R E D I E N T
Atenolol
Clonazepam
Dexamethasone
Diclofenac sodium
Diltiazem
Enalapril maleate
Ketoprofen
Lamotrigine
Penicillamine-D
Thiamine
M O B I L E P H A S E C O M P O S I T I O N
• 1.1 g of sodium 1-heptanesulfonate
• 0.71 g of anhydrous dibasic sodium phosphate
• 700 mL of water
• 2 mL of dibutylamine
• pH 3.0 with 0.8 M phosphoric acid
• 300 mL of methanol
• Methanol
• Acetonitrile
• Water (30:30:40)
• Methanol
• Water
• Glacial acetic acid (55:43:2)
• Methanol
• pH 2.5 phosphate buffer (700:300)
• Acetonitrile
• Methanol
• Solution A* (50:25:25)
*Solution A:
• 1.16 mg/mL d-10-camphorsulfonic
acid in 0.1 M sodium acetate
• pH 6.2 with 0.1 M sodium hydroxide
• Acetonitrile
• 1M phosphate buffer pH 4.0
• Water (3:2:6.8)
• Acetonitrile
• Water
• Buffer*
*Buffer:
• 68 g/L of monobasic potassium
phosphate in water
• pH 3.5 with phosphoric acid
(43:55:2)
• Acetonitrile
• Methanol
• 0.77 g/L ammonium acetate
• pH 4.5 with glacial acetic acid
(30:10:60)
• 6.9 g of sodium monobasic phosphate
• 0.2g of sodium hexanosulphonate in
water (1 L, pH 3.0)
• Methanol
• 0.04 M aqueous monobasic
potassium phosphate (45:55)
W O R K C O N C E N T R A T I O N ( M G / M L ) *
0.01
0.025
0.04 mg/mL in methanol
and water (1:1)
0.75 mg/mL in methanol
and water (70:30)
0.12
1.0
0.002
0.05 mg/mL in acetonitrile,
methanol, and Buffer
(30:30:40)
1.25 mg/mL in 1% aqueous
EDTA
0.05
C O L U M N
L1, 4.6-mm × 25-cm,
5-mcm particle column at
80ºC
L1, 4.6-mm × 10-cm,
5-mcm particle column
L1, 4.6-mm × 25-cm,
5-mcm particle column
L7 (end-capped), 4.6-mm
× 25-cm, 5-mcm particle
column
L1, 4.6-mm × 25-cm,
5-mcm particle column
L7, 4.6-mm × 25-cm,
5-mcm particle column
L1, 4.6-mm × 15-cm,
5-mcm particle column
L1, 3.0-mm × 15-cm,
5-mcm particle column at
40ºC
L1, 4.6-mm × 15-cm,
5-mcm particle column
Varian (USA)
L1, 34.6-mm × 25-cm,
3.5-mcm particle column
F L O W ( M L /M I N )
0.6
1.0
1.5
1.0
1.5
1.5
1.0
1.5
1.6
1.0
U V D E T E C T I O N W A V E L E N G T H ( N M )
226
254
215
254
240
215
233
210
210
254
TABLE 2. Chromatographic Conditions Used in the Stability Study.
*Diluted with mobile phase, unless specified otherwise.
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where a is the slope of the calibration curve, and s is the standard deviation of the y-intercept. The LOD and LOQ were both confirmed by the analysis of chromatograms generated by injecting solutions in their respective limit concentrations.
PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS SUSPENSION SAMPLES The suspensions were compounded at the Ortofarma’s Galenic Laboratory. The API suspensions were prepared per API by adding the required quantity of API to each of a low-actinic prescription bottle. SyrSpend SF PH4 was added using a volumetric pipette to achieve a final volume of 300 mL. The final concentrations are summarized in Table 1 (two bottles per API). The suspensions were then assayed at T = 0h, and then separated in two different
bottles: one sample was stored at USP-controlled13 refrigerated temperature (2ºC to 8ºC), and the other at room temperature (20ºC to 25ºC), for the duration of the study (temperature and humidity checked in real time throughout the whole experiment, using a calibrated thermo-hygrometer). Both samples were protected from light. Before analyses, the bottles were shaken until the API was uniformly dispersed.
STABILITY STUDY The API samples were HPLC-assayed in pre-determined time points to verify the stability of the API in SyrSpend SF PH4. The samples were shaken manually for 1 minute to simulate patient dosing and then adequate volumetric aliquots for quantification (variable for each API) were withdrawn from the middle of
A C T I V EP H A R M A C E U T I C A L I N G R E D I E N T
R A N G E ( M C G /M L )
A N A L Y T I C A L C U R V E R 2
A N O V A ’ S S I G N I F I C A N C E O F R E G R E S S I O N ( F )
A N O V A ’ S L A C K O F F I T ( F ) L O D L O Q
D I S C R E P A N C Y ( % )R E P E A T A B I L I T Y ( C V , % )
I N T E R M E D I A T E P R E C I S I O N ( C V , % ) R E C O V E R Y ( % )
TABLE 3. Summary of Linearity’s Study for the Validation of the High-performance Liquid Chromatographic Method.
L I N E A R I T Y
LOD = Limit of Detection; LOQ = Limit of Quantification; CV = coefficient of variationAcceptance criteria were: R2 > 0.99, F (significance of regression) >> 4.67, F (lack of fit) < 3.71, discrepancy < 2%, repeatability and intermediate precision < 5%, and recovery = 100% ± 2%.All analytical ranges (mcg/mL) were adequate to quantify the active pharmaceutical ingredients in the concentrations used in the suspensions (mg/mL).
S P E C I F I C I T Y P R E C I S I O N A C C U R A C Y
|1.53| 0.12 2.70 100.25
|0.51| 0.39 2.79 100.24
|1.87| 0.78 1.14 100.77
|1.24| 0.97 3.57 99.06
|1.08| 0.11 0.60 99.73
|0.30| 0.50 1.38 100.74
|1.32| 0.21 2.77 100.14
|0.84| 2.40 4.01 99.45
|1.13| 0.37 4.50 100.24
|0.53| 0.64 2.06 99.83
A C T I V EP H A R M A C E U T I C A L I N G R E D I E N T
Atenolol
Clonazepam
Dexamethasone
Diclofenac sodium
Diltiazem
Enalapril maleate
Ketoprofen
Lamotrigine
Penicillamine-D
Thiamine
Atenolol 7.00 to 13.00 y = 50.34x + 86.37 0.990 1290.06 3.65 0.03 0.11
Clonazepam 17.99 to 33.41 y = 98.49x – 100.51 0.997 4372.48 0.62 0.08 0.27
Dexamethasone 28.28 to 52.52 y = 36.79x – 99.55 0.995 2764.77 2.52 0.02 0.07
Diclofenac sodium 525 to 975 y = 31.23x + 2610.67 0.994 2279.89 2.81 0.001 0.003
Diltiazem 84.35 to 156.65 y = 41.396x – 111.16 0.999 3076.87 1.95 0.02 0.06
Enalapril maleate 142.24 to 264.16 y = 59.98x – 1285.88 0.991 1470.46 3.24 0.005 0.016
Ketoprofen 17.15 to 31.85 y = 57.80x + 10.35 0.991 1378.61 3.38 0.15 0.50
Lamotrigine 35.21 to 65.39 y = 171.81x – 374.57 0.992 1621.12 2.08 0.04 0.13
Penicillamine-D 875.00 to 1625.00 y = 1.90x – 53.22 0.998 8913.58 1.90 0.001 0.002
Thiamine 35.14 to 65.26 y = 20.61x – 6.02 0.991 1414.10 2.79 0.07 0.24
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the bottles, without contacting the inner surface of the bottle, and diluted properly in order to obtain work solutions in the concentration described in “Chromatographic Conditions.” Sampling times were: initial (T=0), 7 days (T=7), 14 days (T=14), 30 days (T=30), 60 days (T=60), and 90 days (T=90). All suspensions were assayed six times at each time point. The evaluation parameter was the percent recovery with respect to T=0, using the HPLC method (results given as percentage ± standard deviation).
RESULTS AND DISCUSSIONSTABILITY-INDICATING CHARACTERISTICS AND VALIDATION OF THE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD
The results of specificity, precision, accuracy, and linearity are listed in Table 3. All analysis methods met the respective acceptance criteria. Data from these stability-indicating studies are summarized in Table 4. As can be seen, the majority of the parameters evaluated led to some degree of alteration in the chromatographic peak of the APIs, with only a few exceptions. Only penicillamine-D was stable under heat exposure, and only diltiazem, penicillamine-D, and thiamine were stable to basic stress, while diltiazem, enalapril maleate, thiamine, and penicillamine-D were stable to UV-light exposure. The discrepancy of the chromatographic peaks was high between the API’s samples with and without stress. When there is chemical degradation in the suspensions, the assay would give variable results (higher or lower) than the expected. Thus, these fluctuations in the chromatograms were carefully followed up, as they indicate when degradation would occur within the suspensions.
STABILITY STUDY The concentrations used in the study were selected based on commonly prescribed concentrations and so that expected dosages (from children up to adults) could easily be measured. SyrSpend SF PH4 liquid was used because of its practicality, as it is a ready-for-use vehicle. The results are shown in Table 5, expressed as relative percent of recovery
(initial sampling time = 100%). For the suspensions to be considered stable/compatible, the relative percentage recovery should lie within 90% to 110%, according to the international pharmacopeias used (i.e., USP, British Pharmacopoeia, and European Pharmacopoeia).13-15 Figures A-K that accompany this article represent graphically the stability of the APIs in SyrSpend SF PH4 in terms of absolute nominal concentration. At each sampling time, the visual aspect of the suspensions was also evaluated to verify the homogeneity. This study showed an API stability in SyrSpend SF for 90 days after preparation for all APIs, except for atenolol 1 mg/mL, which was stable until 60 days after preparation. The difference in stability between the 1-mg/mL atenolol suspension and the 5-mg/mL atenolol suspension could be a result of the pseudo zero-order kinetics commonly seen in suspensions. The rate constant for degradation is limited by the solubility of the API in water instead of the concentration of the API, assuming that the API, which is not dissolved, does not interact. In the case of atenolol the solubility is 0.1 mg/mL to 0.3 mg/mL in water, and the rate constant for the degradation processes is therefore limited by the maximum solubility. Although the rate constant is identical for all concentrations above 0.3 mg/mL, the relative impact on the degradation processes is larger for the 1-mg/mL atenolol suspension than for the 5-mg/mL atenolol suspension. Another factor that could play a role in the degradation is the pH of the suspensions. The normal pH range of the SyrSpend SF is 4.0. At the start of the experiment, the pH for atenolol 1 mg/mL was 4.60 and for atenolol 5 mg/mL the pH was 6.92. It was already reported that atenolol suspensions are more stable at a pH between 5.5 and 6.5,16 which is in agreement with the results found here, and that
Note: Results presented as average of 3 replicates, at the work concentration.*%d = percentage of discrepancy between the API peak without degradation (negative control) and the peak of a sample subjected to one of the cited accelerated-deg-radation factors. Areas given as mV. Maximum acceptable = 2%. Bold numbers indicate factors that led to high interference with the analytical peak of the API.API = active pharmaceutical ingredient
TABLE 4. Summary of the Stability-indicating Study for the Active Pharmaceutical Ingredients.
A P I H C L N A O H U V H E A T
A R E A % D * A R E A % D * A R E A % D * A R E A % D *
Atenolol 615.16 -3.85 604.42 -5.53 597.47 -6.62 624.55 -2.38
Clonazepam 2109.33 4.07 1824.34 -10.01 1938.06 -4.39 1900.99 -6.21
Dexamethasone 1369.51 6.74 1208.15 -5.83 1343.69 4.73 1332.44 3.85
Diclofenac sodium 21179.04 -14.77 19407.90 -21.91 25878.18 4.13 25640.38 3.17
Diltiazem 4704.67 -5.86 4975.97 -0.43 4988.20 -0.19 4853.20 -2.89
Enalapril maleate 8173.17 3.01 8154.12 2.77 7847.05 -1.10 8237.64 3.82
Ketoprofen 1334.80 -3.21 1322.76 -4.09 1340.25 -2.82 1345.23 -2.45
Lamotrigine 8324.60 6.85 8520.46 9.37 8672.84 11.32 8665.48 11.23
Penicillamine-D 2209.03 3.67 2152.97 1.03 2156.07 1.18 2114.94 -0.75
Thiamine 987.75 -2.71 1007.31 -0.79 1004.34 -1.08 1037.77 2.21
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TABLE 5. Stability of the Active Pharmaceutical Ingredients in SyrSpend SF PH4.
% R E C O V E R Y % R E C O V E R Y
C O N T R O L L E D C O N T R O L L E D
E L A P S E D R E F R I G E R A T E D R O O M
T I M E T E M P E R A T U R E T E M P E R A T U R E
( D A Y S ) ( 2 º C T O 8 º C ) ( 2 0 º C T O 2 5 º C )
% R E C O V E R Y % R E C O V E R Y
C O N T R O L L E D C O N T R O L L E D
E L A P S E D R E F R I G E R A T E D R O O M
T I M E T E M P E R A T U R E T E M P E R A T U R E
( D A Y S ) ( 2 º C T O 8 º C ) ( 2 0 º C T O 2 5 º C )
ATENOLOL 1 MG/ML
T = 0 100 ± 0.32 100 ± 0.32
T = 7 96.31 ± 0.16 93.45 ± 0.19
T = 14 90.06 ± 1.02 90.19 ± 0.40
T = 30 93.03 ± 0.31 90.03 ± 0.43
T = 60 93.84 ± 0.51 90.27 ± 0.83
T = 90 86.15 ± 1.56 (failed) 89.78 ± 0.86 (failed)
ATENOLOL 5 MG/ML T = 0 100 ± 0.15 100 ± 0.15
T = 7 97.42 ± 0.18 96.51 ± 0.24
T = 14 100.21 ± 0.43 98.79 ± 1.65
T = 30 95.06 ± 0.33 94.50 ± 0.51
T = 60 97.92 ± 0.28 95.79 ± 0.83
T = 90 102.32 ± 0.35 93.90 ± 0.50
CLONAZEPAM 0.2 MG/MLT = 0 100 ± 0.49 100 ± 0.49
T = 7 104.46 ± 0.18 108.74 ± 0.47
T = 14 100.66 ± 0.31 108.24 ± 0.50
T = 30 105.51 ± 0.53 103.74 ± 0.82
T = 60 103.45 ± 0.19 106.89 ± 0.16
T = 90 105.53 ± 0.36 103.18 ± 0.38
DEXAMETHASONE 1 MG/MLT = 0 100 ± 0.76 100 ± 0.76
T = 7 103.20 ± 3.44 97.47 ± 0.40
T = 14 97.24 ± 2.71 97.78 ± 0.89
T = 30 107.31 ± 1.07 103.75 ± 1.01
T = 60 97.02 ± 0.72 102.24 ± 0.22
T = 90 105.97 ± 0.24 103.42 ± 0.52
DICLOFENAC SODIUM 5 MG/MLT = 0 100 ± 0.26 100 ± 0.26
T = 7 103.54 ± 0.87 99.71 ± 0.56
T = 14 102.32 ± 0.77 99.70 ± 0.30
T = 30 105.16 ± 0.08 99.04 ± 0.68
T = 60 104.60 ± 1.33 100.68 ± 0.34
T = 90 96.68 ± 0.31 97.46 ± 1.71
DILTIAZEM 12 MG/MLT = 0 100 ± 0.38 100 ± 0.38
T = 7 94.21 ± 1.30 96.63 ± 0.61
T = 14 90.90 ± 0.79 94.91 ± 0.64
T = 30 97.50 ± 0.40 97.89 ± 0.53
T = 60 97.16 ± 0.18 94.93 ± 0.25
T = 90 99.57 ± 0.79 95.84 ± 1.15
ENALAPRIL MALEATE 1 MG/MLT = 0 100 ± 0.47 100 ± 0.47
T = 7 96.33 ± 0.70 100.41 ± 0.57
T = 14 93.16 ± 0.15 98.15 ± 0.43
T = 30 98.25 ± 1.24 101.55 ± 0.13
T = 60 100.10 ± 0.34 98.25 ± 0.17
T = 90 99.91 ± 0.33 99.21 ± 0.50
KETOPROFEN 20 MG/MLT = 0 100 ± 0.49 100 ± 0.49
T = 7 91.65 ± 0.24 92.40 ± 0.49
T = 14 92.11 ± 0.37 96.37 ± 0.29
T = 30 92.22 ± 0.38 93.59 ± 1.13
T = 60 91.87 ± 1.04 94.02 ± 0.78
T = 90 92.49 ± 0.70 93.56 ± 0.22
LAMOTRIGINE 1 MG/MLT = 0 100 ± 0.56 100 ± 0.56
T = 7 97.65 ± 0.70 91.89 ± 1.67
T = 14 94.98 ± 0.14 97.64 ± 0.14
T = 30 95.48 ± 1.43 94.70 ± 0.76
T = 60 96.97 ± 1.24 97.02 ± 0.77
T = 90 95.95 ± 0.57 97.11 ± 0.63
PENICILLAMINE-D 50 MG/MLT = 0 100 ± 0.41 100 ± 0.41
T = 7 101.33 ± 0.32 94.00 ± 0.11
T = 14 101.41 ± 0.25 100.00 ± 0.32
T = 30 108.03 ± 2.30 100.17 ± 2.59
T = 60 101.92 ± 0.49 95.83 ± 0.21
T = 90 105.67 ± 0.84 94.49 ± 0.81
THIAMINE 100 MG/MLT = 0 100 ± 0.60 100 ± 0.60
T = 7 96.27 ± 1.35 95.43 ± 1.33
T = 14 95.78 ± 0.86 99.12 ± 0.22
T = 30 101.01 ± 0.38 95.86 ± 0.77
T = 60 97.70 ± 0.37 95.80 ± 0.63
T = 90 92.43 ± 1.04 94.82 ± 1.12
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173International Journal of Pharmaceutical Compounding
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1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
LTime (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[L
amot
rigi
ne]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
FIGURES A-K. Plots of active pharmaceutical ingredients in SyrSpend SF PH4 throughout the stability study.
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otri
gine
] m
g/m
L
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
Peer ReviewedESTUDO 16ESTUDO 16
174International Journal of Pharmaceutical CompoundingVol. 20 No. 2 | March | April | 2016
www.IJPC.com
is the reason why some authors adjust the pH of the suspension to this range using citric acid.17 Apart from this, SyrSpend SF PH4 showed to be a very useful suspending vehicle for compounding individualized oral suspensions, as it was compatible with all tested APIs. Therefore, it represents a safe alternative to commercial oral suspensions and even other dosage forms found to be inappropriate by physicians, pharmacists, and patients. In this sense, SyrSpend SF PH4 is a favorable suspension base for a wide range of APIs.
CONCLUSION Based on the results, one can conclude that the suspensions compounded with SyrSpend SF PH4 (atenolol, clonazepam, dexamethasone, diclofenac sodium, diltiazem, enalapril maleate, ketoprofen, lamotrigine, penicillamine-D, thiamine) were compatible for 90 days, when stored at controlled refrigerated temperature (2ºC to 8ºC) conditions and at controlled room temperature (20ºC to 25ºC) conditions, except for atenolol 1 mg/mL, which was compatible for up to 60 days. This shows that SyrSpend SF PH4 is an appropriate suspending vehicle for the preparation of
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
FIGURES A-K CONTINUED. Plots of active pharmaceutical ingredients in SyrSpend SF PH4 throughout the stability study.
individualized compounded oral suspensions with the above-mentioned APIs.
REFERENCES1. Vu NT, Aloumanis V, Ben M et al.
Stability of metronidazole benzoate in SyrSpend SF one-step suspension system. IJPC 2008; 12(6): 558–564.
2. Geiger CM, Voudrie MA II, Sorenson B. Stability of ursodiol in SyrSpend SF Cherry Flavored. IJPC 2012; 16(6): 510–512. Erratum in IJPC 2013; 17(1): 86.
3. Sorenson B, Whaley P. Stability of rifampin in SyrSpend SF. IJPC 2013; 17(2): 162–164.
4. Geiger CM, Sorenson B, Whaley PA. Stability of captopril in SyrSpend SF. IJPC 2013; 17(4): 336–338.
5. Sorenson B, Voudrie MA II, Gehrig D. Stability of gabapentin in SyrSpend SF. IJPC 2012; 16(4): 347–349.
6. Geiger CM, Sorenson B, Whaley PA. Stability of midazolam in SyrSpend SF and SyrSpend SF Cherry. IJPC 2013; 17(4): 344–346.
7. Whaley PA, Voudrie MA II, Sorenson B. Stability of omeprazole in SyrSpend SF Alka (reconstituted). IJPC 2012; 16(2): 164–166.
8. Voudrie MA, Allen DB. Stability of oseltamivir phosphate in SyrSpend SF, Cherry Syrup, and SyrSpend SF (for reconstitution). IJPC 2010; 14(1): 82–85.
9. Whaley PA, Voudrie MA II. Stability of vancomycin in SyrSpend SF. IJPC 2012; 16(2): 167–169. Erratum in IJPC 2013; 17(1): 86.
10. Voudrie MA, Alexander B, Allen DB. Stability of verapamil hydrochloride in SyrSpend SF compared to sorbitol containing syrup and suspending vehicles. IJPC 2011; 15(3): 255–258.
11. Geiger CM, Voudrie MA II, Sorenson B. Stability of propranolol hydrochloride in SyrSpend SF. IJPC 2012; 16(6): 513–515. Erratum in IJPC 2013; 17(1): 86.
12. Helin-Tanninen M, Autio K, Keski-Rahkonen et al. Comparison of six different suspension vehicles in compounding of oral extemporaneous nifedipine suspension for paediatric patients. Eur J Hosp Pharm 2012; 19(5): 432-437.
13. United States Pharmacopeial Convention, Inc. United States Pharmacopeia 38–National Formulary 33. Rockville, MD: US Pharmacopeial Convention, Inc.; Current Edition.
14. British Pharmacopoeia Commission Office. British Pharmacopoeia 2015. London, UK: The Stationery Office; 2015.
15. Council of Europe. European Pharmacopoeia 8.0. Germany: Druckerei C. H. Beck; 2015.
16. Ferreira AO, Souza GF. Preparações orais líquidas 3rd ed. São Paulo: Pharmabooks; 2011.
17. Patel D, Doshi DH, Desai A. Short-term stability of atenolol in oral liquid formulations. IJPC 1997; 1(6): 437–439.
Address correspondence to Ortofarma Laboratório de Controle de Qualidade, BR 040, Empresarial Park Sul, n. 39 - CEP 36120-000 - Matias Barbosa - MG, Brazil.
1.2
1.1
1.0
0.9
0.8
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
y=60.016x + 20.17R = 0.9993
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Ate
nolo
l] m
g/m
L
Time (days)
0 30 60 90
[Atenolol] mg/mL (refrigerated)
[Atenolol] mg/mL (room temperature)
0.24
0.22
0.20
0.18
0.16
[Clo
naze
pam
] m
g/m
L
Time (days)
0 30 60 90
[Clonazepam] mg/mL (refrigerated)
[Clonazepam] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8[Dex
amet
haso
ne]
mg/
mL
Time (days)
0 30 60 90
[Dexamethasone] mg/mL (refrigerated)
[Dexamethasone] mg/mL (room temperature)
14
13
12
11
10[Dic
lofe
nac
Sodi
um]
mg/
mL
Time (days)
0 30 60 90
[Diclofenac Sodium] mg/mL (refrigerated)
[Diclofenac Sodium] mg/mL (room temperature)
6.0
5.5
5.0
4.5
4.0
[Dilt
iaze
m]
mg/
mL
Time (days)
0 30 60 90
[Diltiazem] mg/mL (refrigerated)
[Diltiazem] mg/mL (room temperature)
14
13
12
11
10[Ena
lapr
il M
alea
te]
mg/
mL
Time (days)
0 30 60 90
[Enalapril Maleate] mg/mL (refrigerated)
[Enalapril Maleate] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Ket
opro
fen]
mg/
mL
Time (days)
0 30 60 90
[Ketoprofen] mg/mL (refrigerated)
[Ketoprofen] mg/mL (room temperature)
1.2
1.1
1.0
0.9
0.8
[Lam
otrig
ine]
mg/
mL
Time (days)
0 90
[Lamotrigine] mg/mL (refrigerated)
[Lamotrigine] mg/mL (room temperature)
60
55
50
45
40[Pen
icill
amin
e-D
] m
g/m
L
Time (days)
[Penicillamine-D] mg/mL (refrigerated)
[Penicillamine-D] mg/mL (room temperature)
0 30 60 90
120
110
100
90
80
[Thi
amin
e] m
g/m
L
Time (days)
[Thiamine] mg/mL (refrigerated)
[Thiamine] mg/mL (room temperature)
0 30 60 90
A. Atenolol 1.0 mg/mL
B. Atenolol 5.0 mg/mL
C. Clonazepam 0.2 mg/mL
D. Dexamethasone 1.0 mg/mL
E. Diclofenac Sodium 5.0 mg/mL
F. Diltiazem 12.0 mg/mL
G. Enalapril maleate 1.0 mg/mL
H. Ketoprofen 20.0 mg/mL
I. Lamotrigine 1.0 mg/mL
J. Penicillamine-D 50.0 mg/mL
K. Thiamine 100 mg/mL
Peer ReviewedESTUDO 16ESTUDO 16
Compatibility of caffeine, carvedilol, clomipraminehydrochloride, folic acid, hydrochlorothiazide,loperamide hydrochloride, methotrexate, nadolol,naltrexone hydrochloride and pentoxifylline inSyrSpend SF PH4 oral suspensionsHudson C Polonini, Sharlene L Silva, Thalyta R de Almeida,Marcos Antônio F Brandão, Anderson O Ferreira
Quality Control Laboratories,Ortofarma, Matias Barbosa,Brazil
Correspondence toAnderson Ferreira, OrtofarmaLaboratório de Controle daQualidade, Empresarial ParkSul, n. 39, Matias Barbosa,Minas Gerais 36120-000,Brazil;[email protected]
Received 28 January 2016Revised 29 February 2016Accepted 1 March 2016
To cite: Polonini HC,Silva SL, de Almeida TR,et al. Eur J Hosp PharmPublished Online First:[please include Day MonthYear] doi:10.1136/ejhpharm-2016-000903
ABSTRACTObjectives The objective of this study was to evaluatethe compatibility of 10 commonly used activepharmaceutical ingredients (APIs) compounded in oralsuspensions using a globally available suspending vehicle(SyrSpend SF PH4 liquid): caffeine 10.0 mg/mL,carvedilol 1.0 mg/mL, clomipramine hydrochloride5.0 mg/mL, folic acid 1.0 mg/mL, hydrochlorothiazide5.0 mg/mL, loperamide hydrochloride 1.0 mg/mL,methotrexate 2.5 mg/mL, nadolol 10.0 mg/mL,naltrexone hydrochloride 1.0 mg/mL and pentoxifylline20.0 mg/mL, stored at both controlled refrigerated (2–8°C) and room (20–25°C) temperature.Methods Compatibility was assessed by measuring theper cent recovery at different time points throughout a90-day period. Quantification of the APIs was performedby high performance liquid chromatography (HPLC-UV)using a stability-indicating method.Results Methods were adequately validated. Forceddegradation studies showed that at least one parameterinfluenced the stability of the APIs. All suspensions wereassayed and showed API contents of between 90% and110% over 90 days.Discussion Given the percentage of recovery of theAPIs within the suspensions, the expiration date of thefinal products (API+vehicle) was found to be at least90 days for all suspensions, for both controlledrefrigerated and room temperature.Conclusions The results suggest that SyrSpend SF PH4liquid is a stable suspending vehicle for compoundingAPIs from different pharmacological classes.
INTRODUCTIONExtemporaneous preparation of oral liquid dosageforms is a common and important pharmacy prac-tice for patients who require non-standard doses,have swallowing difficulties or receive medicationvia an enteral feeding tube.1 Oral liquids are com-monly employed in paediatrics2 3 and in thegeneral adult population, where recent studies havedemonstrated a swallowing difficulty prevalence ofup to 22.4%.4 5
Oral liquids are relatively quick and easy toprepare with a limited need for compoundingequipment, and allow for flexibility in dosageadjusted from a single strength preparation.2
The main challenge with compounding oralliquid formulations is the limited availability of
data to support the physical, chemical and micro-biological stability of the formulations.1 2 6 In a UKsurvey it was found that the shelf life of more thanhalf (54%) of extemporaneous formulations wasinadequately supported.2 Due to the limited avail-ability of scientific data, there is little harmonisationof the concentrations or formulations of com-pounded oral liquids.2 7 This poses a patient safetyconcern and a risk for medication errors.7 Therehave been demands for the publication of scientific-ally verified, palatable extemporaneous formula-tions with standardised oral liquid concentrationsto increase patient safety and adherence.2 6–8
The objective of this study was to evaluate thephysical and chemical compatibility of the 10 fre-quently used active pharmaceutical ingredients(APIs) listed in table 1, compounded at a singleconcentration using SyrSpend SF PH4 (liquid) andstored at both refrigerated and room temperature.SyrSpend SF is an internationally available, GMP
produced, ready-to-use taste-masking oral liquidvehicle. Its suspending properties are derived fromstarch without traditionally used excipients that canhave toxicological effects, induce allergic reactionsor cause irritation, such as sugar,9 10 ethanol,11 12
propylene glycol,13 14 sorbitol,15 16 benzylalcohol17–19 and common food allergens.20 21 Thecompatibility of SyrSpend SF with a large numberof APIs has already been demonstrated.22–33 Itsdetailed formulation can be found in table 2, alongwith safety references.In this study, the combined physical and chemical
compatibility was assessed, as a deficit in either ofthe two would result in an out of specificationresult during analysis. The concentration for eachAPI study was selected based on commonly pre-scribed concentrations for children or adults. Tothe best of the authors’ knowledge, there is no pre-vious study in the literature dealing with the stabil-ity of these APIs compounded using SyrSpend SFPH4 (liquid).
MATERIALS AND METHODSReagents, reference standards and materialsAll raw materials and SyrSpend SF PH4 (liquid)were obtained from Fagron (São Paulo, Brazil).High performance liquid chromatography(HPLC)-grade reagents (Vetec, Rio de Janeiro,Brazil) were used. Ultrapure water obtained with an
Polonini HC, et al. Eur J Hosp Pharm 2016;0:1–7. doi:10.1136/ejhpharm-2016-000903 1
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AquaMax-Ultra 370 Series system (Young Lin, Anyang, Korea)(18.2 MΩ cm resistivity at 25°C and <10 ppb total organiccarbon) was used throughout the experiments. The referencestandards used were all work standards obtained using primaryUSP (Rockville, Maryland, USA) reference materials. All mobilephases and receptor media were filtered through a 0.45 mmfilter membrane (RC-45/15 MS; Chromafil, Düren, Germany)and degassed using an ultrasonic apparatus (model 1600A;Unique, Indaiatuba, Brazil) for 30 min immediately before use.All volumetric glassware and analytical balances used werecalibrated.
EquipmentHPLC analyses were performed on a qualified and calibratedchromatography system (Young Lin) consisting of a quaternarygradient pump (YL 9110), a photodiode array (PDA) detector
(YL 9160), a 96-vial programmable autosampler (YL 9150), acolumn oven compartment (YL 9130), a variable sample loopup to 200 mL and a software controller (Clarity).
Chromatographic conditionsThe chromatographic determinations were performed accord-ingly to the official USP method for each API, with minor modi-fications when necessary. The mobile phase used for each API isgiven in table 3. The standards were diluted in the mobile phaseunless otherwise stated. All columns were from Phenomenex(Torrance, California, USA), unless otherwise stated. Thecolumns were connected with a pre-column with the samepacking (4.0×3.0 mm, 5 mm) from the same manufacturer asthe particle column. The injection volume was 20 μL for everychromatographic analysis.
Validation of the HPLC methodThe methods and their acceptance criteria were establishedbased upon the protocols defined by USP49 and ICH(International Conference on Harmonization).50
The specificity of the method was determined by runningHPLC analyses of a standard solution, a SyrSpend SF PH4(liquid) blank solution, and a mobile phase/diluents blank solu-tion. The acceptance criteria were defined as a percentage ofdiscrepancy between the peak areas lower than 2%. In addition,the specificity of the method was obtained through comparisonof standard chromatograms with and without the matrix. Allanalyses were run in triplicate.
For precision, the test was designed to assess the degree of vari-ation among the series of measurements obtained by the sameanalyst (repeatability) and between two analysts and 2 days (within-laboratory variations, intermediate precision) for solutions of theAPI at work concentrations. Repeatability was determined by con-secutively analysing six replicates by a single analyst in a single day.Intermediate precision was also performed on six replicates, but in2 days, by different analysts. An injection precision of more than95% (coefficient of variation, CV) was considered acceptable.
The accuracy of the method was determined throughspike-recovery of the SyrSpend SF PH4 (liquid) matrix, dilutedwithin the range used for final sample measurements, andwithin range of the corresponding calibration curves. Per centrecovery was calculated from the concentration measured rela-tive to the theoretical concentration spiked.
For linearity, the test was conducted by plotting three stand-ard curves (genuine replicates, from three separate samplings),each constructed from the API concentrations of 70–130% ofwork concentrations in order to assess the linear relationshipbetween the concentration of the analyte and the obtainedareas, and in the presence of the SyrSpend SF PH4 (liquid)matrix. For this purpose, the data for each concentration rangeof the curve after fitting by the ordinary least squares methodwere evaluated by analysis of variance (ANOVA) and subjectedto the least squares method to determine the correlation coeffi-cient of the calibration curve.
The limit of detection (LOD) and limit of quantification(LOQ) were determined from three standard calibration curvesof the APIs in the presence of the SyrSpend SF PH4 (liquid)matrix and were calculated as shown in Eqs. (1) and (2), respect-ively:
LOD ¼ s3a
ð1Þ
LOQ ¼ s10a
ð2Þ
Table 2 SyrSpend SF PH4 (liquid) composition
Ingredient Function Safety references
Purified water Liquid phase N/AModified foodstarch
Suspendingagent
FDA 21CFR 172.89234
Sodium citrate Buffering agent FDA GRAS listed35
Citric acid Buffering agent FDA GRAS listed35
Sucralose Sweetener FDA, EC Scientific Committee on Food36 37
Sodiumbenzoate*
Preservative FDA GRAS listed, EC Scientific Committeeon Food, WHO Expert Committee on FoodAdditives38–41
Malic acid Buffering agent FDA GRAS listed42
Simethicone Anti-foamingagent
WHO Expert Committee on FoodAdditives43
*Even though the WHO mentions an acceptable daily intake of 5 mg/kg bodyweightsodium benzoate, it is known that this ingredient can cause metabolic acidosis andneurotoxicity in pre-term neonates and infants (<6 months) due to immaturemetabolism capacity.44–47 The concentration of sodium benzoate in SyrSpend SF PH4(liquid) is low (<0.1%) compared to the concentrations reported in the literature inconnection with fatal accidents,44 and much lower than concentrations to whichneonates are still being exposed in hospital settings today.48 However, as precautioncompounders can also use SyrSpend SF PH4 (dry), a similar, preservative-free, vehicle(ingredients: modified food starch, sodium citrate, citric acid and sucralose) withsimilar API compatibility.29
API, active pharmaceutical ingredient; FDA GRAS, Food and Drug AdministrationGenerally Recognized as Safe.
Table 1 Concentrations of the suspensions used in the study
APIConcentration insuspension (mg/mL) Action and use
Caffeine 10.0 Central nervous systemstimulant
Carvedilol 1.0 β-Adrenoceptor antagonist;arteriolar vasodilator
Clomipraminehydrochloride
5.0 Monoamine reuptakeinhibitor; tricyclicantidepressant
Folic acid 1.0 Vitamin B componentHydrochlorotiazide 5.0 Thiazide diureticLoperamidehydrochloride
1.0 Opioid receptor agonist;antidiarrhoeal
Methotrexate 2.5 Dihydrofolate reductaseinhibitor; cytostatic
Nadolol 10.0 β-Adrenoceptor antagonistNaltrexonehydrochloride
1.0 Opioid receptor antagonist
Pentoxifylline 20.0 Vasodilator
API, active pharmaceutical ingredient.
2 Polonini HC, et al. Eur J Hosp Pharm 2016;0:1–7. doi:10.1136/ejhpharm-2016-000903
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where a is the slope of the calibration curve, and s is the SD ofthe y-intercept. The LOD and LOQ were confirmed by analysisof chromatograms generated by injecting solutions in theirrespective limit concentrations.
Preparation of API suspension samplesThe API suspensions were prepared using the following generalprotocol: (i) the required quantity of each ingredient for thetotal amount to be prepared was calculated; (ii) each ingredientwas accurately weighed; (iii) the API was placed in the mortarand triturated until a fine powder was obtained; (iv) a smallamount of the SyrSpend SF PH4 (liquid) was added to thepowder and mixed to form a uniform paste; (v) the SyrSpendSF PH4 (liquid) continued to be added in approximately geo-metric portions almost to volume, mixing thoroughly after eachaddition; (vi) sufficient SyrSpend SF PH4 (liquid) was added tobring the volume to 300 mL, and then mixed well; and (v) thefinal product was packaged in low-actinic prescription bottlesand labelled.
The final concentrations in the bottles are summarised intable 1. The suspensions were immediately assayed at T=0,and then separated into two different 150 mL bottles: onesample was stored at the USP recommended refrigerated tem-perature (2–8°C) and the other at room temperature(20–25°C), for the duration of the study (temperature and
humidity were checked in real time throughout the entireexperiment, using a calibrated, digital Incoterm thermo-hygrometer). Both samples were protected from light. Beforeanalyses, the bottles were shaken until the API was opticallyuniformly dispersed.
Forced-degradation studies: stability-indicatingcharacteristicsAPI samples were subjected to the following stressing conditionsto determine the capacity of the HPLC method to detect anypossible degradation product produced during storage of theoral suspension: (i) dilution in acid (0.1 M HCl, at 25°C); (ii)dilution in base (0.1 M NaOH, at 25°C); (iii) exposure to ultra-violet light at 365 nm (at 25°C); and (iv) heating at 70°C. Thesesolutions were prepared for each API at its respective work con-centration by means of serial dilution from a stock solution andusing suitable diluents (see table 3). The stock solutions weresonically dispersed for 10 min and the final solutions were fil-tered (15 mm regenerated cellulose syringe filters, with 0.45 μmpore size) before injection onto the HPLC system. Any extrane-ous peaks found in the chromatograms were labelled. The reso-lution was also determined between the degradation productsand the API peaks. A resolution of 1.5 between the peaks wasconsidered full separation.
Table 3 Chromatographic conditions used in the compatibility studies
API Mobile phase compositionWork concentration(μg/mL)* Column
Flow(mL/min)
UV detectionwavelength (nm)
Caffeine Acetonitrile, tetrahydrofuran, and buffer (0.82 g/L ofanhydrous sodium acetate) (25:20:955), adjusted withglacial acetic acid to a pH of 4.5
200.0 Microsorb-MV 100 C18,50×4.6 mm (Varian)
1.0 275
Carvedilol Acetonitrile and pH 2.0 monobasic potassium phosphatebuffer (31:69)
40.0 Kromasil 100-5C8,150×4.6 mm; at 55°C
1.0 254
Clomipraminehydrochloride
20.0 mL of a 55 g/L sodium 1-heptanesulfonate solutionin glacial acetic acid, 2.0 mL of triethylamine, 478 mL ofwater, and 522 mL of acetonitrile. The pH was adjustedwith phosphoric acid to 3.2±0.1
320.0 Luna 5 μm C18(2) 100 Å,300×3.9 mm (Phenomenex)
1.0 254
Folic acid Methanol and 1 M phosphate buffer pH 4.0 (12:88) 100.0 Zorbax Eclipse XDB-C8,250×4.6 mm, 5 μm (Agilent)
0.9 280
Hydrochlorotiazide Acetonitrile and 0.1 M monobasic sodium phosphate(1:9), adjusted with phosphoric acid to a pH of 3.0±0.1
150.0 Zorbax Eclipse XDB-C18,250×4.6 mm, 5 μm (Agilent)
2.0 254
Loperamidehydrochloride
Acetonitrile and pH 2.0 monobasic potassium phosphatebuffer (37:63)
10.0 Kromasil 100-5 C8,150×4.6 mm; at 55°C
2.0 214
Methotrexate Acetonitrile and buffer (0.2 M dibasic sodium phosphateand 0.1 M citric acid, 63:37) (10:90)
100.0 Zorbax Eclipse XDB-C18,250×4.6 mm, 5 μm (Agilent)
1.2 302
Nadolol 5.62 g of sodium hydrochloride and 1.97 g of sodiumacetate in 1000 mL of water. To this mixture, 4 mL ofglacial acetic acid and 800 mL of methanol were added
400.0 (in methanol) Zorbax Eclipse PlusPhenyl-Hexyl, 150×4.6 mm,3.5 μm (Agilent); at 45°C
1.0 270
Naltrexonehydrochloride
600 mL of 0.05 M buffer solution (7.0 g of monobasicsodium phosphate in 1 L of water), 1.1 g of sodium1-octane sulfonate monohydrate and 400 mL of methanol,and adjusted with dilute sodium hydroxide to a pH of 6.7
250.0 Luna 5 μm C18(2) 100 Å,150×3.9 mm (Phenomenex)
1.0 280
Pentoxifylline Acetonitrile and a solution composed of 50 mMmonobasic potassium phosphate buffer, adjusted withphosphoric acid to a pH of 3.2 (30:70). The buffer wasprepared with 0.8 g/L of ammonium acetate in water; toeach litre of this solution, 10 mL of triethylamine wereadded, and the final buffer was adjusted with phosphoricacid to a pH of 5.0
80.0 Zorbax Eclipse XDB-C18,250×4.6 mm, 5 μm(Agilent)
1.0 280
*Diluted with mobile phase, unless specified otherwise.API, active pharmaceutical ingredient.
Polonini HC, et al. Eur J Hosp Pharm 2016;0:1–7. doi:10.1136/ejhpharm-2016-000903 3
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Physical and chemical stability studyThe API samples were HPLC-assayed at pre-determined timepoints to verify the feasibility of using the API in SyrSpend SFPH4 (liquid). The samples were shaken manually for 1 min tosimulate patient dosing and then adequate volumetric aliquots forquantification (variable for each API) were withdrawn from themiddle of the bottles, without contact with the inner surface of thebottle, and diluted properly in order to obtain work solutions inthe concentration described in the Chromatographic conditionssection. Sampling times were: initial (T=0), 7 days (T=7), 14 days(T=14), 30 days (T=30), 60 days (T=60) and 90 days (T=90).All suspensions were immediately assayed six times at each timepoint (samples were diluted, sonicated for 10 min and then filteredin 15 mm regenerated cellulose syringe filters, with 0.45 μm poresize, before injection onto the HPLC system). The evaluation par-ameter was the per cent recovery with respect to T=0, using theHPLC method (results given as percentage±SD).
RESULTS AND DISCUSSIONThe results of specificity, precision, accuracy and linearity testsfor method validation are listed in table 4. All analysis
methods met the respective acceptance criteria,demonstrating that the methods were adequate for quantifica-tion purposes.
Data from these stability-indicating studies are summarised intable 5. The data indicate that the conditions influencing thechemical stability of the APIs varied greatly from each other, butthe HPLC method was able to detect any degradation.
Figure 1 shows the compatibility of the APIs in SyrSpend SFPH4 (liquid) in terms of absolute nominal concentration. Thefigure also shows the relative per cent of recovery (initial samplingtime=100%) at T=90 days. For the suspensions to be consideredcompatible, the relative percentage recovery should be 90–110%.At each sampling time, the visual appearance of the suspensionwas also evaluated to verify homogeneity (data not shown).Throughout the entire study, no phenomena such as precipitation,turbidity, macroscopically visible crystal growth, odour generation,phase separation, flocculation or caking were observed.
All suspensions were stable throughout the duration of thestudy (at least 90 days), whether stored under refrigeration or atroom temperature, as no visual, odour or assay changes weredetected. Losses in API content, with respect to T=0, were no
Table 4 Summary of linearity study for validation of the HPLC method
API
Linearity Specificity Precision Accuracy
Range(mg/mL)
Analyticalcurve R2
ANOVAsignificance ofregression (F)
ANOVAlack offit (F)
LOD(μg/mL)
LOQ(μg/mL)
Discrepancy(%)
Repeatability(CV, %)
Intermediateprecision(CV, %)
Recovery(%)
Caffeine 140.5–261.0 y=71.2x+132.5 0.999 1.4×104 1.74 0.02 0.08 |1.90| 0.61 0.59 99.8Carvedilol 28.2–52.3 y=79.1x−34.2 0.990 1.3×103 2.58 0.12 0.40 |0.23| 1.97 2.07 98.9Clomipraminehydrochloride
224.1–416.2 y=23.3x−206.2 0.997 5.4×103 3.01 0.01 0.02 |1.52| 0.65 2.49 99.5
Folic acid 70.1–130.2 y=61.0x+680.0 0.993 1.9×103 3.67 0.01 0.02 |0.77| 0.83 2.80 99.9Hydrochlorotiazide 105.1–195.2 y=10.4x+26.6 0.997 4.8×103 2.81 0.02 0.07 |0.01| 1.00 1.40 99.8Loperamidehydrochloride
7.2–13.4 y=207.7x−59.2 0.994 2.1×103 2.06 0.48 1.60 |0.74| 0.64 3.13 100.7
Methotrexate 70.3–130.6 y=43.5+113.5 0.995 2.7×103 2.51 0.03 0.09 |0.12| 0.29 0.70 100.3Nadolol 280.3–520.5 y=2.3x−67.4 0.996 3.3×103 2.36 0.003 0.01 |0.37| 0.73 1.04 100.1Naltrexonehydrochloride
175.2–325.4 y=3.3x−100.6 0.998 6.5×103 1.23 0.001 0.003 |1.62| 0.69 1.51 99.8
Pentoxifylline 56.4–104.8 y=31.6x+12.9 0.997 3.8×103 3.40 0.05 0.16 |0.27| 0.25 0.45 101.1
Acceptance criteria were: R2>0.99, F (significance of regression) >4.67, F (lack of fit) <3.71, discrepancy <2%, repeatability and intermediate precision <5%, and recovery 100%±2%.All analytical ranges (μg/mL) were adequate to quantify the APIs in the concentrations used in the suspensions (mg/mL).ANOVA, analysis of variance; API, active pharmaceutical ingredient; CV, coefficient of variation; HPLC, high performance liquid chromatography; LOD, limit of detection; LOQ, limit ofquantification (20 μL injections).
Table 5 Summary of the stability-indicating study for the APIs (results presented as the average of three replicates, at the work concentration)
Acid Alkali UV light HeatAPI %d* %d* %d* %d*
Caffeine |−2.96| |−11.75| ND NDCarvedilol |−8.05| |−28.70| |5.46| |2.17|Clomipramine hydrochloride |7.98| |2.74| ND ND
Folic acid |−91.90| ND |−42.41| NDHydrochlorotiazide |8.56| |8.50| |13.04| |−27.50|Loperamide hydrochloride ND |−7.90| |89.27| |3.33|Methotrexate |−3.23| |−10.87| |10.31| |5.83|Nadolol |11.81| |10.03| |−9.54| |−4.89|Naltrexone hydrochloride |11.48| ND ND |3.38|Pentoxifylline ND |−10.13| |−2.45| ND
*%d indicates percentage of discrepancy between the API peak without degradation (negative control) and the peak of a sample subjected to one of the cited accelerated-degradationfactors.Bold numbers indicate factors that led to high interference with the analytical peak of the API.API, active pharmaceutical ingredient; ND, not detected (below the maximum acceptable of 2%).
4 Polonini HC, et al. Eur J Hosp Pharm 2016;0:1–7. doi:10.1136/ejhpharm-2016-000903
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greater than 10% and generally within 5%, which indicatesgood stability of the APIs and their chemical compatibility withthe vehicle used.
CONCLUSIONSThis study showed that the APIs were all compatible withSyrSpend SF PH4 (liquid) for 90 days after preparation,
when stored refrigerated and at room temperature. As theresults showed, SyrSpend SF PH4 (liquid) is compatible witha wide range of APIs from diverse pharmacologicalclasses. These results validate APIs for use at various dosagesin oral suspensions for drug administration. Thus, SyrSpendSF is shown to be an alternative vehicle for use bycompounders.
Figure 1 Plot of activepharmaceutical ingredients (APIs) inSyrSpend SF PH4 throughout thecompatibility study (dashed linesrepresent the lower and upper limits,corresponding to 90 and 100% oflabelled concentration). Valuesrepresent the relative average per centrecovery (n=6). (A) Caffeine; (B)carvedilol; (C) clomipraminehydrochloride; (D) folic acid; (E)hydrochlorothiazide; (F) loperamidehydrochloride; (G) methotrexate; (H)nadolol; (I) naltrexone hydrochloride;(J) pentoxifylline.
Polonini HC, et al. Eur J Hosp Pharm 2016;0:1–7. doi:10.1136/ejhpharm-2016-000903 5
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Key messages
What is already known on this subject Oral liquids are safe alternatives to solid dosage forms,
particularly for elderly and paediatric patients withdysphagia.
The use of a ready-to-use suspending vehicle such asSyrSpend SF PH4 is convenient for pharmacists as it offers asafe, time-saving and well-studied option.
The compatibility of SyrSpend SF PH4 with some activepharmaceutical ingredients (APIs) has already beenestablished, but it is important to determine thecompatibility of each specific API with the suspendingvehicle as stability is the result of individual behaviourwithin the vehicle.
What this study adds We focused on 10 APIs: caffeine 10.0 mg/mL, carvedilol
1.0 mg/mL, clomipramine hydrochloride 5.0 mg/mL, folicacid 1.0 mg/mL, hydrochlorothiazide 5.0 mg/mL, loperamidehydrochloride 1.0 mg/mL, methotrexate 2.5 mg/mL, nadolol10.0 mg/mL, naltrexone hydrochloride 1.0 mg/mL andpentoxifylline 20.0 mg/mL.
The use by date was ≥90 days for all these suspensions forboth storage conditions.
This is the first report of the compatibility of this vehiclewith these APIs.
Contributors HCP conceived of the study and wrote the manuscript. SLS and TRAperformed the analyses and helped with data interpretation. MAFB and AOFcoordinated the study. All authors contributed to refinement of the study protocoland approved the final manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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in SyrSpend SF PH4 oral suspensionsnaltrexone hydrochloride and pentoxifyllinehydrochloride, methotrexate, nadolol, hydrochlorothiazide, loperamideclomipramine hydrochloride, folic acid, Compatibility of caffeine, carvedilol,
Antônio F Brandão and Anderson O FerreiraHudson C Polonini, Sharlene L Silva, Thalyta R de Almeida, Marcos
published online March 24, 2016Eur J Hosp Pharm
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ORIGINAL ARTICLES
Pharmazie 71 (2016) 185
1. IntroductionExtemporaneous preparation of oral liquid dosage forms is a common and important pharmacy practice for patients that require non-standard doses, experience swallowing difficulties or receive medication via enteral feeding tubes (Glass and Haywood 2006). Oral liquids are not only common practice in pediatrics (Brion et al. 2003; Schirm et al. 2003), but also in the general adult popu-lation, where recent studies have demonstrated that up to 22.4 % have difficulties swallowing (Lau et al. 2015; Marquis et al. 2013). Oral liquids are relatively quick and easy to prepare with limited need for compounding equipment and they allow for flexibility in dosage out of a single strength preparation (Brion et al. 2003).The main challenge with compounding oral liquid formulations is the limited availability of data to support the physical, chem-ical and microbiological stability of the formulations (Glass and Haywood 2006; Brion et al. 2003; Conroy 2003). In a UK survey it was found that in more than half (54 %) of the extemporaneous formulations shelf-life was inadequately supported (Brion et al. 2003). Due to the limited availability of scientific data, there is little harmonization in the concentration or formulation of compounded oral liquids (Brion et al. 2003; Rood et al. 2014). This poses a patient safety concern and a risk for medication errors (Rood et al. 2014). Demands have been made to publish scientifically veri-fied, palatable extemporaneous formulations with standardized oral liquid concentrations to increase patient safety and adherence (Brion et al. 2003; Conroy 2003; Rood et al. 2014; Allen 2008).The objective of this study was to evaluate the physical and chem-ical stabilities of the active pharmaceutical ingredients (APIs) listed
in Table 1, compounded at a single concentration in SyrSpend® SF PH4 (liquid) and stored both refrigerated and at room temperature. SyrSpend® SF is an internationally available, GMP produced, ready-to-use taste-masking oral liquid vehicle. Its suspending properties are derived from starch without traditionally used excip-ients that can have toxicological effects, induce allergic reactions or cause irritation, such as sugar (Hill et al. 1988; Jijo and Flow-erlet 2014), ethanol (Zuccotti and Fabiano 2014; Fiocchi et al. 1999), propylene glycol (Committee on Drugs 1997; Fabiano et al. 2011), sorbitol (Johnston et al. 1994; Payne et al. 1997), benzyl alcohol (Gershanik et al. 1982; Centers for Disease Control 1982; Committee on Fetus and Newborn 1983) and common food aller-gens (Sakai et al. 2012; Audicana Berasategui et al. 2011). The compatibility of SyrSpend® SF with various APIs has already been demonstrated (Geiger et al. 2012a, 2012b, 2013a, 2013b, 2015; Sorenson et al. 2012; Sorenson and Whaley 2012; Voudrie and Allen 2010; Voudrie et al. 2011; Vu et al. 2008; Whaley et al. 2012a, 2012b; Ferreira et al. 2015).In this study the combined physical-chemical compatibility is assessed, as a deficit in either of the two would result in an out of specification during analysis. The concentration for each API studied was selected based on commonly prescribed concentra-tions for children or adults. To the best of the authors’ knowledge, there is no previous stability study in the literature for haloper-idol, imipramine hydrochloride, minocycline hydrochloride and valsartan oral suspensions. No stability studies of the current APIs compounded in SyrSpend® SF PH4 (liquid) have previously been published.
Ortofarma – Quality Control Laboratories, Matias Barbosa, MG, Brazil
Compatibility of cholecalciferol, haloperidol, imipramine hydrochlo-ride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacro-limus monohydrate, terbinafine, tramadol hydrochloride and valsartan in SyrSpend® SF PH4 oral suspensions
H. C. POLONINI, S. L. SILVA, C. N. CUNHA, M. A. F. BRANDÃO, A. O. FERREIRA
Received October 21, 2015, accepted December 2, 2015
Ortofarma – Quality Control Laboratories, BR 040, n. 39, Empresarial Park Sul. 36120-000. Matias Barbosa – MG. [email protected]
Pharmazie 71: 185–191 (2016) doi: 10.1691/ph.2016.5177
A challenge with compounding oral liquid formulations is the limited availability of data to support the physical, chemical and microbiological stability of the formulation. This poses a patient safety concern and a risk for medication errors. The objective of this study was to evaluate the compatibility of the following active pharma-ceutical ingredients (APIs) in 10 oral suspensions, using SyrSpend® SF PH4 (liquid) as the suspending vehicle: cholecalciferol 50,000 IU/mL, haloperidol 0.5 mg/mL, imipramine hydrochloride 5.0 mg/mL, levodopa/carbidopa 5.0/1.25 mg/mL, lorazepam 1.0 mg/mL, minocycline hydrochloride 10.0 mg/mL, tacrolimus monohydrate 1.0 mg/mL, terbinafine 25.0 mg/mL, tramadol hydrochloride 10.0 mg/mL and valsartan 4.0 mg/mL. The suspensions were stored both refrigerated (2 - 8 °C) and at controlled room temperature (20 - 25 °C). This is the first stability study for these APIs in SyrSpend® SF PH4 (liquid). Further, the stability of haloperidol,iImipramine hydrochloride, minocycline, and valsartan in oral suspension has not been previously reported in the literature. Compatibility was assessed by measuring percent recovery at varying time points throughout a 90 days period. Quantification of the APIs was performed by high performance liquid chromatography (HPLC-UV). Given the percentage of recovery of the APIs within the suspensions, the beyond-use date of the final preparations was found to be at least 90 days for most suspensions both refrigerated and at room temperature. Exceptions were: Minocycline hydrochloride at both storage temperatures (60 days), levodopa/carbidopa at room temperature (30 days), and lorazepam at room temperature (60 days). This suggests that compounded suspensions of APIs from different pharmacological classes in SyrSpend® SF PH4 (liquid) are stable.
ESTUDO 14
ORIGINAL ARTICLES
Pharmazie 71 (2016)186
Table 1: Concentrations of the suspensions used in the study
API Concentration in suspension
Action and use
Cholecalciferol (vitamin D3) 50,000 IU/mL Vitamin D analogue
Haloperidol 0.5 mg/mL Dopamine receptor antag-onist; neuroleptic
Imipramine hydrochloride 5.0 mg/mL Monoamine reuptake inhibitor; tricyclic antide-pressant
Levodopa/carbidopa 5.0/1.25 mg/mL Treatment of Parkinson’s disease
Lorazepam 1.0 mg/mL Benzodiazepine
Minocycline hydrochloride 10.0 mg/mL Tetracycline antibacterial
Tacrolimus monohydrate 1.0 mg/mL Immunosuppressant
Terbinafine 25.0 mg/mL Antifungal
Tramadol hydrochloride 10.0 mg/mL Opioid receptor agonist; noradrenaline reuptake inhibitor; analgesic
Valsartan 4.0 mg/mL Angiotensin II (AT1)
receptor antagonist
all conditions. Cholecalciferol and lorazepam decomposed under all stress conditions. After these validations, the stability of the APIs in SyrSpend® SF PH4 (liquid) was assessed. In this study we did not evaluate the uniformity of the drug in the suspension, and expect that any non-soluble drug will exist as insol-uble crystals, particulates, or precipitate. According to the Merck Index 14th edition (2006), these are the solubilities of the APIs in water (major component of the used suspending vehicle): Cholecal-ciferol – practically insoluble; haloperidol – 1.4 mg/100mL; imip-ramine hydrochloride – freely soluble; levodopa – 66 mg/40 mL; lorazepam – 0.08 mg/mL; tacrolimus monohydrate – insoluble in water; terbinafine – slightly soluble; tramadol hydrochloride – soluble; and valsartan – soluble. Therefore, we predict that some heterogeneity of drug distribution will exist for cholecalciferol, levodopa, lorazepam and tacrolimus monohydrate in the stored suspensions and that unsufficient mixing prior to sampling may lead to increased variance in API percentage recovery.The stability results are shown in Table 5 and are expressed as relative percent of recovery (initial sampling time = 100 %). For the suspensions to be considered stable, the relative percentage recovery should lie within 90-110 % (USP 2015; BP 2015; EP 2015). Figure 1 graphically represents the stability of the APIs in SyrSpend® SF PH4 (liquid) in terms of absolute nominal concen-tration.
At each sampling time, the visual appearance of the suspensions was evaluated to verify their homogeneity and physical stability (data not shown). Throughout the whole study, no phenomena such as precipitation, turbidity, macroscopically visible crystal growth, odor generation, phase separation, flocculation or caking were observed, except for minocycline hydrochloride after 60 days of storage. No study on the stability of minocycline hydrochloride in oral liquids was found, but the Merck Index (2006) states that this API is sensitive to light and to surface oxidation (also confirmed in our findings in Table 4). As all suspensions were stored in light-re-sistant bottles, it is likely that the decomposition of minocycline
Table 2: Chromatographic conditions used in the compatibility study
API Mobile phase composition Work concentration(μg/mL)*
Column Flow(mL/min)
UV detection wavelength (nm)
Cholecalciferol (vitamin D3)
Hexane and pentanol (997:3) 100.0; 20 μL injection L3, 4.6-mm × 25-cm; at 25°C1
2.0 254
Haloperidol Methanol and buffer solution (6.8 g/L of monobasic potas-sium phosphate in water, adjusted with phosphoric acid to a pH of 4.0) (55:45)
200.0; 20 μL injection L1, 4.6-mm × 15-cm; at 25°C2
0.8 247
Imipramine hydrochloride
0.06M sodium perchlorate, acetonitrile and trietylamine (625:375:1)
300.0, in water and ace-tonitrile (625:375); 20 μL injection
L1, 3.9-mm × 30-cm; at 25°C3
1.5 269
Levodopa/ Carbidopa
Alcohol and buffer (6.6 g/L of monobasic sodium phos-phate in water, adjusted with phosphoric acid to a pH of 2.2)
250/ 25; 20 μL injection L1, 4.6-mm × 25-cm; at 25°C4
1.0 280
Lorazepam Acetonitrile, glacial acetic acid, and water (45: 0.2: 55) 100.0, in methanol; 20 μL injection
L1, 4.0-mm × 30-cm; at 25°C5
2.0 254
Minocycline, hydrochloride
Dimethylformamide, tetrahydrofuran, 0.2M ammonium ox-alate and 0.01M EDTA (120:80:600:180), with pH adjusted to 7.2 with ammonium hydroxide
500.0; 20 μL injection L1, 4.6-mm × 25-cm; at 40°C6
1.5 280
Tacrolimus monohydrate
Acetonitrile and water (65:35) 50.0; 20 μL injection L1, 4.6-mm × 25-cm; at 70°C7
1.7 214
Terbinafine Acetonitrile and water (2:3), with 0.15 % triethylamine and 0.15 % phosphoric acid
5.0; 20 μL injection L1, 4.6-mm × 15-cm; at 25°C8
0.4 224
Tramadol hydrochloride
Acetonitrile and a solution with 20 mM of phosphoric acid and 4 g/L of sodium 1-hexane sulfonate (50:50)
250.0, acetonitrile and wa-ter (50:50); 20 μL injection
L1, 4.6-mm × 25-cm; at 30°C9
1.0 275
Valsartan Acetonitrile, glacial acetic acid, and water (500:1:500) 500.0; 20 μL injection L1, 4.6-mm × 15-cm; at 25°C10
1.0 273
* diluted with mobile phase, unless specified otherwise.1Zorbax Eclipse Plus 5μ (Agilent). 2Gemini 5μ 110Å (Phenomenex). 3Luna 5μ C18 100Å (Phenomenex). 4Zorbax Eclipse XDB 5μ (Agilent). 5Zorbax Eclipse XDB 5μ (Agilent). 6Zorbax Eclipse XDB 5μ (Agilent). 7Zorbax Eclipse XDB 5μ (Agilent). 8Gemini 5μ 110Å (Phenomenex). 9Zorbax Eclipse XDB 5μ (Agilent). 10Gemini 5μ 110Å (Phenomenex).
2. Investigations, results and discussionValidation studies of all methods of analysis (chromatographic conditions described in Table 2) were performed and all results (Table 3) met the respective acceptance criteria. Stability-indi-cating studies were also conducted. These results are summarized in Table 4. Stability-indicating studies are important to determine if the used methods are fully validated and adequate to identify decomposition of the APIs by chromatographic analysis. The decomposition profile of the APIs notably varied for different stressing conditions. Only levodopa was found to be stable under
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Fig. 1. Plot of APIs in SyrSpend® SF PH4 (liquid) throughout the compatibility study (dashed lines represent the lower and upper limits, corresponding to 90 and 110 % of labeled concentration). Values represents mean ± SD (n=6).A – cholecalciferol 50,000 IU/mL, B – haloperidol 0.5 mg/mL, C – imipramine hydrochloride 5.0 mg/mL, D – levodopa/carbidopa 5.0/1.25 mg/mL, E – lorazepam 1.0 mg/mL, F – minocycline hydrochloride 10.0 mg/mL, G – tacrolimus monohydrate 1.0 mg/mL, H – terbinafine 25.0 mg/mL, I – tramadol hydrochloride 10.0 mg/mL, J – valsartan 4.0 mg/mL.
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Table 3: Summary of linearity’s study for the validation of the HPLC method
API Linearity Specificity Precision Accuracy
Range (μg/mL) Analytical curve R2 ANOVA’s significance of regression (F)
ANOVA’s lack of fit (F)
LOD (μg/mL)
LOQ (μg/mL)
Discrepancy (%)
Repeatability (CV, %)
Intermediate precision (CV, %)
Recovery (%)
Cholecalciferol (vitamin D3)
70.56 – 131.04 y = 125.08x + 221.76 0.9941 2215.06 3.70 0.02 0.08 |1.13| 0.51 0.92 99.67
Haloperidol 140.07 – 260.13 y = 35.89x – 339.96 0.9972 4672.53 3.37 0.01 0.04 |1.22| 0.39 0.28 100.04Imipramine hydrochloride
210.28 – 390.52 y = 14.47x – 113.14 0.9995 26612.58 1.44 0.001 0.003 |0.79| 0.30 2.54 100.16
Levodopa* 175.56 –326.04 y = 15.92x - 271.22 0.9937 2041.11 2.00 0.01 0.03 |0.56| 0.17 3.22 100.54Carbidopa* 17.78 –33.02 y = 15.38x – 3.86 0.9952 2675.60 3.53 0.13 0.52 1.64 0.31 2.45 99.75Lorazepam 35.21 – 65.39 y = 19.44x – 54.86 0.9917 1547.32 0.89 0.05 0.18 |1.49| 0.71 0.56 100.06Minocycline hydrochloride
350.07 – 650.13 y = 17.43x – 142.99 0.9974 5067.23 2.44 0.01 0.03 |0.21| 0.27 0.43 100.36
Tacrolimus monohydrate
70.00 – 130.00 y = 6.67x + 23.13 0.9980 6358.90 3.66 0.01 0.03 |0.42| 0.11 1.03 100.01
Terbinafine 3.57 – 6.63 y = 183.69x + 8.02 0.9978 5906.16 1.13 0.78 2.61 |1.10| 0.35 0.80 99.49Tramadol hydrochloride
175.00 – 435.00 y = 6.11x + 31.99 0.9956 3075.87 0.55 0.01 0.05 |0.53| 0.41 0.90 99.88
Valsartan 350 – 650.26 y = 12.64x + 92.60 0.9961 3359.58 3.67 0.01 0.02 |1.82| 0.44 1.17 99.61
*Method validated for the combination of the APIs.LOD: Limit of Detection. LOQ: Limit of Quantification (20 μL injections). CV: coefficient of variation. Acceptance criteria were: R2 > 0.99, F (significance of regression) >> 4.67, F (lack of fit) < 3.71, discrepancy < 2 %, repeatability and intermediate precision < 5 %, and recovery = 100 % ± 2 %. All analytical ranges (μg/mL) were adequate to quantify the APIs in the concentrations used in the suspensions (mg/mL).
Table 4: Summary of the stability-indicating study for the APIs
API HCl NaOH UV Heat H2O
2
Area %d* Area %d* Area %d* Area %d* Area %d*
Cholecalciferol (vitamin D3)
0.00 |-100.00| 207.45 |-98.61| 14960.11 |0.04| 8642.87 |-42.21| 4627.40 |-69.06|
Haloperidol 6580.82 |0.53| 2320.02 |-64.56| 7146.31 |9.16| 6489.87 |-0.86| 5697.64 |-12.97|Imipramine hydrochloride
4045.03 |-2.96| 3979.50 |-4.53| 3607.85 |-13.45| 4212.22 |1.05| 4191.83 |0.57|
Levodopa 3750.61 |1.38| 3715.46 |0.43| 3690.97 |-0.23| 3762.34 |1.69| 3667.44 |-0.87|Carbidopa 282.79 |4.21| 193.85 |-28.56| 278.80 |2.74| 280.33 |3.31| 267.04 |-1.59|Lorazepam 2266.58 |-24.67| 2494.96 |-17.08| 2512.16 |-16.51| 2698.65 |-10.31| 2711.76 |-9.87|Minocycline hydrochloride
8795.76 |1.30| 8786.12 |1.19| 8636.63 |-0.53| 8699.92 |0.20| 0.00 |-100.00|
Tacrolimus monohydrate
655.23 |-1.71| 0.00 |-100.00| 671.86 |0.79| 696.08 |4.41| 597.06 |-10.44|
Terbinafine 929.78 |-0.39| 931.14 |-0.25| 937.94 |0.48| 906.43 |-2.89| 911.75 |-2.32|Tramadol hydrochloride
1532.61 |-0.18| 1551.04 |1.02| 1580.75 |2.95| 1576.36 |2.67| 1538.22 |0.18|
Valsartan 6458.88 |1.45| 1111.01 |-82.55| 6621.43 |4.01| 6483.83 |1.85| 6451.30 |1.33|
(Results presented as average of 3 replicates, at the work concentration)*%d = percentage of discrepancy between the API peak without submission to stressing factors (negative control) and the peak of a sample subjected to one of the cited accelerated-degradation factors. Areas given as mV. Maximum acceptable = 2 % (values higher than this are in bold).
Table 5: Stability of the APIs in SyrSpend® SF PH4 (liquid)
Elapsed time (days) % Recovery
Refrigerated Temperature(2-8 ºC)
Controlled Room Temperature (20-25 ºC)
Cholecalciferol 50,000 IU/mL
T = 0 100 ± 0.11 100 ± 0.11T = 7 99.79 ± 1.01 100.01 ± 0.48T = 14 100.58 ± 1.00 101.01 ± 0.60T = 30 101.72 ± 0.62 100.46 ± 1.02T = 60 102.00 ± 0.39 100.99 ± 0.63T = 90 100.83 ± 0.26 101.84 ± 0.28
Haloperidol 0.5 mg/mL
T = 0 100 ± 0.11 100 ± 0.11
Elapsed time (days) % Recovery
Refrigerated Temperature(2-8 ºC)
Controlled Room Temperature (20-25 ºC)
T = 7 99.85 ± 0.28 99.85 ± 0.37T = 14 99.95 ± 0.25 100.06 ± 0.26T = 30 98.70 ± 0.08 99.68 ± 0.28T = 60 95.86 ± 0.79 96.68 ± 1.81T = 90 97.59 ± 0.30 98.11 ± 0.28
Imipramine hydrochloride 5.0 mg/mL
T = 0 100 ± 0.65 100 ± 0.65T = 7 100.14 ± 0.88 100.44 ± 0.16T = 14 99.47 ± 0.62 99.42 ± 0.55T = 30 99.33 ± 0.62 100.00 ± 0.49
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Elapsed time (days) % Recovery
Refrigerated Temperature(2-8 ºC)
Controlled Room Temperature (20-25 ºC)
T = 60 99.49 ± 0.56 100.01 ± 0.73T = 90 97.59 ± 1.13 99.07 ± 0.58
Levodopa 5.0 mg/mL*
T = 0 100 ± 0.53 100 ± 0.53T = 7 100.23 ± 0.33 99.16 ± 0.55T = 14 96.20 ± 0.92 98.62 ± 0.70T = 30 100.37 ± 0.36 99.66 ± 0.33T = 60 95.47 ± 0.39 95.90 ± 0.33T = 90 96.04 ± 0.36 96.49 ± 0.35
Carbidopa 1.25 mg/mL*
T = 0 100 ± 0.32 100 ± 0.32T = 7 99.25 ± 0.35 97.32 ± 0.46T = 14 102.69 ± 0.44 98.64 ± 0.33T = 30 99.27 ± 0.36 98.90 ± 0.30T = 60 90.93 ± 0.21 67.55 ± 0.38T = 90 91.22 ± 0.34 66.72 ± 0.64
Lorazepam 1.0 mg/mL
T = 0 100 ± 0.17 100 ± 0.17T = 7 100.01 ± 0.27 100.03 ± 0.18T = 14 99.82 ± 0.31 99.96 ± 0.27T = 30 100.68 ± 0.20 100.67 ± 0.36T = 60 100.22 ± 0.33 99.93 ± 0.17T = 90 99.24 ± 0.55 83.04 ± 0.47
Minocycline hydrochloride 10.0 mg/mL
T = 0 100 ± 0.27 100 ± 0.27T = 7 99.51 ± 0.05 100.01 ± 0.31T = 14 100.10 ± 0.73 100.52 ± 0.76T = 30 101.34 ± 0.31 101.39 ± 0.24T = 60 100.46 ± 0.30 100.57 ± 0.14T = 90 Interrupted (physical
instability)Interrupted (physical instability)
Tacrolimus monohydrate 1.0 mg/mL
T = 0 100 ± 0.16 100 ± 0.16T = 7 100.21 ± 0.33 100.40 ± 0.45T = 14 100.24 ± 0.15 100.40 ± 0.18T = 30 99.53 ± 0.12 99.91 ± 0.29T = 60 98.29 ± 0.66 100.03 ± 0.37T = 90 99.33 ± 0.32 100.54 ± 0.42
Terbinafine 25.0 mg/mL
T = 0 100 ± 0.12 100 ± 0.12T = 7 100.18 ± 1.02 99.12 ± 0.30T = 14 100.41 ± 0.65 99.53 ± 0.48T = 30 97.92 ± 0.45 99.08 ± 0.29T = 60 99.47 ± 0.41 100.27 ± 0.16T = 90 99.53 ± 0.22 99.60 ± 0.19
Tramadol hydrochloride 10.0 mg/mL
T = 0 100 ± 0.38 100 ± 0.38T = 7 98.66 ± 0.15 98.77 ± 0.18T = 14 96.68 ± 0.28 96.68 ± 0.24T = 30 98.74 ± 0.24 98.93 ± 0.27T = 60 96.77 ± 0.19 95.21 ± 0.21T = 90 96.89 ± 0.08 96.65 ± 0.08
Varsartan 4.0 mg/mL
T = 0 100 ± 1.06 100 ± 1.06T = 7 101.62 ± 0.36 101.46 ± 0.19T = 14 98.37 ± 0.98 98.57 ± 0.36
(color changes in the suspension, Fig. 2) is due to oxidation reac-tions. Additionally, the suspension thickened after 60 days to a point that a chromatographic injection was not recommended and accurate patient dosing would be challenging.
Fig. 2. Minocycline hydrochloride syrup at a) T = 0 and b) T = 90 days.
Cholecalciferol (vitamin D3) was stable for at least 90 days in our study. This is longer than some of the results found by Connors et al. (1986), who evaluated cholecalciferol syrups containing different stabilizers (ethyl gallate 0.01 %; butylated hydroxytol-uene 0.01 %; citraconic acid 0.1 % and butylated hydroxytoluene 0.01 %; citric acid 0.1 % and butylated hydroxytoluene 0.01 %; butylated hydroxytoluene 0.01 % and ascorbic acid 0.01 %). They found a maximum stability of two months for these syrups when stored at 37 °C. When stored at 17 °C, the syrups were stable for six months, but only with the added stabilizers.Lorazepam oral suspension stored at 2-8 °C was stable for at least 90 days, while the same suspension stored at 20-25 °C presented a 17 % loss in concentration (average) in the same period. This suggests that the lorazepam oral suspension could be used for up to 60 days after compounding when stored at room temperature or 90 days when refrigerated. No report was found evaluating a loraz-epam oral suspension, but a study conducted by Stiles et al. (1996) with a lorazepam injection packaged in polypropylene-pump syringes found that 23-26 % degradation of the API occurred in 10 days when stored at either ambient or refrigerated temperatures.The combination levodopa/carbidopa stored at 2-8 °C was found to be stable for at least 90 days, while the suspension stored at
Elapsed time (days) % Recovery
Refrigerated Temperature(2-8 ºC)
Controlled Room Temperature (20-25 ºC)
T = 30 99.95 ± 0.13 101.34 ± 0.26T = 60 100.33 ± 0.31 100.37 ± 0.60T = 90 101.50 ± 0.24 100.78 ± 0.60
*Assayed in a single suspension containing both levodopa and carbidopa.
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20-25 °C showed unacceptable degradation (>10 %) of Carbidopa after 30 days of storage. This instability in an aqueous system was already reported by Pappert et al. (1996), with losses in concen-tration of up to 60 % independently of the storage temperature. Interestingly, the SyrSpend® SF PH4 (liquid) vehicle was able to increase the stability of this combination of APIs even though it is an aqueous vehicle. Nahata et al. (2000) also studied a levodopa/carbidopa oral suspension with the same concentration as the current study, but using a mixture of equal parts of the vehicles Ora-Plus® and Ora-Sweet®. This suspension remained stable for 42 days of storage when refrigerated, and the addition of ascorbic acid (2 mg/mL) increased the decomposition rate of the product. Nahata and colleagues also noticed a darker yellow color appearing in the product during longer storage. It seems that SyrSpend® SF PH4 (liquid) was able to maintain the potency and the phys-ical characteristics of the Levodopa/Carbidopa suspension for a longer period, in comparison with the Ora-Plus® and Ora-Sweet® suspending vehicles.A longer beyond-use date was also found for tacrolimus mono-hydrate in SyrSpend® SF PH4 (liquid) (at least 90 days at both studied temperatures) when compared to a previous study by Jacobson et al. (1997). In this work, a tacrolimus 0.5 mg/mL oral suspension was prepared from capsules using a mixture of equal parts of Ora-Plus® and simple syrup. This suspension was found to be stable for 56 days when stored at 25 °C, compared to 90 days found in SyrSpend® SF PH4 (liquid).Terbinafine hydrochloride in SyrSpend® SF PH 4 (liquid) showed a stability of at least 90 days when stored at both refrigerated and at room temperature, while Abdel-Rahman and Nahata (1999) reported a maximum stability of 42 days for syrups of this API compounded with Ora-Plus® and Ora-Sweet® (1:1, v/v) in the same concentration and stored at 4 °C and 25 °C.Tramadol Hydrochloride 10 mg/mL in SyrSpend® SF PH 4 (liquid) presented similar results to other works, although all these studies evaluated products with concentrations lower than 10 mg/mL. Wagner et al. (2003) evaluated 5 mg/mL syrups compounded with equal parts mixtures of Ora-Plus® with strawberry syrup or Ora-Sweet®. No significant loss of API in either formulation at two storage conditions (3-5 °C and 23-25 °C) over 91 days was reported. Johnson et al. (2004) evaluated the same suspending vehicles for compounding a combination of tramadol hydrochlo-ride 7.5 mg/mL and acetaminophen 65 mg/mL, and found equal stability results up to 90 days. These two studies, however, were conducted using syrups compounded from commercial tablets.Finally, for haloperidol, imipramine hydrochloride, minocycline, and valsartan oral liquids, the authors found no previous reports in the literature. This makes this work the first report of the stability of these APIs in compounded oral liquids.In conclusion, this study demonstrates that most of the aforemen-tioned suspensions of 11 APIs in SyrSpend® SF PH4 (liquid) were stable for at least 90 days after preparation, when stored both at refrigerated and at room temperature. Exceptions with shorter stability are: Minocycline hydrochloride at both storage tempera-tures (60 days), levodopa/carbidopa at room temperature (30 days), and lorazepam at room temperature (60 days). This indicates that SyrSpend® SF PH4 (liquid) is a suitable vehicle for compounding with a wide range of APIs from diverse pharmacological classes. It also suggests probable success for validating the APIs evaluated in this study for use in multiple-use oral suspensions, likely to be used in clinical applications by pharmacists or drug manufacturers.
3. Experimental
3.1. Reagents, reference standards and materialsAll API raw materials and SyrSpend® SF PH4 (liquid) (batch number 14F02-U59-019404) were obtained from Fagron (St. Paul, MN, USA). HPLC-grade reagents (Panreac, Barcelona, Spain) were used. Ultrapure water obtained with an Aqua-Max-Ultra 370 Series (Young Lin, Anyang, Korea) (18.2 MΩ·cm resistivity at 25°C and <10 ppb total organic carbon) was used throughout the experiments. The reference standards used were all work standards obtained using primary USP (Rockville, MD, USA) reference materials. All the mobile phases and receptor media were filtered through a 0.45 μm filter membrane (RC-45/15 MS, Chromafil, Düren, Germany) and degassed using an ultrasonic apparatus (model 1600A, Unique, Indaiatuba, Brazil) for
30 min, immediately before use. All volumetric glassware and analytical balance used were previously calibrated.
3.2. EquipmentHPLC analyses were performed on a qualified and calibrated chromatography system (Young Lin, Anyang, Korea) composed of a quaternary gradient pump (YL 9110), a photodiode array (PDA) detector (YL 9160), a 96-vial programmable autosampler (YL 9150), a column oven compartment (YL 9130), a variable sample loop up to 200 μL and a software controller (Clarity).
3.3. Chromatographic conditionsThe chromatographic determinations were based upon USP methods for the APIs or their final products, with minor modifications when necessary. The exact chro-matographic conditions used for each API are stated in Table 2. The columns were connected with a pre-column with the same packing (4.0 × 3.0 mm, 5 μm) from the same vendor of the columns.
3.4. Validation of the HPLC methodValidation protocol and the acceptance criteria were established based upon USP (2015) and ICH (International Conference on Harmonization) (2005) guidelines.Specificity of the method was determined by running HPLC analyses of a standard solution, a SyrSpend® SF PH4 (liquid) blank solution, and a mobile phase/diluents blank solution. The acceptance criterion was defined as a percentage of discrepancy | [(standard area – sample area) / standard area] x 100 | between the peak areas of less than 2 %. In addition, the specificity of the method was obtained through comparison of standard chromatograms with and without the SyrSpend® SF PH4 (liquid) matrix. All analyses were run in triplicate.Precision was evaluated as repeatability and intermediate precision. Repeatability was determined by consecutively analyzing six replicates by a single analyst in a single day. Intermediate precision was also performed in six replicates, but over two days, by different analysts. An injection precision of more than 95 % (coefficient of variation, CV) was considered acceptable.The accuracy of the method was determined through spike-recovery of the SyrSpend® SF PH4 (liquid) matrix, diluted within the range used for final sample measurements (to the calibration curves). Percent recovery was calculated from the concentration measured relative to the theoretical concentration spiked.For linearity, concentrations from 70-130 % of the working concentration of the API in SyrSpend® SF PH4 (liquid) were prepared, and analyzed. The data from each experiment was fitted by ordinary least squares method and was evaluated by analysis of variance (ANOVA).The limit of detection (LOD) and limit of quantification (LOQ) were determined from three standard calibration curves of the APIs in the presence of the SyrSpend® SF PH4 (liquid) matrix and were calculated as shown in Eqs. (1) and (2), respectively:
LOD s
a3
(1)
LOQ s
a10
(2)
where a is the slope of the calibration curve, and s is the standard deviation of the y-intercept. The LOD and LOQ were confirmed by the analysis of chromatograms generated by injecting solutions in their respective limit concentrations.
3.5. Preparation of API suspension samplesThe API suspensions were prepared using the following general protocol: (i) the required quantity of each ingredient for the total amount to be prepared was calcu-lated; (ii) each ingredient was accurately weighed; (iii) the API was placed in a mortar and triturated until a fine powder was obtained; (iv) a small amount of the SyrSpend® SF PH4 (liquid) was added to the powder and mixed to form a uniform paste; (v) the SyrSpend® SF PH4 (liquid) was further added in approximately geometric portions almost to volume, mixing thoroughly after each addition; (vi) sufficient SyrSpend® SF PH4 (liquid) was added to bring the volume to 300 mL, and then mixed well; (v) the final product was packaged in low-actinic, light-resistant prescription bottles and labeled. The final concentrations in the bottles are summarized in Table 1. The suspensions were then immediately assayed at T = 0, and then separated into two different 150 mL bottles: one sample was stored at refrigerated (2-8 ºC) and the other at controlled room temperature (20-25 ºC), for the duration of the study (temperature and humidity were checked in real time throughout the whole experiment, using a calibrated, digital thermo-hygrometer (Incoterm)).
3.6. Forced-degradation studies: stability-indicating characteristicsAPI samples were subjected to the following stressing conditions to determine the capacity of the HPLC method to detect any possible degradation products that may arise during storage of the oral suspension: (i) dilution in acid (0.1M HCl, at 25 °C); (ii) dilution in base (0.1M NaOH, at 25 °C); (iii) exposure to ultraviolet light at 365 nm (at 25 °C); (iv) heating at 70 °C; and (v) dilution in H
2O
2 35 % (v/v) (at 25 °C). These
solutions were prepared for each API at its respective work concentration by means of serial dilution from a stock-solution and using suitable diluents (see Table 2). The stock-solutions were sonically dispersed by 10 minutes and the final solutions were filtered (15 mm regenerated cellulose syringe filters, with 0.45 μm pore size) before injection onto the HPLC system. Any extraneous peaks found in the chromatograms
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were labeled. A resolution of 1.5 between the peaks of the degradation products and the API was considered full separation. Also, a discrepancy greater than 2 % between the stressed sample peak and the standard, non-stressed sample peak was considered indicative of API decomposition.
3.7. Stability studyThe API samples were assayed by HPLC at pre-determined time points to verify the stability of the API in SyrSpend® SF PH4 (liquid). Before analyses, the bottles were shaken until the API was uniformly dispersed by visual inspection. Aliquots for quantification (variable for each API) were withdrawn from the middle of the bottles, without contact with the inner surface of the bottle, and diluted in order to obtain work solutions in the concentration described in Table 2. Sampling times were: initial (T = 0), 7 days (T = 7), 14 days (T = 14), 30 days (T = 30), 60 days (T = 60) and 90 days (T = 90). All suspensions were immediately assayed six times (6 aliquots) at each time point (samples were diluted, sonicated for 10 minutes and then filtered in 15 mm regenerated cellulose syringe filters, with 0.45 μm pore size, before injection onto the HPLC system). The evaluation parameter was the percent recovery with respect to T = 0, using the HPLC method (results given as percentage ± standard deviation).
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ICH - International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use (2005). Validation of Analytical Procedures: text and methodology Q2(R1).
Jacobson PA, Johnson CE, West NJ, Foster JA (1997) Stability of tacrolimus in an extemporaneously compounded oral liquid. Am J Health Syst Pharm 54: 178-180.
Jijo A, Flowerlet M (2014) Taste masking of peadiatric formulation: a review on tech-nologies, recent trends and regulatory aspects. Int J Pharm Pharm Sci 6: 12-19.
Johnson CE, Wagner DS, DeLoach SL, Cichon-Hensley BK (2004) Stability of tramadol hydrochloride-acetaminophen (Ultracet) in strawberry syrup and in a sugar-free vehicle. Am J Health Syst Pharm 61: 54-57.
Johnston KR, Govel LA, Andritz MH (1994) Gastrointestinal effects of sorbitol as an additive in liquid medications. Am J Med 97: 185-191.
Lau ETL, Steadman KJ, Mak M, Cichero JAY, Nissen LM (2015) Prevalence of swal-lowing difficulties and medication modification in customers of community phar-macists. J Pharm Pract Res 45: 18-23.
Marquis J, Schneider MP, Payot V, Cordonier AC, Bugnon O, Hersberger KE (2013) Swallowing difficulties with oral drugs among polypharmacy patients attending community pharmacies. Int J Clin Pharm 35: 1130-1136.
The Merck Index (2006) 14th ed. Merck & Co., Inc. Whitehouse Station, NJ.Nahata MC, Morosco RS, Leguire LE (2000) Development of two stable oral suspen-
sions of levodopa-carbidopa for children with amblyopia. J Pediatr Ophtalmol Stabismus 37: 333-337.
Pappert EJ, Lipton JW, Goetz CG, Ling ZD, Stebbins GT, Carvey PM (1996) The stability of carbidopa in solution. Movement Disorders 11: 24-26.
Payne ML, Craig WJ, Williams AC (1997) Sorbitol is a possible risk factor for diar-rhea in young children. J Am Diet Assoc 97: 532-534.
Sakai S, Adachi R, Miyazaki T, Aso Y, Okuda H, Teshima R (2012) Studies on the food allergenic proteins contained in pharmaceutical excipients. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku 130: 58-65.
Schirm E, Tobi H, de Vries TW, Choonara I, De Jong-van den Berg LTW (2003) Lack of appropriate formulations of medicines for children in the community. Acta Paediatr 92: 1486-1489.
Sorenson B, Whaley P (2012) Stability of Rifampin in SyrSpend SF. Int J Pharm Compd 17: 162-164.
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Rood JM, Engels MJ, Ciarkowski SL, Wagenknecht LD, Dickinson CJ, Stevenson JG (2014) Variability in compounding of oral liquids for pediatric patients: A patient safety concern. JAPhA 54: 383-389.
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ESTUDO 14
Journal of Pharmaceutical and Biomedical Analysis 118 (2016) 105–112
Contents lists available at ScienceDirect
Journal of Pharmaceutical and Biomedical Analysis
journa l homepage: www.e lsev ier .com/ locate / jpba
Short communication
Feasibility of amlodipine besylate, chloroquine phosphate, dapsone,phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine,tetracycline hydrochloride, trimethoprim and zonisamide inSyrSpend® SF PH4 oral suspensions
Anderson O. Ferreiraa,b, Hudson C. Poloninia,b, Sharlene L. Silvaa, Fernando B. Patrícioa,Marcos Antônio F. Brandãoa,b, Nádia R.B. Raposoa,b,∗
a Ortofarma—Quality Control Laboratories, Matias Barbosa, MG, Brazilb NUPICS—Núcleo de Pesquisa e Inovacão em Ciências da Saúde, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
a r t i c l e i n f o
Article history:Received 9 July 2015Received in revised form 5 October 2015Accepted 19 October 2015Available online 27 October 2015
Keywords:SyrSpendFeasibilityStabilityCompounding pharmacy
a b s t r a c t
The objective of this study was to evaluate the feasibility of 10 commonly used active phar-maceutical ingredients (APIs) compounded in oral suspensions using an internationally usedsuspending vehicle (SyrSpend® SF PH4 liquid): (i) amlodipine, (as besylate) 1.0 mg/mL; (ii) chloroquinephosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochlo-ride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracyclinehydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspen-sions were stored both at controlled refrigeration (2–8 C) and controlled room temperature (20–25 C).Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-dayperiod. API quantification was performed by high-performance liquid chromatography (HPLC-UV), viaa stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, theexpiration date of the final products (API + vehicle) was at least 90 days for all suspensions with regardto both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs fromdifferent pharmacological classes.
© 2015 Elsevier B.V. All rights reserved.
1. Introduction
Oral liquids are safe alternatives to solid dosage forms, notablyfor elderly and pediatric patients who present with dysphagia [1].For these patients, a liquid dosage form facilities treatment adher-ence and potentially reduces dosage errors [2]. However, there is aneed to study the physicochemical stability of these formulationsto prevent non-homogeneous dosing, which can lead to medicationerrors [3].
The application of ready-to-use suspending vehicles is a poten-tially useful resource for pharmacists. In this study, we usedSyrSpend® SF PH4 (liquid) (Fagron, St. Paul, USA), a ready-to-
∗ Corresponding author at: Universidade Federal de Juiz de Fora, Rua JoséLourenco Kelmer, s/n—Campus Universitário, 36036-900 Juiz de Fora, MG, Brazil.Fax: +55 32 2102 3809.
E-mail address: [email protected] (N.R.B. Raposo).
use suspending vehicle that has been attracting attention incompounding pharmacies worldwide. It is an alcohol- and asorbitol-free agent that helps in masking the unpleasant taste and isformulated with starch, which is considered an almost inert ingre-dient. Although the compatibility of SyrSpend® SF PH4 (liquid) withvarious active pharmaceutical ingredients (APIs) has already beenshown [4–14], it is important to determine the feasibility of addingdifferent APIs to the suspending vehicle. A large percentage of theSyrSpend® SF PH4 (liquid) is composed of water. The solubility ofthe individual APIs in water will largely determine what fraction ofthe API is suspended and what percentage is in solution. The sta-bility of the API in SyrSpend® SF PH4 (liquid) is determined by thecombined physical and chemical compatibility. In this study, thiscombined compatibility is assessed, as a deficit in any of the twowould result in an out of specification during analysis.
In this study, we focused on 10 active pharmaceutical ingre-dients (APIs) representing different pharmacological classes,including (i) amlodipine besylate (calcium channel blocker), (ii)
http://dx.doi.org/10.1016/j.jpba.2015.10.0320731-7085/© 2015 Elsevier B.V. All rights reserved.
ESTUDO 13
106 A.O. Ferreira et al. / Journal of Pharmaceutical and Biomedical Analysis 118 (2016) 105–112
Table 1Concentrations of the suspensions used in the study.
API Concentration in suspension (mg/mL)
Amlodipine (as besylate) 1.0Chloroquine phosphate 15.0Dapsone 2.0Phenytoin 15.0Pyridoxine 50.0Sulfadiazine 100.0Sulfasalazine 100.0Tetracycline hydrochloride 25.0Trimethoprim 10.0Zonisamide 10.0
chloroquine phosphate (4-aminoquinoline compound for malariaand extraintestinal amebiasis), (iii) dapsone (antibacterial agent),(iv) phenytoin (anticonvulsant), (v) pyridoxine hydrochloride(nutritional supplement), (vi) sulfadiazine (antibacterial agentof the sulfonamide class), (vii) sulfasalazine (antiinflammatoryagent), (viii) tetracycline hydrochloride (antibacterial agent), (ix)trimethoprim (antibacterial agent), and (x) zonisamide (anticon-vulsant). For feasibility studies, a single concentration for each drugstudy was selected based on commonly prescribed concentrationsfor children or adults. The objective of this study was to evaluate thefeasibility of the oral suspensions listed in Table 1, compounded ata single concentration using SyrSpend® SF PH4 (liquid) and storedboth at refrigerated and at room temperature. To the best of theauthors’ knowledge, there are no previous studies in the litera-ture dealing with the stability of these APIs compounded usingSyrSpend® SF PH4 (liquid).
2. Material and methods
2.1. Reagents, reference standards, and materials
All API raw materials and SyrSpend® SF PH4 (liquid) wereobtained from Fagron (batch number 14F02-U59-019404; St. Paul,MN, USA), and HPLC-grade reagents (Vetec, Rio de Janeiro, Brazil)were used. Ultrapure water obtained with an AquaMax-Ultra370 Series [Young Lin, Anyang, Korea (18.2 M cm resistivity at25 C and total organic carbon content of <10 ppb)] was also usedthroughout the experiments. The reference standards were workstandards obtained using primary USP (Rockville, MD, USA) refer-ence materials. All of the mobile phases and receptor media werefiltered through a 0.45-m filter membrane (RC-45/15 MS; Chro-mafil, Düren, Germany) and degassed using an ultrasonic apparatus(model 1600A, Unique, Indaiatuba, Brazil) for 30 min immediatelybefore use. All volumetric glassware and analytical balances werepreviously calibrated.
2.2. Equipment
HPLC analyses were performed on a qualified and calibratedchromatography system (Young Lin, Anyang, Korea) comprisinga quaternary gradient pump (YL 9110), a photodiode array (PDA)detector (YL 9160), a 96-vial programmable autosampler (YL 9150),a column oven compartment (YL 9130), a variable sample loop upto 200 L, and a software controller (Clarity).
2.3. Chromatographic conditions
The chromatographic determinations were based upon USPmethods for the APIs or their final products, with minor modifi-cations when necessary [15–24]. The chromatographic conditionsused for each API are stated in Table 2. The standards were diluted inthe mobile phase unless stated otherwise. The columns were con-
nected with a pre-column with the same packing (4.0 × 3.0 mm;5 m) from the same vendor and used at room temperature(15–25 C), except for the analysis of phenytoin (30 C). The injec-tion volume was 20 L for every chromatographic analysis.
2.4. Validation of the HPLC method
The methods and their acceptance criteria were established onthe basis of USP protocols [25] and ICH International Conference onHarmonization (ICH) guidelines [26].
Specificity of the method was determined by HPLC analyses ofa standard SyrSpend® SF PH4 (liquid) and mobile phase/diluentsblank solutions. The acceptance criterion was defined as the per-centage of discrepancy of <2% between peak areas. In addition, thespecificity of the method was obtained through a comparison ofstandard chromatograms with and without the matrix. All analyseswere run in triplicates.
For precision, the test was designed to assess the degree of dis-persion among a series of measurements obtained by the sameanalyst (repeatability) and between two analysts over 2 days(within-lab variations, intermediate precision) for API solutions atworking concentrations. Repeatability was determined by consec-utively analyzing six replicates by a single analyst in a single day.Intermediate precision was also performed in six replicates butover 2 days by different analysts. An injection precision of >95%[coefficient of variation (CV)] was considered to be acceptable.
The accuracy of the method was determined through spikerecovery of the SyrSpend® SF PH4 (liquid) matrix, diluted withinthe range used for final sample measurements, and within range ofthe corresponding calibration curves. Percent recovery was calcu-lated from the concentration measured relative to the theoreticalconcentration spiked.
For linearity, the test was conducted by plotting three stan-dard curves (genuine replicates, from three separate samplings).Each curve was constructed from the API working concentrations of70%–130% in the presence of the SyrSpend® SF PH4 (liquid) matrixto assess the linear relationship between the concentration of theanalyte and the obtained areas. For this purpose, the data for eachconcentration range of the curve after fitting by the ordinary leastsquares method were evaluated by analysis of variance (ANOVA)and subjected to the least squares method to determine the corre-lation coefficient of the calibration curve.
The limits of detection (LOD) and the limits of quantification(LOQ) were also determined from three standard calibration curvesof the APIs in the presence of the SyrSpend® SF PH4 (liquid) matrixand were calculated as shown in Eqs. (1) and (2), respectively:
LOD = s3a
(1)
LOQ = s10a
(2)
where a is the slope of the calibration curve and s is the standarddeviation of the y-intercept. LOD and LOQ were confirmed by theanalysis of chromatograms generated by injecting solutions in theirrespective limiting concentrations.
2.5. Preparation of API suspension samples
The API suspensions were prepared using the following gen-eral protocol: (i) the required quantity of each ingredient for thetotal amount to be prepared was calculated; (ii) each ingredientwas accurately weighed; (iii) the API was placed to the mortar andtriturated until a fine powder was obtained; (iv) a small amountof the SyrSpend® SF PH4 (liquid) was added to the powder andmixed to form a uniform paste; (v) the SyrSpend® SF PH4 (liquid)was continued to be added in approximately geometric portions
ESTUDO 13
A.O. Ferreira et al. / Journal of Pharmaceutical and Biomedical Analysis 118 (2016) 105–112 107
Tab
le2
Ch
rom
atog
rap
hic
con
dit
ion
su
sed
inth
efe
asib
ilit
yst
ud
y.
API
Mob
ile
ph
ase
com
pos
itio
nW
ork
con
cen
trat
ion
(g/
mL)
aC
olu
mn
Flow
(mL/
min
)U
Vd
etec
tion
wav
elen
gth
(nm
)
Am
lod
ipin
ebe
syla
teM
eth
anol
,ace
ton
itri
lean
dbu
ffer
(7.0
mL
oftr
ieth
ylam
ine
inw
ater
,pH
adju
sted
to3.
0w
ith
ph
osp
hor
icac
id)
(35:
15:5
0)
507
.00
L1,3
.9-m
m×
15-c
m;
at25
Cb
1.0
237
Ch
loro
quin
ep
hos
ph
ate
Ace
ton
itri
lean
dbu
ffer
solu
tion
(20
mM
1-h
epta
nes
ulf
onic
acid
adju
sted
toa
pH
of3.
4)(3
4:66
)
150
L1,4
.6-m
m×
25-c
m;
at25
Cc
1.5
340
Dap
son
eA
ceto
nit
rile
and
50m
Mam
mon
ium
ph
osp
hat
eso
luti
onad
just
edto
ap
Hof
4.6
(12:
88)
50L1
,3.0
-mm
×15
-cm
;at
25 C
d0.
729
5
Phen
ytoi
nW
ater
,met
han
ol,a
ceto
nit
rile
,0.5
%tr
ieth
ylam
ine
inw
ater
,an
d1.
74N
acet
icac
id(1
91:1
00:4
0:1.
3:1)
625
L1,4
.6-m
m×
15-c
m;
at30
Ce
1.5
229
Pyri
dox
ine
10m
Lof
glac
iala
ceti
cac
id,0
.6g
ofso
diu
m1-
hex
anes
ulf
onat
e,an
d70
0m
Lof
wat
erin
a10
00m
Lvo
lum
etri
cfl
ask;
adju
sted
wit
hgl
acia
lac
etic
acid
or1
Nso
diu
m
500
L1,4
.6-m
m×
25-c
m;
at25
Cf
1.5
280
Sulf
adia
zin
eA
ceto
nit
rile
,wat
er,a
nd
glac
iala
ceti
cac
id(1
2:87
:1)
1000
(in
0.02
5N
NaO
H)
L1,4
.6-m
m×
25-c
m;
at25
Cg
2.0
254
Sulf
asal
azin
eIs
opro
pan
ol,a
ceto
nit
rile
,wat
er,a
nd
glac
ial
acet
icac
id(1
1:7:
22:0
.4)
60 (in
0.1N
NaO
H).
L1,4
.6-m
m×
25-c
m;
at25
Ch
1.0
254
Tetr
acyc
lin
eh
ydro
chlo
rid
e68
0m
Lof
0.1
Mam
mon
ium
oxal
ate,
270
mL
ofd
imet
hyl
form
amid
e,an
d50
mL
of0.
2M
dib
asic
amm
oniu
mp
hos
ph
ate,
adju
stin
gw
ith
3N
amm
oniu
mh
ydro
xid
eor
3N
ph
osp
hor
icac
idto
ap
Hof
7.6–
7.7
500(
ina
mix
ture
of68
0m
Lof
0.1
Mam
mon
ium
oxal
ate
and
270
mL
ofd
imet
hyl
form
amid
e)
L7,4
.6-m
m×
25-c
m;
at25
Ci
2.0
280
Trim
eth
opri
m1%
Gla
cial
acet
icac
idin
wat
er(v
/v)
and
acet
onit
rile
(21:
4)20
0(i
nm
eth
anol
)L1
,4.6
-mm
×25
-cm
;at
25 C
j2.
025
0
Zon
isam
ide
Ace
ton
itri
le,m
eth
anol
,an
dbu
ffer
(1.3
6g/
Lof
mon
obas
icp
otas
siu
mp
hos
ph
ate
inw
ater
,w
ith
pH
adju
sted
to3.
0±
0.1
wit
h10
%p
hos
ph
oric
acid
)(1
:1:8
)
100
L1,4
.6-m
m×
25-c
m;
at25
Ck
1.5
240
aD
ilu
ted
wit
hm
obil
ep
has
e,u
nle
sssp
ecifi
edot
her
wis
e.b
Lun
a5
C
18(2
)10
0Å
(Ph
enom
enex
).c
Kro
mas
il5
10
0Å
(Kro
mas
il).
dLu
na
5
C18
(2)
100
Å(P
hen
omen
ex).
eSy
ner
gi4
Fu
sion
RP
80Å
(Ph
enom
enex
).f
Kro
mas
il5
10
0Å
(Kro
mas
il).
gK
rom
asil
5
100
Å(K
rom
asil
).h
Hyp
erC
lon
e5
12
0Å
(Ph
enom
enex
).i
Mic
roso
rb-M
V5
10
0Å
(Agi
len
t).
jLu
na
5
100
Å(P
hen
omen
ex).
kK
rom
asil
5
100
Å(K
rom
asil
).
ESTUDO 13
108 A.O. Ferreira et al. / Journal of Pharmaceutical and Biomedical Analysis 118 (2016) 105–112
almost to volume, mixing thoroughly after each addition; (vi) suf-ficient SyrSpend® SF PH4 (liquid) was added to bring the volume to300 mL, and then mixed well; (v) the final product was packagedin low-actinic prescription bottles and labeled.
The final concentrations in the bottles are summarized inTable 1. The suspensions were then immediately assayed at T = 0and separated into two different 150 mL bottles. One samplewas stored at the USP controlled refrigeration (2–8 C) and theother at controlled room temperature (20–25 C) during the study[temperature and humidity were checked in real time through-out the experiment using a calibrated digital thermo-hygrometer(Incoterm)]. Both samples were protected from light. Before anal-yses, the bottles were shaken until the API was observed to beuniformly dispersed.
2.6. Forced-degradation studies: stability-indicatingcharacteristics
API samples were subjected to the following denaturing con-ditions to determine the capacity of the HPLC method to detectany possible degradation products produced during the storageof the oral suspension: (i) dilution in acid (0.1 M HCl at 25 C),(ii) dilution in base (0.1 M NaOH at 25 C), (iii) exposure to ultra-violet light at 365 nm (at 25 C), and (iv) heating at 70 C. Thesesolutions were prepared for each API at its respective work concen-tration by means of serial dilution from a stock solution and usingsuitable diluents (see Table 2). The stock solutions were sonicallydispersed by 10 min and the final solutions were filtered (15 mmregenerated cellulose syringe filters, with 0.45 m pore size) beforeinjection onto the HPLC system. Any extraneous peaks found in thechromatograms were labeled. The resolution was also determinedbetween the degradation products and API peaks. A resolution of1.5 between the peaks was considered to be complete separation.
2.7. Feasibility study
The API samples were assayed by HPLC at pre-determined timepoints to verify the feasibility of the API in SyrSpend® SF PH4(liquid). The samples were shaken manually for 1 min to simu-late patient dosing. Adequate volumetric aliquots for quantification(variable for each API) were withdrawn from the middle of the bot-tles without contacting the inner surface of the bottle; then, theywere appropriately diluted to obtain work solutions in the con-centrations described under chromatographic conditions. Sampleswere taken at several time points, including 0 (baseline), 7, 14,30, 60, and 90 days (T = 0, 7, 14, 30, 60, or 90); all suspensionswere immediately assayed six times at each time point (sampleswere diluted, sonicated for 10 min and then filtered in 15 mmregenerated cellulose syringe filters, with 0.45 m pore size, beforeinjection onto the HPLC system). The evaluation parameter was thepercent recovery (assay, %) with respect to T = 0 using HPLC (resultsrepresented as percentage ± standard deviation).
3. Results and discussion
For the methods validation, specificity, precision, accuracy, andlinearity are listed in Table 3. All analytical methods met the respec-tive acceptance criteria.
Data from the stability-indicating studies are summarized inTable 4. Acid (0.1 M HCl) led to differences in the chromatograms ofall APIs compared with non-acid-treated controls, except chloro-quine phosphate; this result is in agreement with the study byOdusote and Nasipuri [27] who found that acidic pH did not inter-fere with the stability of this substance’s syrup. Base (0.1 M NaOH)caused alterations in the chromatograms of all APIs, except dap-sone and zonisamide; these results are also corroborated with Ta
ble
3Su
mm
ary
ofli
nea
rity
’sst
ud
yfo
rth
eva
lid
atio
nof
the
HPL
Cm
eth
od.
API
Lin
eari
tySp
ecifi
city
Prec
isio
nA
ccu
racy
Ran
ge(
g/m
L)A
nal
ytic
alcu
rve
R2
AN
OV
A’s
sign
ifica
nce
ofre
gres
sion
(F)
AN
OV
A’s
lack
offi
t(F
)LO
D(
g/m
L)LO
Q(
g/m
L)D
iscr
epan
cy(%
)R
epea
tabi
lity
(CV
,%)
Inte
rmed
iate
pre
cisi
on(C
V,%
)R
ecov
ery
(%)
Am
lod
ipin
ebe
syla
te35
0.07
–650
.13
y=
41.3
0x+
1916
.97
0.99
3921
45.0
32.
550.
002
0.00
6|0
.83|
0.79
2.07
99.9
Ch
loro
quin
ep
hos
ph
ate
105.
14–1
95.2
6y
=23
.16x
+69
.93
0.99
2818
00.1
83.
180.
020.
05|0
.76|
0.57
0.53
99.4
Dap
son
e35
0.70
–651
.30
y=
10.3
x+
92.8
80.
9974
4878
.30
3.39
0.01
0.03
|1.2
2|0.
742.
3710
0.1
Phen
ytoi
n43
5.40
–812
.50
y=
11.0
23x
+26
4.94
0.99
6840
39.1
63.
590.
002
0.00
7|1
.34|
1.63
2.26
99.7
Pyri
dox
ine
35.0
7–65
.13
y=
24.3
3x+
35.5
90.
9923
1682
.95
1.54
0.03
0.08
|0.9
1|0.
522.
0610
0.0
Sulf
adia
zin
e70
.00–
130.
00y
=39
.96x
+71
7.54
0.99
0613
76.4
43.
450.
005
0.01
7|1
.47|
0.26
2.14
99.2
Sulf
asal
azin
e42
.00–
78.0
0y
=50
.62x
−29
4.72
0.99
9421
240.
691.
000.
010.
03|1
.78|
0.67
2.38
99.8
Tetr
acyc
lin
eh
ydro
chlo
rid
e35
0.00
–650
.00
y=
38.4
1x+
378.
620.
9954
2795
.72
1.94
0.01
0.02
|1.8
3|0.
720.
9510
0.8
Trim
eth
opri
m14
0.70
–261
.30
y=
16.4
4x−
205.
710.
9978
5174
.63
3.23
1.23
4.09
|1.2
1|0.
602.
4010
0.1
Zon
isam
ide
70.2
8–13
0.52
y=
33.4
2x+
2.19
0.99
4222
14.6
02.
990.
050.
16|1
.08|
0.20
0.59
99.8
LOD
:li
mit
ofd
etec
tion
.LO
Q:
lim
itof
quan
tifi
cati
on(2
0
Lin
ject
ion
s).C
V:
coef
fici
ent
ofva
riat
ion
.A
ccep
tan
cecr
iter
iaw
ere:
R2
>0.
99,F
(sig
nifi
can
ceof
regr
essi
on)»
4.67
,F(l
ack
offi
t)<
3.71
,dis
crep
ancy
<2%
,rep
eata
bili
tyan
din
term
edia
tep
reci
sion
<5%
,an
dre
cove
ry=
100
±2%
.All
anal
ytic
alra
nge
s(
g/m
L)w
ere
adeq
uat
eto
quan
tify
the
API
sin
the
con
cen
trat
ion
su
sed
inth
esu
spen
sion
s(m
g/m
L).
ESTUDO 13
108 A.O. Ferreira et al. / Journal of Pharmaceutical and Biomedical Analysis 118 (2016) 105–112
almost to volume, mixing thoroughly after each addition; (vi) suf-ficient SyrSpend® SF PH4 (liquid) was added to bring the volume to300 mL, and then mixed well; (v) the final product was packagedin low-actinic prescription bottles and labeled.
The final concentrations in the bottles are summarized inTable 1. The suspensions were then immediately assayed at T = 0and separated into two different 150 mL bottles. One samplewas stored at the USP controlled refrigeration (2–8 C) and theother at controlled room temperature (20–25 C) during the study[temperature and humidity were checked in real time through-out the experiment using a calibrated digital thermo-hygrometer(Incoterm)]. Both samples were protected from light. Before anal-yses, the bottles were shaken until the API was observed to beuniformly dispersed.
2.6. Forced-degradation studies: stability-indicatingcharacteristics
API samples were subjected to the following denaturing con-ditions to determine the capacity of the HPLC method to detectany possible degradation products produced during the storageof the oral suspension: (i) dilution in acid (0.1 M HCl at 25 C),(ii) dilution in base (0.1 M NaOH at 25 C), (iii) exposure to ultra-violet light at 365 nm (at 25 C), and (iv) heating at 70 C. Thesesolutions were prepared for each API at its respective work concen-tration by means of serial dilution from a stock solution and usingsuitable diluents (see Table 2). The stock solutions were sonicallydispersed by 10 min and the final solutions were filtered (15 mmregenerated cellulose syringe filters, with 0.45 m pore size) beforeinjection onto the HPLC system. Any extraneous peaks found in thechromatograms were labeled. The resolution was also determinedbetween the degradation products and API peaks. A resolution of1.5 between the peaks was considered to be complete separation.
2.7. Feasibility study
The API samples were assayed by HPLC at pre-determined timepoints to verify the feasibility of the API in SyrSpend® SF PH4(liquid). The samples were shaken manually for 1 min to simu-late patient dosing. Adequate volumetric aliquots for quantification(variable for each API) were withdrawn from the middle of the bot-tles without contacting the inner surface of the bottle; then, theywere appropriately diluted to obtain work solutions in the con-centrations described under chromatographic conditions. Sampleswere taken at several time points, including 0 (baseline), 7, 14,30, 60, and 90 days (T = 0, 7, 14, 30, 60, or 90); all suspensionswere immediately assayed six times at each time point (sampleswere diluted, sonicated for 10 min and then filtered in 15 mmregenerated cellulose syringe filters, with 0.45 m pore size, beforeinjection onto the HPLC system). The evaluation parameter was thepercent recovery (assay, %) with respect to T = 0 using HPLC (resultsrepresented as percentage ± standard deviation).
3. Results and discussion
For the methods validation, specificity, precision, accuracy, andlinearity are listed in Table 3. All analytical methods met the respec-tive acceptance criteria.
Data from the stability-indicating studies are summarized inTable 4. Acid (0.1 M HCl) led to differences in the chromatograms ofall APIs compared with non-acid-treated controls, except chloro-quine phosphate; this result is in agreement with the study byOdusote and Nasipuri [27] who found that acidic pH did not inter-fere with the stability of this substance’s syrup. Base (0.1 M NaOH)caused alterations in the chromatograms of all APIs, except dap-sone and zonisamide; these results are also corroborated with Ta
ble
3Su
mm
ary
ofli
nea
rity
’sst
ud
yfo
rth
eva
lid
atio
nof
the
HPL
Cm
eth
od.
API
Lin
eari
tySp
ecifi
city
Prec
isio
nA
ccu
racy
Ran
ge(
g/m
L)A
nal
ytic
alcu
rve
R2
AN
OV
A’s
sign
ifica
nce
ofre
gres
sion
(F)
AN
OV
A’s
lack
offi
t(F
)LO
D(
g/m
L)LO
Q(
g/m
L)D
iscr
epan
cy(%
)R
epea
tabi
lity
(CV
,%)
Inte
rmed
iate
pre
cisi
on(C
V,%
)R
ecov
ery
(%)
Am
lod
ipin
ebe
syla
te35
0.07
–650
.13
y=
41.3
0x+
1916
.97
0.99
3921
45.0
32.
550.
002
0.00
6|0
.83|
0.79
2.07
99.9
Ch
loro
quin
ep
hos
ph
ate
105.
14–1
95.2
6y
=23
.16x
+69
.93
0.99
2818
00.1
83.
180.
020.
05|0
.76|
0.57
0.53
99.4
Dap
son
e35
0.70
–651
.30
y=
10.3
x+
92.8
80.
9974
4878
.30
3.39
0.01
0.03
|1.2
2|0.
742.
3710
0.1
Phen
ytoi
n43
5.40
–812
.50
y=
11.0
23x
+26
4.94
0.99
6840
39.1
63.
590.
002
0.00
7|1
.34|
1.63
2.26
99.7
Pyri
dox
ine
35.0
7–65
.13
y=
24.3
3x+
35.5
90.
9923
1682
.95
1.54
0.03
0.08
|0.9
1|0.
522.
0610
0.0
Sulf
adia
zin
e70
.00–
130.
00y
=39
.96x
+71
7.54
0.99
0613
76.4
43.
450.
005
0.01
7|1
.47|
0.26
2.14
99.2
Sulf
asal
azin
e42
.00–
78.0
0y
=50
.62x
−29
4.72
0.99
9421
240.
691.
000.
010.
03|1
.78|
0.67
2.38
99.8
Tetr
acyc
lin
eh
ydro
chlo
rid
e35
0.00
–650
.00
y=
38.4
1x+
378.
620.
9954
2795
.72
1.94
0.01
0.02
|1.8
3|0.
720.
9510
0.8
Trim
eth
opri
m14
0.70
–261
.30
y=
16.4
4x−
205.
710.
9978
5174
.63
3.23
1.23
4.09
|1.2
1|0.
602.
4010
0.1
Zon
isam
ide
70.2
8–13
0.52
y=
33.4
2x+
2.19
0.99
4222
14.6
02.
990.
050.
16|1
.08|
0.20
0.59
99.8
LOD
:li
mit
ofd
etec
tion
.LO
Q:
lim
itof
quan
tifi
cati
on(2
0
Lin
ject
ion
s).C
V:
coef
fici
ent
ofva
riat
ion
.A
ccep
tan
cecr
iter
iaw
ere:
R2
>0.
99,F
(sig
nifi
can
ceof
regr
essi
on)»
4.67
,F(l
ack
offi
t)<
3.71
,dis
crep
ancy
<2%
,rep
eata
bili
tyan
din
term
edia
tep
reci
sion
<5%
,an
dre
cove
ry=
100
±2%
.All
anal
ytic
alra
nge
s(
g/m
L)w
ere
adeq
uat
eto
quan
tify
the
API
sin
the
con
cen
trat
ion
su
sed
inth
esu
spen
sion
s(m
g/m
L).
ESTUDO 13
108 A.O. Ferreira et al. / Journal of Pharmaceutical and Biomedical Analysis 118 (2016) 105–112
almost to volume, mixing thoroughly after each addition; (vi) suf-ficient SyrSpend® SF PH4 (liquid) was added to bring the volume to300 mL, and then mixed well; (v) the final product was packagedin low-actinic prescription bottles and labeled.
The final concentrations in the bottles are summarized inTable 1. The suspensions were then immediately assayed at T = 0and separated into two different 150 mL bottles. One samplewas stored at the USP controlled refrigeration (2–8 C) and theother at controlled room temperature (20–25 C) during the study[temperature and humidity were checked in real time through-out the experiment using a calibrated digital thermo-hygrometer(Incoterm)]. Both samples were protected from light. Before anal-yses, the bottles were shaken until the API was observed to beuniformly dispersed.
2.6. Forced-degradation studies: stability-indicatingcharacteristics
API samples were subjected to the following denaturing con-ditions to determine the capacity of the HPLC method to detectany possible degradation products produced during the storageof the oral suspension: (i) dilution in acid (0.1 M HCl at 25 C),(ii) dilution in base (0.1 M NaOH at 25 C), (iii) exposure to ultra-violet light at 365 nm (at 25 C), and (iv) heating at 70 C. Thesesolutions were prepared for each API at its respective work concen-tration by means of serial dilution from a stock solution and usingsuitable diluents (see Table 2). The stock solutions were sonicallydispersed by 10 min and the final solutions were filtered (15 mmregenerated cellulose syringe filters, with 0.45 m pore size) beforeinjection onto the HPLC system. Any extraneous peaks found in thechromatograms were labeled. The resolution was also determinedbetween the degradation products and API peaks. A resolution of1.5 between the peaks was considered to be complete separation.
2.7. Feasibility study
The API samples were assayed by HPLC at pre-determined timepoints to verify the feasibility of the API in SyrSpend® SF PH4(liquid). The samples were shaken manually for 1 min to simu-late patient dosing. Adequate volumetric aliquots for quantification(variable for each API) were withdrawn from the middle of the bot-tles without contacting the inner surface of the bottle; then, theywere appropriately diluted to obtain work solutions in the con-centrations described under chromatographic conditions. Sampleswere taken at several time points, including 0 (baseline), 7, 14,30, 60, and 90 days (T = 0, 7, 14, 30, 60, or 90); all suspensionswere immediately assayed six times at each time point (sampleswere diluted, sonicated for 10 min and then filtered in 15 mmregenerated cellulose syringe filters, with 0.45 m pore size, beforeinjection onto the HPLC system). The evaluation parameter was thepercent recovery (assay, %) with respect to T = 0 using HPLC (resultsrepresented as percentage ± standard deviation).
3. Results and discussion
For the methods validation, specificity, precision, accuracy, andlinearity are listed in Table 3. All analytical methods met the respec-tive acceptance criteria.
Data from the stability-indicating studies are summarized inTable 4. Acid (0.1 M HCl) led to differences in the chromatograms ofall APIs compared with non-acid-treated controls, except chloro-quine phosphate; this result is in agreement with the study byOdusote and Nasipuri [27] who found that acidic pH did not inter-fere with the stability of this substance’s syrup. Base (0.1 M NaOH)caused alterations in the chromatograms of all APIs, except dap-sone and zonisamide; these results are also corroborated with Ta
ble
3Su
mm
ary
ofli
nea
rity
’sst
ud
yfo
rth
eva
lid
atio
nof
the
HPL
Cm
eth
od.
API
Lin
eari
tySp
ecifi
city
Prec
isio
nA
ccu
racy
Ran
ge(
g/m
L)A
nal
ytic
alcu
rve
R2
AN
OV
A’s
sign
ifica
nce
ofre
gres
sion
(F)
AN
OV
A’s
lack
offi
t(F
)LO
D(
g/m
L)LO
Q(
g/m
L)D
iscr
epan
cy(%
)R
epea
tabi
lity
(CV
,%)
Inte
rmed
iate
pre
cisi
on(C
V,%
)R
ecov
ery
(%)
Am
lod
ipin
ebe
syla
te35
0.07
–650
.13
y=
41.3
0x+
1916
.97
0.99
3921
45.0
32.
550.
002
0.00
6|0
.83|
0.79
2.07
99.9
Ch
loro
quin
ep
hos
ph
ate
105.
14–1
95.2
6y
=23
.16x
+69
.93
0.99
2818
00.1
83.
180.
020.
05|0
.76|
0.57
0.53
99.4
Dap
son
e35
0.70
–651
.30
y=
10.3
x+
92.8
80.
9974
4878
.30
3.39
0.01
0.03
|1.2
2|0.
742.
3710
0.1
Phen
ytoi
n43
5.40
–812
.50
y=
11.0
23x
+26
4.94
0.99
6840
39.1
63.
590.
002
0.00
7|1
.34|
1.63
2.26
99.7
Pyri
dox
ine
35.0
7–65
.13
y=
24.3
3x+
35.5
90.
9923
1682
.95
1.54
0.03
0.08
|0.9
1|0.
522.
0610
0.0
Sulf
adia
zin
e70
.00–
130.
00y
=39
.96x
+71
7.54
0.99
0613
76.4
43.
450.
005
0.01
7|1
.47|
0.26
2.14
99.2
Sulf
asal
azin
e42
.00–
78.0
0y
=50
.62x
−29
4.72
0.99
9421
240.
691.
000.
010.
03|1
.78|
0.67
2.38
99.8
Tetr
acyc
lin
eh
ydro
chlo
rid
e35
0.00
–650
.00
y=
38.4
1x+
378.
620.
9954
2795
.72
1.94
0.01
0.02
|1.8
3|0.
720.
9510
0.8
Trim
eth
opri
m14
0.70
–261
.30
y=
16.4
4x−
205.
710.
9978
5174
.63
3.23
1.23
4.09
|1.2
1|0.
602.
4010
0.1
Zon
isam
ide
70.2
8–13
0.52
y=
33.4
2x+
2.19
0.99
4222
14.6
02.
990.
050.
16|1
.08|
0.20
0.59
99.8
LOD
:li
mit
ofd
etec
tion
.LO
Q:
lim
itof
quan
tifi
cati
on(2
0
Lin
ject
ion
s).C
V:
coef
fici
ent
ofva
riat
ion
.A
ccep
tan
cecr
iter
iaw
ere:
R2
>0.
99,F
(sig
nifi
can
ceof
regr
essi
on)»
4.67
,F(l
ack
offi
t)<
3.71
,dis
crep
ancy
<2%
,rep
eata
bili
tyan
din
term
edia
tep
reci
sion
<5%
,an
dre
cove
ry=
100
±2%
.All
anal
ytic
alra
nge
s(
g/m
L)w
ere
adeq
uat
eto
quan
tify
the
API
sin
the
con
cen
trat
ion
su
sed
inth
esu
spen
sion
s(m
g/m
L).
A.O. Ferreira et al. / Journal of Pharmaceutical and Biomedical Analysis 118 (2016) 105–112 109
Tab
le4
Sum
mar
yof
the
stab
ilit
y-in
dic
atin
gst
ud
yfo
rth
eA
PIs
(res
ult
sp
rese
nte
das
aver
age
of3
rep
lica
tes,
atth
ew
ork
con
cen
trat
ion
).
API
HC
lN
aOH
UV
Hea
t
Are
a%
da
Are
a%
da
Are
a%
da
Are
a%
da
Am
lod
ipin
ebe
syla
te22
768.
30|1
3.29
|20
698.
69|2
.99|
2623
8.89
|30.
56|
2216
3.91
|10.
28|
Ch
loro
quin
ep
hos
ph
ate
3566
.63
|1.3
3|18
18.5
9|4
9.69
|32
83.8
7|9
.15|
3670
.14
|1.5
4|D
apso
ne
4438
.72
|9.1
7|49
45.9
7|1
.21|
4788
.61
|2.0
1|50
66.2
5|3
.67|
Phen
ytoi
n29
77.2
8|5
5.29
|63
15.2
5|5
.16|
5912
.90
|11.
21|
5990
.80
|10.
04|
Pyri
dox
ine
1227
.54
|3.9
5|11
26.4
4|1
1.85
|12
81.8
4|0
.31|
1122
.03
|12.
20|
Sulf
adia
zin
e52
07.6
6|3
.15|
4877
.38
|3.3
9|48
87.9
7|3
.18|
4948
.60
|1.9
8|Su
lfas
alaz
ine
2485
.25
|6.5
1|23
81.6
1|2
.07|
2405
.61
|3.1
0|23
41.8
2|0
.36|
Tetr
acyc
lin
eh
ydro
chlo
rid
e16
676.
10|1
2.73
|94
13.4
7|5
0.73
|19
640.
18|2
.79|
1922
5.68
|0.6
2|Tr
imet
hop
rim
2378
.81
|22.
25|
3236
.68
|5.7
9|30
41.5
7|0
.59|
2890
.69
|5.5
2|Zo
nis
amid
e21
26.6
2|3
4.36
|33
00.4
5|1
.89|
3254
.62
|0.4
8|33
12.7
5|2
.27|
aPe
rcen
tage
ofd
iscr
epan
cybe
twee
nth
eA
PIp
eak
wit
hou
td
egra
dat
ion
(neg
ativ
eco
ntr
ol)
and
the
pea
kof
asa
mp
lesu
bjec
ted
toon
eof
the
cite
dac
cele
rate
d-d
egra
dat
ion
fact
or.A
reas
give
nas
mV
.Max
imu
mac
cep
tabl
e=
2%(v
alu
esh
igh
erth
anth
isar
ein
bold
).
the studies by Nahata et al. [28] as well as Abobo et al. [29]. UVexposure did not influence the chromatographic response of pyri-doxine hydrochlorides, trimethoprim, and zonisamide; zonisamidehas previously been evaluated and results similar to ours have beenobtained [28]. Finally, the effects of heat (70 C) were assessed, andwe observed that only chloroquine phosphate, sulfadiazine, sul-fasalazine, and tetracycline hydrochloride were unaffected becausetheir chromatographic peaks remained with a low discrepancycompared with those of their standards; this observation is inaccordance with those available in the literature [30].
The feasibility results are shown in Table 5 and are expressed asthe relative percentage of recovery (initial sampling time = 100%).For the suspensions to be considered as feasible, the relative per-centage of recovery should lie within 90–110% according to theinternational pharmacopeias, including the United States, British,and European Pharmacopoeias [4–6]. Fig. 1 graphically representsthe feasibility of APIs in SyrSpend® SF PH4 (liquid) in terms ofabsolute nominal concentrations. At each sampling time, the visualaspect of the suspensions was also evaluated to verify their homo-geneity.
In this study, we did not evaluate the uniformity of the drug inthe suspension and expect that any non-soluble drugs will exist asinsoluble crystals, particulates, or precipitate.
The majority of the studied APIs are not soluble at the con-centrations listed in Table 1: amlodipine besylate (0.073 mg/mL),dapsone (practically insoluble), phenytoin (practically insolu-ble), sulfadiazine (2 mg/mL), sulfasalazine (practically insoluble),trimethoprim (0.40 mg/mL), zonisamide (0.80 mg/mL). The only 3drugs soluble at the concentrations stated in Table 1 are chloro-quine phosphate, pyridoxine, and tetracycline hydrochloride. Weexpect that these non-soluble drugs are solubilized only whendiluted for analysis in the chromatographic mobile phase, whichcontains a high percentage of organic solvent, as indicated inTable 2. Therefore, we predict some heterogeneity of drug dosageswill exist in the storage bottle, and without suitable mixing prior tosampling may show increased variance. Therefore, all suspensionswere stable throughout the study (at least for 90 days), regardless oftheir storage at refrigeration temperature or at room temperature,because no visual, odor, or assay changes were detected. Losses inthe content of APIs with respect to T = 0 were not >1.0% and, gener-ally, even <5%, thereby indicating good API stability and chemicalcompatibility/feasibility with the vehicle.
4. Conclusions
This study indicated the feasibility of using suspensions ofAPIs with SyrSpend® SF PH4 (liquid) within a 90-day period afterpreparation when stored both at controlled refrigeration and atcontrolled room temperature. As demonstrated in the results,SyrSpend® SF PH4 (liquid) is feasible for a wide range of APIs fromdiverse pharmacological classes. These feasibility results indicatethe probable success of validating the APIs evaluated in this studyfor the multiple dosages likely to be used in clinical applicationsby pharmacists or drug manufacturers interested in using oral sus-pensions for drug administration.
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Table 5Feasibility of the APIs in SyrSpen d® SF PH4 (liquid).
Elapsed time (days) % Recovery
Controlled refrigerated temperature (2–8 C) Controlled room temperature (20–25 C)
Amlodipine (as besylate) 1.0 mg/mLT = 0 100 ± 1.46 100 ± 1.46T = 7 104.43 ± 0.16 104.32 ± 0.34T = 14 107.96 ± 0.47 99.13 ± 0.25T = 30 108.04 ± 0.93 97.49 ± 2.43T = 60 108.23 ± 0.36 95.51 ± 0.76T = 90 103.80 ± 0.83 97.91 ± 0.75
Chloroquine phosphate 15.0 mg/mLT = 0 100 ± 0.22 100 ± 0.22T = 7 100.19 ± 0.20 100.58 ± 0.50T = 14 101.04 ± 0.50 101.12 ± 0.29T = 30 99.86 ± 0.84 101.93 ± 1.39T = 60 100.39 ± 0.75 101.56 ± 0.55T = 90 100.92 ± 0.48 101.48 ± 0.56
Dapsone 2.0 mg/mLT = 0 100 ± 1.78 100 ± 1.78T = 7 102.87 ± 0.43 101.60 ± 0.23T = 14 101.59 ± 0.59 100.60 ± 0.61T = 30 98.95 ± 0.17 101.14 ± 0.27T = 60 97.54 ± 0.35 104.29 ± 0.33T = 90 102.55 ± 0.21 104.02 ± 0.11
Phenytoin 15.0 mg/mLT = 0 100 ± 1.41 100 ± 1.41T = 7 96.12 ± 0.37 100.95 ± 0.26T = 14 102.24 ± 0.45 108.32 ± 0.35T = 30 103.52 ± 0.17 102.73 ± 0.30T = 60 105.17 ± 1.38 99.49 ± 0.56T = 90 101.25 ± 0.29 101.46 ± 0.31
Pyridoxine 50.0 mg/mLT = 0 100 ± 0.91 100 ± 0.91T = 7 104.42 ± 0.33 102.81 ± 1.23T = 14 103.27 ± 0.34 103.46 ± 0.50T = 30 102.88 ± 0.32 102.90 ± 0.31T = 60 98.04 ± 1.17 102.22 ± 0.84T = 90 101.26 ± 0.42 102.81 ± 0.68
Sulfadiazine 100.0 mg/mLT = 0 100 ± 0.70 100 ± 0.70T = 7 100.11 ± 2.97 98.66 ± 1.05T = 14 106.14 ± 1.14 92.58 ± 0.93T = 30 100.74 ± 0.41 99.28 ± 0.28T = 60 100.63 ± 0.17 100.57 ± 0.31T = 90 98.98 ± 0.77 99.04 ± 0.78
Sulfasalazine 100.0 mg/mLT = 0 100 ± 0.39 100 ± 0.39T = 7 99.05 ± 0.80 99.00 ± 0.25T = 14 97.76 ± 0.20 100.32 ± 0.40T = 30 99.38 ± 0.70 99.72 ± 0.55T = 60 98.10 ± 0.32 98.33 ± 0.50T = 90 98.14 ± 0.46 99.50 ± 0.26
Tetracycline hydrochloride 25.0 mg/mLT = 0 100 ± 0.46 100 ± 0.46T = 7 96.73 ± 1.45 96.81 ± 0.76T = 14 93.88 ± 0.80 93.61 ± 2.05T = 30 96.38 ± 1.19 96.03 ± 1.47T = 60 95.07 ± 0.77 94.86 ± 0.25T = 90 95.16 ± 0.18 95.15 ± 0.30
Trimethoprim 10.0 mg/mLT = 0 100 ± 0.98 100 ± 0.98T = 7 103.68 ± 0.45 103.49 ± 1.05T = 14 96.67 ± 1.17 102.02 ± 0.78T = 30 98.89 ± 0.97 102.26 ± 1.44T = 60 101.88 ± 1.31 102.50 ± 0.43T = 90 102.21 ± 0.27 101.95 ± 0.82
Zonisamide 10.0 mg/mLT = 0 100 ± 0.46 100 ± 0.46T = 7 94.93 ± 0.38 100.13 ± 0.33T = 14 99.15 ± 1.17 91.31 ± 0.89T = 30 96.80 ± 1.19 94.69 ± 0.33T = 60 96.40 ± 0.83 95.62 ± 0.72T = 90 95.04 ± 0.94 94.91 ± 0.23
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Fig. 1. Plot of APIs in SyrSpend® SF PH4 (liquid) throughout the feasibility study (dashed lines represent the lower and upper limits, corresponding to 90 and 110% of labeledconcentration). Values represents mean ± SD (n = 6).A – amlodipine (as besylate) 1.0 mg/mL, B – chloroquine phosphate 15.0 mg/mL, C – dapsone 2.0 mg/mL, D – phenytoin 15.0 mg/mL, E – pyridoxine 50.0 mg/mL, F – sulfadiazine100.0 mg/mL, G – sulfasalazine 100.0 mg/mL, H – tetracycline hydrochloride 25.0 mg/mL, I – trimethoprim 10.0 mg/mL, J – zonisamide 10.0 mg/mL.
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[1] T. Bauters, B. Claus, E. Willems, J. De Porre, J. Verlooy, Y. Benoit, H. Robays,What’s in a drop? Optimizing strategies for administration of drugs inpediatrics, Int. J. Clin. Pharm. 4 (2012) 679–681.
[2] L.V. Allen, Dosage form design and development, Clin. Ther. 30 (2008)2102–2111.
[3] N. Provenza, A.C. Calpena, M. Mallandrich, L. Halbaut, B. Clares, Design andphysicochemical stability studies of paediatric oral formulations of sildenafil,Int. J. Pharm. 460 (2014) 234–239.
[4] N.T. Vu, V. Aloumanis, M. Ben, Stability of metronidazole benzoate in SyrSpendSF one-step suspension system, Int. J. Pharm. Compd. 12 (2008) 558–564.
[5] C.M. Geiger, M.A. Voudrie, B. Sorenson, Stability of ursodiol in SyrSpend SFcherry flavored, Int. J. Pharm. Compd. 16 (2012) 510–512.
[6] B. Sorenson, P. Whaley, Stability of rifampin in SyrSpend SF, Int. J. Pharm.Compd. 17 (2013) 162–164.
[7] C.M. Geiger, B. Sorenson, P.A. Whaley, Stability of captopril in SyrSpend SF,Int. J. Pharm. Compd. 17 (2013) 336–338.
[8] B. Sorenson, M.A. Voudrie, D. Gehrig, Stability of gabapentin in SyrSpend SF,Int. J. Pharm. Compd. 16 (2012) 347–349.
[9] C.M. Geiger, B. Sorenson, P.A. Whaley, Stability of midazolam in SyrSpend SFand SyrSpend SF cherry, Int. J. Pharm. Compd. 17 (2013) 344–346.
[10] P.A. Whaley, M.A. Voudrie, B. Sorenson, Stability of omeprazole in SyrSpendSF Alka (reconstituted), Int. J. Pharm. Compd. 16 (2012) 164–166.
[11] M.A. Voudrie, D.B. Allen, Stability of oseltamivir phosphate in SyrSpend SF,cherry syrup, and SyrSpend SF (for reconstitution), Int. J. Pharm. Compd. 14(2010) 82–85.
[12] P.A. Whaley, M.A. Voudrie, B. Sorenson, Stability of vancomycin in SyrSpendSF, Int. J. Pharm. Compd. 16 (2012) 167–169.
[13] M.A. Voudrie, B. Alexander, D.B. Allen, Stability of verapamil hydrochloridecompared to sorbitol containing syrup and suspending vehicles, Int. J. Pharm.Compd. 15 (2011) 255–258.
[14] C.M. Geiger, M.A. Voudrie, B. Sorenson, Stability of propranolol hydrochloridein SyrSpend SF, Int. J. Pharm. Compd. 16 (2012) 513–515.
[15] United States Pharmacopeial Convention, Inc. Amlodipine Tablets. UnitedStates Pharmacopeia 38–National Formulary 33, v. 2, p. 2209-2210. Rockville,MD: US Pharmacopeial Convention, Inc., 2015.
[16] United States Pharmacopeial Convention, Inc. Chloroquine Phosphate OralSuspension. United States Pharmacopeia 38–National Formulary 33, v. 2, p.2770-2771. Rockville, MD: US Pharmacopeial Convention, Inc., 2015.
[17] United States Pharmacopeial Convention, Inc. Dapsone. United StatesPharmacopeia 38–National Formulary 33, v. 2, p. 3002-3003. Rockville, MD:US Pharmacopeial Convention, Inc., 2015.
[18] United States Pharmacopeial Convention, Inc. Phenytoin Oral Suspension.United States Pharmacopeia 38–National Formulary 33, v. 3, p. 4287-4288.Rockville, MD: US Pharmacopeial Convention, Inc., 2015.
[19] United States Pharmacopeial Convention, Inc. Pyridoxine. United StatesPharmacopeia 38–National Formulary 33, v. 3, p. 5092-5093. Rockville, MD:US Pharmacopeial Convention, Inc., 2015.
[20] United States Pharmacopeial Convention, Inc. Sulfadiazine. United StatesPharmacopeia 38–National Formulary 33, v. 5382-5383. Rockville, MD: USPharmacopeial Convention, Inc., 2015.
[21] United States Pharmacopeial Convention, Inc. Sulfasalazine Delayed-releaseTablets. United States Pharmacopeia 38–National Formulary 33, v. 3, p.5403-5404. Rockville, MD: US Pharmacopeial Convention, Inc., 2015.
[22] United States Pharmacopeial Convention, Inc. Tetracycline HydrochlorideOral Suspension. United States Pharmacopeia 38–National Formulary 33, v. 3,p. 5517. Rockville, MD: US Pharmacopeial Convention, Inc., 2015.
[23] United States Pharmacopeial Convention, Inc. Trimethoprim. United StatesPharmacopeia 38–National Formulary 33, v. 3, p. 5693-5694. Rockville, MD:US Pharmacopeial Convention, Inc., 2015.
[24] United States Pharmacopeial Convention, Inc. Zonisamide. United StatesPharmacopeia 38–National Formulary 33, v. 3, p. 5860-5861. Rockville, MD:US Pharmacopeial Convention, Inc., 2015, 1445-1450.
[25] United States Pharmacopeial Convention, Inc. <1225> Validation ofCompendial Procedures. United States Pharmacopeia 38–National Formulary33, v. 1, p. 1445-1450. Rockville, MD: US Pharmacopeial Convention, Inc.,2015.
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[29] C.V. Abobo, B. Wei, D. Liang, Stability of zonisamide in extemporaneouslycompounded oral suspensions, Am. J. Health Syst. Pharm. 66 (2009)1105–1109.
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420International Journal of Pharmaceutical CompoundingVol. 19 No. 5 | September | October | 2015
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Christine M. Geiger, MSBridget Sorenson, BSPaul Whaley, BS
INTRODUCTION The majority of all patients receiving drugs can be treated with commercially available medication. However, there are specific patient groups that have difficulty swallowing commercially available solid-dosage forms or require frequent dose adjustments. Examples of these patient groups include: pediatric, elderly, cancer, or hospitalized patients. For these patients, there is a need for a homogenous liquid, readily adjustable dosage form that can eas-ily be applied in the hospital or at home. Compounding tailor-made oral liquid medi-cation is challenging for the pharmacist. The formulation needs to assure accurate dosing throughout the course of treatment, and must guarantee safety for vulnerable patients during short or chronic use. In addition, the medication needs to have a sufficient pleasant taste to ensure patient adherence throughout the duration of the therapy; this is especially important for pediatric patients.1
From a technical perspective, many active pharmaceutical ingredients (APIs) are either insufficiently soluble in aqueous solutions, have a very profound taste, or are not com-mercially available as raw material. Commer-cially available tablets or capsules regularly have non-soluble components. Therefore, pharmacists are often required to compound a suspension instead of an oral solution. A great challenge for suspensions is to make them physically and chemically stable.
Stability Assessment of 10 Active Pharmaceutical Ingredients Compounded in SyrSpend SF
The authors’ affiliations are: Christine M. Geiger, Lab Technician III, Dynalabs, LLC, Saint Louis, Missouri; Bridget Sorenson, Project Manager, Sigma Aldrich, Saint Louis, Missouri; Paul Whaley, Laboratory Manager, Advanced Pain Center, Festus, Missouri.
ABSTRACTThe stability of 10 active pharmaceutical ingredients was studied in SyrSpend SF PH4 or SyrSpend SF Alka at room and/or refrigerated temperature (2°C to 8°C). An oral suspension of each active pharmaceutical ingredient was compounded in low actinic plastic bottles at a specific concentration in SyrSpend SF PH4 or SyrSpend SF Alka. Samples were assessed for stability immediately after preparation (day 0) followed by storage at room temperature and/or at refrigerated temperature. At set time points, the samples were removed from storage and assayed using a high-performance liquid chromatographic stability-indicating method. The active pharmaceutical ingredient was considered stable if the suspension retained 90% to 110% of the initial concentration. Furosemide was stable for at least 14 days in SyrSpend SF Alka at refrigerated conditions. Prednisolone sodium phosphate in SyrSpend SF PH4 was stable for at least 30 days at room temperature and refrigerated conditions. Ranitidine hydrochloride suspensions in SyrSpend SF PH4 at room temperature and refrigerated conditions were stable for at least 30 days and 58 days, respectively. Hydrocortisone hemisuccinate and sodium phosphate retained greater than 90% for at least 60 days at both room temperature and refrigerated samples in SyrSpend SF PH4. Amiodarone hydrochloride and nifedipine suspensions at both room temperature and refrigerated conditions retained greater than 90% of the initial concentrations for at least 90 days in SyrSpend SF PH4. Refrigerated samples of simvastatin in SyrSpend SF PH4 were stable for at least 90 days. Spironolactone in SyrSpend SF PH4 at room temperature retained more than 90% of the initial concentration for at least 90 days. Phenobarbital in SyrSpend SF PH4 retained above 90% of initial concentration for at least 154 days at room temperature. This study demonstrated the stability of a wide range of frequently used active pharmaceutical ingredients, tested in SyrSpend SF PH4 and SyrSpend SF Alka at different storage conditions.
When compounding suspensions, it is difficult to produce a physically stable, homogenous mixture that remains uniform in time.2,3 If the solid particles in the suspen-sion are sufficiently small and light, fluffy conglomerates are formed, which settle rap-idly, and are easily resuspended.4-8 Too rapid clearance of the supernatant in a flocculated system, however, produces the risk of inac-curate dosing.4,6 In contrast, deflocculated particles settle slowly and form sediment, solid aggregates, and finally a cake, that is difficult to resuspend.8
Each API in the suspension has to retain its chemical integrity and labeled potency within the specified limits.9 Chemical degradation reactions include hydrolysis, oxidation, isomerization, polymerization, and photodegradation.10 These reactions can all result in a loss of potency of the drug and potentially failure of the therapy. In essence, correct patient dosing is the result of physical and chemical suspension stability combined. Physical instability of the suspension leads to inhomogeneity, whereas chemical instability leads to lower API activ-
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ity. Either way, the suspension will be out of specification and the dosing unreliable. The importance of a well-compounded suspension is illustrated by the report of a neonate readmitted to the hospital with an arrhythmia because an amiodarone suspension had been incorrectly compound-ed and the solids had settled into a hard mass at the bottom of the container.11 SyrSpend SF PH4 is an innovative starch-based sus-pension base designed to contain optimal suspension and rheology features when compared with traditional cellulose-based suspending vehicles, in order to prevent both caking and too rapid clearance of the supernatant. Both the thixotropic and pseudoplastic properties of SyrSpend SF PH4 contribute to continuous dosage consistency and accuracy. The thixotropic properties of SyrSpend SF PH4 prevent the suspended API(s) from settling at the bottom of the container. The major benefits of thixotropy appear during “shelf” time, when increased viscosity prevents the API(s) from getting caught in an ir-reversible sediment cake.12 Pseudoplastic properties of the SyrSpend SF PH4 facilitate quick and low-effort homogenization of the API(s) by lowering the viscosity of the vehicle when shaken or stirred. Pseudoplasticity also guarantees reversibility of the viscosity at rest, ensuring quick, homogenous redistribution of the API(s) throughout the oral liquid dosage form. SyrSpend SF PH4 has been specifically designed to have extensive compatibility behavior and can therefore be used with a wide range of APIs.13-23 Because of their irregular spherical form, the starch types used in SyrSpend SF PH4 are mostly inert for chemical reactions. SyrSpend SF PH4 also stabilizes the suspended API(s) by buffer-ing: SyrSpend SF PH4 is buffered at pH 4.2 to resemble the pH of the stomach, at which most APIs are stable. For APIs which are acid labile, such as omeprazole, SyrSpend SF Alka dry provides an alkaline pH formulation.20
The goal of the study was to study the combined physical and chemical stability of 10 different APIs that are frequently used in pediatric and geriatric health care.
METHODSCHEMICAL REAGENTS Amiodarone hydrochloride (Lot 061M1422V; Sigma-Aldrich, St. Louis, Missouri), furosemide (Lot VG0951; Spectrum Chemicals, New Brunswick, New Jersey), hydrocortisone hemisuccinate (Lot 030M5032V; Sigma-Aldrich), hydrocortisone sodium phosphate (Lot 21611; Santa Cruz Biotech, Santa Cruz, California), nifedipine (Lot 76371/J; Medisca, Plattsburgh, New York), phenobarbital (Lot 031M1417V; Sigma-Aldrich), prednisolone sodium phosphate (Lot AA23619-001834; Fagron, Inc., St. Paul, Minnesota), ranitidine hydrochloride (Lot AA23620-000632; Fagron, Inc.), simvastatin (Lot I1H070; United States Pharmacopeia, Rockville, Maryland), and spironolactone (Lot 77822/D; Medisca) raw powders were received. SyrSpend SF PH4 (Lot 1110358V14), SyrSpend SF Alka (Lot 101215L12), and SyrSpend SF PH4 Cherry flavored (Lot 1108205T14) were received from Fagron, Inc. High-performance liquid chromato-graphic (HPLC)-grade methanol (Lot D1066; Honeywell, Muskegon,
Michigan), HPLC-grade acetonitrile (Lot DC353; Honeywell), 1N hy-drochloric acid (Lot 101680; ThermoFisher, Waltham, Massachusetts), 10N sodium hydroxide (Lot 1041408; BDH, London, UK), 35% hydro-gen peroxide (Lot WG0767, Spectrum), acetic acid (Lot A0318913; Acros, New Jersey), 85% phosphoric acid (Lot 2011052000, CCI, Columbus, Ohio), glycerin (Lot 80175/H; Medisca), monobasic sodium phosphate monohydrate (Lot 107148; ThermoFisher), dibasic sodium phosphate heptahydrate (Lot B0131737; Acros), sodium acetate trihy-drate (Lot 120722; ThermoFisher), 1-octane sulfonic acid sodium salt (Lot SHBC1400; Sigma-Aldrich) were used in these studies. HPLC-grade water was supplied by filtering deionized water from a Millipore Elix through a Millipore Simplicity (Billerica, Massachusetts).
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ASSAY A Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quaternary gradient solvent, a dual wavelength UV/VIS detector, and a 100-vial programmable autosampler with a Peltier tray, 200-mcL sample loop, and a 250-mcL syringe was used for the validation and the stability study. A second LC system, used for forced degradation studies, was a Varian Prostar (Palo Alto, California) HPLC equipped with a tertiary gradient solvent delivery system, a photodiode array detector (PDA), and a 84-vial programmable autos-ampler with a 100-mcL sample loop and a 250-mcL syringe was used. To collect and analyze data, Totalchrom chromatography software and Galaxie chromatography software were used for the Perkin Elmer and the Varian HPLC, respectively. The method parameters for each API are listed in Table 1. RP-HPLC columns were purchased from Phenomenex (Torrence, California).
METHOD VALIDATION Linearity was exhibited within a set concentration range for each API. All HPLC methods were shown to be stability indicating by forc-ibly degrading the API and separating the degradant peaks from that of the main analyte. A coefficient of determination of greater than 0.999 was observed for the standard curve for each API. Acceptable precision and accuracy were acquired by the methods. Accuracy was run at 80%, 100%, and 120% of target concentration and recovery was 97.5% to 102.5%. Precision met specifications of % relative standard deviation (RSD) less than 2.0 for all nine preparations. Samples were analyzed during validation and each was prepped six times. The acceptance criteria for sample precision were %RSD less than 5.0. Method validation results for each API are shown in Table 2. Interme-diate precision was performed for each analytical method to ensure the method would provide comparable results when similar samples were analyzed. Samples were stressed and assayed to determine the specificity of the HPLC method to any possible degradation product produced during storage of an oral suspension. They were each diluted to the standard concentrations in solutions of acid (0.1 M HCl), base (0.1 M NaOH), and hydrogen peroxide (3.5%), in addition to exposure to stan-dard light for photosensitivity and heat at 70°C. Samples were exposed to the stressor for 3 hours. Any extraneous degradant peaks found in
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TABLE 1. Stability-indicating High-performance Liquid Chromatographic Method Parameters for Each Active Pharmaceutical Ingredient.
A C T I V E F L O W I N J E C T I O NP H A R M A C E U T I C A L W A V E L E N G T H M O B I L E R A T E V O L U M EI N G R E D I E N T C O L U M N D I L U E N T ( N M ) P H A S E ( M L / M I N ) ( M C L )
Amiodarone hydrochloride Luna C8 Mobile phase 254 75% Methanol, 24% HPLC 2.0 100 grade water, 1% Glacial acetic acid
Furosemide Gemini C18 HPLC grade water, 271 0.25 M Phosphoric Acid: 1.5 50 pH 9.0 Acetonitrile gradient (82%:18% to 15%:85%)
Hydrocortisone hemisuccinate Gemini C18 Mobile phase 244 70% HPLC grade water, 1.5 100 30% Acetonitrile, 0.01% 85% phosphoric acid
Hydrocortisone sodium Gemini C18 Mobile phase 244 75% HPLC grade water, 1.0 25phosphate 25% Acetonitrile with 5.3g dibasic sodium phosphate heptahydrate per liter, pH 6.5
Nifedipine Gemini C18 Mobile phase 235 60% Methanol, 40% HPLC 1.0 50 grade water
Phenobarbital Gemini C18 Mobile phase 240 70% HPLC grade water, 2.0 100 30% Methanol with 2.7 g sodium acetate trihydrate per liter, pH 5.6
Prednisolone sodium Gemini C18 Mobile phase 248 75% HPLC grade water, 1.0 25phosphate 25% Acetonitrile with 5.3g dibasic sodium phosphate heptahydrate per liter, pH 6.5
Ranitidine hydrochloride Gemini C18 Mobile phase 226 77% 0.25 M Phosphoric 1.5 100 Acid with 10 mM 1- octanesulfonic acid sodium salt, monohydrate, 23% Acetonitrile
Simvastatin Gemini C18 Mobile phase 235 60% Acetonitrile, 40% HPLC 1.5 100 grade water, 0.04% 85% phosphoric acid
Spironolactone Gemini C18 Mobile phase 240 65% Methanol, 35% HPLC grade 1.0 100 water with 1.38g monobasic sodium phosphate monohydrate per liter, pH 3.0
HPLC = high-performance liquid chromatography
the chromatogram were labeled and the resolution (United States Pharmacopeia [USP]) was determined between the degradant and the API peak. Purity calculations were performed with the use of Galaxie software using a minimum of three points on the API and using the controlled unstressed standard as a reference. The methods were stability indicating and any degradants present were completely separated from the analyte with acceptable resolu-tion. Amiodarone hydrochloride degraded in the presence of base and oxidizer. Furosemide was sensitive to light. Hydrocortisone hemis-uccinate degraded with base, while the sodium phosphate form de-graded slightly in the presence of an oxidizer and significantly in base at 70°C. Nifedipine was both sensitive to oxidizers and light. Pheno-barbital showed degradation in the presence of base and oxidizer. An oxidizer and light caused some degradation to prednisolone sodium phosphate. Ranitidine hydrochloride showed some degradation to base and significant degradation to oxidizer. Simvastatin degraded
in acid and heat and more significantly in the presence of base. Base significantly degraded spironolactone.
SAMPLE PREPARATION FOR THE STABILITY STUDY The sample suspensions were prepared by adding a calculated amount of API powder to the SyrSpend SF PH4 or SyrSpend SF Alka (Fagron, Inc.) product used. The samples were mixed by shaking or stirring until homogeneous. The appropriate vehicle was chosen for each API in advance based on API properties. Concentrations were chosen on API concentrations that are used globally. SyrSpend SF PH4 Cherry flavored was chosen to mask the taste of certain APIs (amiodarone hydrochloride, nifedipine, phenobarbital, prednisolone sodium phosphate, and spironolactone), and SyrSpend SF Alka was used in the case of furosemide to assure optimal stability. SyrSpend SF PH4 was used for all others. The initial concentration for each API was set by the result at T=0 shown in Table 3. If the study was run at
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both room tempera-ture (RT) and refrig-erated conditions (2°C to 8°C), the contents were split in half, stored in low ac-tinic plastic prescrip-tion bottles in the respective locations, and submitted for stability assessment. Time points were determined for each stability study. The evaluation parameter was percent recovery assay. The stability of each API in suspen-sion was defined by percent recovery with respect to T=0 using a validated HPLC method. After mixing, aliquots of the sample were taken from the cen-ter of the container six times and diluted to the final standard and sample con-centration listed in Table 3.
DATA ANALYSIS The stability of each API in the SyrSpend SF PH4 or SyrSpend SF Alka vehicle was deter-mined by calculating the percentage of the initial concen-tration remaining at each time point. A suspension was defined stable when there was between 90% and 110% re-tention of the initial concentration as referenced in USP <795>.24
RSD = relative standard deviation
TABLE 2. Active Pharmaceutical Ingredient Method Validation Summary.
A C T I V E A N A L Y T I C A L S A M P L EP H A R M A C E U T I C A L R A N G E L I N E A R I T Y A C C U R A C Y P R E C I S I O N P R E C I S I O NI N G R E D I E N T ( M C G / M L ) R 2 ( % R E C O V E R Y ) ( % R S D ) ( % R S D )
Amiodarone hydrochloride 5 to 100 0.9997 102.19 0.71 0.76
Furosemide 2 to 20 0.9997 100.59 1.26 2.3
Hydrocortisone hemisuccinate 2.5 to 75 0.9997 100.72 0.68 3.13
Hydrocortisone sodium phosphate 2.5 to 75 1.0000 99.64 0.37 4.86
Nifedipine 4 to 64 0.9997 101.11 1.09 2.75
Phenobarbital 5 to 150 0.9999 98.84 1.66 2.47
Prednisolone sodium phosphate 2.5 to 72.5 0.9999 100.59 1.63 0.82
Ranitidine hydrochloride 2 to 50 0.9998 99.49 0.41 1.1
Simvastatin 5 to 25 0.9999 99.89 0.87 1.07
Spironolactone 2.5 to 45 1.0000 98.6 0.86 0.73
TABLE 3. Storage Location and Concentration of Active Pharmaceutical Ingredient in SyrSpend SF.
S T A N D A R DA C T I V E S T O R E D A N D S A M P L EP H A R M A C E U T I C A L V E H I C L E C O N C E N T R A T I O NI N G R E D I E N T V E H I C L E C O N C E N T R A T I O N S T O R A G E ( M C G / M L )
Amiodarone hydrochloride SyrSpend SF PH4 4.90 mg/mL Room temperature 30 Cherry flavored
Amiodarone hydrochloride SyrSpend SF PH4 4.90 mg/mL 2°C to 8°C 30 Cherry flavored
Furosemide SyrSpend SF Alka 9.64 mg/mL 2°C to 8°C 10
Hydrocortisone hemisuccinate SyrSpend SF PH4 2.05 mg/mL Room temperature 25
Hydrocortisone hemisuccinate SyrSpend SF PH4 2.05 mg/mL 2°C to 8°C 25
Hydrocortisone sodium phosphate SyrSpend SF PH4 2.05 mg/mL Room temperature 25
Hydrocortisone sodium phosphate SyrSpend SF PH4 2.05 mg/mL 2°C to 8°C 25
Nifedipine SyrSpend SF PH4 4.12 mg/mL Room temperature 20 Cherry flavored
Nifedipine SyrSpend SF PH4 4.12 mg/mL 2°C to 8°C 20 Cherry flavored
Phenobarbital SyrSpend SF PH4 9.26 mg/mL Room temperature 50
Phenobarbital SyrSpend SF PH4 8.98 mg/mL Room temperature 50 Cherry flavored
Prednisolone sodium phosphate SyrSpend SF PH4 1.32 mg/mL Room temperature 25
Prednisolone sodium phosphate SyrSpend SF PH4 1.32 mg/mL 2°C to 8°C 25
Prednisolone sodium phosphate SyrSpend SF PH4 1.40 mg/mL Room temperature 25 Cherry flavored
Prednisolone sodium phosphate SyrSpend SF PH4 1.40 mg/mL 2°C to 8°C 25 Cherry flavored
Ranitidine hydrochloride SyrSpend SF PH4 14.49 mg/mL Room temperature 20
Ranitidine hydrochloride SyrSpend SF PH4 14.49 mg/mL 2°C to 8°C 20
Simvastatin SyrSpend SF PH4 1.11 mg/mL 2°C to 8°C 12.5
Spironolactone SyrSpend SF PH4 25.79 mg/mL Room temperature 20
Spironolactone SyrSpend SF PH4 25.02 mg/mL Room temperature 20 Cherry flavored
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RESULTSHIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ASSAY The stability of each API per vehicle and storage condition is shown in Table 4. Figures 1 through 10 show the data in terms of percent recovery for each API in SyrSpend SF PH4, SyrSpend SF PH4 Cherry flavored, or SyrSpend SF Alka at RT and/or refrigerated conditions and that the suspension remained within specification (90%<[API at T=0]<110%) throughout the duration of the stability study. Figure 1 shows the percent recovery over 14 days for furosemide in SyrSpend SF Alka at refrigerated temperatures. The assay results varied 9.64 mg/mL (100.0%, T=0) and 9.29 mg/mL (96.4%, T=14). Figure 2 shows prednisolone sodium phosphate results in SyrSpend SF PH4 and SyrSpend SF PH4 Cherry flavored at both RT and refriger-ated conditions. The assay results for prednisolone sodium phosphate varied between 1.32 mg/mL (100.0%, T=0) and 1.29 mg/mL (97.6%, T=30) for RT storage conditions, and between 1.34 mg/mL (101.3%, T=21) and 1.30 mg/mL (98.5%, T=30) for refrigerated conditions in SyrSpend SF PH4. In SyrSpend SF PH4 Cherry flavored, the assay re-sults varied between 1.40 mg/mL (100.0%, T=0) and 1.31 mg/mL (93.5, T=15) for RT storage conditions and between 1.40 mg/mL (100.0%,
T=0) and 1.37 mg/mL (97.8%, T=30) for refrigerated conditions. Ranitidine hydrochloride in SyrSpend SF PH4 at RT and refrig-erated conditions have assay re-sults that range from 14.00 mg/mL (96.6%, T=36) and 14.63 (101.0%, T=7) and 14.02 mg/mL (96.8%, T=50) and 14.71 mg/mL (101.5%, T=7), respectively, and percent recoveries are shown in Figure 3. Hydrocortisone hemisucci-nate results in SyrSpend SF PH4 ranged between 2.02 mg/mL (98.5%, T=30) and 2.13 mg/mL (103.7%, T=14) for RT, and 2.00 mg/mL (97.5%, T=45) and 2.13 mg/mL (103.5%, T=14) for refrigerated samples. Hydro-cortisone sodium phosphate in SyrSpend SF PH4 varied from 2.05 mg/mL (100.0%, T=0) to 2.11 mg/mL (103.2%, T=7) for RT, and, for refrigerated, the assay value varied from 2.05 mg/mL (100.0%, T=0) to 2.10 mg/mL (102.7%, T=14). Percent recovery results for hydrocortisone hemis-uccinate and hydrocortisone sodium phosphate are depicted in Figures 4 and 5, respectively. Figure 6 shows the assay results
Peer Reviewed
TABLE 4. Stability of Active Pharmaceutical Ingredient in SyrSpend SF.
A C T I V E M I N I M U MP H A R M A C E U T I C A L S T A B I L I T Y % RECOVERY I N G R E D I E N T V E H I C L E S T O R A G E ( D A Y S ) F I N A L
Amiodarone hydrochloride SyrSpend SF PH4 Room temperature 91 99.14 ± 1.73 Cherry flavored
Amiodarone hydrochloride SyrSpend SF PH4 Cherry flavored 2°C to 8°C 91 97.91 ± 1.83
Furosemide SyrSpend SF Alka 2°C to 8°C 14 96.40 ± 2.91
Hydrocortisone hemisuccinate SyrSpend SF PH4 Room temperature 60 102.36 ± 1.55
Hydrocortisone hemisuccinate SyrSpend SF PH4 2°C to 8°C 60 101.76 ± 2.63
Hydrocortisone sodium phosphate SyrSpend SF PH4 Room temperature 60 101.23 ± 0.58
Hydrocortisone sodium phosphate SyrSpend SF PH4 2°C to 8°C 60 102.28 ± 0.50
Nifedipine SyrSpend SF PH4 Room temperature 92 94.03 ± 1.97 Cherry flavored
Nifedipine SyrSpend SF PH4 2°C to 8°C 92 90.83 ± 4.30 Cherry flavored
Phenobarbital SyrSpend SF PH4 Room temperature 154 103.61 ± 2.51
Phenobarbital SyrSpend SF PH4 Room temperature 154 107.54 ± 1.53 Cherry flavored
Prednisolone sodium phosphate SyrSpend SF PH4 Room temperature 30 97.58 ± 0.66
Prednisolone sodium phosphate SyrSpend SF PH4 2°C to 8°C 30 98.47 ± 1.54
Prednisolone sodium phosphate SyrSpend SF PH4 Room temperature 30 96.85 ± 0.77 Cherry flavored
Prednisolone sodium phosphate SyrSpend SF PH4 2°C to 8°C 30 97.83 ± 0.70 Cherry flavored
Ranitidine hydrochloride SyrSpend SF PH4 Room temperature 36 96.63 ± 0.70
Ranitidine hydrochloride SyrSpend SF PH4 2°C to 8°C 58 99.31 ± 1.01
Simvastatin SyrSpend SF PH4 2°C to 8°C 90 104.82 ± 1.68
Spironolactone SyrSpend SF PH4 Room temperature 90 99.86 ± 1.23
Spironolactone SyrSpend SF PH4 Room temperature 90 101.63 ± 1.81 Cherry flavored
Are
a (m
cgV/
sec)
mA
U
0 2 4 6 8 10 12 14
110
108
106
104
102
100
98
96
94
92
90
Days
% R
ecov
ery
SyrSpend SF Alka Refrigerated
% R
ecov
ery
Days
0 5 10 15 20 25 30
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 RefrigeratedSyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
FIGURE 1. Stability of Furosemide.
for amiodarone hydrochloride in SyrSpend SF PH4 Cherry fla-vored. The results for amiodarone hydrochloride varied between
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4.61 mg/mL (94.1%, T=31) and 4.90 mg/mL (100.0%, T=0) for RT stor-age, and between 4.71 (96.0%, T=64) and 5.09 mg/mL (103.8%, T=35) for refrigerated conditions. The percent recoveries throughout the stability study of nifedipine in SyrSpend SF PH4 Cherry flavored are shown in Figure 7. The assay results for nifedipine varied between 3.81 mg/mL (92.5%, T=32) and 4.12 mg/mL (100.0%, T=0) for RT storage, and between 3.74 mg/mL (94.0%, T=92) and 4.12 mg/mL (100.0%, T=0) for refrigerated conditions. The assay results for simvastatin in SyrSpend SF PH4 at refriger-ated conditions vary from 1.07 mg/mL (96.5%, T=32) and 1.17 mg/mL (104.8%, T=90), and percent recovery data is shown in Figure 8. Spironolactone in SyrSpend SF PH4 assay results range from 24.94 mg/mL (96.7%, T=31) to 25.82 mg/mL (100.1%, T=62), and in
Are
a (m
cgV/
sec)
mA
U
0 2 4 6 8 10 12 14
110
108
106
104
102
100
98
96
94
92
90
Days
% R
ecov
ery
SyrSpend SF Alka Refrigerated
% R
ecov
ery
Days
0 5 10 15 20 25 30
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 RefrigeratedSyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
Are
a (m
cgV/
sec)
mA
U
0 2 4 6 8 10 12 14
110
108
106
104
102
100
98
96
94
92
90
Days
% R
ecov
ery
SyrSpend SF Alka Refrigerated
% R
ecov
ery
Days
0 5 10 15 20 25 30
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 RefrigeratedSyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
FIGURE 2. Stability of Prednisolone Sodium Phosphate.
FIGURE 3. Stability of Ranitidine Hydrochloride.
Are
a (m
cgV/
sec)
mA
U
0 2 4 6 8 10 12 14
110
108
106
104
102
100
98
96
94
92
90
Days
% R
ecov
ery
SyrSpend SF Alka Refrigerated
% R
ecov
ery
Days
0 5 10 15 20 25 30
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 RefrigeratedSyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
FIGURE 4. Stability of Hydrocortisone Hemisuccinate.
Are
a (m
cgV/
sec)
mA
U
0 2 4 6 8 10 12 14
110
108
106
104
102
100
98
96
94
92
90
Days
% R
ecov
ery
SyrSpend SF Alka Refrigerated
% R
ecov
ery
Days
0 5 10 15 20 25 30
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 RefrigeratedSyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
FIGURE 5. Stability of Hydrocortisone Sodium Phosphate.
SyrSpend SF PH4 Cherry flavored results varied from 25.02 mg/mL (100.0%, T=0) to 26.65 (106.5%, T=7 and T=31), both stored at RT. Figure 9 demonstrates the associated percent recoveries for spirono-lactone in both unflavored and cherry flavored SyrSpend SF PH4. Results for phenobarbital in SyrSpend SF PH4 and SyrSpend SF PH4 Cherry flavored both stored at RT are shown in Figure 10. Phenobarbital in SyrSpend SF PH4 results varied from 9.26 mg/mL (100.0%, T=0) to 9.60 mg/mL (103.6%, T=154), and results varied from 8.96 mg/mL (99.8%, T=33) and 9.84 (109.6%, T=14) for pheno-barbital in SyrSpend SF PH4 Cherry flavored.
DISCUSSION The findings of these studies show that several API/SyrSpend SF combinations, stored in a plastic low actinic container, are
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Peer Reviewed
stable. SyrSpend SF PH4 is suitable as an oral sweetened suspend-ing vehicle for preparing individual compounded hydrocortisone hemisuccinate, hydrocortisone sodium phosphate, phenobarbital, prednisolone sodium phosphate, ranitidine hydrochloride, simvas-tatin, and spironolactone formulations. SyrSpend SF PH4 Cherry flavored when stored in the appropriate low actinic container under the appropriate conditions is a suitable vehicle for the following APIs: amiodarone hydrochloride, nifedipine, phenobarbital, prednisolone sodium phosphate, and spironolactone. SyrSpend SF PH4 Cherry flavored had a similar stability profile to that of SyrSpend SF PH4, indicating that the addition of the cherry flavor had no influence on the API stability. SyrSpend SF Alka is a suitable suspending vehicle for furosemide. Variable stability has been reported for furosemide in aqueous vehicles and is reported to be more stable at alkaline pH.25 Current results suggest that additional stability may be gained by the addition of soluble buffers.
CONCLUSION Furosemide at 9.6 mg/mL was stable for 14 days refrigerated in SyrSpend SF Alka. Prednisolone sodium phosphate at 1.4 mg/mL was stable in both SyrSpend SF PH4 and SyrSpend SF PH4 Cherry flavored at RT and refrigerated conditions for 30 days. Ranitidine hydrochloride at 14.5 mg/mL was stable in SyrSpend SF PH4 for 36 days at RT and 58 days refrigerated. Hydrocortisone hemisucci-nate and hydrocortisone sodium phosphate at 2 mg/mL were stable in SyrSpend SF PH4 at RT and refrigerated conditions for 60 days. Simvastatin at 1 mg/mL was stable for 90 days in SyrSpend SF PH4 refrigerated. Spironolactone was stable for 90 days in SyrSpend SF PH4 at 26 mg/mL and SyrSpend SF PH4 Cherry flavored at 25 mg/mL at RT. Amiodarone hydrochloride was stable in SyrSpend SF PH4 Cherry flavored at 5 mg/mL for 91 days at RT and refrigerated
Are
a (m
cgV/
sec)
mA
U
0 2 4 6 8 10 12 14
110
108
106
104
102
100
98
96
94
92
90
Days
% R
ecov
ery
SyrSpend SF Alka Refrigerated
% R
ecov
ery
Days
0 5 10 15 20 25 30
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 RefrigeratedSyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 10 20 30 40 50 60
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
FIGURE 6. Stability of Amiodarone Hydrocloride.
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
% R
ecov
ery
Days
0 25 50 75 100 125 150
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
FIGURE 7. Stability of Nifedipine.
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
% R
ecov
ery
Days
0 25 50 75 100 125 150
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
FIGURE 8. Stability of Simvastatin.
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
% R
ecov
ery
Days
0 25 50 75 100 125 150
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
FIGURE 9. Stability of Spironolactone.
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Peer Reviewed
conditions. Nifedipine was stable in SyrSpend SF PH4 Cherry fla-vored at 4 mg/mL for 92 days when stored at RT and refrigerated con-ditions. Phenobarbital was stable at RT for 154 days in both SyrSpend SF PH4 at 9.3 mg/mL and SyrSpend SF PH4 Cherry flavored at 9.0 mg/mL. The results of the current studies support the already estab-lished13-23 broad usage of the SyrSpend SF family of products for the compounding of suspensions. This gives greater confidence when using these vehicles for vulnerable patient groups (e.g., neonates, intensive care patients, elderly patients) that rely on accurate dosing.
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9. Allen LV Jr. Compounding with manufactured products. IJPC 2010; 14(6): 448.
10. Barnes AR. Product stability and stability testing. In: Aulton ME. Aulton’s Pharmaceutics, The Design and Manufacture of Medicines. 3rd ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2007: 650–665,
11. Hurtado J, Moffett BS. Pediatric oral formulations: A continual chal-lenge. IJPC 2007; 11(1): 17–19.
12. Thompson JE. Powders. In: Thompson JE, ed. A Practical Guide to Contemporary Pharmacy Practice. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009: 299–331.
13. Geiger CM, Sorenson B, Whaley PA. Stability of captopril in SyrSpend SF. IJPC 2013; 17(4): 336–338.
14. Geiger CM, Sorenson B, Whaley PA. Stability of midazolam in SyrSpend SF and SyrSpend SF Cherry. IJPC 2013; 17(4): 344–346.
15. Sorenson B, Whaley P. Stability of rifampin in SyrSpend SF. IJPC 2013; 17(2): 162–164.
16. Geiger CM, Voudrie MA 2nd, Sorenson B. Stability of ursodiol in SyrSpend SF Cherry flavored. IJPC 2012; 16(6): 510–512. Erratum in: IJPC 2013; 17(1): 86.
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
104
102
100
98
96
94
92
90
SyrSpend SF PH4 Cherry Flavored Room TemperatureSyrSpend SF PH4 Cherry Flavored Refrigerated
% R
ecov
ery
Days
0 15 30 45 60 75 90
110
108
106
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SyrSpend SF PH4 Refrigerated
% R
ecov
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SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
% R
ecov
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0 25 50 75 100 125 150
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SyrSpend SF PH4 Room TemperatureSyrSpend SF PH4 Cherry Flavored Room Temperature
FIGURE 10. Stability of Phenobarbital.
17. Geiger CM, Voudrie MA 2nd, Sorenson B. Stability of propranolol hydrochloride in SyrSpend SF. IJPC 2012; 16(6): 513–515. Erratum in: IJPC 2013; 17(1): 86.
18. Vu NT, Aloumanis V, Ben M et al. Stability of metronidazole benzoate in SyrSpend SF One-Step Suspension System. IJPC 2008; 12(6): 558–564.
19. Whaley PA, Voudrie MA 2nd. Stability of vancomycin in SyrSpend SF. IJPC 2012; 16(2): 167–169. Erratum in: IJPC 2013; 17(1): 86.
20. Whaley PA, Voudrie MA 2nd, Sorenson B. Stability of omeprazole in SyrSpend SF Alka (reconstituted). IJPC 2012; 16(2): 164–166.
21. Voudrie MA, Allen DB. Stability of oseltamivir phosphate in SyrSpend SF, Cherry Syrup, and SyrSpend SF (for reconstitution). IJPC 2010; 14(1): 82–86.
22. Sorenson B, Voudrie MA 2nd, Gehrig D. Stability of gabapentin in SyrSpend SF. IJPC 2012; 16(4): 347–349.
23. Voudrie MA, Alexander B, Allen DB. Stability of verapamil hydro-chloride in SyrSpend SF compared to sorbitol containing syrup and suspending vehicles. IJPC 2011: 3(3): 255–258.
24. United States Pharmacopeial Convention, Inc. United States Pharma-copeia 37–National Formulary 32. Rockville, MD: US Pharmacopeial Convention, Inc.; 2014.
25. Bing CD, Nowobilski-Vasilios A. Extended Stability for Parenteral Drugs. 5th ed. Bethesda, MD: ASHP; 2013: 193.
Address correspondence to Christine M. Geiger, Dynalabs, LLC, 2327 Chouteau Avenue, Saint Louis, Missouri 63103. E-mail: [email protected]
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Christine M. Geiger, MSBridget Sorenson, BS, CAPMPaul A. Whaley, BS
INTRODUCTION Midazolam, a short-acting drug in the benzodiazepine class, is used for treatment of acute seizures, moderate to severe insom-nia, and for inducing sedation and amnesia before medical pro-
Dormicum, and Hypnovel and is also available generically from several manufacturers.1 Midazolam is a very bitter white or yellowish powder. It is avail-able as an injection, tablet, and oral syrup.2 An oral preparation formulation containing a sweetener would provide a masking effect for the bitter taste, thereby increasing the palpability of an oral dose form. However, the inclusion of alcohol or sorbitol in a vehicle especially for elderly or pediatric patients can pose con-cerns about drug-drug and drug-disease state interactions, as well as complications for a patient’s activities of daily living. SyrSpend SF (Fagron US [formerly Gallipot], St. Paul, Minnesota) is a sugar- and sorbitol-free suspending vehicle which could serve as an alternative for formulating midazolam oral suspensions. The objective of this study was to examine the stability of midazolam prepared in oral suspensions using SyrSpend SF and SyrSpend SF Cherry. The suspensions were stored in low-actinic
United States Pharmacopeia (USP) refrigerated (2°C to 8°C) storage condi-tions and at room temperature conditions. Stability was assessed by percent recovery studies performed at varying time points throughout 58 days.
MATERIALS AND METHODS Chemical Reagents Midazolam hydrochloride (HCl) injection was purchased from APP Pharmaceuticals (Lot 6003904; Schaumburg, Illinois). High-performance liquid chromatographic (HPLC)-grade methanol (Lot DG 295; Honeywell, Michigan), sodium acetate trihydrate (Lot
B0522653, Acros, Belgium) were used in this study. HPLC-grade water was supplied by filtering deionized water from a Millipore Elix through a Millipore Simplicity (Billerica, Massachusetts).
Peer Reviewed
Stability of Midazolam in SyrSpend SF and SyrSpend SF Cherry
The authors are affiliated with Dynalabs, LLC, located in St. Louis, Missouri.
ABSTRACTMidazolam is a short-acting benzodiazepine central nervous system depressant available as an injection, tablet, or oral syrup. The need for alternative dosage form options for patients unable to take tablets and shortages of other forms of the drug have led com-pounding pharmacies to seek alternatives, mainly solu-tions and suspensions. Additionally, some patients are unable to use suspending agents containing alcohol or sorbitol. The objective of this study was to determine the stability of midazolam in sorbitol-free, alcohol-free SyrSpend SF and SyrSpend SF Cherry suspending agents. The studied samples were compounded into a 1-mg/mL suspension and stored in low-actinic plas-tic bottles at temperatures between 2°C to 8°C and at room temperature conditions. Six samples were as-sayed at each time point out to 58 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specificity through forced-degradation studies. The samples re-mained within 90% to 110% of the initial concentration throughout the course of the study. Based on the data collected, the beyond-use date of these preparations is at least 58 days when protected from light at both re-frigerated and room temperature storage conditions.
Equipment and Chromatographic Conditions Two different types of HPLCs were used. The first, used for validation and the stability study, was a Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quaternary gradient
100-vial programmable autosampler with a Peltier tray, 200-mcL sample loop, and 250-mcL syringe. The second HPLC system, used
-ifornia), equipped with a tertiary gradient solvent delivery system, a photodiode array detector, and a 84-vial programmable autosampler with a 100-mcL sample loop, and a 250-mcL syringe. The Perkin Elmer HPLC was operated and data was collected using Perkin
HPLC used Galaxie chromatography software. The mobile phase
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delivered at 1.5
California) Gemini C18 column with 5 mcm particle packing. The mobile phase was used as a solvent in diluting the standard and
prior to injection. The assay was monitored at 221 nm following a 25-mcL injection.
Validation of Forced-degradation Studies to Determine Stability-indicating Characteristics of High-Performance Liquid Chromatographic Method Midazolam samples were stressed and assayed to determine the specificity of the HPLC method to any possible degradation prod-uct produced during storage of an oral suspension. Midazolam
-
each stressor was three hours and was compared to a controlled, unstressed standard. Any extraneous peaks found in the chro-matogram were labeled, and the resolution (USP) was determined between the degradant and the midazolam. A resolution of 1.5 was considered full separation. Purity calculations were performed in Galaxie on the midazolam peak using the controlled, unstressed standard as a reference.
Preparation of Midazolam Suspension Samples The first midazolam suspension was prepared by adding 10 mL of
HPLC grade water to a 50-mL “to contain” graduated cylinder. The cylinder was brought to volume using SyrSpend SF. The cylinder was inverted to mix until a homogenous preparation was achieved
between two plastic amber bottles and one stored at USP-controlled refrigerated temperatures (2°C to 8°C) and one stored at room temperatures for the stability study. The preparation was repeated using SyrSpend SF Cherry.
Stability Study The samples of midazolam suspended in SyrSpend SF and
-ted for stability. The samples were packaged in low-actinic plastic bottles and stored at USP-controlled refrigerated temperature (2°C to 8°C) using a digitally controlled laboratory refrigerator from Forma Scientific (Edison, New Jersey) and at room temperature.
evaluation parameter was percent recovery assay. The stability of midazolam in suspension was defined by the percent recovery with
was prepared six times by adding 200 mcL with a Gilson pipette to
10 mL with mobile phase. The average and standard deviation of all replicate injections at each time point were used to calculate the percent recovery.
RESULTS The stability of midazolam in SyrSpend SF and SyrSpend SF Cherry is shown in Table 1 and Table 2, respectively. For the suspen-
-quent time points were compared to this value. For the suspension
subsequent time points were compared to this value. Figures 1 and 2 show the data in terms of concentration and show that the con-centration of each suspension remained within the specification
both refrigerated and room temperature conditions.
DISCUSSION The HPLC method was shown to be stability indicating by forc-ibly degrading midazolam and separating the degradant peaks from that of the main analyte. Midazolam was stable to acid, oxidizer, and heat. Base and light caused slight degradation. Additionally, valida-tion parameters listed in Table 3 show that all system suitability results met acceptance criteria.
T A B L E 2 . Stability of Midazolam in SyrSpend SF Cherry for 58 Days.
ELAPSED % RECOVERY AT % RECOVERYTIME ROOM TEMPERATURE AT 2°C - 8°CT=0 100.00 100.00
T=7 99.83 ± 1.41 100.92 ± 1.11
T=14 93.83 ± 0.97 98.53 ± 0.95
T=30 99.51 ± 0.65 99.18 ± 0.53
T=42 99.07 ± 1.63 98.48 ± 2.19
T=58 99.59 ± 1.77 99.91 ± 1.46
T A B L E 1 . Stability of Midazolam in SyrSpend SF for 58 Days.
ELAPSED % RECOVERY AT % RECOVERYTIME ROOM TEMPERATURE AT 2°C - 8°CT=0 100.00 100.00
T=7 100.25 ± 1.01 99.36 ± 2.10
T=14 93.79 ± 1.07 97.71 ± 0.41
T=30 98.86 ± 0.93 99.14 ± 0.66
T=42 100.09 ± 0.702 99.80 ± 0.54
T=58 99.29 ± 1.81 99.13 ± 0.70
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T A B L E 3 . Summary of the Validation Parameters for the High-performance Liquid Chromatographic Method Used in the Stability Study of Midazolam.
VALIDATION PARAMETER RESULTS
2 = 1.000
Extraction precision (SyrSpend SF) n
1.15
1.1
1.05
1
0.95
0.90 10 20 30 40 50 60
Elapsed Time (days)
[Mid
azol
am] m
g/m
L
0.9
0.85
0.8
0.75
0.7
0.65
0.60 5 10 15 20 25 30
Elapsed Time (days)
[Cap
topr
il] m
g/m
L
Room TemperatureRefrigerated
1.15
1.1
1.05
1
0.95
0.90 10 20 30 40 50 60
Elapsed Time (days)
[Mid
azol
am] m
g/m
L
0.9
0.85
0.8
0.75
0.7
0.65
0.60 5 10 15 20 25 30
Elapsed Time (days)
[Cap
topr
il] m
g/m
L
Room TemperatureRefrigerated
FIGURE 1. Plot of midazolam concentration in SyrSpend SF Suspension.
FIGURE 2. Plot of midazolam concentration in SyrSpend SF Cherry Suspension.
Midazolam Hydrochloride Injection in SyrSpend SF Suspension The initial potency of the midazolam in SyrSpend SF suspension
-
result was set as the baseline for all other time points tested. The
refrigerated conditions. All sample preparations at each time point were within specifications, with a high relative standard deviation
for refrigerated conditions. Every replicate chromatogram for every time point was clear of degradant peaks and had the same chro-matographic profile.
Midazolam Hydrochloride Injection in SyrSpend SF Cherry Suspension The initial potency of the midazolam in SyrSpend SF Cherry
time point were within specifications, with a high relative standard
-gram for every time point was clear of degradant peaks and had the same chromatographic profile.
CONCLUSION Midazolam was stable in SyrSpend SF and SyrSpend SF Cherry for 58 days when stored under both refrigerated (2°C to 8°C) conditions and at room temperature conditions when com-pounded from midazolam HCl injection. The samples were still within specifications at day 58; therefore, the beyond-use date is concluded to be 58 days. The findings of this study show that SyrSpend SF and SyrSpend SF Cherry is an acceptable oral syrup and suspending vehicle for preparing individual compounded mid-azolam formulations. This formulation has the added advantage of helping to mask the bitter taste while remaining alcohol, sorbitol, and sugar free. The formulations would be viable alternatives to commercially available tablets when that dosage form is found to be inappropriate.
REFERENCE 1. MedlinePlus: A Service of the U.S. National Library of Medicine,
National Institutes of Health. Midazolam Injection. [Medlin-ePlus Website.] Updated as of November 1, 2010. Available at:
Accessed February 20, 2013.2. Mayo Clinic; Micromedex. Midazolam (Oral Route). [Mayo
Clinic.] Updated as of December 1, 2012. Available at: www.
February 20, 2013.
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Peer Reviewed
Christine M. Geiger, MSBridget Sorenson, BS, CAPMPaul A. Whaley, BS
INTRODUCTION Captopril is an angiotensin-converting enzyme (ACE) inhibi-tor used for the treatment of hypertension and congestive heart failure.1 Captopril is commonly marketed by Bristol-Myers Squibb under the trade name Capoten and is available generically from several manufacturers. Captopril is available as tablets1 in strengths of 12.5 mg, 25 mg, 50 mg, and 100 mg for oral adminis-tration.2 Captopril is a white to off-white crystalline powder that may have a slight sulfurous odor. An oral preparation containing a sweetener may increase the palatability of an oral dose form. Some patients are unable to use suspending agents containing sorbitol or alcohol. SyrSpend SF (Fagron US [formerly Gallipot], St. Paul, Minnesota) is an alcohol- and sorbitol- free suspending agent which could serve as a suitable suspending agent for compounding captopril oral suspensions. The objective of this study was to examine the stability of cap-topril in an oral suspension using SyrSpend SF. The suspension was stored in a low-actinic plastic bottle at a concentration of 0.8
by percent recovery studies performed at varying time points throughout 32 days.
MATERIALS AND METHODS Chemical Reagents Captopril powder (Lot AA14409-002569) was received from Fagron US [formerly Gallipot]. SyrSpend SF (Lot 1006242R14) also was received from Fagron US [formerly Gallipot]. High-performance liquid chromatographic (HPLC)-grade methanol
acid (Lot 2011052000; CCI, Columbus, Wisconsin), and tetrahy-drofuran (Lot WW0200; Spectrum, Gardena, California) were used in this study. HPLC-grade water was supplied by filter-ing deionized water from a Millipore Elix through a Millipore Simplicity (Billerica, Massachusetts).
Equipment and Chromatographic Conditions Two different types of HPLCs were used. The first, used for validation and the stability study, was a Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quaternary gradi-
Stability of Captopril in SyrSpend SF
The authors are affiliated with Dynalabs, LLC, located in St. Louis, Missouri.
ABSTRACT Captopril is an angiotensin-converting enzyme inhibi-tor available as a tablet. Patients who are unable to take tablets have led compounding pharmacies to seek alternative dosage forms including solutions and suspensions. The objective of this study was to determine the stability of captopril in sorbitol-free, alcohol-free SyrSpend SF suspending agent. The studied samples were compounded into a 0.8-mg/mL suspension and stored in low-actinic plastic bottles at temperatures between 2°C to 8°C. Six samples were assayed at each time point out to 32 days by a sta-bility-indicating high-performance liquid chromatog-raphy method. The samples remained within 90% to 110% of the initial concentration throughout day 14 of the study. Based on the data collected, the beyond-use date of these preparations is 14 days when pro-tected from light and refrigerated.
-tor, and a 100-vial programmable autosampler with a Peltier tray, 200-mcL sample loop, and a 250-mcL syringe. The second
Prostar (Palo Alto, California) equipped with a tertiary gradient solvent delivery system, a photodiode array detector (PDA), and an 84-vial programmable autosampler with a 100-mcL sample loop and a 250-mcL syringe. The Perkin Elmer HPLC was oper-ated and data was collected using Perkin Elmer Totalchrom
chromatography software. The mobile phase for the HPLC method
Phenomenex (Serial No. 610040-9; Torrence, California) Gemini C18 column with 5-mcm particle packing. The mobile phase was used as a solvent to dilute the standard and assay preparations to
assay was monitored following a 100-mcL injection.
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Validation of Forced-Degradation Studies to Determine Stability-indicating Characteristics of the High-performance Liquid Chromatographic Method Captopril samples were stressed and assayed at 220 nm to determine the specificity of the HPLC method to any possible degradation product during storage of an oral suspension.
three hours. Any extraneous peaks found in the chromatogram were labeled and the resolution (United States Pharmacopeia) was determined between the degradant and the captopril. Purity calculations were performed in Galaxie on the captopril peak using the controlled unstressed standard as a reference.
Preparation of Captopril Suspension Samples The captopril suspension was prepared by adding 100 mL of
to a low actinic prescription bottle. Another 100-mL aliquot of
and assay). The suspension was stored at refrigerated conditions between 2°C to 8°C for the duration of the study.
Stability Study The sample of captopril suspended in SyrSpend SF at a con-
sample was packaged in a low actinic plastic prescription bottle and stored at refrigerated conditions between 2°C to 8°C. Time
assay. The stability of captopril in suspension was defined by the
method. The sample stock was prepared six times by adding 1 mL of suspension with a volumetric pipette to a 20-mL flask and diluting to volume with mobile phase. The average and standard deviation of all replicate injections at each time point were used to calculate the percent recovery.
RESULTS The stability of captopril in SyrSpend SF is shown in Table
-centration for the study, and all subsequent time points were compared to this value. The Figure depicts the data in terms of concentration of the suspension that remained within the speci-
the study.
DISCUSSION The HPLC method was shown to be stability indicating by forc-ibly degrading captopril and separating the degradant peaks from that of the main analyte. Captopril was stable to acid and light; however, oxidizer and heat created some degradation. Base created significant degradation. The degradants present were all separated from the analyte with acceptable resolution. Additionally, valida-tion parameters listed in Table 2 show that all system suitability results met acceptable criteria.
T A B L E 1 . Stability of Captopril in SyrSpend SF Refrigerated (2°C to 8°C) for 32 Days.
ELAPSED TIME % RECOVERYT=0 100.00
T=12 96.72 ± 0.26
T=14 95.06 ± 0.56
T=32 86.02 ± 0.77
F I G U R E . Plot of captopril concentration in SyrSpend SF suspension.
Note: Dashed lines represent upper and lower limits of captopril specifications.
0.9
0.85
0.8
0.75
0.7
0.65
0.60 5 10 15 20 25 30
Elapsed Time (days)
[Cap
topr
il] m
g/m
L
T A B L E 2 . Summary of the Validation Parameters for the High-performance Liquid Chromatographic Method Used in the Stability Study of Captopril.
VALIDATION PARAMETER RESULTS
2 = 0.9995
Extraction precision (SyrSpend SF) n
RSD = relative standard deviation
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The initial potency of captopril in SyrSpend SF suspension was
time point were within specification with the exception of those
Every replicate chromatogram for every time point was clear of degradant peaks and had the same chromatographic profile.
CONCLUSION Captopril was stable in SyrSpend SF for 14 days when stored under refrigerated conditions (2°C to 8°C) when compounded from powder. The sample was still within specification at day 14; therefore, the beyond-use date is concluded to be 14 days. By day 32, the sample was no longer within specifications. The findings of this study show that SyrSpend SF is an acceptable oral syrup and suspending vehicle for preparing individual captopril formula-tions when stored refrigerated between 2°C to 8°C. This formula-tion has the added advantage of helping to mask the bitter taste while remaining alcohol, sorbitol, and sugar free. The formulation would be a viable alternative to commercially available tablets when that dosage form is found to be inappropriate.
REFERENCES 1. MedlinePlus: A Service of the U.S. National Library
of Medicine, National Institutes of Health. Captopril. [MedlinePlus Website.] Updated as of October 15, 2012.
2. RxList: The Internet Drug Index. Capoten (Captopril Tablets, USP). [RxList Website.] Updated as of October 9, 2012.
Accessed March 28, 2013.
Address correspondence to Bridget Sorenson, BS, CAPM, 2327 Chouteau Avenue, Saint Louis, MO 63103. E-mail: [email protected]
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Bridget Sorenson, BS, CAPMPaul Whaley, BS
INTRODUCTION Rifampin (USAN), also referred to as Rifampicin (INN), is a broad spectrum antibiotic produced from the bacterium Streptomyces mediterranei. It is of the class known as rifamycins. Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase. It is the most commonly used member of its class because of its clin-ical indication for diseases such as tubercu-losis, meningitis, and leprosy. Rifampin is a red to orange powder. It is very slightly soluble in water, acetone, carbon tetrachloride, alcohol, and ether. It is freely soluble in chloroform and in dimethyl sulfoxide, and soluble in ethyl acetate, methyl alcohol, and tetrahydrofuran. SyrSpend SF (Fagron US—formerly Gallipot, St. Paul, Minnesota) is a sugar- and sorbitol-free suspending agent which could serve as an alternative for formulating rifampin oral suspensions extemporaneously. The objective of this study was to exam-ine the stability of rifampin prepared in an oral suspension using SyrSpend SF. Two suspensions were compounded with rifampin raw powder in the SyrSpend SF suspension to a final concentration of approximately 25 mg/mL. The compounded suspensions were stored in low-actinic pre-scription bottles under two different stor-age conditions: United States Pharmacopeia (USP) refrigerated (2ºC to 8ºC) storage, and USP room temperature (18ºC to 26ºC) storage. Stability was assessed by percent recovery studies performed at varying time points over 60 days.
Peer Reviewed
ABSTRACT Rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semi-synthetic drug produced from the bacterium Streptomyces mediterranei. Rifampin is commonly manufactured in capsule, tablet, and syrup dosage forms. Some patients, however, cannot tolerate solid dosage forms or oral solutions containing alcohol or sorbitol. The objective of this study was to determine the stability of rifampin in SyrSpend SF. The studied samples were compounded into 25-mg/mL suspensions and stored in low-actinic bottles at room temperature and refrigerated conditions. Samples were assayed at each time point out to 60 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specificity through forced-degradation studies. The sample remained within 90% to 110% of the initial concentration throughout the course of the study. Based on data collected, the beyond-use date of the preparation is at least 60 days when refrigerated or stored at room temperature and protected from light.
The authors are affiliated with Dynalabs, LLC, located in St. Louis, Missouri.
Stability of Rifampin in SyrSpend SF
MATERIALS AND METHODS Chemical Reagents Rifampin USP raw powder was pur-chased from Sigma (Lot 011M1159V; St. Louis, Missouri). High-performance liquid chromatographic (HPLC)-grade acetoni-trile (Lot DG046; Burdick & Jackson, Mus-kegon, Michigan), monosodium phosphate monohydrate (Lot 113670; Fisher Chemical, Whippany, New Jersey), disodium phos-phate heptahydrate (Lot 115824; Fisher Chemical), and 85% phosphoric acid (Lot 2011052000; CCI, Scottsburg, Indiana) were used in this study. HPLC-grade water was obtained by filtering deionized water from a Millipore (Billerica, Massachusetts) Elix through a Millipore Simplicity.
Equipment and Chromatographic Conditions Two different types of HPLCs were used. The first, used for validation and the stabil-ity study, was a Perkin Elmer (Waltham, Massachusetts) 200-Series equipped with a quaternary gradient solvent delivery sys-tem, a dual wavelength UV/Vis detector,
and a 100-vial programmable autosampler with a peltier tray, 200-mcL sample loop, and a 250-mL syringe. The second HPLC system, used for forced degradation studies, was a Varian Prostar (Palo Alto, California) equipped with a tertiary gradient solvent delivery system, a photodiode array detec-tor, and an 84-vial programmable autos-ampler with a 100-mcL sample loop and a 250-mcL syringe. The Perkin Elmer HPLC was operated and data was collected using Perkin Elmer Totalchrom chromatography software, while the Varian HPLC used Gal-axie chromatography software. The mobile phase for the HPLC method was made using 600 mL of HPLC-grade water, 1.49 grams of monosodium phosphate monohydrate, 0.31 grams of disodium phosphate heptahy-drate, and 400 mL of acetonitrile (to yield 1 liter), using 85% phosphoric acid to pH mobile phase to 5.87. The mobile phase was delivered at 1.2 mL/min. Chromatographic separation was achieved using a 150 × 4.6 mm Phenomenex (Torrence, California) Gemini C18 column with 5-mcm particle packing. The mobile phase was used as a solvent in diluting the standard and assay prepa-
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rations to 100 mcg/mL. The assay was monitored at 254 nm following a 10-mcL injection.
Validation of Forced-degradation Studies to Determine Stability-indicating Characteristics of the High-performance Liquid Chromatography Method Rifampin samples were stressed and assayed to determine the specificity of the HPLC method to any possible degradation product produced during storage of an oral suspension. Rifampin was diluted to 100 mcg/mL in a solution of acid (0.1M HCl), base (0.1 M NaOH), and hydrogen peroxide (3.5%), in addition to exposure to ultravio-let light at 365 nm and heat at 70ºC. Time under each stressor varied due to the rela-tive stability of rifampin to each individual degradation pathway. Any extraneous peaks found in the chromatogram were labeled, and the resolution, based on USP guidelines, was determined between the degradant and the rifampin. A resolution of 1.5 was con-sidered full separation. Purity calculations were performed in Galaxie on the rifampin peak using the controlled unstressed stan-dard as a reference.
Preparation of Rifampin Suspension Samples Rifampin suspension was prepared by adding 5 grams of rifampin powder to a 250-mL amber bottle. While hand stir-ring to prevent air bubbles from forming in the suspension, 200 mL of SyrSpend were added to the bottle. The suspension was then divided into two bottles, each containing approximately 100 mL. One suspension was stored at USP-controlled refrigerated temperature and the other at USP-controlled room temperature for the duration of the stability study.
Stability Study The rifampin samples suspended in SyrSpend SF at a concentration of 25 mg/mL were submitted for stability. One sample was packaged in a low-actinic flask and stored at USP-controlled refrig-
erated temperature (2ºC to 8ºC) using a laboratory refrigerator with digitally-con-trolled temperature from Forma Scientific (Edison, New Jersey). The other sample was packaged in low-actinic flasks and stored at USP-controlled room tempera-ture condition (18ºC to 26ºC). Time points for the study were initial (T=0), 7 days (T=7), 14 days (T=14), 35 days (T=35), and 60 days (T=60). The evaluation parameter was percent recovery assay. The stability of rifampin in suspension was defined by the percent recovery with respect to T=0 using the validated HPLC method. The sample stock was prepared by adding 100 mcL of suspension with a Gilson positive displacement pipette to a 25-mL amber flask. The flask was brought to volume with the mobile phase. The average and standard deviation of all replicate injec-tions at each time point was used to calcu-late the percent recovery.
RESULTS The stability of rifampin in SyrSpend SF at room temperature is shown in Table 1. The stability of rifampin in SyrSpend SF at refrigerated temperature is shown in Table 2. The result of 25.07 mg/mL for the refrig-erated and room temperature was set as the initial concentration for the study, and all subsequent time points were compared to this value. Figures 1 and 2 depict the data in terms of concentration of the suspen-sion remained within the specification (90%<[rifampin]<110%) throughout the duration of the study.
DISCUSSION The HPLC method was shown to be stabil-ity indicating by forcibly degrading rifampin and separating the degradant peaks from that of the main analyte. Degradation was seen with acid, base, light, heat, and oxida-tion. Additionally, validation parameters listed in Table 3 show that all system suit-ability results met acceptance criteria.
GALLIPOT SYRSPEND RIFAMPIN SUSPENSION The initial potency of the rifampin suspensions was 25.07 mg/mL, as shown
T A B L E 1 . Stability of Rifampin in SyrSpend SF Stored at Room Temperature (18ºC to 26ºC) for 60 Days.
ELAPSED TIME % RECOVERYT=0 100 ± 0.873
T=7 99.83 ± 2.202
T=14 100.24 ± 1.259
T=35 101.94 ± 1.916
T=60 98.20 ± 1.33
T A B L E 2 . Stability of Rifampin in SyrSpend SF Refrigerated (2ºC-8ºC) for 60 Days.
ELAPSED TIME % RECOVERYT=0 100 ± 0.873
T=7 99.67 ± 1.794
T=14 100.74 ± 1.897
T=35 98.34 ± 4.635
T=60 98.33 ± 0.755
T A B L E 3 . Summary of the Validation Parameters for the High-performance Liquid Chromatographic Method Used in the Stability Study of Rifampin in SyrSpend SF.
VALIDATION PARAMETER RESULTSPeak tailing 1.183
Theoretical plates 4769.02
Linear range (254 nm) 10 mcg/mL to 200 mcg/mL (R2=0.995)
Extraction precision n=6 % Relative standard deviation=0.18
Accuracy (20, 100, 160 mcg/mL) % Target=98.14%, 99.00%, 99.79%
Specificity (resolution from main Res (USP)=4.32
degradant peak)
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in Figures 1 and 2. This concentration was 100.29% (room temperature and refrigeration of the 25-mg/mL target concentration). The T=0 result was set as the baseline for all other time points. The assay results varied between 24.65 mg/mL (T=60) and 25.26 mg/mL (T=14) for the preparation stored at refrigerated temperature, and between 24.62 mg/mL (T=60) and 25.56 mg/mL (T=35) for the preparation stored at room
Note: Dashed lines represent upper and lower limits of rifampin specification.
F I G U R E 1 . Plot of refrigerated rifampin concentration in SyrSpend SF.
F I G U R E 2 . Plot of room temperature rifampin concentration in SyrSpend SF.
Note: Dashed lines represent upper and lower limits of rifampin specification.
29.6 -
28.4 -
27.2 -
26 -
24.8 -
23.6 -
22.4 -
21.2 -
20 -0 7 14 35 60
- - - -
Rif
amp
icin
mg
/mL
Elapsed Time (days)
29.6 -
28.4 -
27.2 -
26 -
24.8 -
23.6 -
22.4 -
21.2 -
20 -0 7 14 35 60
- - - -
Rif
amp
icin
mg
/mL
Elapsed Time (days)
29.6 -
28.4 -
27.2 -
26 -
24.8 -
23.6 -
22.4 -
21.2 -
20 -0 7 14 35 60
- - - -
Rif
amp
icin
mg
/mL
Elapsed Time (days)
29.6 -
28.4 -
27.2 -
26 -
24.8 -
23.6 -
22.4 -
21.2 -
20 -0 7 14 35 60
- - - -
Rif
amp
icin
mg
/mL
Elapsed Time (days)
temperature. All sample preparations at each time point were within specifica-tions and all percent relative standard deviations (RSDs) were below 5.0%. Each replicate for every time point was clear of any degradant peaks and had the same chromatographic profile.
CONCLUSION Rifampin was stable in SyrSpend SF for 60 days when stored under room tempera-
ture (18ºC to 26ºC) conditions. Rifampin was stable for 60 days when stored under refrigerated (2ºC to 8ºC) conditions. Con-centrations of both storage conditions remained steady during the course of the study, and this data was used to obtain the beyond-use-date of 60 days. The findings of this study show that SyrSpend is an acceptable suspending vehicle for preparing individually-com-pounded rifampin formulations. This for-mulation is acceptable as an alcohol- and sorbitol-free suspension for use when the patient is unable to tolerate the solid dos-age form or suspensions that contain alco-hol or sorbitol.
REFERENCE1. Rifampin. U.S. National Library of Medi-
cine. [U.S. National Library of Medicine Website.] Available at: www.pubchem.ncbi.nlm.nih.gov/summary/summary.cgi. Accessed July 3, 2012.
Address correspondence to Bridget Sorenson, BS, CAPM, 2327 Chouteau Avenue, Saint Louis, MO 63103. E-mail: [email protected]
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Christine M. Geiger, MSMark A. Voudrie II, MS, PMPBridget Sorenson, BS, CAPM
INTRODUCTION Ursodiol is a naturally occurring bile acid found in small quantities in normal human bile and in the biles of certain other mam-mals. An oral form of ursodiol is approved for use for patients with radiolucent, non-calcified gallbladder stones at surgical risk and for the prevention of gallstone forma-tion in obese patients experiencing rapid weight loss.1 Ursodiol is a bitter-tasting white crystal-line powder. The bitter taste presents an issue for patients who are incapable of swal-lowing the capsules whole. A suspending agent containing a sweetener would provide a masking effect for the bitter taste, increas-ing the palatability of an oral dose form to increase therapeutic compliance. SyrSpend SF Cherry Flavored (Fagron US—formerly
and sorbitol-free suspending agent which could serve as a suitable alternative for compounding ursodiol oral suspensions. The objective of this study was to exam-ine the stability of ursodiol in an oral suspension using SyrSpend SF Cherry Flavored. The suspension was stored in a low-actinic plastic bottle at a concentration
United States Phar-macopeia (USP) refrigerated (2°C to 8°C) storage conditions. Stability was assessed by percent recovery studies performed at varying time points throughout 66 days.
MATERIALS AND METHODS Chemical Reagents Ursodiol raw powder was purchased
Stability of Ursodiol in SyrSpend SF Cherry Flavored
The authors are affiliated with Dynalabs, LLC, located in St. Louis, Missouri.
ABSTRACTUrsodiol is used in the treatment and prevention of certain types of gall-stones and for patients with primary biliary cirrhosis. Ursodiol is mar-keted for this purpose by Watson Pharma, Inc. as ACTIGALL, by Axcan Scandipharm Inc. as URSO 250 and URSO Forte, and by a number of generic manufacturers. Ursodiol is available as capsules of varying strengths. The need for other dose-form options for those patients who cannot take capsules has led compounding pharmacies to seek other alternatives, namely oral solutions and suspensions. Additionally, some patients are unable to tolerate suspending agents containing alcohol or sorbitol. The objective of this study was to determine the stability of ursodiol in SyrSpend SF Cherry Flavored which does not contain sorbi-tol or alcohol. The studied sample was compounded into a 30-mcg/mL suspension and stored in a low-actinic plastic bottle at temperatures between 2°C and 8°C. Six samples were assayed at each time point out to 66 days by a stability-indicating high-performance liquid chromatogra-phy method. The method was validated for its specificity through forced degradation studies. The sample remained within 90% to 110% of the initial concentration throughout the course of the study. The beyond-use-date of this product is at least 66 days, based on data collected when refrigerated and protected from light.
New York). SyrSpend SF Cherry Flavored was received from Fagron US—formerly
--
Scientific, Pittsburgh, Pennsylvania), and
Pharmco-Aaper, Butler, Wisconsin) were
supplied by filtering deionized water from a Millipore Elix through a Millipore Sim-plicity (Billerica, Massachusetts).
Equipment and Chromatographic Conditions A Varian Prostar (Palo Alto, California)
solvent delivery system, a photodiode array detector (PDA), an evaporative light
84-vial programmable autosampler with
was water, acetonitrile, and methanol
was adjusted to 4.00 with acetic acid -
matographic separation was achieved using a 150 × 4.6 mm Phenomenex (Tor-
nebulizer was set to 35°C, the evaporator
water:acetonitrile:methanol (30:35:35) diluent was used for standard curve
-
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Validation of Forced-degradation Studies to Determine Stability Indicating Characteristics of the High-performance Liquid Chromatography Method Due to the mode of detection, the
-tor; therefore, a PDA was used to ana-lyze the forced-degradation samples. Ursodiol samples were stressed and assayed at 214 nm to determine the
possible degradation product produced during storage of an oral suspension.
addition to exposure to ultraviolet light at 365 nm and heat at 70°C. Time under each stressor varied due to the relative stability of ursodiol to each individual degradation pathway. Any extraneous peaks found in the chromatogram were labeled and checked for separation from the ursodiol peak. Purity calcula-
the ursodiol peak using the controlled unstressed standard as a reference.
Preparation of Ursodiol Suspension Samples The ursodiol suspension was pre-pared by adding 3.32 g of ursodiol to a 4-oz low actinic cylindrical prescription
SF Cherry Flavored were added to the bottle and stirred vigorously fol-
of SyrSpend SF Cherry Flavored was
stirred until a homogeneous prepara-tion was achieved. The contents were stored at USP-controlled refrigerated temperature (2°C to 8°C) for the stabil-ity study.
STABILITY STUDY The sample of ursodiol suspended in SyrSpend SF Cherry Flavored at a con-
for stability. The sample was packaged in 4-oz low-actinic plastic prescription bot-tles, and stored at USP controlled tempera-ture (2°C to 8°C) using a digitally controlled laboratory refrigerator from Forma Scien-tific (Edison, New Jersey). Time points for the study were initial (T=0), 1 day (T=1), 8 days (T=8), 11 days (T=11), 15 days (T=15), 30 days (T=30), and 66 days (T=66). The evaluation parameter was percent recovery assay. The stability of ursodiol in suspension was defined by the percent recovery with
method. The sample stock was prepared six
-
flask. One milliliter of that stock was pipet-
volumetric flask and brought to volume us-ing a water:acetonitrile:methanol (30:35:35) diluent. The average and standard deviation of all replicate injections at each time point was used to calculate the percent recovery.
RESULTS The stability of ursodiol in SyrSpend SF Cherry Flavored is shown in Table 1. The
the initial concentration for the study, and all subsequent time points were compared to this value. The Figure that accompanies this article shows the data in terms of con-centration and also shows that the concen-tration of the suspension remained within the specification (90%<[ursodiol]<110%) throughout the duration of the study.
DISCUSSION stability indicating by forcibly degrading ursodiol and separating the degradant peaks from that of the main analyte. Ursodiol was stable to heat; however, acid, oxidizer,
T A B L E 1 . Stability of Ursodiol in SyrSpend SF Refrigerated (2°C to 8°C) for 66 Days.
ELAPSED TIME % RECOVERYT=0 100.00
T=1 102.53 ± 0.89
T=8 100.72 ± 1.57
T=11 101.53 ± 2.22
T=15 101.57 ± 1.71
T=30 100.15 ± 0.72
T=45 97.69 ± 1.97
T=66 99.73 ± 1.36
F I G U R E . Plot of ursodiol concentration in SyrSpend SF Cherry Flavored suspension.
Note: Dashed lines represent upper and lower limits of ursodiol specifications.
33323130292827262524
[Urs
odio
l] m
g/m
L
Elapsed Time (days)
0 10 20 30 40 50 60 70
[Pro
pran
olol
Hyd
roch
lori
de] m
g/m
L
Elapsed Time (days)
1.2
1.15
1.1
1.05
1
0.95
0.90 4020 60 80
- - - -
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and light created slight degradation. Base created significant degradation. The degradants present were all completely separated from the analyte with accept-able resolution. Additionally, the valida-tion parameters listed in Table 2 show that all system suitability results met acceptable criteria.
Ursodiol United States Pharmacopeia Raw Powder (Medisca) in SyrSpend SF Cherry Flavored Suspension The initial potency of the Ursodiol USP Raw Powder in SyrSpend SF Cherry Fla-
is shown in the Figure that accompanies this article. This concentration was 96.8%
The T=0 result was set as the baseline for all other time points tested. The assay results
-tions at each time point were within speci-fication, with a high % relative standard deviation of 2.22% (T=11). Every replicate chromatogram for every time point was clear of the degradant peaks and had the same chromatographic profile.
CONCLUSION Ursodiol was stable in SyrSpend SF Cherry Flavored for 66 days when stored
T A B L E 2 . Summary of the Validation Parameters for the High-performance Liquid Chromatographic Method Used in the Stability Study of Ursodiol in SyrSpend SF.
VALIDATION PARAMETER RESULTSPeak tailing 1.32
Theoretical plates 6443.6
Range 2.65 to
105.84 mcg/mL
R2 = 0.9999
Extraction precision % Relative standard
(SyrSpend SF Cherry deviation = 4.78
Flavored) n=6
Accuracy (mcg/mL) % Target = 101.09
under refrigerated (2°C to 8°C) conditions and compounded from the raw powder. The samples were still within specifications
observed during the course of the study; therefore, the beyond-use date is concluded to be 66 days. The findings of this study show that SyrSpend SF Cherry Flavored is an accept-able oral syrup and suspending vehicle for preparing individual compounded ursodiol formulations. This formulation has the added advantage of helping to mask the bit-ter taste while remaining alcohol, sorbitol, and sugar free. The formulations would be viable alternatives to commercially avail-able capsules when that dosage form is found to be inappropriate.
REFERENCE1 -
uct information] Corona, CA: Watson
2009. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=aeb6c8c8-4dec-4574-8f26-b6b701b04b25. Accessed February 28, 2012.
Address correspondence to Bridget Sorenson, BS, CAPM, 2327 Choteau Avenue, Saint Louis, MS 63103. E-mail: [email protected]
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Christine M. Geiger, MSMark A. Voudrie II, MS, PMPBridget Sorenson, BS, CAPM
INTRODUCTION -
selective beta-adrenergic receptor blocking agent. Oral forms are approved for use in patients with hypertension, abnormal heart rhythms, heart disease, angina, pheochro-mocytoma, migraines, and certain types of tremors.1 It also improves survival post myocardial infarction.
-less, white crystalline powder. The bitter taste is an issue for patients incapable of swallowing the tablets or capsules whole. A suspending agent containing a sweetener would provide a masking effect for the bit-ter taste thus increasing the palpability of an oral liquid dosage form and improving therapeutic compliance. Some patients are unable to use suspending agents containing sorbitol or alcohols. SyrSpend SF (Fagron
is an alcohol- and sorbitol-free suspending agent which could serve as a suitable alter-
oral suspensions. The objective of this study was to exam-
oral suspension using SyrSpend SF. The suspension was stored in a low-actinic
at room temperature storage conditions. Stability was assessed by percent recovery studies performed at varying time points throughout 90 days.
MATERIALS AND METHODS Chemical Reagents
Stability of Propranolol Hydrochloride in SyrSpend SF
The authors are affiliated with Dynalabs, LLC, located in St. Louis, Missouri.
ABSTRACT Propranolol hydrochloride is a beta blocker used to treat high blood pres-sure, abnormal heart rhythms, heart disease, pheochromocytoma, and certain types of tremors. Propranolol is marketed by Wyeth (now a part of Pfizer) and AstraZeneca under the brand names Inderal, Inderal LA, Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilium, Bedranol SR (Sandoz). It is also available generically from several manu-facturers. Propranolol hydrochloride is available as tablet, capsule, and oral liquid dosage forms in several strengths. Some patients are unable to tolerate oral tablets and capsules, challenging compounding pharma-cies to seek alternative dosing options; namely oral solutions and sus-pensions. The objective of this study was to determine the stability of propranolol hydrochloride in SyrSpend SF. The drug was compounded into a 1-mg/mL suspension using SyrSpend SF and subsequently stored in a low-actinic plastic prescription bottle at room temperature condi-tions. Six samples were assayed at each specific time point extending to 90 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specificity through forced-deg-radation studies. Based on the data collected, when protected from light at room temperature, the beyond-use date of propranolol hydrochloride in SyrSpend SF was shown to be at least 90 days.
-ized water from a Millipore Elix through a Millipore Simplicity (Billerica, Massachusetts).
Equipment and Chromatographic Conditions study, was a Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quater-nary gradient solvent delivery system, a dual wavelength UV/VIS detector, and a 100-vial
(Palo Alto, California) equipped with a tertiary gradient solvent delivery system, a photo-
-
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50 mM ammonium phosphate monohy-drate with 0.5% tetraethylamine and ace-tonitrile (750:250). The mobile phase was
Chromatographic separation was achieved using a 150 × 4.6 mm Phenomenex (Tor-
5-mcm particle packing. The mobile phase was used as solvent to dilute the standard
injection.
Validation of Forced-degradation Studies to Determine Stability-indicating Characteristics of the High-performance Liquid Chromatography Method and assayed at 290 nm to determine the
-sible degradation product produced during storage of an oral suspension. Propranolol
hydrogen peroxide (3.5%), in addition to exposure to ultraviolet light at 365 nm and heat at 70°C. Time under each stressor varied due to the relative stability of pro-
pathway. Any extraneous peaks found in the chromatogram were labeled and the resolu-tion (United States Pharmacopeia [USP]) was determined between the degradant
-
unstressed standard as a reference.
Preparation of Propranolol Hydrochloride Suspension Samples prepared by adding 103.4 g of propranolol
Two aliquots of SyrSpend SF were added to the bottle using a volumetric pipette to
temperature for the duration of the study.
STABILITY STUDY -pended in SyrSpend SF at a concentration
sample was packaged in a low-actinic plas-tic prescription bottle and stored at room temperature. Time points for the study were initial (T=0), 20 days (T=20), 32 days (T=32), and 90 days (T=90). The evaluation parameter was percent recovery assay. The
was defined by the percent recovery with
method. The sample stock was prepared six
flask and diluting to volume with mobile phase. The average and standard deviation of all replicate injections at each time point were used to calculate the percent recovery.
RESULTS SyrSpend SF is shown in Table 1. The result
concentration for the study, and all subse-quent time points were compared to this value. The Figure that accompanies this arti-cle depicts the data in terms of concentration of the suspension that remained within the
throughout the duration of the study.
DISCUSSION stability indicating by forcibly degrad-
degradant peaks from that of the main ana-
heat; however, base and light created slight degradation. Oxidizer created significant degradation. The degradants present were all completely separated from the analyte
T A B L E 1 . Stability of Propranolol Hydrochloride in SyrSpend SF at Room Temperature for 90 Days.
ELAPSED TIME % RECOVERYT=0 100.00
T=20 100.90 ± 2.69
T=32 102.13 ± 1.04
T=90 97.68 ± 1.674
F I G U R E . Plot of propranolol hydrochloride concentration in SyrSpend SF Suspension.
33323130292827262524
[Urs
odio
l] m
g/m
L
Elapsed Time (days)
0 10 20 30 40 50 60 70
[Pro
pran
olol
Hyd
roch
lori
de] m
g/m
L
Elapsed Time (days)
1.2
1.15
1.1
1.05
1
0.95
0.90 4020 60 80
- - - -
Note: Dashed lines represent upper and lower limits of propranolol hydrochloride specifications.
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with acceptable resolution. Additionally, validation parameters listed in Table 2 show that all system suitability results met accept-able criteria.
Propranolol Hydrochloride USP Raw Powder (Medisca) in SyrSpend SF Suspension
Figure that accompanies this article. This concentration was 108%
as the baseline for all other time points tested. The assay results
sample preparations at each time point were within specification, with a high percent relative standard deviation of 2.69% (T=20). Every replicate chromatogram for every time point was clear of the degradant peaks and had the same chromatographic profile.
CONCLUSION stable in SyrSpend SF for 90 days when stored at room temperature conditions. The samples were still within specifications at day 90, therefore, the beyond-use date is concluded to be 90 days. The findings of this study show that SyrSpend SF is an accept-able oral syrup and suspending vehicle for preparing individually
has the added advantage of helping to mask the bitter taste while remaining alcohol, sorbitol, and sugar free. The formulation would be a viable option for those patients who are unable to tolerate solid dosage forms.
REFERENCES 1 -
Pharmaceuticals Inc. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b4f0efb8-b5e0-4efc-6e8d-525a93446ad8. Accessed June 27, 2012.
T A B L E 2 . Summary of the Validation Parameters for the High-performance Liquid Chromatographic Method Used in the Stability Study of Propranolol Hydrochloride in SyrSpend SF.
VALIDATION PARAMETER RESULTSPeak tailing 1.72 % RSD = 0.73
Theoretical plates 6420.13 % RSD = 0.98
Range 5.05 to 121.30 mcg/mL
R2 = 0.9994
Extraction precision (SyrSpend SF) n=6 % RSD = 4.50
Accuracy (mcg/mL) % Target = 99.74%
RSD = relative standard deviation
Address correspondence to Bridget Sorenson, BS, CAPM, 2327 Choteau Avenue, Saint Louis, MS 63103. E-mail: [email protected]
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INTRODUCTION Gabapentin is a GABA analogue anticonvulsant originally used to treat epilepsy, and is now also used to relieve neuropathic pain and hot flashes. Gaba-pentin is available as commercially-prepared capsules, tablets, and oral solutions. Gabapentin acts in epileptic patients with specific seizure disorders to decrease abnormal excitement in the brain. Gabapentin is also used as an adjunctive analgesic in herpetic neural-gia (PHN) and diabetic neuropathy. The extended-release form is used to treat restless legs syndrome (RLS).1 Gabapentin is a white to off-white crystalline solid. It is freely soluble in water and in both basic and acidic aque-ous solutions. SyrSpend SF ([Fagron US-formerly Gallipot], St. Paul, Min-nesota) is a sugar- and sorbitol-free sus-pending agent which could serve as an alternative for formulating gabapentin oral suspensions extemporaneously. The objective of this study was to examine the stability of gabapentin prepared in an oral suspension using SyrSpend SF. Two suspensions were compounded with gabapentin raw pow-der in the SyrSpend SF suspension to a final concentration of approximately 50 mg/mL. The compounded suspensions were stored in low actinic prescrip-tion bottles under two different storage conditions: United States Pharmacopeia (USP) refrigerated (2ºC to 8ºC) storage, and USP room temperature (18ºC to 26ºC) storage. Stability was assessed by percent recovery studies performed at varying time points over 90 days.
Stability of Gabapentin in SyrSpend SF
The authors are affiliated with Dynalabs, LLC, located in St. Louis, Missouri.
ABSTRACTGabapentin is used with other medications to control and prevent seizures. It is also used to treat neuropathic pain following surgery due to shingles. Gabapentin comes in many different forms, including capsules, tablets, and oral solutions. Some patients, however, cannot use oral solutions con-taining alcohol or sorbitol. The objective of this study was to determine the stability of gabapentin in SyrSpend SF, a suspending agent that does not contain either sorbitol or alcohol. The studied samples were com-pounded into a 50-mg/mL suspension and stored in low actinic bottles at room temperature and refrigerated conditions. Samples were assayed at each time point out to 90 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specific-ity through forced-degradation studies. The samples remained within 90% to 110% of the initial concentration throughout the course of the study. Based on data collected, the beyond-use date of this product is at least 90 days when refrigerated or stored at room temperature and protected from light. Based on the final potency data at day 90, the beyond-use date may be longer, but 90 days was the limit of this study.
MATERIALS AND METHODS Chemical Reagents Gabapentin USP raw powder was purchased from Medisca (Lot 77375/E; Plattsburg, New York). High-performance liquid chromatographic (HPLC)-grade ace-tonitrile (Lot DE551; Burdick & Jackson, Kalamazoo, Michigan), and HPLC-grade methanol (Lot K22E17; J.T. Baker, Center Valley, Pennsylvania) were used in this study. HPLC-grade water was obtained by filtering deionized water from a Millipore Elix through a Millipore Simplicity (Bil-lerica, Massachusetts).
Equipment and Chromatographic Conditions Two different types of HPLC’s were used. The first, used for validation and the stability study, was a Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quaternary gradient sol-vent delivery system, a dual wavelength
UV/Vis detector, and a 100-vial program-mable autosampler with a peltier tray, 200-mcL sample loop, and a 250-mL syringe. The second HPLC system, used for forced degradation studies, was a Varian Prostar (Palo Alto, California) equipped with a tertiary gradient solvent delivery system, a photodiode array detector (PDA), and an 84-vial programmable autosampler with a 100-mcL sample loop and a 250-mcL syringe. The Perkin Elmer HPLC was operated and data was collected using Perkin Elmer Totalchrom chromatography software, while the Varian HPLC used Gal-axie chromatography software. The mobile phase for the HPLC method was HPLC-grade water, methanol, and acetonitrile (950 mL: 30 mL: 20 mL). The mobile phase was delivered at 1.5 mL/min. Chromato-graphic separation was achieved using a 150 × 4.6 mm Phenomenex (Torrence, Cali-fornia) Gemini C18 column with 5-mcm particle packing. The mobile phase was used as solvent in diluting the standard and assay preparations to 250 mcg/mL. The assay was monitored at 210 nm follow-ing a 100-mcL injection.
Bridget Sorenson, BS, CAPMMark A. Voudrie II, MS, PMPDan Gehrig, BS
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Validation of Forced-Degradation Studies to Determine Stability Indicating Characteristics of the High-performance Liquid Chromatographic Method Gabapentin samples were stressed and assayed to determine the specificity of the HPLC method to any possible degradation product produced during storage of an oral suspension. Gabapentin was diluted to 250 mcg/mL in a solution of acid (0.1M HCl), base (0.1 M NaOH) and, hydrogen peroxide (3.5%), in addition to exposure to ultra-violet light at 365 nm and heat at 70ºC. Time under each stressor varied due to the relative stability of gabapentin to each individual degradation pathway. Any extra-neous peaks found in the chromatogram were labeled and the resolution (USP) was determined between the degradant and the gabapentin. A resolution of 1.5 was considered full separation. Purity calculations were performed in Galaxie on the Gabapentin peak using the controlled unstressed standard as a reference.
Preparation of Gabapentin Suspension Samples Gabapentin suspension was prepared by adding 5 grams of gabapentin powder into a 100-mL low actinic volumetric flask. Added to the flask while stirring with a stir bar was 100 mL of SyrSpend SF. This pro-cedure was repeated to obtain two suspen-sions. One suspension was stored at USP controlled refrigerated temperature and the other at USP controlled room tempera-ture for the duration of the stability study.
Stability Study The gabapentin samples suspended in SyrSpend SF at a concentration of 50 mg/mL was submitted for stability. One sample was packaged in a low actinic flask and stored at USP controlled refrigerated temperature (2ºC to 8ºC) using a labora-tory refrigerator with digitally-controlled temperature from Forma Scientific (Edi-son, New Jersey). The other sample was packaged in low actinic flasks and stored at USP controlled room temperature condition (18ºC to 26ºC). Time points for the study were initial (T=0), 7 days (T=7), 14 days (T=14), 31 days (T=31), 46 days (T=46), 61 days (T=61), and 90 days (T=90). The evaluation parameter
was percent recovery assay. The stability of gabapentin in suspension was defined by the percent recovery with respect to T=0 using the validated HPLC method. The sample stock was prepared by adding 1 mL of suspension with a volumetric pipette to 250 mL with water. The average and standard deviation of all replicate injections at each time point was used to calculate the percent recovery.
RESULTS The stability of gabapentin room temperature in SyrSpend SF is shown in Table 1. The stability of gabapentin refrigerated in SyrSpend SF is shown in Table 2. The result of 48.555 mg/mL for the refrigerated and 49.100 mg/mL for the room temperature was set as the initial concentration for the study, and all subsequent time points were compared to this value. Figures 1 and 2 show the data in terms of concentration of the suspension
the study.
DISCUSSION The HPLC method was shown to be stability indicating by forcibly degrading gabapen-tin and separating the degradant peaks from that of the main analyte. Gabapentin was stable to acid, base, light, and heat. Slight degradation was seen with oxidation. Addition-ally, validation parameters listed in Table 3 show that all system suitability results met acceptance criteria.
Gallipot SyrSpend Gabapentin Suspension The initial potencies of the gabapentin suspensions were 49.1 mg/mL and 48.555 mg/mL for the preparations stored at room temperature and in a refrigerator, respectively, as shown in Figures 1 and 2. These concentrations were 98.2% (room temperature) and 97.11% (refrig-erated) of the 50-mg/mL target concentration. The T=0 result was set as the baseline for all
T A B L E 1 . Stability of Gabapentin in SyrSpend SF at Room Temperature (18ºC to 26ºC) for 90 Days.
ELAPSED TIME % RECOVERY T=0 100 +/- 1.253
T=14 104.96 +/- 0.845
T=31 107.15 +/- 0.3304
T=46 103.65 +/- 1.429
T=67 109.45 +/- 1.16
T=98 104.32 +/- 0.891
T A B L E 2 . Stability of Gabapentin in SyrSpend SF Refrigerated (2ºC to 8ºC) for 90 Days.
ELAPSED TIME % RECOVERY T=0 100 +/- 1.633
T=14 101.49 +/- 1.501
T=31 105.46 +/- 0.4137
T=46 101.84 +/- 1.516
T=61 108.27 +/- 1.479
T=125 104.63 +/- 0.56
T A B L E 3 . Summary of the Validation Parameters for the High-performance Liquid Chromatographic Method Used in the Stability Study of Gabapentin in SyrSpend SF.
VALIDATION PARAMETER RESULTS Peak Tailing 1.059 %RSD = 0.22
Theoretical Plates 6558.528
Linear range (210 nm) 2 to 600 mcg/mL R2 = 1.00
Extraction Precision n=6 %RSD = 1.25
Accuracy (20, 100, 300 mcg/mL) %Target = 100.62%, 100.26%, 100.08%
Specificity (resolution from
main degradant peak) Res (USP) = 4.36
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F I G U R E 1 . Plot of refrigerated gabapentin concentration in SyrSpend SF.
(Dashed lines represent upper and lower limits of gabapentin specification.)
(Dashed lines represent upper and lower limits of gabapentin specification.)
F I G U R E 2 . Plot of room temperature gabapentin concentration in SyrSpend SF.
other time points. The assay results varied between 48.56 mg/mL (T=0) and 52.57 mg/mL (T=61) for the refrigerated, and between 49.1 mg/mL (T=0) and 53.74 mg/mL (T=67) for the preparation stored at room temperature. All sample preparations at each time point were within specifications and all %RSDs were below 2.0%. Each replicate for every time point was clear of any degradant peaks and had the same chromatographic profile.
CONCLUSION Gabapentin was stable in SyrSpend for 98 days when stored under room temperature (18ºC to 26ºC) conditions. Gabapen-tin was stable for 125 days when stored under refrigerated (2ºC to 8ºC) conditions. Concentrations of both storage conditions trended upward during the course of the study. This trend was
used to determine the beyond-use date as 120 days for refrigerated and 90 days for room temperature storage. The findings of this study show that SyrSpend is an acceptable suspending vehicle for preparing individually-compounded gaba-pentin formulations. This formulation is acceptable as an alcohol- and sorbitol-free suspension. The formulations would be a viable alternative to commercially available capsules when that dose form is inappropriate.
REFERENCES 1. U.S. National Library of Medicine. Gabapentin. [U.S. National
Library of Medicine Website.] July 15, 2011. Available at: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000940. Accessed March 6, 2012.
Address correspondence to Bridget Sorenson, BS, CAPM, 2327 Choteau Avenue, Saint Louis, MS63103. Email: [email protected]
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INTRODUCTION
Vancomycin hydrochloride (HCl) is a glycopeptide antibiotic used in the treat-ment of infections caused by Gram-positive bacteria. An oral form of vancomycin HCl was originally approved by the U.S. Food and Drug Administration for the treatment of Clostridium difficile (C. difficile)-induced pseudomembranous colitis.1 It is not orally absorbed into the blood and remains in the gastrointestinal tract to eradicate C. difficile. Vancomycin is also used for the treatment of enterocolitis caused by Staph-ylococcus aureus (including methicillin-resistant strains). Vancomycin HCl is a white crystalline solid with a very bitter taste. The bitter taste presents an issue for patients who are incapable of swallowing the capsules whole. An oral preparation formulation containing a sweetener would provide a masking effect for the bitter taste, thereby increasing the palpability of an oral dose form as a way to increase therapeutic compliance. SyrSpend SF (Fagron US [formerly Gallipot], St. Paul, Minnesota) is a sugar- and sorbitol-free suspending agent which could serve as an alternative for formulating vancomycin HCl oral suspensions. The objective of this study was to exam-ine the stability of vancomycin HCl pre-pared in an oral suspension using SyrSpend SF. The decision was made to compound two suspensions, one compounded with vancomycin HCl raw powder and the second compounded with commercially available sterile pharmacy bulk product. The suspensions were stored in low-actinic plastic, amber bottles at a concentration of 50 mg/mL under United States Pharmaco-peia (USP) refrigerated (2oC to 8oC) storage conditions. Stability was assessed by per-cent recovery studies performed at varying time points throughout 90 days.
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ABSTRACT Vancomycin is administered orally for the treatment of pseudomembra-nous colitis induced by Clostridium difficile. Vancomycin is marketed for this purpose by ViroPharma as VANCOCIN in 125-mg and 250-mg capsules. The need for other dose form options for those patients who cannot take capsules has led compounding pharmacies to seek other alternatives, namely oral solutions and suspensions. Additionally, some patients are unable to use suspending agents containing alcohol or sor-bitol. The objective of this study was to determine the stability of van-comycin in SyrSpend SF, a suspending agent containing neither sorbi-tol nor alcohol. The studied sample was compounded into a 50-mg/mL suspension and stored in a low-actinic plastic bottle at temperatures between 2oC and 8oC. Six samples were assayed at each time point out to 90 days by a stability-indicating high-performance liquid chroma-tography method. The method was validated for its specificity through forced-degradation studies. The sample remained within 90% to 110% of the initial concentration throughout the course of the study. Based on data collected, the shelf life of this product is at least 90 days when refrigerated and protected from light. Based on the final potency data at day 90, the beyond-use date may be longer, but 90 days was the limit of this study.
Stability of Vancomycin in SyrSpend SF
The authors are affiliated with Dynalabs, LLC, St. Louis, Missouri
MATERIALS AND METHODSChemical Reagents Vancomycin HCl raw powder was purchased from [Fagron] Gallipot Inc. (Lot 1103457J12; St. Paul, Minnesota). Sterile Vancomycin HCl USP raw powder was purchased from Hospira (Lot 903003A; Lake Forest, Illinois). High-performance liquid chromatographic (HPLC)-grade acetonitrile (Lot CZ629; Burdick and Jackson, Kalamazoo, Michigan), triethyl-amine (Lot B0521038; Acros Organics, Geel, Belgium), tetrahydrofuran (Lot 2AH0452; Spectrum Chemical, New Brunswick, New Jersey), and 85% phosphoric acid ACS-grade (Lot 201103115; CCI, New Delhi, India) were used in the study. HPLC-grade water was supplied by filtering deionized water from a Millipore Elix through a Millipore Simplicity (Billerica, Massachusetts).
Equipment and Chromatographic Conditions Two different types of HPLCs were used. The first, used for validation and the stabil-
ity study, was a Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quaternary gradient solvent delivery sys-tem, a dual wavelength UV/VIS detector, and a 100-vial programmable autosampler with a Peltier tray, 200-mcL sample loop, and 250-mL syringe. The second HPLC sys-tem, used for forced-degradation studies, was a Varian Prostar (Palo Alto, California), equipped with a tertiary gradient solvent delivery system, a photodiode array detec-tor, and a 84-vial programmable autos-ampler with a 100-mcL sample loop, and 250-mcL syringe. The Perkin Elmer HPLC was operated and data was collected using Perkin Elmer Totalchrom chromatography software while the Varian HPLC used Gal-axie chromatography software. The mobile phase for the HPLC method was water, acetonitrile, triethylamine, tetrahydrofuran (4500:300:7:50). The mobile phase’s pH was adjusted to 3.00 with 85% phosphoric acid and was delivered at 1.8 mL/min. Chromatographic separation was achieved using a 150 × 4.6 mm Phenomenex (Tor-
Paul A. Whaley, BSMark A. Voudrie II, MS, PMP
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rence, California) Gemini C18 column with 5 mcm particle packing. The mobile phase was used as solvent in diluting the standard and assay preparations to 50 mcg/mL. The assay was monitored at 280 nm following a 100-mcL injection.
Validation of Forced-degradation Studies to Determine Stability Indicating Characteristics of the High-Performance Liquid Chromatographic Method Vancomycin HCl samples were stressed and assayed to determine the specificity of the HPLC method to any possible degrada-tion product produced during storage of an oral suspension. Vancomycin was diluted to 50 mcg/mL in solutions of base (0.1N NaOH), acid (0.1M HCl), hydrogen peroxide (3.5%), in addition to exposure to UV light at 365 nm and heat at 70°C. Time under each stressor varied due to the relative stability of vancomycin to each individual degrada-tion pathway. The time was tailored to pro-vide approximately 15% degradation when compared to a controlled, unstressed stan-dard. Any extraneous peaks found in the chromatogram were labeled and the resolu-tion (USP) was determined between the degradant and the vancomycin. A resolution of 1.5 was considered full separation. Purity calculations were performed in Galaxie on the vancomycin peak using the controlled, unstressed standard as a reference.
Preparation of Vancomycin Hydrochloride Suspension Samples The first vancomycin HCl suspension was prepared by adding 250 mg of vanco-mycin HCl powder to a 500-mL volumetric flask, followed by 100 mL of SyrSpend SF. The contents were stirred on a stir plate while adding another 300 mL of SyrSpend SF. The flask was brought to volume with SyrSpend SF and then stirred until a homogenous preparation was achieved. The second vancomycin HCl suspension was prepared by adding 250 mg of vancomycin HCl sterile pharmacy bulk product to a 500-mL volumetric flask, followed by 100 mL of SyrSpend SF. The contents were stirred on a stir plate while adding another 300 mL of SyrSpend SF. The flask was brought to volume with SyrSpend SF and then stirred until a homogenous preparation
was achieved. The contents of each flask were poured into 60-mL amber prescrip-tion bottles and stored at USP-controlled refrigerated temperature (2oC to 8oC) for the stability study.
Stability Study The samples of vancomycin HCl sus-pended in SyrSpend SF at a concentration of 50 mg/mL were submitted for stabil-ity. The samples were packaged in 60-mL low-actinic plastic prescription bottles, and stored at USP-controlled refrigerated temperature (2oC to 8oC) using a digitally controlled laboratory refrigerator from Forma Scientific (Edison, New Jersey). Time points for the study were initial (T=0), 6 days (T=6), 7 days (T=7), 14 days (T=14), 30 days (T=30), 63 days (T=63), and 90 days (T=90). The evaluation parameter was per-
cent recovery assay. The stability of vanco-mycin HCl in suspension was defined by the percent recovery with respect to T=0 using the validated HPLC method. The sample stock was prepared six times by adding 5 mL of suspension with a volumetric pipette to 100 mL with water. Each sample stock was further diluted by adding 1 mL of stock to 25 mL with water. The average and stan-dard deviation of all replicate injections at each time point were used to calculate the percent recovery.
RESULTS The stability of vancomycin HCl in SyrSpend SF is shown in Table 1. For the suspension compounded with raw powder, the result of 48.82 mg/mL at T=0 was set as the initial concentration for the study, and all subsequent time points were compared
TABLE 1. Stability of Vancomycin Hydrochloride in SyrSpend SF Refrigerated (2oC to 8oC) for 90 days.Elapsed Time % Recovery (Raw Powder) % Recovery (Sterile Raw Powder)T=0 100.00 100.00 T=6 107.47 ± 0.39% 105.62 ± 0.77%T=7 101.74 ± 3.22% 104.09 ± 0.87%T=14 101.00 ± 1.18% 102.09 ± 0.84%T=30 99.64 ± 2.84% 101.82 ± 1.61%T=63 106.47 ± 2.41% 106.72 ± 2.15%T=90 105.46 ± 3.27% 107.67 ± 2.00%
FIGURE 1. Plot of vancomycin hydrochloride concentration (raw powder) in SyrSpend SF Suspension.
Note: Dashed lines represent upper and lower limits of vancomycin hydrochloride specifications.
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to this value. For the suspension compounded with sterile raw powder, the result of 59.41 mg/mL at T=0 was set as the initial concentration for the study, and all subsequent time points were compared to this value. Figures 1 and 2 show the data in terms of concentra-tion and show that the concentration of each suspension remained within the specification (90%<[vancomycin HCl]<115%) throughout the duration of the study.
DISCUSSION The HPLC method was shown to be stability-indicating by forcibly degrading vancomycin HCl and separating the degradant peaks from that of the main analyte. Vancomycin HCl was stable to acid and ultraviolet light; however heat, base, and oxidizer created significant deg-radation. The degradants present in the base, heat, and oxidation were all completely sepa-rated from the analyte with acceptable resolution. Additionally, validation parameters listed in Table 2 show that all system suitability results met acceptance criteria.
Vancomycin Hydrochloride USP Raw Powder (Fagron US [formerly Gallipot]) in SyrSpend SF Suspension The initial potency of the Vancomycin HCl USP (raw powder) in SyrSpend SF suspen-sion was 48.82 mg/mL, which is shown in Figure 1. This concentration was 97.6% of the compounding target of 50 mg/mL. The T=0 result was set as the baseline for all other time points tested. The assay results varied between 48.65 mg/mL (T=30) and 52.46 mg/mL
TABLE 2. Summary of the Validation Parameters for the High-Performance Liquid ChromatographicMethod Used in the Stability Study of Vancomycin Hydrochloride in SyrSpend SF.Validation Parameter ResultsPeak tailing 0.984 % RSD = 1.53Theoretical plates 1983.0 % RSD = 1.40Linear range (254 nm) 40 to 200 mcg/mL R2 = 0.9997Extraction precision SyrSpend SF) n=6 % RSD = 1.88Accuracy (20, 100, 160 mcg/mL) % Target = 100.9%, 100.3%, 99.6%Specificity (resolution between main degradant peaks) Res (USP) = 4.39 Res (USP) = 2.21
(T=6). All sample preparations at each time point were within specification, with a high % RSD of 3.27% (T=90). Every replicate chromatogram for every time point was clear of degradant peaks and had the same chromatographic profile.
Vancomycin Hydrochloride USP Sterile Raw Powder (Hospira) in SyrSpend SF Suspension The initial potency of the Vancomycin HCl USP (sterile raw powder) in SyrSpend SF suspension was 59.41 mg/mL, which is shown in Figure 2. This concentration was 118.8% of the compounding target of 50 mg/mL. The T=0 result was set as the baseline for all other time points tested. The assay results varied between 59.41 mg/mL (T=0) and 63.97 mg/mL (T=90). All sample prepa-rations at each time point were within speci-fication with a high % RSD of 2.15% (T=83). Every replicate chromatogram for every time point was clear of the degradant peaks and had the same chromatographic profile.
CONCLUSION Vancomycin HCl was stable in SyrSpend SF for 90 days when stored under refriger-ated (2oC to 8oC) conditions when com-pounded from either the raw powder or ster-ile raw powder. The samples were still within specification at day 90; however, no general trend was observed during the course of the study. Therefore, the beyond-use date is concluded to be 90 days. The findings of this study show that SyrSpend SF is an accept-able oral syrup and suspending vehicle for preparing individual compounded vancomy-cin HCl formulations. This formulation has the added advantage of helping to mask the bitter taste while remaining alcohol-, sorbi-tol-, and sugar-free. The formulations would be viable alternatives to commercially avail-able capsules when that dosage form is found to be inappropriate.
REFERENCE1. Vancocin HCl (vancomycin hydrochlo-
ride) capsules [product information]. Exton, PA: ViroPharma Incorporated; October 2005. [ViroPharma Incorporated Website.] Available at: www.viropharma.com/physicians/vancocin%20overview/vancocin%20package%20insert.aspx. Accessed January 12, 2011.
FIGURE 2. Plot of vancomycin hydrochloride concentration (sterile raw powder) in SyrSpend SF Suspension.
Note: Dashed lines represent upper and lower limits of vancomycin hydrochloride specifications.
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INTRODUCTION Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD), laryngopha-ryngeal reflux (LPR), and Zollinger–Ellison syndrome.1 It is used to treat a wide range of the patient population, including both infant and geriatric patients. These two groups in particular may experience dif-ficulty in swallowing whole capsules or tablets. In the past, sodium bicarbonate has been used with omeprazole to create an oral solution. Sodium bicarbonate does little to mask the bitter taste of omeprazole. An alkaline suspending agent containing a sweetener masks the bitter taste and increases the palpability of omeprazole. This is of particular importance when considering the treatment of infants, as the masking of the taste increases end-user compliance. Some compounding vehicles contain alcohol and sorbitol. SyrSpend SF Alka (for reconstitution) (Fagron [formerly Gallipot], St. Paul, Minnesota) is a sorbi-tol- and alcohol-free alkaline suspending agent which could serve as an appropriate vehicle for compounding an omeprazole oral suspension. The objective of this study was to exam-ine the stability of omeprazole when pre-pared in an oral suspension using SyrSpend SF Alka (for reconstitution). The suspen-sion was stored in a low-actinic plastic prescription bottle at a concentration of 2 mg/mL under United States Pharmaco-peia (USP) refrigerated (2oC to 8oC) storage conditions. Stability was assessed by per-cent recovery studies performed at varying time points throughout 92 days.
Stability of Omeprazole in SyrSpend SF Alka (Reconstituted)
ABSTRACT Omeprazole is used in the treatment of dyspepsia, peptic ulcer dis-ease, gastroesophageal reflux disease, laryngopharyngeal reflux, and Zollinger–Ellison syndrome. Omeprazole is marketed by AstraZeneca under a number of names, most notably Prilosec and Losec, as well as being available from a number of generic manufacturers. Omeprazole is available in both tablet and capsule form, with varying strengths of each. The need for other administration options for those patients who can-not take tablets or capsules has led compounding pharmacies to seek other alternatives. One possible alternative is the use of a suspending agent to create an oral solution or suspension. In the past, this has been accomplished using a sodium bicarbonate solution as the vehicle. How-ever, sodium bicarbonate/omeprazole combination imparts a bitter and unpleasant taste. SyrSpend SF Alka (reconstituted) is a vehicle for mak-ing a suspension which has a pleasant taste, thus increasing palpability and compliance. The objective of this study was to determine the stabil-ity of omeprazole in SyrSpend SF Alka (for reconstitution). The studied sample was compounded into a 2-mg/mL suspension and stored in a low-actinic plastic prescription bottle at temperatures between 2oC and 8oC. Six samples were assayed at each time point out to 92 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specificity through forced degradation studies. The shelf life of this product is at least 92 days, based on data collected when refrigerated and protected from light.
The authors are affiliated with Dynalabs, LLC, St. Louis, Missouri.
Paul A. Whaley, BSMark A. Voudrie II, MS, PMPBridget Sorenson, CAPM
MATERIALS AND METHODS Chemical Reagents Omeprazole raw powder was obtained from Gallipot (Lot 0906145D12; St. Paul, Minnesota). High-performance liquid chro-matographic (HPLC)-grade acetonitrile (Lot CZ629; Burdick and Jackson, Kalamazoo, Michigan), 85% phosphoric acid ACS-grade (Lot 201103115; CCI, New Delhi, India), monosodium phosphate monohydrate (Lot 107148; Fisher Scientific, Pittsburgh, Pennsylvania), disodium phosphate hep-tahydrate (Lot B0131737; Acros Organics, Geel, Belgium), and octanesulfonic acid (Lot 038K0815; Sigma Aldrich, St. Louis, Mis-souri) were used in the study. HPLC-grade
water was supplied by filtering deionized water from a Millipore Elix through a Milli-pore Simplicity (Billerica, Massachusetts). Equipment and Chromatographic Conditions Two different types of HPLCs were used. The first, used for validation and the stabil-ity study, was a Perkin Elmer 200-Series (Waltham, Massachusetts) equipped with a quaternary gradient solvent delivery sys-tem, a dual wavelength UV/VIS detector, and a 100-vial programmable autosampler with a Peltier tray, 200-mcL sample loop, and 250-mL syringe. The second LC sys-tem, used for forced degradation studies, was a Varian Prostar (Palo Alto, California) equipped with a tertiary gradient solvent delivery system, a photodiode array detec-
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tor (PDA), and an 84-vial programmable autosampler with a 100-mcL sample loop, and 250-mcL syringe. The Perkin Elmer HPLC was operated and data was collected using Perkin Elmer Totalchrom chroma-tography software, while the Varian HPLC used Galaxie chromatography software. The mobile phase for the HPLC method was buffer (50 mM phosphate), acetoni-trile, and Octanesulfonic acid (700 mL:300 mL:4.0999 g). The mobile phase’s pH was adjusted to 7.00 with 85% phosphoric acid and was delivered at 1.0 mL/min. Chro-matographic separation was achieved using a 150 × 4.6 mm Phenomenex (Tor-rence, California) Gemini C18 column with 5-mcm particle packing. The mobile phase was used as solvent in diluting the standard and assay preparations to 80 mcg/mL. The assay was monitored at 301 nm following a 10-mcL injection.
Validation of Forced-degradation Studies to Determine Stability-indicating Characteristics of the High-performance Liquid Chromatographic Method Omeprazole samples were stressed and assayed to determine the specificity of the HPLC method to any possible degradation product produced during storage of an oral suspension. Omeprazole was diluted to 80 mcg/mL in a solution of acid (0.1M HCl), in addition to exposure to ultraviolet light at 365 nm and heat at 70°C. Time under each stressor varied due to the relative stability of omeprazole to each individual degradation pathway. Any extraneous peaks found in the chromatogram were labeled and the resolution (USP) was determined between the degradant and the omeprazole. A resolution of 1.5 was con-sidered full separation. Purity calculations were performed in Galaxie on the omepra-zole peak using the controlled unstressed standard as a reference.
Preparation of Omeprazole Suspension Samples Omeprazole suspension was prepared by adding 240 mg of omeprazole powder to a plastic prescription bottle. SyrSpend SF Alka was reconstituted by adding 100 mL water per 6.43 g of SyrSpend SF Alka. Of the reconstituted suspension, 120 mL
was added to the prescription bottle con-taining the omeprazole powder. The bottle was shaken until the omeprazole was uni-formly dispersed. The flask was stored at USP-controlled refrigerated temperature (2oC to 8oC) for the stability study.
Stability Study The sample of omeprazole suspended in reconstituted SyrSpend SF Alka at a concentration of 2 mg/mL was submitted for stability. The sample was packaged in a low-actinic plastic prescription bottles and stored at USP-controlled refriger-ated temperature (2oC to 8oC) using a digitally controlled laboratory refrigera-tor from Forma Scientific (Edison, New Jersey). Time points for the study were initial (T=0), 9 days (T=9), 14 days (T=14), 22 days (T=22), 30 days (T=30), 50 days (T=50), 62 days (T=62), and 92 days (T=92). The evaluation parameter was percent recovery assay. The stability of omeprazole in suspension was defined by the percent recovery with respect to T=0 using the validated HPLC method. The sample stock was prepared six times by adding 1 mL of suspension with a volumet-ric pipette to 25 mL with mobile phase. The average and standard deviation of all replicate injections at each time point was used to calculate the percent recovery.
RESULTS The stability of omeprazole in recon-stituted SyrSpend SF Alka is shown in Table 1. The result of 2.0483 mg/mL at T=0 was set as the initial concentration for the study, and all subsequent time points were compared to this value. The Figure included with this manuscript shows the data in terms of concentration and that the concentration of the suspen-sion remained within the specification (90%<[omeprazole]<110%) throughout the 62 days of the study. The HPLC method was shown to be stability indicating by forcibly degrading omeprazole and separating the degradant peaks from that of the main analyte. Omeprazole was stable to light, with slight
TABLE 1. Stability of Omeprazole in Reconstituted SyrSpend SF Alka Refrigerated (2oC to 8oC) for 90 days. Elapsed Time % RecoveryT=0 100.00T=9 96.24 ± 1.80%T=14 96.32 ± 3.87%T=22 94.69 ± 1.71%T=30 96.32 ± 0.66%T=50 95.76 ± 4.45%T=62 92.87 ± 1.79%T=92 90.98 ± 2.72%
Note: Dashed lines represent upper and lower limits of Omeprazole specification.
FIGURE. Plot of omeprazole concentration in SyrSpend SF Alka (reconstituted).
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TABLE 2. Summary of the Validation Parameters for the High-Performance Liquid Chromatographic Method Used in the Stability Study of Omeprazole in SyrSpend SF Alka (Reconstituted).Validation Parameter ResultsPeak Tailing 1.33 % RSD = 1.99Theoretical Plates 4398.5 % RSD = 0.67Linear range (301 nm) 20 to 200 mcg/mL R2=0.9998Extraction Precision n=6 %RSD = 1.23 Accuracy (50, 100, 180 mcg/mL) %Target = 98.61%, 98.53%, 99.67%Specificity (resolution between main degradant peaks) Res (USP) = 11.27
degradation under acid stress. There was significant degradation created by heat. The degradants present in the acid and heat conditions were all completely separated from the analyte with accept-able resolution. Additionally, validation parameters listed in Table 2 show that all system suitability results met acceptance criteria.
Gallipot SyrSpend SF Alka (Reconstituted) Omeprazole Suspension The initial potency of the omeprazole suspension was 2.0483 mg/mL, as shown in the Figure included with this manu-script. This concentration was 102.4% of the compounding target of 2 mg/mL. The T=0 result was set as the baseline for all other time points tested. The assay results showed an overall downward trend to a low point of 1.8635 mg/mL at T=92. Every rep-licate chromatogram for every time point was clear of degradant peaks and had the same chromatographic profile.
CONCLUSION Omeprazole was stable in SyrSpend SF Alka (reconstituted) for 92 days when stored under refrigerated (2oC to 8oC) conditions. The sample was still within specification at day 92. However, the overall trend is that of decreasing con-centration during the course of the study. The beyond-use-date should be set to 60 days. The findings of this study show that SyrSpend SF Alka (reconstituted) is an acceptable suspending vehicle for prepar-ing individual compounded omeprazole formulations. This formulation has the added advantage of helping to mask the bitter taste while remaining alcohol and sorbitol free. The formulations would be viable alternatives to commercially avail-able capsules when that dosage form is found to be inappropriate.
REFERENCE1. U.S. National Library of Medicine.
Omeprazole. [National Center for Bio-technology Information Website.] May 16, 2011. Available at: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000936. Accessed January 16, 2012.
Address correspondence to Paul Whaley, BS, Method Development Chemist, Dynalabs, LLC, 2327 Chouteau Avenue, St. Louis, MO 63103. E-mail: [email protected]
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T A B L E 2 . Summary of the Validation Parameters for the High-Performance Liquid Chromatographic Method Used in the Stability Study of Omeprazole in SyrSpend SF Alka (Reconstituted).
VALIDATION PARAMETER RESULTSPeak Tailing 1.33 % RSD = 1.99
Theoretical Plates 4398.5 % RSD = 0.67
Linear range (301 nm) 20 to 200 mcg/mL R2=0.9998
Extraction Precision n=6 %RSD = 1.23
Accuracy (50, 100, 180 mcg/mL) %Target = 98.61%, 98.53%, 99.67%
Specificity (resolution between main
degradant peaks) Res (USP) = 11.27
Extraction Precision n=6 %RSD = 1.23
Accuracy (50, 100, 180 mcg/mL) %Target = 98.61%, 98.53%, 99.67%
Specificity (resolution between main
degradant peaks) Res (USP) = 11.27
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Mark A.Voudrie II, MS, PMPBridget Alexander, BS, CAPMD. Brett Allen, BSDynalabs, LLCSt. Louis, Missouri
INTRODUCTION Verapamil hydrochloride (HCl) is a phe-nylalkylamine calcium channel blocker which was introduced in 1962 as an antiarrhythmic and antianginal agent.1 Although verapamil is mainly used in cardiovascular diseases, it has become a regularly prescribed high-dose prophylactic treatment of both episodic and chronic cluster headaches.2 It has also been shown to be an effective therapeutic agent for the treatment of hypertrophic cardiomyopa-thy in children.3
Due to the varying uses of verapamil, it is prescribed to a large cross-section of the population ranging from pediatrics to geriat-rics. Although the vast majority of patients’ cluster headache onset tends to be in the late 20s and early 30s,4 chronic cluster headaches tend to last upwards of 20 to 30 years, which would place them in an elderly demographic. Additionally, Fields et al studied adult hyper-tension, for which verapamil is an effective treatment, between 1999 and 2000 and found increasing percentages of hypertension at increased ages (18 to 34 6.00%, 35 to 44 16.00%, 45 to 54 31.00%, 55 to 64 58.00%, 65 to 74 65.10%, and 75+ 77.60%).5
Verapamil is currently commercially supplied as intravenous injections and both immediate- and slow-release tablets. With the increasing ages of patients requiring verapamil and its uses in pediatrics, addi-tional dosage delivery forms are necessary for patients that cannot administer oral tablets because they might be incapable of swallow-ing the tablets.6 Verapamil is a white crystalline solid that has a bitter taste which benefits from a
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Stability of Verapamil Hydrochloride in SyrSpend SF Compared to Sorbitol Containing Syrup and Suspending Vehicles
ABSTRACTVerapamil hydrochloride is widely prescribed to treat multiple cardiovas-cular diseases. There are a number of generic manufacturers of verapamil tablets and injectables. The need for other administration options for pa-tients who cannot take tablets has led compounding pharmacies to seek other alternatives, namely, oral solutions and suspensions. The stability of these compounded verapamil oral liquid preparations is a concern to anyone making them. The objective of this study was to determine the stability of verapamil hydrochloride in SyrSpend SF in comparison to sta-bility of verapamil hydrochloride in Ora-Sweet SF:Ora-Plus (1:1). The two samples were compounded in 50-mL batches and stored in amber 60-mL plastic prescription bottles at United States Pharmacopeia refrigerated conditions. Five replicates at each pre-defined time point were assayed by a stability-indicating high performance liquid chromatographic method with an end date of 60 days. No degradation peaks were seen in the chro-matograms for either preparation at any time point and the recovery of verapamil hydrochloride was within 90% to 110% of the initial concentra-tion for all replicates. Verapamil hydrochloride is stable in amber plastic prescription bottles for 60 days when refrigerated for both SyrSpend SF and Ora-Sweet SF:Ora-Plus (1:1).
sweetener in oral preparation formulations. Stability studies in Ora-Sweet SF:Ora-Plus (Paddock Laboratories Inc., Minneapolis, Minnesota) (1:1) have been completed and showed refrigerated stability of verapamil out 60 days.7 Ora-Sweet SF and Ora-Plus sus-pending vehicles both contain sorbitol, which increases the osmolality of the verapamil solutions, possibly leading to negative patient side effects. Sorbitol can also cause nausea, which is already a potential side effect of verapamil treatment, and could exacerbate the reaction. SyrSpend SF (Gallipot, St. Paul, Min-nesota) is a sugar- and sorbitol-free suspend-ing agent with a low osmolality. The cherry flavored variety provides a masking effect for the bitter verapamil and could be an alterna-tive for creating verapamil oral solutions or suspensions. The objective of this study was to compare the stability of verapamil HCl oral solutions
using either Ora-Sweet SF:Ora-Plus (1:1) or SyrSpend SF as solution vehicles and stored in amber prescription vials at a concentra-tion of 50 mg/mL stored at United States Pharmacopeia (USP) refrigerated conditions (2°C to 8°C). Stability was assessed by per-cent recovery studies at varying time points throughout 60 days.
MATERIALS AND METHODSChemical Reagents Two separate lots of Verapamil HCl were purchased from two separate vendors; Spec-trum Chemical (Lot YR3110; Gardena, Cali-fornia) and Sigma Aldrich (Lot 118K1197; St. Louis, Missouri). High-performance liquid chromatographic (HPLC)-grade acetonitrile (Lot CZ629; Burdick & Jackson, Kalamazoo, Michigan) and methanol (Lot 09253-74; Pharmco-Aaper, Brookfield, Connecticut), anhydrous sodium acetate (Lot 46177843;
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EMD, Gibbstown, New Jersey), and Glacial Acetic Acid (Lot 067970; Fairlawn, New Jersey) were used in the study. HPLC-grade water was supplied by filtering deionized water from a Millipore Elix through a Millipore Simplicity (Billerica, Massachusetts).
Equipment and Chromatographic Conditions The HPLC instrument was a Varian Prostar (Palo Alto, Califor-nia) equipped with a model 230 tertiary gradient solvent delivery system, a model 335 photodiode array detector, and a model number 410 programmable autosampler fitted with a 100-mcL sample injec-tion loop and 250-mcL syringe. The HPLC was operated and data was quantitated using Galaxie software from Varian. The mobile phase for the system was 50 mM sodium acetate, acetonitrile, metha-nol (540:360:100), adjusted to a pH of 4.25 with glacial acetic acid and delivered at 1.5 mL/minute. Chromatographic separation was achieved using a 150 mm × 4.6 mm Phenomenex (Torrance, Califor-nia) Gemini C18 column with 5-mcm particle packing. The mobile phase was used as solvent in diluting the standard and assay prepara-tions to 25 mcg/mL. Assay and standard preparations were moni-tored at 271 nm following 100-mcL full-sample loop injections. Validation of Forced-degradation Studies to Determine Stability-indicating Characteristics of the High-performance Liquid Chromatographic Method Verapamil HCl samples were stressed and assayed to determine the sensitivity of the HPLC method regarding the analyte of inter-est and any possible degradant or impurities. Verapamil HCl was diluted to 25 mcg/mL in solutions of base (0.1N NaOH), acid (0.1N HCl), and hydrogen peroxide (3.5%), in addition to exposure to ultraviolet (UV) light at 365 nm and heat at 70°C. Time under these stressors varied due to the relative stability of verapamil to each individual condition. Additional peaks found in the chromatograms were labeled and the resolution (USP) was determined between the degradant and the verapamil. A resolution of 1.5 was considered full separation. Peak purity calculations were performed on verapamil based on an external reference spectrum and on the peak’s apex.
Preparation of Verapamil Hydrochloride Suspension Samples The compounding of the samples was loosely based on a formula-tion that was written by Dr. Loyd V. Allen Jr. and published in the International Journal of Pharmaceutical Compounding.8
Verapamil HCl in Ora-Sweet SF:Ora-Plus (1:1) was prepared by adding an appropriate amount of verapamil HCl (Sigma Aldrich) into a [ceramic] mortar and grinding into a uniform powder. To a 50-mL volumetric flask, 2.5 g of powder was added, followed by 10 mL of Ora-Sweet SF using a volumetric pipette. The flask contents were stirred on a stir plate while adding another 15 mL of Ora-Sweet SF. To bring the contents of the flask to volume, 25 mL of Ora-Plus was used, and it was stirred until a homogeneous preparation was achieved. The contents of the flask were poured into a 60-mL amber prescription bottle and stored for stability studies. After approxi-mately 15 minutes of stirring, extra solid precipitate appeared in the suspension. This precipitate was not identified.
Verapamil HCl in SyrSpend SF was prepared similarly to the previous solution. After weighing 2.5 g of uniform powder to a 50-mL volumetric flask, 25 mL of SyrSpend SF was added and stirred. The preparation was brought to volume with SyrSpend SF, stirred until homogenous, placed into a 60-mL amber plastic prescription bottle, and stored for stability studies.
Stability Study Two different samples were submitted for stability: verapamil HCl 50-mg/mL suspension in Paddock Laboratories Ora-Sweet SF:Ora-Plus (1:1) (Lot 9439089 and 9499528, respectively) and verapamil HCl 50-mg/mL suspension in Gallipot Inc. SyrSpend SF (Lot 0909185J12). The samples were packaged in 60-mL low actinic plastic prescription bottles, each containing 50 mL suspen-sion and stored at USP controlled refrigerated temperature (2°C to 8°C) using a digitally controlled laboratory refrigerator from Forma Scientific (Edison, New Jersey). Time points for the study were initial (T=0), 1 day (T=1), 7 days (T=7), 11 days (T=11), 14 days (T=14), 28 days (T=28), 36 days (T=36), 47 days (T=47), and 60 days (T=60). The evaluation parameter was percent recov-ery assays. The stability of verapamil HCl in each of the suspen-sions was defined by the percent recovery with respect to T=0 using the validated HPLC method. The samples were prepared five times by adding 0.5 mL of suspension with a volumetric pipette to 1000 mL mobile phase for a 1:2000 total dilution and calculating the averages and standard deviations for all replicate injections.
RESULTS The stability of verapamil HCl in either Ora-Sweet SF:Ora-Plus (1:1) or SyrSpend SF is shown in Table 1. The beginning analyses of 50.32 mg/mL for Ora-Sweet SF:Ora-Plus (1:1) and 46.14 mg/mL for SyrSpend SF at T=0 were set as the initial concentrations of the study and all subsequent time points were compared to these values. Figures 1 and 2 show the data in terms of concentration and show that both suspensions remained within specifications (90%< [verapamil HCl] <110%) throughout the duration of the study.
TABLE 1 . Stability of Verapamil Hydrochloride in Ora-Sweet SF:Ora-Plus (1:1) and SyrSpend SF Refrigerated (2°C to 8°C) for 60 Days.
Ora-Sweet SF:Ora-Plus SyrSpend SF %Elapsed Time (1:1) % Recovery Recovery
T=0 100 100
T=1 100.86 99.79
T=7 101.47 104.06
T =11 95.33 98.99
T=14 97.66 96.6
T=28 98.95 96.54
T=36 102.75 94.18
T=47 104.08 104.47
T=60 101.92 102.52
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DISCUSSION The HPLC method was shown to be stability-indicating by forcibly degrading verapamil HCl and separating the degradant peaks from that of the main analyte. Verapamil HCl was stable to heat, UV light, acid and base; however, oxidizer created an initial degradant peak.
FIGURE 1 . Plot of verapamil hydrochloride concentration in Ora-Sweet SF: Ora Plus (1:1) Suspension.(Dashed lines represent upper and lower limits of verapamil hydrochloride specifications.)
FIGURE 2 . Plot of verapamil hydrochloride concentration in SrySpend SF Suspension.(Dashed lines represent upper and lower limits of verapamil hydrochloride specifications.)
Figure 3 shows a standard unstressed vera-pamil sample overlaid with an oxidized stressed verapamil sample. The main degradant was completely separated from the analyte with acceptable resolution. Addition-ally, validation parameters listed in Table 2 show that all system suitability results met acceptance criteria.
Paddock Laboratories Inc. Ora-Sweet SF:Ora-Plus (1:1) Verapamil Hydrochloride Suspension
Table 1 and Figure 1 show the stability data for a verapamil in Ora-Sweet SF:Ora-Plus (1:1) suspension stored refrigerated and light-protected for 60 days. The sample’s potency began at 50.32 mg/mL, which was 100.64% of the compounding target of 50 mg/mL. This value was set as the baseline for all the subsequent time points. All of the time points had consistent chromatographic profiles as T=0, and no degradant peaks were visualized throughout the study. The data followed no specific concentration profile or general trend and appeared to remain con-stant with all results falling within two T=0 standard deviations from the initial concen-tration. At no time in the study did the stan-dard deviation from any time point place the sample outside of the acceptable limits.
Gallipot SyrSpend SF Verapamil Hydrochloride Suspension
The initial potency of the verapamil HCl SyrSpend SF suspension was 46.14 mg/mL, which is shown in Figure 2. This concentra-tion was 92.3% of the compounding target of 50 mg/mL. The T=0 result was set as the baseline for all other time points tested. The assay results were congruent with the Ora-Sweet SF:Ora-Plus (1:1) suspension results because they vary at time points and do not follow any discernable trend. The assay results varied between 43.45 mg/mL (T=36) and 48.01 mg/mL (T=7). Day 36, the time point with the lowest results, did have a standard deviation (results of 42.22 mg/mL, 42.29 mg/mL, 47.85 mg/mL, 41.95 mg/mL, and 42.96 mg/mL) that could place the sample just out of specification, although every sample replicate and the average were above the acceptable limits. Every replicate chromatogram for every time point was clear of degradant peaks and had the same chro-matographic profiles.
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TABLE 2 . Summary of the Validation Parameters for the High-performance Liquid Chromatographic Method Used in the Stability Study of Verapamil Hydrochloride.Validation Parameter Results
Peak Tailing 1.29 %RSD = 1.5
Theoretical Plates 2248.8 %RSD = 0.8
Linear Range (271 nm) 6-115 mcg/mL R2 = 0.9997
Extraction Precision Ora-Sweet SF:Ora-Plus (1:1) n=6 %RSD = 0.5
Extraction Precision (SyrSpend SF) n=6 %RSD = 0.37
LOQ and LOD 3.7 mcg/mL and 0.7 mcg/mL
Accuracy (105, 60, 25 mcg/mL) %Target = 99.9%, 100.0%, 100.4%
Ruggedness (2 days, 2 analysts, 2 instruments) %RSD = 0.3 %Target = 100.0%
Ruggedness (10% change in % organic and pH) %RSD = 1.7 %Target = 99.8%
Specificity (Resolution between main degradant peak) RT = 6.51 Res(USP) = 2.95
CONCLUSION Previous studies have shown that verapamil HCl is stable for 60 days in Ora-Sweet SF:Ora-Plus (1:1) which lends support to the findings in this study.7 Verapamil HCl was stable in Ora-Sweet SF:Ora-Plus (1:1) and SyrSpend SF for 60 days when refrigerated. The shelf-life could not be extended past 60 days with the data acquired since there was no general trend within the 60 days. Varying temperatures were also not addressed in this study. The findings of this study show that SyrSpend SF is an acceptable oral syrup and suspending vehicle for preparing individual compounded verapamil HCl formulations that are alcohol-, sorbitol-, and sugar-free, while still masking the bitter taste of the raw powder. The formulations would be possible alternatives to injections and tablets when
these commercially-available dosage forms are inappropriate for pediatric, geriatric, and other special-needs patient populations.
REFERENCES 1. Singh BN, Ellrodt G, Peter CT. Verapamil:
A review of its pharmacological proper-ties and therapeutic use. Drugs 1978; 15(3): 169–197.
2. Tfelt-Hansen P, Tfelt-Hansen J. Verapamil for cluster headache. Clinical pharmacol-ogy and possible mode of action. Headache 2009; 49(1): 117–125.
3. Spicer RL, Rocchini AP, Crowley DC et al. Hemodynamic effects of verapamil in children and adolescents with hypertrophic cardiomyopathy. Circulation 1983; 67(2): 413–420.
4. Rozen TD, Niknam RM, Shechter AL et al. Cluster headache in women: Clinical characteristics and comparison with cluster headache in men. J Neurol Neurosurg Psy-chiatry 2001; 70(5): 613–617.
5. Fields LE, Burt VL, Cutler JA et al. The burden of adult hypertension in the United States 1999 to 2000: A rising tide. Hyperten-sion 2004; 44(4): 398–404.
6. Purkiss R, Kayes AJ. A survey of extempo-raneous oral liquid formulations. Pharm J 1981; 226(6127): 588–589.
7. Allen Loyd V. Jr.. Erickson III. Stability of extemporaneously prepared pediatric formulations using Ora-Plus® with Ora-Sweet® and Ora-Sweet SF® – Part II. Secundum Artem 6(1); Minneapolis, MN: Paddock Laboratories, Inc.
8. Allen Loyd V. Jr. Verapamil hydrochloride 50-mg/mL oral liquid. IJPC 1997; 1(3): 188.
Address correspondence to Mark A. Voudrie II, Ana-lytical Chemist, Dynalabs, 3830 Washington Boule-vard, St. Louis, MO 63108. E-mail: [email protected]
FIGURE 3 . Chromatograms of verapamil hydrochloride.
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INTRODUCTION H1N1 flu is a major health concern in the U.S. The sad fact is hundreds of pediatric deaths associated with 2009 pandemic Influ-enza A H1N1) virus have been reported regu-larly by the Centers for Disease Control and Prevention (CDC) since April 26, 2009.1 The situation has become so serious that the CDC now devotes a website to H1N1.2 Oseltamivir (Tamiflu; manufactured by Roche, Nutley, New Jersey) is an important treatment for this disease, especially for debilitated patients and very young children. The pandemic created high demand for oseltamivir, resulting in shortages of Tami-flu, particularly of the oral liquid dose form. When shortages of the liquid dose form occur, pharmacists compound oral liquids extem-poraneously from Tamiflu capsules. Some compounding vehicles contain sorbitol and alcohol. Administration of alcohol-containing substances to children, especially infants, has been a concern,3 and the inclusion of sorbitol in a vehicle for elderly, debilitated, or pediatric patients can pose complications for diet and therapy because introducing high osmolality can create loose stools and diarrhea, leading to dehydration. In fact, a patient with H1N1 may be experiencing diarrhea and dehydration before oseltamivir treatment is begun. High osmolality preparations would exacerbate this condition. Therefore, a suitable vehicle con-taining neither ethanol nor sorbitol was sought. Pharmacists need access to additional vehicles with documented stability studies involving Tamiflu.
This study used three recognized vehicles:
1. Cherry Syrup (Gallipot, Inc., St. Paul, Min-nesota) has a long history as an alcohol-free
Stability of Oseltamivir Phosphate in SyrSpend SF, Cherry Syrup, and SyrSpend SF (For Reconstitution)
ABSTRACTOseltamivir (Tamiflu) is widely prescribed to treat and prevent influenza virus A, influenza virus B, and H1N1 Flu. It is manufactured by Roche in 75-mg capsules. The need for other administration options for patients who cannot take capsules and cannot use suspending agents which contain alcohol, sorbitol, or preservatives has led to the compounding of oselta-mivir into three suspending vehicles that do not contain these chemicals. All three contain neither alcohol nor sorbitol; the third also has no pre-servatives, a distinct advantage for special patient situations. The objec-tive of this study was to determine the stability of oseltamivir in three different suspending agents: SyrSpend SF, Cherry Syrup, and SyrSpend SF (for reconstitution). The studied samples were compounded into 15-mg/mL suspensions and stored in low actinic plastic prescription bottles at temperatures between 2°C and 8°C. Triplicate samples were assayed at time intervals out to 30 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specific-ity through forced degradation studies. All of the samples tested remained within 90% to 110% of their initial concentrations throughout the course of the study. The shelf life of these products is at least 30 days, based on data collected when the aforementioned products are refrigerated and protected from light. Based on the final potency data at day 30, the shelf life may extend past the scope of this study, but 30 days was the limit of this study.
Mark A.Voudrie II, BSD. Brett Allen, BSDynalabs, LLCSt. Louis, Missouri
syrup vehicle; its wide use made it a good candidate for the study.
2. SyrSpend SF (Gallipot, Inc.) is a hydro-lyzed starch-based suspending/syrup vehicle. Suspending and sugar-free flavor-ing components are both combined in one bottle for ease of use. SyrSpend SF provides a suspending vehicle with neither sorbi-tol (therefore, minimal osmolality issues) nor alcohol. Moreover, it contains no dyes and, in the unflavored version, contains no flavoring agents.
3. SyrSpend SF (for reconstitution) (Gallipot, Inc.) contains neither ethanol nor sorbitol and also contains no preservatives, coloring agents, nor flavoring agents (in the unfla-vored version.)
Due to ongoing demands for extempora-neous compounding of Tamiflu suspension
and shortages of some vehicles in the fall of 2009, stability studies were undertaken using Tamiflu in Cherry Syrup and in SyrSpend SF, both readily available vehicles. The studies were performed by DynaLabs, an independent analytical laboratory in St. Louis, Missouri.
MATERIALS AND METHODSChemical Reagents Oseltamivir phosphate in capsule form (Lot U2082; Tamiflu) was generously provided by Gallipot, Inc. and Bellevue Pharmacy Solu-tions (St. Louis, Missouri). High-performance liquid chromatographic (HPLC)-grade acetonitrile (Lot CZ629; Burdick & Jackson, Kalamazoo, Michigan), triethylamine (Lot 47270751; EMD, Gibbstown, New Jersey), for-mic acid (Lot A0266198; Acros Organics, Fair
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Lawn, New Jersey), and ammonium formate (Lot 0001422904; Fluka, Milwaukee, Wiscon-sin) were used in the study. HPLC-grade water was supplied by filtering deionized water from a Millipore Elix through a Millipore Simplic-ity (Billerica, Massachusetts).
Equipment and Chromatographic Conditions The HPLC instrument was a Varian Prostar (Palo Alto, California) equipped with a model 230 tertiary gradient solvent delivery system, a model 335 photodiode array (PDA) detector, and a model number 410 programmable au-tosampler fitted with a 100-mcL sample injec-tion loop and a 250-mcL syringe. The HPLC was operated and data was quantitated using Galaxie software from Varian. The mobile phase for the system was 20 mM ammonium formate pH 3.3 with formic acid, triethylam-ine, acetonitrile (500:2.8:500) and was delivered at 1.5 mL/minute. Chromatographic separa-tion was achieved using a 150 mm × 4.6 mm Phenomenex (Torrance, California) Gemini C18 column with 5-mcm particle packing. The mobile phase was used as solvent in diluting the standard and assay preparations to 100 mcg/mL. Assay and standard preparations were monitored at 254 nm following 100-mcL full sample loop injections.
Validation of Forced-Degradation Studies to Determine Stability-Indicating Characteristics of the HPLC Method Oseltamivir samples were stressed and assayed to determine the sensitivity of the HPLC method regarding the analyte of inter-est and any possible degradant or impurities. Oseltamivir, in capsule form, was diluted to 100 mcg/mL in solutions of base (0.05 N NaOH), acid (0.05 N HCl), and hydrogen peroxide (35%), in addition to exposure to ultraviolet (UV) light at 365 nm and heat at 120°C. Time under these stressors varied due to the relative stability of oseltamivir to each individual condition. Additional peaks found in the chromatograms were labeled and the resolution was determined (based on United States Pharmacopeia (USP) guidelines) between the degradant and the oseltamivir; a resolution of 1.5 was considered full separation.
Preparation of Oseltamivir Suspension Samples The compounding of the samples was based on a study by Winiarski et al.4 SyrSpend SF (for
reconstitution) was reconstituted with 60 mL of HPLC-grade water. The three oseltamivir suspensions (SyrSpend SF, Cherry Syrup, and SyrSpend SF [for reconstitution]) were all compounded in the same manner. Forty Tami-flu capsules were weighed in bulk, opened, their contents poured into a low actinic plastic prescription bottle, and set aside. The empty capsules were cleaned of any residual powder by reaming with cotton swabs and weighed in bulk. From these weights the average capsule fill weight was determined to be 165.28 mg, of which 75 mg (from the label claim), or 45.3775%, was oseltamivir base (as the phos-phate). The capsules were then discarded. Approximately 826.4 mg powder was carefully added to a ceramic mortar and ground until a fine uniform particle size was achieved. A 10-mL volume of the appropriate suspend-ing vehicle was added to the mortar and, after thorough mixing, the suspension was poured into a suitable low actinic volumetric flask. Two 5-mL aliquots of suspending vehicle were added to wash thoroughly any residual powder out of the mortar and into the flask. The flask content was brought to volume (25 mL) with suspending vehicle, thoroughly mixed, and were poured into a low actinic plastic pre-scription bottle for storage at USP-controlled refrigerated temperature (2°C to 8°C).
Stability Study Three dierent samples were submit-ted for stability: (1) oseltamivir 15-mg/mL suspension in Gallipot, Inc. Cherry Syrup (Lot 0909326J11), (2) oseltamivir 15-mg/mL suspension in Gallipot, Inc. SyrSpend SF (Lot 0909135J12), and (3) oseltamivir 15-mg/mL suspension in Gallipot, Inc. SyrSpend SF (for reconstitution) (Lot 0812299). The samples were packaged in 60-mL low actinic plastic prescription bottles, each containing 25 mL of suspension, and stored at USP-controlled refrigerated temperature (2°C to 8°C) using a digitally controlled laboratory refrigerator from Forma Scientific (Edison, New Jersey). Time points for the study were initial (T=0), 3 days (T=3), 7 days (T=7), 14 days (T=14), and 30 days (T=30). The evaluation param-eters were appearance and percent recovery assays. Appearance was evaluated by visual inspection of both the suspension and the con-tainer. The acceptance criteria for the Cherry Syrup suspension were the retention of the pinkish-red color, the homogeneity of the sus-pension, and the intact container closure sys-tem. The acceptance criteria for the SyrSpend
SF and the SyrSpend SF (for reconstitution) were the retention of the opaque color, the homogeneity of the suspension, and the intact container closure system. The stability of os-eltamivir in each of the three suspensions was defined by the percent recovery in respect to T=0 using the validated HPLC method. The samples were prepared in triplicate by adding 0.5 mL of suspension with a volumetric pipette to 75 mL mobile phase for a 1:151 total dilu-tion and calculating the averages and standard deviations for all replicate injections.
RESULTS The stability of oseltamivir in Cherry Syrup, SyrSpend SF (for reconstitution), and SyrSpend SF are shown in Tables 1, 2, and 3, respectively. The results of 14.42 mg/mL for Cherry Syrup, 14.83 mg/mL for SyrSpend SF (for reconstitution), and 14.11 mg/mL for SyrSpend SF at T=0 were set as the initial concentration of the study, and all subsequent time points were compared to these values. Figures 1, 2, and 3 show the data in terms of concentration and show that all three suspen-sions remained within specifications (90% < [oseltamivir] < 110%) throughout the dura-tion of the study.
DISCUSSION The HPLC method was shown to be stabil-ity indicating by forcibly degrading oseltamivir and separating the degradant peaks from that of the main analyte. Oseltamivir was relatively stable to heat, UV light, and acid; however, base and oxidizer created an initial degradant peak in 30 minutes. The chromatograms of the base (0.05M NaOH), oxidizer (35% H2O2), and standard are shown in Figure 4. Figure 5 shows the PDA purity channel of the oselta-mivir peak for the base, oxidizer, and standard as well. Table 4 shows the purity calculations Galaxie performed on the oseltamivir peak for all three chromatograms listed. Additionally, validation parameters listed in Table 5 show that all system suitability results met accep-tance criteria. Cherry Syrup (Lot 0909326J11) Table 1 and Figure 1 show the stability data for an oseltamivir Cherry Syrup suspension stored refrigerated and light protected for 30 days. The sample’s potency began at 14.42 mg/mL which was 96.13% of the compounding target of 15 mg/mL. This value was set as the baseline for all the subsequent time points. The
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sample’s potency increased slowly for the fi rst 14 days, reaching a maximum at 15.12 mg/mL, which was 100.8% of the compounding target and 104.9% recovery of the T=0 concentra-
tion. The next time point, T=30, gave a 5.5% decrease in potency from T=14; however, this was still 99.4% of the compounding target. No other time points were tested between T=14 and T=30, therefore, no current estimation of the time in which the sample would become subpotent could be hypothesized; however, the data did start to take on a parabolic shape. The sample showed no discoloration, and no degradant peaks were seen in any time point’s chromatograms.
SyrSpend SF (For Reconstitution) (Lot 0812299) The initial potency for the oseltamivir SyrSpend SF (for reconstitution) suspension was 14.83 mg/mL, which is shown in Figure 2. This concentration was 98.7% of the com-pounding target of 15 mg/mL. The accurate compounding of this preparation was related to the reconstituted solution being less dense than the other suspensions tested, therefore measurements were easier. The T=0 result was set as the baseline for all other time points tested. The assay results varied up and down with no general discernible trend. The lowest result was 14.60 mg/mL, which was 97.3% of the compounding target and 98.4% of the baseline value. The percent recoveries for all of the time points can be seen in Table 2. The T=30 assay result had a 99.7% recovery which shows the oseltamivir was stable throughout the entire study. Again, the color, homogene-ity, and chromatograms showed no signs of instability.
SyrSpend SF (Lot 0909135J12) The initial potency for the oseltamivir SyrSpend SF suspension was 14.11 mg/mL, which is shown in Figure 3. Of all three sus-pensions tested, this was the least accurately compounded preparation, being 94.1% the compounding target of 15 mg/mL. The T=0 assay result was set as the baseline for all other time points. The assay results followed the same trend as the Cherry Syrup previously mentioned. The concentration slowly increased to a maximum of 14.93 mg/mL at T=14 and lost 3% potency from T=14 to T=30. With a percent recovery of 102.6% at T=30, the assay result was still higher than T=0. The data,
FL = front (low)RBL = rear baselineRH = rear (high)RL = rear (low)
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TABLE 1. Stability of Oseltamivir in Gallipot, Inc. Cherry Syrup Refrigerated (2°C to 8°C) for 30 Days.Elapsed Time Appearance Recovery (%)T=0 Pinkish Red 100.0 Homogenous Container Closure Intact T=3 Pinkish Red 101.7 Homogenous Container Closure IntactT=7 Pinkish Red 103.3 Homogenous Container Closure IntactT=14 Pinkish Red 104.9 Homogenous Container Closure IntactT=30 Pinkish Red 99.4 Homogenous Container Closure Intact
TABLE 2. Stability of Oseltamivir in Gallipot, Inc. SyrSpend SF (For Reconstitution) Refrigerated (2°C to 8°C) for 30 Days.Elapsed Time Appearance Recovery (%)T=0 Opaque 100.0 Homogenous Container Closure Intact T=3 Opaque 98.4 Homogenous Container Closure Intact T=7 Opaque 100.6 Homogenous Container Closure Intact T=14 Opaque 100.1 Homogenous Container Closure Intact T=30 Opaque 99.7
TABLE 3. Stability of Oseltamivir in Gallipot, Inc. SyrSpend SF Refrigerated (2°C to 8°C) for 30 Days.Elapsed Time Appearance Recovery (%)T=0 Opaque 100.0 Homogenous Container Closure Intact T=3 Opaque 102.6 Homogenous Container Closure Intact T=7 Opaque 104.4 Homogenous Container Closure Intact T=14 Opaque 105.8 Homogenous Container Closure Intact T=30 Opaque 102.6 Homogenous Container Closure Intact
TABLE 4. Purity Percentages and Purity Values for Coordinates of Oseltamivir Peak.Sample Standard Base Stressed Oxidizer StressedArea Impure [%] 0.386 0.807 0.672Area Medium [%] 0.432 0.425 0.240Area Pure [%] 99.182 98.768 99.088Purity [APEX] 1000.000 1000.000 1000.000Purity [FBL] 632.483 719.950 449.828Purity [FH] 999.689 999.297 999.007Purity [FL] 998.636 994.276 995.759Purity [RBL] 632.566 719.856 449.851Purity [RH] 999.536 997.747 998.827Purity [RL] 997.046 998.763 996.474
APEX = apex of peakFBL = front baselineFH = front (high)
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much like what was seen in the cherry syrup, began to take on a parabolic shape. Throughout the study, the sample retained its opaque appearance and no degradants ap-peared in the chromatograms.
CONCLUSION This study showed that oseltamivir (as the phosphate) compounded from Tamifl u capsules into sorbitol-free and alcohol-free suspensions is stable for 30 days when stored in low actinic plastic prescription bottles and refrigerated between 2°C and 8°C. No sample fell below 98.4% of the initial concentration throughout the 30 days. Two of the
TABLE 5. Summary of the Validation Parameters for the High-Performance Liquid Chromatographic Method Used in the Stability Study of Oseltamivir in Gallipot, Inc. Suspension Vehicles.Validation Parameter ResultsPeak Tailing 1.39 % RSD = 0.54Theoretical Plates 3758.8 % RSD = 1.35Linear Range (254 nm) 50 to 200 mcg/mL R2 = 0.9994Extraction Precision (Cherry) n = 6 % RSD = 1.59Extraction Precision (SyrSpend SF (For Reconstitution) n = 6 % RSD = 1.54Extraction Precision (SyrSpend SF) n = 6 % RSD = 0.37Accuracy (70.53, 122.88, 199.38 mcg/mL, respectively) % Target = 103.7%, 100.5%, 100.6%Ruggedness (2 days, 2 analysts, 2 instruments) % RSD = 0.98 % Target = 100.5%Robustness (10% change in % organic and pH) % RSD = 3.1 % Target = 97.8%Specifi city (Resolution between main degradant peaks) RT = 2.00 Res (USP) = 11.71 RT = 5.12 Res (USP) = 3.0
RSD = relative standard deviation, SF = sugar free, USP = United States Pharmacopeia
FIGURE 1. Plot of Oseltamivir Concentration in Cherry Syrup Suspension
FIGURE 2. Plot of Oseltamivir Concentration in SyrSpend SF (For Reconstitution) Suspension
FIGURE 3. Plot of Oseltamivir Concentration in SyrSpend SF Suspension
(The dashed lines in Figures 1, 2, and 3, represent upper and lower limits of oseltamivir specifi cations.)
samples tested, the Cherry Syrup and the SyrSpend SF, appeared to have a parabolic assay shape with slight increases in concentration between T=0 and T=14 and then decreasing to T=30. Extrapolation of the data to future time points is challenging due to the lack of time points between 14 days and 30 days; however, the data suggest that the suspensions would be stable past the 30 days; however, this study was limited to 30 days.
REFERENCES1 . U.S. Department of Health and Human Services. Centers for Disease Control and
Prevention. Notifi able Diseases/Deaths in Selected Cities Weekly Information. Morbid-ity and Mortality Weekly Report. [CDC Website.] November 19, 2009. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm5845md.htm. Accessed November 23, 2009.
2. U.S. Department of Health and Human Services. Centers for Disease Control and Prevention. 2009 N1N1 Flu: Situation Update. [CDC Website.] Updated December 18, 2009. Available at: www.cdc.gov/h1n1fl u. Accessed November 23, 2009.
3. Buck ML, ed. Children’s Medical Center at the University of Virginia. Pediatric Pharmacotherapy Newsletter. 1996; 2(9). Available at: www.healthsystem.virginia.edu/alive/pediatrics/PharmNews/199609.pdf. Accessed November 25, 2009.
4. Winiraski AP, Infeld MH, Tscheme R et al. Preparation and stability of extem-poraneous oral liquid formulations of oseltamivir using commercially available capsules. J Am Pharm Assoc 2007; 47(6): 747–755.
Address correspondence to Mark A. Voudrie II, BS, Analytical Chemist, Dynalabs, 3830 Wash-ington Boulevard, St. Louis, MO 63108. E-mail: [email protected]
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Stability of Metronidazole Benzoate in SyrSpend SF One-Step Suspension System
Nicole T. Vu, PhDVasileios Aloumanis, MSMichel J. Ben, MS Thomas C. Kupiec, PhDAnalytical Research Laboratories, Inc.Oklahoma City, Oklahoma
Evelyn K. Patterson, BSUniversity of OklahomaCollege of PharmacyOklahoma City, Oklahoma
Joshua Radke, BA, PhDMartin A. Erickson III, RPh Gary Schneider, RPh, FACAGallipot, Inc.St. Paul, Minnesota
ABSTRACTThe objective of this study was to determine the stability of metronidazole benzoate suspension in SyrSpend SF One-Step Suspension System. The studied samples were packaged in 60-mL amber plastic prescription bottles, which were stored protected from light under controlled environmental conditions for a period of 360 days. Stability of metronidazole benzoate suspension in SyrSpend SF was assessed based on retention of initial color or appearance, pH of suspension, and recovery of metronidazole benzoate from the packaged product. Duplicate samples were evaluated at each prede ned time interval. An assay method by high performance liquid chromatography was validated for its speci city and stability-indicating characteristics through a forced-degradation study, and was used in metronidazole benzoate assay. Metronidazole benzoate in SyrSpend SF retained its normal appearance of an opaque suspension, with acceptable pH values ranging from 4.43 to 4.53 (range 4.45 ± 0.5). Recovery of metronidazole benzoate at subsequent time points was within 90% to 110% of initial concentration for samples stored at refrigerated temperature (2°C to 8°C), and ambient condition (25°C/60% relative humidity), with no detectable changes in chromatographic pro le for most tested samples. The rates of change in potency for metronidazole benzoate were determined under the assumptions of rst-order kinetics, and the time to reach 90% to 110% initial concentration was determined to be 366 days for samples in ambient storage, or 716 days for samples stored at refrigerated temperature. Metronidazole benzoate in SyrSpend SF, which was packaged in amber plastic prescription bottles, is stable for at least 1 year when stored protected from light at ambient condition (25°C/60% relative humidity). The shelf life for this product may be extended to 2 years when stored at refrigerated temperature.
INTRODUCTION Metronidazole belongs to the nitroimi-dazole group of antibiotics whose antimi-crobial properties are thought to derive from the formation of toxic-free radicals by intracellular reduction. Metronidazole activity is partially inhibited by the presence of oxygen, thus it is commonly used in anaerobic infections, although it is also ef-fective in the treatment of trichomoniasis.1 Additionally, metronidazole is the agent of choice in patients with antibiotic-associated colitis due to Clostridium dif cile.2
Both parenteral and enteral routes have been used to administer metronidazole. Nevertheless, the need for additional dos-age forms has been warranted for patients who require a different dosage form than what is commercially available (e.g., pa-tients who are incapable of swallowing tab-lets or capsules, or pediatric patients who are incapable of swallowing the available dosage forms).3 Recently, oral dosage forms of metronidazole were extemporaneously prepared using a 1:1 mixture of Ora-Sweet and Ora-Plus, a 1:1 mixture of Ora-Sweet SF and Ora-Plus, or cherry syrup. These mixtures, through stability testing, have shown to retain up to 93% of the initial drug activity at 60 days.4 Similarly, metron-
idazole benzoate is often used in oral liquid dosage forms due to its non-bitter taste. The solubility for metronidazole benzoate, an ester derivative of metronidazole, was estimated to be 0.1 mg/mL in water.5 Compounding liquid dosage forms with metronidazole benzo-ate, therefore, requires the use of suspending agents. SyrSpend SF (Gallipot, St. Paul, Minnesota) is a starch-based and sugar-free suspension system with characteristics of low osmolality (<50 mOsmol).6 Its use is associated with low gas production and fewer laxative effects due to the absence of methylcellulose and sorbitol. These outstanding advantages of SyrSpend SF lend itself well as a formulation vehicle, and its use as a suspending base is currently a consideration in the formulation of metronidazole benzoate for an oral liquid dosage form. The objective of this study was to determine the stability of metronidazole benzoate sus-pension in SyrSpend SF packaged in 60-mL amber plastic prescription bottles. Assessment of stability was based on maintenance of initial physical characteristics, and recovery of metronidazole benzoate from the packaged product stored under controlled environmental conditions for 90 to 360 days.
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MATERIALS AND METHODSChemicals and Reagents Chemicals and reagents used in this study were United States Pharmacopeia–National Formulary, British Pharmacopeia (BP), or American Chemical Society grade, and were used as supplied. The reference material was Metronidazole Benzoate, BP 100.0% pure, which was obtained from Spectrum (Lot SX0972; Gardena, California). Acetonitrile was obtained in chromatographic grade from Pharmco (Lot PL00063SACN, Fort Worth, Texas). Puri ed water Type I ASTM analytical grade (purity 18 MΩ-cm) was gener-ated in-house (Barnstead NANOPure Water Puri cation System; Dubupue, Iowa).
Equipment and Chromatographic Conditions The high-performance liquid chromatography (HPLC) instru-ment was the Hewlett-Packard (HP) Series 1100 (Agilent Tech-nologies, Santa Clara, California), which was operated using HP ChemStation software (Windows version A.10.02). The instru-
ment is equipped with a diode array detector, an auto-sampler, a programmable injector, and a solvent delivery system that consists of a quaternary gradient pump, and a solvent module with online vacuum degasser. The mobile phase had a ow rate of 1.0 mL/min, which was a 50:50:0.05 mixture of acetonitrile, water, and glacial acetic acid, respectively. Chromatographic separation was per-formed using a Gemini C18 5-mcm analytical column with dimen-sions 4.6-mm × 150-mm (Phenomenex, Torrance, California). The mobile phase was used as a solvent in the preparation of standard and assay preparations, and the reference standard used for metron-idazole benzoate assay was a solution of 0.4 mg/mL Metronidazole Benzoate, BP (Lot SX9072; Spectrum) in mobile phase. Sample and standard preparations were evaluated at 314 nm by 10-mcL injec-tion volume. The pH of samples was measured using Corning pH/Ion analyzer 350 and Acumet electrode (13620183, Fisher Scien-ti c, Pittsburgh, Pennsylvania).
TABLE 1. Stability Data for Metronidazole Benzoate in SyrSpend SF at Refrigerated Condition (2°C to 8°C) for 360 days. Elapsed Appearance pH RecoveryTime (%)(day) T0 Opaque suspension 4.43 100.0a
Normal appearance 15 Opaque suspension 4.44 100.7 Normal appearance 30 Opaque suspension 4.43 101.3 Normal appearance 45 Opaque suspension Normal appearance 4.48 101.654 Opaque suspension Normal appearance 4.46 100.075 Opaque suspension Normal appearance 4.47 104.490 Opaque suspension Normal appearance 4.50 102.6120 Opaque suspension Normal appearance 4.37 99.3180 Opaque suspension Normal appearance 4.43 104.8270 Opaque suspension Normal appearance 4.49 105.3360 Opaque suspension Normal appearance 4.44 104.3Limits Opaque suspension Normal appearance 4.45 ± 0.5 90-110
aInitial concentration was 69.77 mg/mL.Initial time (T0) results for metronidazole benzoate were established as target values. The assay results for subsequent time points were expressed as percentage of initial value. Average data were reported for duplicate samples.
TABLE 2. Stability Data for Metronidazole Benzoate in SyrSpend SF at Ambient Condition (25°C/60% RH) for 360 days.Elapsed Appearance pH RecoveryTime (%)(day) T0 Opaque suspension 4.43 100.0a
Normal appearance 15 Opaque suspension 4.44 102.4 Normal appearance 30 Opaque suspension 4.42 103.1 Normal appearance 45 Opaque suspension 4.48 102.8 Normal appearance 54 Opaque suspension 4.45 101.9 Normal appearance 75 Opaque suspension 4.46 105.8 Normal appearance 90 Opaque suspension 4.50 102.0 Normal appearance 120 Opaque suspension 4.35 103.9 Normal appearance 180 Opaque suspension 4.43 103.8 Normal appearance 270 Opaque suspension 4.50 107.0 Normal appearance 360 Opaque suspension 4.44 111.7 Normal appearance Limits Opaque suspension Normal appearance 4.45 ± 0.5 90-110
aInitial concentration was 69.77 mg/mL.Initial time (T0) results for metronidazole benzoate were established as target values. The assay results for subsequent time points were expressed as percentage of initial value. Average data were reported for duplicate samples.
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Validation for Stability-Indicating Characteristics of the HPLC Method Stress studies were conducted to ensure that the HPLC method employed had the ability to monitor and detect low level of degra-dants and impurities. Thus, test samples of metronidazole benzoate containing approximately 80-mg/mL suspension in SyrSpend SF were diluted to 0.4 mg/mL in mobile phase for exposure to heat (80°C) and ultraviolet (254nm to 400 nm), or diluted with solu-tions of acid (1 N HCl), base (1 N NaOH), and hydrogen peroxide (3% H2O2). Assay and chromatographic pro les for metronidazole benzoate under the effects of stressors were obtained after 72 hours of exposure, or for a time period where metronidazole benzoate content was reduced to about 90% compared to the control sample. Additional peaks representing decomposition products of metron-idazole benzoate or formulation components in these samples were then identi ed by relative retention time (rRT), and were separated from the main metronidazole benzoate peak.
Preparation of Metronidazole Suspension Samples7 Metronidazole benzoate in SyrSpend SF 70 mg/mL sample was compounded by placing the Metronidazole Benzoate, BP (Lot MB/60110; Medisca, Plattsburg, New York) in a suitable mortar. The powder was triturated with 1.25 g of Propylene Glycol, NF (Lot STCOK; Professional Compounding Centers of America, Houston, Texas) to a smooth paste, then increasing the amount of SyrSpend SF that was added and mixed until the suspension was pourable. The liquid suspension was transferred to a suitable gradu-ated container and the mortar was rinsed with three small aliquots
of SyrSpend SF, which were added to the suspension. Additional SyrSpend SF was used to bring the suspension to the nal volume of 750 mL. The well-mixed suspension was then packaged in 60-mL amber plastic prescription bottle for stability study.
Stability Study Samples submitted for stability study were supplied as metron-idazole benzoate 80-mg/mL suspension in SyrSpend SF One-Step Suspension System (Lot DBAF:73; Gallipot), which were packaged in 60-mL amber plastic prescription bottles. A total of 33 samples each containing 20-mL suspension were allocated for storage pro-tected from light, at controlled temperatures and relative humidities (RH). Stability was investigated for samples, which were stored at 2°C to 8°C, with the use of a temperature controlled refrigerator (Model 13-986-272GR, Lot 1556060242164; Fisher Scienti c, Pittsburgh, Pennsylvania), and two environmental chambers (Model 9010L, Lot 0600102; and Lot 05021205; VWR International, Inc., West Chester, Pennsylvania), which were set at 25°C/60% RH and 40°C/75% RH, respectively. In addition, an incubator (Model 1545; Lot 1100293; VWR International, Inc.) were employed in acceler-ated testing and set at 55°C. Sampling occurred at 15-day intervals for the rst 75 days, and subsequently, at 90-, 120-, 180-, 270-, and 360-day periods. The evaluation parameters were appearance, pH, and assay. Appearance of each sample was evaluated by visual inspection of the suspension and the integrity of its container. The acceptance criterion for sample appearance was the retention of the original opaque suspension with intact container and closure. Sample pH was determined for duplicate preparations at each time point, and the limits for pH stability were 4.5 ± 0.5. Chemical sta-
TABLE 3. Stability Data for Metronidazole Benzoate in SyrSpend SF at Accelerated Condition (40°C/75% RH) for 90 days. Elapsed Appearance pH RecoveryTime (%)(day) T0 Opaque suspension 4.43 100.0a
Normal appearance 15 Opaque suspension 4.44 101.3 Normal appearance 30 Opaque suspension 4.43 102.1 Normal appearance 45 Opaque suspension 4.49 99.3 Normal appearance 54 Opaque suspension 4.46 103.1 Normal appearance 75 Opaque suspension 4.47 106.6 Normal appearance 90 Opaque suspension 4.50 104.8 Normal appearance Limits Opaque suspension Normal appearance 4.45 ± 0.5 90-110
aInitial concentration was 69.77 mg/mL.Initial time (T0) results for metronidazole benzoate were established as target values. The assay results for subsequent time points were expressed as percentage of initial value. Average data were reported for duplicate samples.
TABLE 4. Stability Data for Metronidazole Benzoate in SyrSpend SF at Accelerated Condition (55°C) for 90 days. Elapsed Appearance pH RecoveryTime (%)(day)T0 Opaque suspension 4.43 100.0a
Normal appearance 15 Opaque suspension 4.44 104.8 Normal appearance 30 Opaque suspension 4.44 107.1 Normal appearance 45 Opaque suspension 4.50 111.9 Normal appearance 54 Opaque suspension 4.47 112.3 Normal appearance 75 Opaque suspension 4.47 130.2 Normal appearance 90 Opaque suspension 4.53 126.6 Normal appearance Limits Opaque suspension Normal appearance 4.45 ± 0.5 90-110
aInitial concentration was 69.77 mg/mL.Initial time (T0) results for metronidazole benzoate were established as target values. The assay results for subsequent time points were expressed as percentage of initial value. Average data were reported for duplicate samples.
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TABLE 5. Estimated Stability Parameters for Metronidazole Benzoate in SyrSpend SF. Parameter Refrigeration Ambient Accelerated Accelerated (2°C-8°C) (25°C/60% RH) (40°C/75% RH) (55°C)k 0.00006 0.00010 0.00026 0.00126(day-1)a t90-110%
b 716 366 167 37Shelf-life 23.9 12.2 5.6 1.2(month) ak: First-order rate constant in unit of reciprocal of time (day-1)bt90-110%: Time (days) to reach 90% - 110% concentration for metronidazole benzoate. Stability data for the submitted Lot DBAF:73 were obtained over a period of 90 to 360 days under controlled stor-age conditions: Refrigeration (2°C to 8°C), ambient (25°C/60% RH), and accelerated temperatures (40°C/75% RH or 55°C).
LOD = limit of detection; LOQ = limit of quantitation; N = number of equivalent theoretical plates; |RD| = abso-lute relative deviation; |RE| = absolute relative error; RSD = relative standard deviation; R2 = regression coef cient of determination
bility was de ned in terms of metronidazole benzoate average recovery from duplicate sample preparations using the validated HPLC method, and the assay limits were 90% to 110% of initial drug concentration. Sample preparation for metronidazole ben-zoate assay was made by diluting 0.5 mL of the suspension in mobile phase.
RESULTS Stability data of metronidazole benzoate suspension in SyrSpend SF (Lot DBAF:73) are shown in Tables 1 through 5. The as-say result for metronidazole benzoate at
initial time (T0) was established as target value, which was determined to be 69.77 mg/mL, and results for subsequent time points were expressed relative to concentra-tion at T0. Metronidazole benzoate recov-ery at subsequent time points was found to be within ± 10% of initial concentration for most studied samples. However, the drug concentration reached 110% limit at ambi-ent storage after 360 days, and after 37 days at 55°C (Figures 1 and 2). Visual inspection of samples and pH measurements were within normal limits for all tested samples. Rates of change in potency for metro-
nidazole benzoate were determined under the assumptions of rst-order kinetics, and probable shelf life for the submitted Lot DBAF:73 was estimated to be approxi-mately one year at 25°C/60% RH (Figures 3 and 4).
DISCUSSION The HPLC method was demonstrated to be stability indicating through forced degradation studies and was suitable for testing stability samples of metronidazole benzoate suspension in SyrSpend SF. An ex-ample chromatographic pro le of a stressed sample in the combined presence of oxida-tive agent and heat (3% hydrogen peroxide and 80°C) is presented in Figure 5, which shows metronidazole benzoate was separated from other components in the sample with acceptable resolution (R ≥1.5). Additionally, parameters that demonstrated system suit-ability for the validated HPLC method are shown in Table 6, with all chromatographic parameters meeting acceptance criteria for metronidazole benzoate assay.7
Refrigerated Samples (at 2°C to 8°C) Table 1 shows stability data for samples from Lot DBAF:73 in refrigerated storage over the testing period of 360 days. The average assay results for metronidazole benzoate at latter time points varied from 99.3% to 105.3% of initial value (Figure 1), and the pH values for these samples were 4.45 ± 0.05, which was within ± 10% when compared to the initial pH value 4.43. All samples maintained normal appearance of an opaque suspension, and the chro-matographic pro le for this lot over the testing period was consistent with sample pro le at T0 with no detectable signs of decomposition. Plots of log metronidazole benzoate concentrations were regressed on time, which yielded rate of change k2-8°C = -0.00006·day-1 for metronidazole benzo-ate (Figure 3). The time to reach 90% concentration was estimated at about 2 years (CI95% = 1.3-7.6 years). Thus, based on 360-day stability data, the shelf life for this product was estimated to be 2 years at refrigerated temperature (Table 5).
Samples Stored at Ambient Condition (25°C/60% RH) The average assay recovery of met-ronidazole benzoate from samples stored at 25°C/60% RH is presented in
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TABLE 6. Summary of System Suitability Parameters for the Stability-Indicating High-Performance Liquid Chromatographic Method Used in the Stability Study of Metronidazole Benzoate in SyrSpend SF.Evaluation Parameters System Suitability (Determined from metronidazole benzoate peak) Linear range
Precision Accuracy Sensitivity
Ruggedness(Inter-assay variation) Robustness (10% change in HPLC conditions) Speci city
ResultsPeak tailing = 1.28RSD = 0.07%N = 95950.1 – 0.5 mg/mLR2 = 0.9998RSD: 0.09 – 0.13%|RE| = 0.8 – 1.8%LOQ = 0.12 mcg/mL (0.03% of assay concentration)LOD = 0.05 mcg/mL (0.01% of assay concentration)|RD| = 0.1%
|RD| <5.0%
Metronidazole benzoate and impurities (or decomposition products) identi ed by relative retention time (rRT)Metronidazole benzoate: 1.0Impurities: 0.3, 0.6, 0.7, and 0.8
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E laps ed T ime (day)
0 100 200 300 400
60
65
70
75
80
110% initial concentration
90% initial concentration
2-8οC25οC/60% RH
E laps ed T ime (day)
0 20 40 60 80 100
60
65
70
75
80
110% initial concentration
90% initial concentration
40oC/75% RH
55oC
Table 2. Thus, except for the nal time point, all assay values were within ± 10% of the initial concentration (Figure 1). The average pH values for these samples were 4.46 ± 0.05, and all samples maintained normal appearance of an opaque suspen-sion. The chromatographic pro le for this lot over the testing period was consistent with sample pro le at T0 (Figure 6) with no detectable signs of decomposition. Plots of log metronidazole benzoate concentra-tions were regressed on time, which yielded rate of change k25°C/60%RH = -0.00010·day-1 for metronidazole benzoate (Figure 4). The time to reach 90% concentration was estimated at about 1.02 years (CI95% = 0.8 to 1.4 years). Thus, based on 360-day stabil-ity data, the shelf life for this product was estimated to be at least 1 year at ambient condition (Table 5).
Samples Stored at 40°C/75% RH The average assay recovery of metron-idazole benzoate from samples stored at 40°C/75% RH is presented in Table 3. Thus, all assayed values were within ± 10% of the initial concentration (Figure 2). The average pH values for these samples were 4.46 ± 0.02, and all samples maintained normal appearance of an opaque suspen-sion. The chromatographic pro les for this lot were consistent with the sample pro le at T0, although there was one decomposi-tion product detected at less than 0.01% of total sample response. The rate of change for metronidazole benzoate k40°C/75%RH = -0.00026·day-1, and the time to reach 90% concentration was estimated at about 0.5 year (CI95% ≥0.3 year). Thus, based on 90-day stability data, the shelf life for this product was projected to be not more than 6 months at 40°C/75% RH storage condi-tion (Table 5).
Samples Stored at 55°C The average assay recovery of metron-idazole benzoate from samples stored at 55°C is presented in Table 4. Metronidazole benzoate content exceeded 110% concen-tration limit after 45 days (Figure 2), and chromatographic pro les of these samples exhibited one decomposition product, which contributed not more than 0.05% of total sample response. The average pH values for these samples were 4.47 ± 0.04, and all samples maintained normal appear-ance of an opaque suspension. The rate of
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Note: Dotted lines represent lower and upper limits for metronidazole benzoate concentration.
FIGURE 2. Plots of metronidazole benzoate concentration (mg/mL) relative to the initial concentration when samples were stored at 40°C/75% RH, and 55°C for 90 days.
FIGURE 1. Plots of metronidazole benzoate concentration (mg/mL) relative to the initial concentration when stored at 2°C to 8°C (refrigeration), and 25°C/60% relative humidity for 360 days.
Note: Dotted lines represent lower and upper limits for metronidazole benzoate concentration.
Met
ron
idaz
ole
Ben
zoat
e (m
g/m
L)M
etro
nid
azo
le B
enzo
ate
(mg
/mL)
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E laps ed T ime (day)
0 200 400 600 800
1.75
1.80
1.85
1.90
Log 110%
Log 90%
2-8οC Data
E laps ed T ime (day)
0 100 200 300 400 500
1.75
1.80
1.85
1.90
1.95
Log 110%
Log 90%
25οC/60% RH data
change for metronidazole benzoate k55°C = -0.00126·day-1 and the time to reach 90% concentration was estimated at about 37 days (CI95% ≥26 - 47 days). Thus, based on 90-day stability data, the shelf life for this product was projected to be about one month at 55°C storage condition (Table 5).
CONCLUSION As previously discussed, the 60-day stability of extemporaneous formulations of metronidazole has been well established with previous results lending support to the present study.4 This report has demonstrat-ed that except for the accelerated conditions (55°C), all samples were found to be within acceptable ranges for assay recovery. In addition, sample appearance and pH were determined to be within normal limits for all tested samples. Thus, real-time chemi-cal and physical data for metronidazole benzoate suspension in SyrSpend SF (Lot DBAF:73) have indicated that the described formulation is stable for at least 1 year in ambient storage. Better preservation of the sample was observed at refrigerated condi-tion, and, therefore, is the recommended storage temperature for this preparation. The most signi cant effect in storage was determined to be a result of solvent loss due to evaporation and/or permeation, which was accelerated at higher temperatures and in drier environments such as the storage conditions at 40°C to 55°C. Alternatively, impervious glass containers may be used for packaging of liquid formulations to reduce solvent loss and to further extend the shelf life of these products.
REFERENCES1. Müller M. Reductive activation of
nitroimidazoles in anaerobic microor-ganisms. Biochem Pharmacol 1986; 35(1): 37–41.
2. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 2002; 346(5): 334–339.
3. Purkiss R, Kayes AJ. A survey of ex-temporaneous oral liquid formulations. Pharm J 1981; 226: 588–559.
4. Allen LV Jr, Erickson MA 3rd. Stability of ketoconazole, metolazone, metron-idazole, procainamide hydrochloride, and spironolactone in extemporaneously compounded oral liquids. Am J Health Syst Pharm 1996; 53(17): 2073–2078.
5. Mathew M, Das Gupta V, Bethea C. Sta-
FEATURE IJPC
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FIGURE 3. Plot depicts rate of change (k2-8°C ) for metronidazole benzoate concentration in refrigerated storage (2°C-8°C). Time to reach concentration limits was estimated at approximately 2 years (or 716 days).
FIGURE 4. Plot depicts rate of change (k25°C/60%RH) for metronidazole benzoate concentration in ambient storage (25°C/60% RH). Time to reach concentration limits was estimated at ~ 1 year (or 366 days).
Note: Red dotted lines represent 95% con dence interval (CI95%) of prediction; dash lines represent log metronidazole benzoate concentration at 90% to 110% of initial concentration.
Note: Red dotted lines represent 95% con dence interval (CI95%) of prediction; dash lines represent log metronidazole benzoate concentration at 90% to 110% of initial concentration.
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ESTUDO 01
564International Journal of Pharmaceutical CompoundingVol. 12 No. 6 | November/December 2008
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FIGURE 5. Chromatograms of metronidazole benzoate in SyrSpend SF following exposure to 3% hydrogen peroxide and heat at 80°C.
FIGURE 6. Typical chromatographic pro les for metronidazole benzoate in SyrSpend SF sample stored at ambient condition (25°C/60% RH).
mAU
0
0.1
0.2
0.3
0.4
DAD1 A, Sig=314,4 Ref=360,100 (X:\DATA\HPLC9\DATA\092906\METRO046.D)
Note: Metronidazole benzoate contributed 99.95% of total detected area (%TDA); degradant peaks identi ed at retention time 1.84 (0.01%), 2.70 (0.01%), 2.83 (0.02%), and 3.52 (0.01%). Blank artifact peaks were not included in TDA calculation. Sample pro les are shown for stressed sample (a) and control sample (b).
A.) B.)
mAU
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DAD1 A, Sig=314,4 Ref=360,100 (X:\DATA\HPLC9\DATA\100506\METRON51.D)
Note: Sample pro les were obtained (a) initially (T-0), and (b) at the end of the 360 days (T-360). HPLC pro les were obtained on two different instruments.
A.) B.)
bility of metronidazole benzoate in suspensions. J Clin Pharm Ther 1994; 19(1): 31–34.
6. SyrSpend SF - PT – 106025 [product information]. St. Paul, MN: Gallipot, Inc. Available at: www.gallipot.com. Accessed March 27, 2008.
7. Allen LV Jr. Metronidazole benzoate 400 mg/5 mL oral suspen-sion. IJPC 2001; 5(1): 46.
8. United States Pharmacopeial Convention, Inc. United States Pharmacopeia 30–National Formulary 25. Rockville, MD: US Pharmacopeial Convention, Inc.; 2008: 683–687.
Address correspondence to Nicole T. Vu, PhD, Scienti c Director, Analyti-cal Research Laboratories, 840 Research Parkway, Suite 546, Oklahoma City, OK 73104. E-mail: [email protected]
1.84
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ESTUDO 01
Compatibilidade com Sondas Nasogástricas
Administration of example APIs through 3 commonly used nasogastric tubes in pediatric care
Thomas Hofman, Trainee, Fagron Group.Sander van Rijn, PharmD, Global Management Trainee, Fagron Group.Eli Dijkers, PharmD, PhD, Hospital Pharmacist, Global Compounding Knowledge Manager, Fagron Group
IntroductionGastric-enteral feeding plays an important role in the management of patients with poor voluntary oral intake, chronic neurological, mechanical dysphagia, intestinal failure, and in critically ill patients.1Administration of medication through nasogastric tubes can be challenging, especially in pediatric care, due to the small size of the nasogastric tubes used. Blockage of the tubes frequently occurs, leading to high disease burden and increase complication risk, such as aspiration pneumonia.1-3The goal of the current study is to investigate the compatibility of compounded medication with SyrSpend® SF in nasogastric tubes compared to Nexium® granules and omeprazole Sandoz®. As a worst case scenario, high doses of paracetamol (acetaminophen) and (es)omeprazole were exami-ned in the smallest available nasogastric tubes. During the study, the three most commonly used materials in nasogastric tubes (silicone, polyvinylchloride (PVC) and polyurethane (PUR)) were tested.
Materials and methodsVygon Nutrisafe nasogastric tubes, all with an external diameter of 5 French (1.65 mm) were used for the study: Silicone (REF 2331.052, LOT 231014EG, 50 cm), PUR (REF 1363.052, LOT 150115FE, 75 cm) and PVC (REF 363.052, LOT 060415FE, 75 cm). Vygon C-GON 20 ml enteral syringes were used throughout the experiment.SyrSpend® SF PH4 (liquid) (LOT 14E07/J), SyrSpend® SF PH4 (dry) (LOT 14F16-B04-298936, SyrS-pend® SF Alka (dry) (LOT 13F12-U18-612443), paracetamol (acetaminophen, 45 mesh, LOT 13J31--B01-293080) and omeprazole (LOT 15B26-B01-304376) were retrieved from Fagron BV. Omepra-zole Sandoz® 40 mg granules were obtained from Novartis (LOT LC21231). Nexium® (esomeprazo-le) 10 mg granules were purchased from Astra Zeneca. Aqua purificata was obtained from Certa and was used to reconstitute the SyrSpend® SF PH4 and Alka (dry) and to dilute the Nexium® granules.
In order to obtain a 5 mg/ml omeprazole suspension, the omeprazole Sandoz® granules were dispersed in unbuered acidic aqueous solution (pH 4) to prevent degradation of the omeprazole granules. The Nexium® granules were dissolved in water to obtain 0.67 mg/ml, in accordance with the information supplied by the manufacturer5, and additionally a 5 mg/ml was prepared to test a concentration comparable to the SyrSpend® SF omeprazole suspension.Administration of the APIs through the nasogastric tube was performed in correspondence with current pediatric care protocol standards. The nasogastric tubes were placed in a downward angle of 30-45°, to simulate the semi-Fowler position of a patient receiving medication. The estimated volume of the nasogastric tube is 1.1 ml and 1.6 ml for the 50 cm and 75 cm nasogastric tubes respectively.
Fagron.com
All suspensions were made according to the instructions and concentrations listed in table 1. The tests were performed in triplicate for silicone, PUR and PVC nasogastric tubes. The recovery was based on weight, by comparing the actual weight pre - and afte r administration to the nasogastric tube. Table 1. Test congurations (n=3, for silicone, PUR and PVC each)
API
Concentration
Vehicle
- -
SyrSpend® SF PH4 (liquid)
- -
SyrSpend® SF PH4 (dry)
- -
SyrSpend® SF Alka (dry)
Paracetamol (acetaminophen) 50 mg/ml
SyrSpend® SF PH4 (liquid)
Paracetamol (acetaminophen) 50 mg/ml
SyrSpend® SF PH4 (dry)
Omeprazole powder 5 mg/ml
SyrSpend® SF Alka (dry)
Omeprazole Sandoz® granules 5 mg/ml Acid solution (pH 4) Nexium® granules 0.67 mg/ml Water 5 mg/ml
Administration of the medication is performed according to the following protocol:
1. Flush the tube with 5 ml water. 2. Attach a second syringe with of the product to administer, while ensuring there is an airtight
connection between the syringe and the nasogastric tube. 3. Administer 5 ml of the product to the tube. Use pulsatile ushing if needed. 4. Check the ow and uid ity of the suspension through the tube. 5. Flush the tube with 5 ml water. 6. Check the tube visually for possible residue, blockages and general ow. 7. Flush the nasogastric tube with water, in case of a blockage, up to a maximum of 30 ml.
Results SyrSpend® SF PH4 (liquid), SyrSpend® SF PH4 (dry), SyrSpend® SF Alka (dry) and high -dosed paracetamol (acetaminophen) in SyrSpend® SF PH4 (liquid) and omeprazole in SyrSpend® SF Alka (dry) all owed freely without any obstruction. The SyrSpend® SF PH4 (dr y) and SyrSpend® SF Alka (dry) appeared to be more viscous than SyrSpend® SF PH4 (liquid) and were therefore a little more dicult to administer.
Fagron.com
Nexium® granules 0. 67 mg/ml showed a good ow and did not obstruct the tubes. After administration of approximately 20% of the dose, the Nexium® granules 5 mg/ml caused irreversible obstruction of the nasogastric tube. The in acid solution dispersed omeprazole Sandoz® granu les were too large for the nasogastric tube to enter and could therefore not be administered. The performed recovery for SyrSpend® SF showed an overall recovery over 95% for all 3 nasogastric tubes for all administered SyrSpend® SF vehicles combined: SyrS pend® SF PH4 (liquid), SyrSpend® SF PH4 (dry), SyrSpend® SF Alka (dry), SyrSpend® SF PH4 (liquid) with paracetamol (acetaminophen), SyrSpend® SF PH4 (dry) with paracetamol (acetaminophen) and SyrSpend® SF Alka (dry) with omeprazole. The recovery of the Nex ium® granules was comparable with SyrSpend® SF when administered in a concentration of 0.67 mg/ml, but only around 20% when administered in a concentration of 5 mg/ml. The omeprazole Sandoz® granules could not be administered , resulting in a recovery of 0% . All results are summarized in table 2. Table 2: Overall recovery with all SyrSpend ® SF vehicles (n=1, for silicone, PUR and PVC each) Silicone PUR PVC All SyrSpend® SF vehicles 96.0% 99.9% 99.6% Nexium® granules (0.67 mg/ml) 98.0% 98.8% 97.9% Nexium® granules (5 mg/ml) Not obtainable* Not obtainable* Not obtainable* Omeprazole Sandoz® 0% 0% 0%
* Estimated at 20%. Table 3: Nasogastric tube obstructions (n=3, for silicone, PUR and PVC each)
Silicone nasogastric tube
API/vehicle Visual obstruction Freely Flowing
SyrSpend® SF PH4 (liquid) No Yes
SyrSpend® SF PH4 (dry) No Yes
SyrSpend® SF Alka (dry) No Yes
SyrSpend® SF PH4 (liquid) with paracetamol
(acetaminophen)
No Yes
SyrSpend® SF PH4 (dry) with paracetamol
(acetaminophen)
No Yes
SyrSpend® SF Alka (dry) with omeprazole No Yes Omeprazole Sandoz® granules Yes* No Nexium® granules (0.67 mg/ml) No Yes Nexium® granules (5 mg/ml) Yes** No
* Could not be administered due to the size of the granules. ** Irreversible blocking occurred after administration of approximately 20% of the dose.
Fagron.com
PUR nasogastric tube
API/vehicle Visual obstruction Freely Flowing
SyrSpend® SF PH4 (liquid) No Yes
SyrSpend® SF PH4 (dry) No Yes
SyrSpend® SF Alka (dry) No Yes
SyrSpend® SF PH4 (liquid) with paracetamol
(acetaminophen)
No Yes
SyrSpend® SF PH4 (dry) with paracetamol
(acetaminophen)
No Yes
SyrSpend® SF Alka (dry) with omeprazole No Yes Omeprazole Sandoz® granules Yes* No Nexium® granules (0.67 mg/ml) No Yes Nexium® granules (5 mg/ml) Yes** No
PVC nasogastric tube
API/vehicle Visual obstruction Freely Flowing
SyrSpend® SF PH4 (liquid) No Yes
SyrSpend® SF PH4 (dry) No Yes
SyrSpend® SF Alka (dry) No Yes
SyrSpend® SF PH4 (liquid) with paracetamol
(acetaminophen)
No Yes
SyrSpend® SF PH4 (dry) with paracetamol
(acetaminophen)
No Yes
SyrSpend® SF Alka (dry) with omeprazole No Yes Omeprazole Sandoz® granules Yes* No Nexium® granules (0.67 mg/ml) No Yes Nexium® granules (5 mg/ml) Yes** No
* Could not be administered due to the size of the granules. ** Irreversible blocking occurred after administration of approximately 20% of the dose.
Fagron.com
Discussion and conclusion In conclusion, SyrSpend® SF PH4 (liquid), SyrSpend® SF PH4 (dry), SyrSpend® SF Alka (dry) and high -dosed paracetamol (acetaminophen) in SyrSpend® SF PH4 (liquid) and 5 mg/ml omeprazole in SyrSpend® SF Alka (dry)4 could be successfully administered through a nasogastric tube. There was no visual residue and the recovery was over 95%. Omeprazole Sandoz® - on the contrary - could not be administered without blocking the nasogastric tube, due to the large granule size. Nexium® granules could only be administered with 0.67 mg/ml dose omeprazole. Nexium® 5 mg/ml granules blocked the nasogas tric tube. in accordance with our study, two published articles indicate that the transit of an ecient concentration of proton pump inhibitors can’t be guaranteed due to the low recovery rates of the omeprazole, and esomeprazole. 6,7 As shown in our study, SyrSpend® SF PH4 and Alka are excellent options to administer omeprazole through small nasogastric tube with high recovery rates. SyrSpend® SF oers a good alternative to commercial available medication, especially in pediatric care. References 1. Blumenstein I, Shastri YM, Stein J. Gastroenteric tube feeding: techniques, problems and solutions. World J
Gastroenterol. 2014. 20:8505 -24. 2. Williams, NT. Am J Health -Syst Pharm. 2008. 65:2347 -57. 3. Wohlt PD, Zheng L, Gunderson S et al . Am J Health -Syst Pharm. 2009; 66:1458 -67. 4. Whaley PA, Voudrie MA, Sorenson B. Stability of Omeprazole in SyrSpend SF Alka (Reconstituted). Int J
Pharm Compd. 2012 Mar -Apr; 16(2):164 -6 . 5. Product information Nexium ® . AstraZeneca. 6. Messaouik D, Sautou -Miranda V, Bag el-Boithias S, Chopineau J. Comparative study and optimisation of the
administration mode of three proton pump inhibitors by nasogastric tube. Int J Pharm. 2005. 299:65 -72. 7. Ponrouch MP, Sautou -Miranda V, Boyer A, Bourdeaux D, Montagner A, Chopineau J. Pro ton pump inhibitor
administration via nasogastric tube in pediatric practice: comparative analysis with protocol optimization. Int J Pharm. 2010. 390:160 -4.
Fagron.com
Estudo da Reologia SyrSpend® SF
247International Journal of Pharmaceutical Compounding
Vol. 22 No. 3 | May | June | 2018www.IJPC.com
INTRODUCTION Pharmaceutical suspensions are oral semi-liquid dosage forms. Important target groups for oral liquid forms are (small) children and elderly who are unable to swallow a solid medicine or those patients who suffer from swallowing problems.1 In case of swallowing prob-lems, capsules may be opened and the content mixed with food or liquid. However, this may have a negative influence on the taste.1 Moreover, extemporaneously prepared capsules display a larger vari-ation in uniformity of content compared to pharmaceutical suspen-sions.2 An important additional advantage of an oral liquid dosage form over a solid one is the flexibility of dose adjustment as created by accurate volume measurement.1
A pharmaceutical suspension consists of a poorly water soluble active pharmaceutical ingredient (API), dispersed in an aqueous solu-tion—the vehicle. The physical stability of suspensions is principally poor. The suspended API will settle after preparation. Before dosing, the sediment should be resuspended by shaking to yield a suspension with evenly distributed drug particles. If resuspension is done improp-erly, the uniformity of the dose will be jeopardized, hence the pharma-cotherapeutic outcome and safety in the patient. According to Stoke’s law the physical stability of a suspension can be enhanced by reducing the particle size of the suspended API as well as by increasing the viscosity of the vehicle. The rheological properties of the vehicle, determined by the viscosity enhancer(s) used, are an important determinant of the product quality as well. Most favorable for pharmaceutical applications are systems with pseudo-plastic (non-Newtonian) properties. This means that viscos-ity is relatively high in rest but decreases under the influence of shear forces. Translated for practice, the suspension gets thinner with agitation and thicker upon standing. As a result, a relatively stable system is obtained in which the particles will settle less rapidly and in a more controlled way than in a vehicle with Newtonian behav-ior, in which viscosity is constant and independent of shear forces. Viscosity reduction upon shaking makes a pseudo-plastic suspension easily pourable, while this is not possible with a Newtonian liquid with a high viscosity in rest. Pseudo-plastic properties are the best guarantee for uniform doses of pharmaceutical suspensions, a pre-condition for safe use in patients.3,4
The purpose of the present study was to compare the rheological behavior of commercially available ready-to-use vehicles for oral pharmaceutical preparations and to investigate the sedimentation of a model API, paracetamol (acetaminophen), dispersed in these vehicles.
Comparison of Rheological and Sedimentation Behavior of Commercially Available Suspending Vehicles for Oral Pharmaceutical Preparations
J. Carolina Visser, PhD, PharmDInge E. J. ten Seldam, BSc PharmIsabella J. van der Linden, BSc PharmWouter L. J. Hinrichs, PhDReinier F. H. Veenendaal, MSc, PharmDEli C. F. Dijkers, PhD, PharmDHerman J. Woerdenbag, PhD, PharmD
The authors’ affiliations are: J. Carolina Visser, Inge E. J. ten Seldam, Isabella J. van der Linden, Wouter L. J. Hinrichs, and Herman J. Woerdenbag, University of Groningen, Department of Pharmaceutical Technology and Biopharmacy, Groningen, The Netherlands; Reinier F. H. Veenendaal and Eli C. F. Dijkers (hospital pharmacist), Fagron BV, Rotterdam, The Netherlands.
ABSTRACTA pharmaceutical suspension is a semi-liquid dosage form suitable for patients being unable to swallow solid medicines such as tablets and capsules. A vehicle used for the preparation of pharmaceutical oral suspensions preferably shows pseudo-plastic behavior. In a product that gets thinner with agitation and thicker upon standing, slow settlement of the suspended active pharmaceutical ingredient is combined with good pourability and rehomogenization. This gives the best guarantee of uniformity of dose for oral suspensions. In this study, the rheological behavior of commercially available ready-to-use vehicles for oral pharmaceutical preparations was compared, and the sedimentation of paracetamol dispersed in these vehicles was investigated. With SuspendIt and SyrSpend SF PH4 (Liquid), both pseudo-plastic vehicles, very stable paracetamol suspensions were obtained. Of these two vehicles, SyrSpend SF PH4 (Liquid) displayed somewhat higher viscosity, which is a favorable quality characteristic for suspensions.
PEER REVIEWED
248International Journal of Pharmaceutical CompoundingVol. 22 No. 3 | May | June | 2018
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Peer Reviewed
MATERIAL AND METHODSVEHICLES FOR SUSPENSION Commercially available vehicles for pharmaceutical suspensions were chosen instead of extemporaneously compounded suspen-sions because of their reproducibility and user friendliness. The fol-lowing vehicles were used:
• Base for Suspension (Lot 1957; Fagron, Capelle aan den Ijssel, The Netherlands)
• SyrSpend SF PH4 (Liquid) (Lot 1503260; Fagron)• Ora-Blend (Lot NDC 0574-0311-16; Perrigo, Minneapolis,
Minnesota)• Ora-Blend SF (Lot NDC 0574-312-16; Perrigo)• SuspendIt (Lot 7287294, Qty7; Professional Compounding
Centers of America, Houston, Texas)• Simple Syrup (negative control) (Lot 51552-0692-06; Fagron)• Water (negative control)
The vehicles were selected based on their global use. Simple syrup was traditionally used in The Netherlands and still is used in a number of countries. Base for suspensions is commonly used in The Netherlands. The Ora-Blend vehicles are internationally com-monly used. SuspendIt and SyrSpend SF PH4 (Liquid) are new and innovative vehicles for pharmaceutical suspensions. The viscosity enhancers used in the vehicles for suspensions are listed in Table 1.
VISCOSITY MEASUREMENTS Viscosities of all vehicles were measured (in triplicate) at ambi-ent temperature (20°C ± 2°C) using a Brookfield DV-E viscom-eter (Brookfield, Middleboro, Massachusetts). Depending on the viscosity, spindle 1 (Simple Syrup), 2 (Ora-Blend), or 3 (Base for Suspension, SuspendIt, SyrSpend SF PH4 (Liquid)) was used. Prior to viscosity measurement, each vehicle was shaken for 30 seconds. Then, 600 mL was poured into a 1000-mL beaker and allowed to stand for 1 hour. Rheograms were obtained by applying shear forces induced by rotation of the spindles at a speed of 0.3 rpm to 50 rpm. The method to assess dynamic viscosity is described in both the European Pharmacopoeia and the United States Pharmacopeia.10,11
PREPARATION OF SUSPENSIONS AND SEDIMENTATION Paracetamol was chosen as a model API and obtained from Fagron. Paracetamol is poorly water soluble and available in dif-ferent particle sizes. The sedimentation behavior of two different particle sizes was examined and compared. Suspensions of paracetamol in two particle sizes: 45 μm (Lot 13J31-B01-289547; Fagron) and 180 μm (Lot 13B13-B02-308210; Fagron), and in two concentrations, 25 mg/g and 50 mg/g, were pre-pared. Paracetamol (45 μm) contains 97% particles <45 μm12 and paracetamol (180 μm) contains 95% <180 μm and 90% <125 μm.13
Both concentrations amply exceed the water solubility of paracetamol (14 mg/g).14 The suspensions were prepared by hand, using a mortar and pestle. Paracetamol was dispersed by trituration in a small quantity of medium and gradually diluted further under gentle but thorough mixing to obtain the final concentration. The obtained suspensions were free from agglomerates as observed by visual inspection. Sedimentation was evaluated by pouring 45 mL of a freshly pre-pared suspension in a 100-mL beaker (height of the liquid column approximately 5 cm) and leaving it to stand for 14 days at ambient conditions. The standing period of 14 days was sufficiently long for testing the resuspendability and for evaluating caking. The vol-ume of the sediment in relation to the total volume was measured. Purified water was used as a control for non-retarded sedimenta-tion. The degree of sedimentation was calculated using the formula:
Degree of sedimentation (%) = (Volume of sediment [mm]/ Total volume of suspension [mm]) × 100%.
The resuspendability of suspensions showing clear sedimenta-tion was determined. About 45 mL of a freshly prepared suspension was transferred into a stoppered cylinder (height of the liquid col-umn approximately 25 cm). After 14 days of settling, the sediment was resuspended by moving the cylinder upside down one or more times. The number of turnings to completely resuspend the sedi-ment was recorded. The sedimentation speed was assessed by suspending 0.5 g of dark-red, grinded rock with a particle size between 400 μm and 800 μm in 100 mL of suspension vehicle in a capped jar (height of the liquid column approximately 8 cm). After 30 seconds of shaking, the jars were allowed to stand for 10 minutes, and the sedimentation was evaluated visually. If applicable, the time until complete sedi-mentation was recorded.
RESULTS AND DISCUSSIONVISCOSITY OF THE VEHICLES FOR SUSPENSION For the preparation of pharmaceutical suspensions, a vehicle (with pseudo-plastic properties) is essential. Water and Simple Syrup are, therefore, unsuitable, but these vehicles were included in our study as negative controls. The viscosity of the vehicles for pharmaceutical suspensions under the influence of different shear forces was measured using
T A B L E 1 . VISCOSITY ENHANCERS USED IN THE VEHICLES FOR SUSPENSION.
V E H I C L E C O M P O S I T I O N
ORA-BLEND AND ORA- • Microcrystalline celluloseBLEND SF • Carboxymethylcellulose sodium
• Xanthan gum
• Carrageenan5
BASE FOR SUSPENSION • Carboxymethylcellulose
• Aluminum magnesium silicate6
SUSPENDIT Synergistic polymer complex consisting of
xanthan gum and konjac powder
(patent pending)7,8
SYRSPEND SF PH4 (LIQUID) Modified food starch9
249International Journal of Pharmaceutical Compounding
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F I G U R E 2 : COMPARISON OF THE DYNAMIC VISCOSITIES OF THE VEHICLES FOR SUSPENSION. THE MEASUREMENTS AT 50 RPM ARE PLOTTED ON THE Y-AXIS, AND THE MEASUREMENTS AT 5 RPM ARE PLOTTED ON THE X-AXIS.
F I G U R E S 1 A A N D 1 B : RHEOGRAMS OF THE VEHICLES FOR SUSPENSION.
a rotational viscometer.3 Rheograms of the suspension vehicles tested are provided in Figure 1A and Figure 1B. Note that the rheo-grams comprise different maximum values on the y-axis of both Figure 1A and Figure 1B.
All vehicles, except Simple Syrup, as expected, showed pseudo-plastic behavior. The viscosity decreased with increasing shear forces (increasing rotation speed of the spindle). For Simple Syrup, the viscosity was nearly independent of the applied sheer force, meaning that Simple Syrup behaves as a Newtonian fluid. Ora-Blend and Ora-Blend SF had the lowest viscosity over the entire range of sheer force applied, but were clearly pseudo-plastic. The highest viscosity in the low range of sheer force was found, in increasing order, for Base for Suspension, SuspendIt, and SyrSpend SF PH4 (Liquid). In Figure 2 the dynamic viscosities of all pseudo-plastic vehicles are compared at low (5 rpm, x-axis) and high (50 rpm, y-axis) sheer force. The largest difference in viscosity related to applied sheer force is seen for Base for Suspension, SuspendIt, and SyrSpend SF PH4 (Liquid), meaning that these vehicles display the most pro-nounced pseudo-plastic properties.
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Synthroid 15 Eltroxin 25 Eltroxin 15
Simple Syrup
Ora-blend
Ora-blend SF
Ora-blendSimple Syrup
Ora-blend SF
Base for Suspensions
SuspendIt
SyrSpend®SF PH4 (Liquid)
Base for Suspensions
SuspendIt
SyrSpend SF PH4 (Liquid)
0 10 20 30 40 50
20000
18000
16000
14000
12000
10000
8000
6000
4000
2000
0
rpm
MPa
.s
Base for Suspensions
SuspendIt
SyrSpend SF PH4 (Liquid)
0 1 0 20 30 40 50
2000
1500
1000
500
0
rpm
MPa
.s
Mercury 25 Mercury 15 Synthroid 25Synthroid 15 Eltroxin 25 Eltroxin 15
Simple Syrup
Ora-blend
Ora-blend SF
0 200 400 600 800 1000 1200
4500
4000
3500
3000
2500
2000
1500
1000
500
0
MPa.s at 5 rpm
MPa
.s a
t 50
rpm
Synthroid 15 Eltroxin 25 Eltroxin 15
Simple Syrup
Ora-blend
Ora-blend SF
Ora-blendSimple Syrup
Ora-blend SF
Base for Suspensions
SuspendIt
SyrSpend®SF PH4 (Liquid)
Base for Suspensions
SuspendIt
SyrSpend SF PH4 (Liquid)
FIGURE 1A
FIGURE 1B
SEDIMENTATION AND RESUSPENDABILITY OF PARACETAMOL In Table 2, the degree of sedimentation of paracetamol in two dif-ferent concentrations (25 mg/g and 50 mg/g) and two different par-ticle sizes (45 μm and 180 μm) is given for all vehicles tested. Base for Suspension, SuspendIt, and SyrSpend SF PH4 (Liquid) yielded suspensions that did not settle. In Simple Syrup, no sedimenta-tion was measurable. Both particle sizes of paracetamol floated in the vehicle and, upon standing, cracks were visible. This indicates a lower physical stability of the vehicle. In the suspensions that showed sedimentation, the degree of sedimentation was less for the
250International Journal of Pharmaceutical CompoundingVol. 22 No. 3 | May | June | 2018
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Note: The resuspendability is provided in parentheses (number of turnings required to fully resuspend the settled paracetamol).
T A B L E 2 . DEGREE OF SEDIMENTATION (%) OF PARACETAMOL SUSPENSIONS, PARTICLE SIZE 45 μM AND 180 μM AND CONCENTRATION 25 MG/G AND 50 MG/G, AFTER 14 DAYS.
P A R A C E T A M O L P A R A C E T A M O L P A R A C E T A M O L P A R A C E T A M O L 4 5 μM , 4 5 μM , 1 8 0 μM , 1 8 0 μM ,V E H I C L E 2 5 M G / G 5 0 M G / G 2 5 M G / G 5 0 M G / GWATER 9 (3) 13 (2)) 7 (3) 14 (2)
ORA-BLEND 46 (2) 74 (2) 33 (2) 51 (3)
ORA-BLEND SF 46 (3) 65 (3) 40 (5) 48 (5)
SIMPLE SYRUP Not Applicable Not Applicable Not Applicable Not Applicable
BASE FOR Not Applicable Not Applicable Not Applicable Not ApplicableSUSPENSION
SUSPENDIT Not Applicable Not Applicable Not Applicable Not Applicable
SYRSPEND SF PH4 Not Applicable Not Applicable Not Applicable Not Applicable(LIQUID)
T A B L E 3 . SEDIMENTATION SPEED OF DARK-RED, GRINDED ROCK IN THE VEHICLES TESTED.
T I M E U N T I L C O M P L E T E V E H I C L E S E D I M E N T A T I O N ( S E C O N D S )WATER 0
SIMPLE SYRUP 90
ORA-BLEND 180
ORA-BLEND SF 300
BASE FOR SUSPENSION 230
SUSPENDIT No sedimentation after 600 seconds
SYRSPEND SF PH4 (LIQUID) No sedimentation after 600 seconds
smaller paracetamol particles. With Ora-Blend and Ora-Blend SF a more loose sediment was obtained. In Table 2, the resuspendability of the settled suspensions also is shown. Ora-Blend and Ora-Blend SF were easily resuspendable, while Simple Syrup required more frequent turning to become homo-geneous again. Resuspending the paracetamol sediment in water was easy as well, but was followed by an immediate resettlement. More paracetamol in the Simple Syrup formulation required more turnings to resuspend. The particle size of paracetamol did not influ-ence resuspendability in our experiments. In Base for Suspensions, SuspendIt, and SyrSpend SF PH4 (Liquid), no sedimentation was observed after 14 days standing at ambient conditions. Dark-red, grinded rock was chosen to be suspended in all vehicles because of its “extreme” material properties: big particle size and high density. These material properties make sedimentation speed distinctly visible. The sedimentation speed of the dark-red, grinded rock in the various vehicles is listed in Table 3. SyrSpend SF PH4 (Liquid) and SuspendIt did not show any sedi-mentation after 10 minutes, in contrast to all other vehicles. The two types of Ora-Blend yielded sub-optimal suspensions in terms of sedimentation behavior, but resuspendability, was good. Base for Suspension yielded lower quality suspensions with paracetamol than SyrSpend SF PH4 (Liquid) and SuspendIt. The physical stability of the suspensions prepared with both SyrSpend SF PH4 (Liquid) and SuspendIt was very good. Of these two vehicles, SyrSpend SF PH4 (Liquid) displayed somewhat higher viscosities than SuspendIt at the shear forces applied. Earlier studies on SuspendIt showed uniformity of content of freshly prepared suspensions of nine APIs6:
1. Omeprazole 6. Nystatin2. Captopril 7. Rifampin3. Enalapril maleate 8. Spironolactone4. Hydrochlorothiazide 9. Vancomycin hydrochloride
Physical and chemical stability after 6 months of storage of clindamycin hydrochloride and spironolactone in SuspendIt has recently been demonstrated.15,16
SyrSpend SF PH4 (Liquid) has been shown to be a suitable vehicle for a broad range of APIs.17-35 Over one hundred stability studies have been conducted and ninety-three studies have been published supporting the compatibility of the vehicle. The results of our study further strengthen the scientific support for the use of SyrSpend SF PH4 (Liquid) and SuspendIt as vehicles for the preparation of oral pharmaceutical suspensions. Ready-to-use vehicles for suspension contribute to quality assurance in compounding pharmacies and are convenient in use for the com-pounding staff.
CONCLUSION For the preparation of pharmaceutical suspensions for oral use, SyrSpend SF PH4 (Liquid) and SuspendIt are the best vehicles because of their pronounced pseudo-plastic properties. This is reflected in slow sedimentation combined with good resuspend-ability and pourability. Both vehicles are sugar free and contain no
parabens for preser-vation. Of these two vehicles, SyrSpend SF PH4 (Liquid) displayed somewhat higher viscosity, which is a favorable quality characteris-tic for suspensions. A final choice can be based on taste and mouthfeel, as well as on the com-mercial availability of the product in the country were the compounding is conducted.
Peer Reviewed
251International Journal of Pharmaceutical Compounding
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Peer Reviewed
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Address correspondence to J. Carolina Visser; E-mail: [email protected]