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www.ujpsr.com 12 Vol.2, Issue 2

RESEARCH ARTICLEDepartment of Pharmaceutical Chemistry

Lobna et.al / UJPSR / 2 (2), 2016, 12-22 e ISSN: 2454-3764

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Abstract

In the present study two rapid, inexpensive and direct chiral chromatographic methods were developed and validated for enantioseparation of racemic citalopram hydrobromide and ibuprofen and determination of their eutomers; escitalopram oxalate and dexibuprofen. The first method was based on ligand exchange reversed phase HPLC for enantioseparation of citalopram enantiomers, using 50 mM CuSO and 100 4

mM L-histidine in water/methanol on C column. The second method was 18

based on the use of mucopolysaccharide (pentosane polysulphate) as chiral selector for stereoselective separation of ibuprofen enantiomers on cyano column. The stereochemical separation factor (Ü) and the stereo chemical resolution factor (R ) obtained were 1.52 and 3.67 for citalopram s

hydrobromide and 1.97 and 6.96 for ibuprofen, respectively. Calibration curves were linear in the range of 0.4 – 2.4 µg/mL and 1.0– 80.0 µg/mL for escitalopram oxalate and dexibuprofen, respectively. The methods are specific and sensitive with lower limits of detection and quantifications of 0.109, 0.359 and 0.211, 0.696 for escitalopram oxalate and dexibuprofen, respectively.

Key words

Chiral mobile phase additives, Dexibuprofen, Escitalopram oxalate, Copper ligand, Pentosane polysulphate.

INTRODUCTION

DOI: 10.21276/UJPSR.2016.02.02.22

DIRECT STEREOCHEMICAL RESOLUTION AND ENANTIOSELECTIVE DETERMINATION OF CITALOPRAM

HYDROBROMIDE AND IBUPROFEN ENANTIOMERS BY LIGAND EXCHANGE AND MUCOPOLYSACCHARIDE AS

CHIRAL SELECTORS ON REVERSE PHASE LIQUID CHROMATOGRAPHY

1 2 1 2 Nahla N. Salama, Hala E. Zaazaa, Lobna M. Abd El Halim*, Maissa Y. Salem,Laila3E. Abd El Fattah

1Pharmaceutical Chemistry Department, National Organization for Drug Control and Research [NODCAR], 6 Abu Hazem Street, Pyramids Ave, P.O. Box 29, Giza, EGYPT

2 Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El Ü Aini Street, Cairo 11562, EGYPT

3Analytical Chemistry Department, Faculty of Pharmacy, Misr University for Science & Technology, Al-

ARTICLE INFO: Article history: Received:22 August 2016Received in revised form:26 September 2016Accepted: 01 October 2016Available online: 10 November 2016

Corresponding Author: Lobna M. Abd El Halim

Quality Control Specialist

National Organization for Drug Control and Research [NODCAR], Giza, Egypt, Raw Materials Department 6 Abou Hazem Street, Pyramids Ave, P.O. Box 29, Cairo, EGYPT.

Email:

Phone: + 202-35851299

[email protected]

In the chiral separation by HPLC technique, the resolution between isomers is only possible by the transient formation of a pair of diastereomers with different free energy, chemical properties and consequent ly d i fferent re tent iv i t ies . These diastereomeric complexes are formed by different chiral separation mechanisms. Based on this fact, two chiral

switching drugs; citalopram hydrobromide and ibuprofen are taken as examples of enantiomar separation using different mechanisms that are applied using ligand exchange reagent and mucopolysaccharide as chiral mobile phase additives for citalopram hydrobromide and ibuprofen, respectively [1,2].

Citalopram hydrobromide (CIT): (RS)-1-(3-


dimethylaminopropyl)-1-(4-fluorophenyl)-1, 3-dihydro iso benzo furan-5-carbonitrile, HBr is selective serotonin reuptake inhibitors (SSRI) used for the treatment of various affective disorders [3]. Pharmacological effect is mainly due to the S-(+) enantiomer while R-(-) enantiomer is considered to be inactive [4]. Different techniques have been reported for separation of c i ta lopram enant iomer such as th in layer chromatography [5-7] high performance liquid chromatography [8-10] and capillary electrophoretic methods [11,12]. Ibuprofen(IBU): (RS)-2-(4-(2-methylpropyl) phenyl) propanoic acid is a non-steroidal anti-inflammatory drug (NSAID) widely used for the treatment of pain and inflammation in rheumatic disease

and other musculoskeletal disorders and is marketed as a racemate [3]. The anti-inflammatory action is mainly associated with the (+)-(S)-enantiomer [3]. Different techniques have been reported for separation of rac-ibuprofen, including high performance liquid chromatography [13-26], Capillary electrophoresis (CE) using variety of chiral selectors [27-35] and thin layer chromatography [36]. In the literature, there is no reference for direct HPLC methods using copper (II)-histidine reagent or pentosan polysulfate sodium (PPSS) as a chiral selector on C and cyano column for chiral 18

separation of racemic mixtures of CIT and IBU enantiomers. Therefore these mechanisms were chosen for rapid chiral separation of the studied drugs.

EXPERIMENTAL

APPARATUS

Analytical chromatography was performed on a HPLC system, Agilent technologies 1200 series, Germany, consisting of Agilent 1200 series variable wavelength detector G1314B/G13145 (SL), Agilent 1200 series vacuum degasser (20 µL), Agilent 1200 series manual injector and Agilent 1200 series quaternary pump G1310 A, G1311 A. Agilent Syringe, LC 50 µL, (USA) was used

for injection. Luna C column, 250 mm × 4.6 mm, 10 mm 18

(Phenomenex, USA) was used for separation of citaloptam hydrobromide enantiomers. Cyano Zorbax column, 250 mm × 4.6 mm, 5 µm (Agilent, USA) was used for separation of ibuprofen enantiomers. Cellulose acetate filter papers dimension 47 mm, pore size 0.45 µm, (ChromTech, USA) was used for filtration.

SAMPLES

PURE SAMPLES

Citalopram hydrobromide was supplied from Multi Apex Pharma (Cairo, Egypt) and its purity was found be 99.54 ± 0.824 [37]. Escitalopram oxalate oxalate was supplied from Hikma Pharma (Gizah, Egypt) and its purity was labeled to be 100.38± 0.148. L-Histidine (Otsuka Pharmaceutical, Japan) was used as chiral selector.

Ibuprofen and dexibuprofen were supplied from Sigma Pharmaceutical Industries (Cairo, Egypt) and their purities ± RSD were labeled to be 99.49 ±1.08 and 99.12 ± 0.749 respectively. Pentosane polysulphate ester sodium (Sanofi Aventis, Egypt) was used as chiral selector.

MARKET SAMPLES

Depram ® tablet was labeled to contain 20 mg citalopram / tablet, manufactured by Multi Apex Pharma (Cairo, Egypt). Estican ® tablet was labeled to contain 20 mg escitalopram oxalate/ tablet, manufactured by Hikma Pharma (Giza, Egypt). Brufen®, effervescent granules was labeled to contain 600 mg ibuprofen/sachet,

CHEMICALS AND REAGENTS

All solvents used were of HPLC grade and chemicals were of analytical grade. Potassium dihydrogen orthophosphate (Qualikems, India), Copper sulphate (Adwic Co., Egypt), acetonitrile (Poch S. A., Poland), methanol (Scarlau, Spain), isopropanol, triethylamine (Sigma Aldrich, Germany), ethanol, ethyl acetate

manufactured by El Kahira Pharmaceuticals And Chemical Industries Company (Cairo, Egypt). Flamotal ® topical gel was labeled to contain 5 g Ibuprofen /100 g cream manufactured by Global Napi Pharmaceuticals (GNP, Cairo, Egypt).

(Fischer Scientific, UK), trifluroacetic acid (Acros Organics, USA), tetrahydrofuran (Sigma Aldrich, Germany), ortho-phosphoric acid (Lab. Scan, Ireland). Water for HPLC was prepared by double glass distillation and filtration through 0.45 µm membrane filter.



Print ISSN: 2454-3756DOI: 10.21276/UJPSR.2016.02.02.22


STANDARD STOCK SOLUTIONS

Rac-citalopram hydrobromide, escitalopram oxalate (0.1 mg/mL) and rac-ibuprofen, dexibuprofen (1 mg/mL),

WORKING STANDARD SOLUTIONS

Working standard solutions were prepared in concentration ranges of, 0.8 - 4.8 µg/mL and 0.4 - 2.4 µg/mL of rac-citalopram hydrobromide and its pure isomer escitalopram oxalate and from 2.0 - 160.0 µg/mL

CHROMATOGRAPHIC CONDITIONS

HPLC was carried out at 10 °C on Luna C column (250 18

mm × 4.6 mm, 10 µm) and mobile phase consisted of 50 mM CuSO and 100 mM L-histidine in 50 mM 4

potassium phosphate buffer (pH 5) adjusted with o-phosphoric acid: methanol: acetonitrile: tetrahydrofuran (70: 20: 10: 0.6, v/v) for CIT. While for IBU, the mobile phase consisted of 100 mg of PPSS dissolved in 75 mL of methanol to which was added 25 mL of ethyl acetate and

APPLICATION TO PHARMACEUTICAL DOSAGE FORMS

Ten tablets of Depram and Estican were weighed and ground to a fine powder. An equivalent weight corresponding to 10 mg of each was extracted with 10 mL methanol by sonication for 15 min. and filtered. The residue was washed several times with small volume of methanol. The combined extract was quantitatively transferred to 100-mL calibrated volumetric flask and evaporated. The volume was completed to the mark with mobile phase. The content of ten sachets Brufen effervescent granules was weighted and finely

RESULTS AND DISCUSSIONMobile phase additives are widely used in HPLC to regulate analyte retention behavior. The commercially available chiral stationary phases (CSP) for HPLC are very useful but extremely expensive, with short lifetimes and limited ranges 1. The basic principle of ligand exchange 2 is the involvement of L-histidine, water and

+2bivalence copper (Cu ), into CIT isomers to be resolved, through the formation of diastereomeric ternary complexes; selector/metal ion/analyte. Since the analytes and the selectors used in chiral LEC incorporate strongly polar functional groups, they are usually better dissolved in water, alcohols, or other strongly polar solvents. Any difference in stability or energy of these diasteromeric complexes results in different chromatographic

were prepared in methanol.

rac-ibuprofen and 1.0 - 80.0 µg/mL of its pure isomer dexibuprofen by appropriate dilution of standard solutions with mobile phase.

0.10 mL of TFA (concentrated), pH 3, and separation was carried out on Cyano column (250 mm × 4.6 mm, 5µm). The mobile phases were filtered using 0.45 µm membrane filter followed by degassing with ultrasonic vibration and delivered at 1 mL/min for CIT and 2.5 mL/min for IBU. The injection volume was 20 µL. Detection was achieved with UV detector at 254 nm for both drugs.

powdered. A portion equivalent to 500 mg ibuprofen was accurately transferred to 25 mL volumetric flask and extracted with about 20 mL (18: 2 methanol and water) and sonicated for 20 minutes. Then the extract was diluted to 25 mL with methanol and filtered. An accurately weighted amount of Flamotal 5% topical gel corresponding to 500 mg ibuprofen was dissolved in 20 mL methanol and transferred to 25-mL volumetric flask, sonicated for 15 minutes and diluted to the mark with methanol.

behaviors and enantiomers can be separated. The enantiorecognition of IBU isomers requires the knowledge of chiral resolution mechanism of mucopolysaccharide as chiral selector. The chiral recognition mechanism is achieved through the different hydrogen, ð-ð, and dipole-induced dipole interactions between the chiral selector, stationary phase and the enantiomers [36]. It has been observed that PPSS has greater resolution capacity than most known mucopolysaccharide attributed to the fact that the PPSS are more helical in nature and possess well-defined grooves. The schematic enantioseparation mechanism of CIT and IBU was illustrated in Figure (1) and (2).








Fig. 1: Schematic enantioseparation mechanism of the ternary complex formation of citalopram and L-histidine amino acid with Cu (II).

Fig.2: Schematic enantioseparation mechanism of the complex formed between pentosane polysaccharide and ibuprofen.

The optimized mobile phase for enantioseparation of CIT was 50 mM CuSO and 100 mM L-histidine in 50 4

mM potassium phosphate buffer (pH 5): methanol : acetonitrile: THF (70: 20: 10: 0.6, v/v) and detection at 254 nm. The order of elution was R (-) enantiomer then S (+) enantiomer with retention times of 2.18 and 2.99 respectively (Figure 3). The optimized mobile phase of

IBU racemic mixture was 100 mg of PPSS dissolved in 75 mL of methanol to which was added 25 mL of ethyl acetate and 0.10 mL of TFA (concentrated), pH 3 and detection at 254 nm. The order of elution was R (-) enantiomer then S (+) enantiomer and their retention times were 1.16 and 1.71 in drug substance and drug product respectively (Figure 4).




Print ISSN: 2454-3756DOI: 10.21276/UJPSR.2016.02.02.22METHOD VALIDATION [38]

The validation parameters of the optimized methods were given in Table (1). Good linearity was observed for the active isomers of the studied drugs over the concentration range of 0.4 - 2.4 µg/mL with a linear regression equation, y = 1623.2x + 72.33 (r = 0.9995, n = 6) for CIT and 1 - 80 µg/mL with a linear regression equation, y = 25.64 x + 61.71 (r = 0.9995, n = 6) for IBU. The LOD and LOQ were calculated and found to be 0.109, 0.359 for CIT and 0.211, 0.696 for IBU respectively. The results of method precisions are expressed in terms of RSD% values for retention times and peak areas for the active isomers are presented in Table (1). The RSD% for repeatability (within-day precision, n=3) and RSD for reproducibility

Fig. 3: A typical HPLC chromatogram of (A) 0.8 µg /ml racemic CIT in drug substance, (B) 0.8 µg /ml pure escitalopram (C) 4.8 µg /ml racemic CIT in Depram ®tablet, (D) sequential concentration of racemic citalopram (0.8 - 4.8 µg /ml) at conditions of a Luna C column (250 mm × 4.6 mm, i.d., 10 ìm) eluting 18

with the mobile phase of 50 mM CuSO and 100mM L-histidine in 50 mM potassium phosphate buffer 4

(pH 5) adjusted with o-phosphoric acid : methanol: acetonitrile: THF (70:20:10:0.6) and detection at 254 nm

(between-day precision, n=3) for each enantiomer at three different quantification concentrations were found to be less than 2%. These results confirmed the good precision of the methodGood recoveries were obtained for the active and racemic forms in drug substances and pharmaceutical dosage forms as represented in Tables (2) and (3). Robustness of the methods was assessed by evaluating the influence of small change of experimental conditions, such as organic strength, pH and flow rate, and the system suitability parameters were evaluated as represented in Table (4) and (5). The methods showed acceptable robustness as deliberated changes of any variable Therefore, the methods are robust and reliable.

17 Vol.2, Issue 1




Fig. 4: A typical HPLC chromatogram of (A) racemic IBU in drug substance, (B) pure dexibuprofen, (C) and (D) ) racemic IBU in Brufen effervescent granules and Flamotal topical gel, (E) sequential

concentration of ibuprofen (1 - 40 µg /ml) at conditions of Cyano Zorbax column, 250 mm × 4.6 mm, 5 ìm; Mobile phase, 100 mg pentosane polysulphate sodium in methanol: ethyl acetate: TFA (75:25:0.1), pH 3;

flow-rate, 2.5 mL /min; detection wavelength, 254 nm.

Table 1: Validation and regression equations parameters for the proposed chiral HPLC methods for the determination of escitalopram and dexibuprofen in drug substances

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Parameters Escitalopram Dexibuprofen

Linearity range 0.4 – 2.4 1.0 – 80.0

LOD (µg/mL)LOQ (µg/mL)

0.1090.359

0.2110.696

AccuracyaMean ± RSD% bMean ± RSD% cMean ± RSD%

97.82 ± 0.795

48.80 ± 1.450

101.52 ± 0.63954.44 ± 0.63056.10 ± 2.13656.40 ± 2.153

Precision Instrumental repeatability t r

Peak areasMethod repeatability t r

Peak areasInterday precision t rPeak areas

0.1630.4810.2200.3820.2620.585

0.6930.7000.6770.7620.6250.629

25.6480.389

24.56-26.7261.7117.47

13.18 -110.240.999526.62

1623.21425.617

1552.09-1694.3372.3339.905

-38.64 -183.120.999542.865

Regression equation-SlopeSE of the slope

eCL of the slope -InterceptSE of the intercept

eCL of the intercept-Correlation coefficient-SE of estimation

a. Drug substance (pure isomer). b. Drug substance (racemic form).c. Pharmaceutical formulation (racemic form).d. Pharmaceutical formulation (racemic form). e. 95 % Confidence limit.




Print ISSN: 2454-3756DOI: 10.21276/UJPSR.2016.02.02.22Table (2a): Accuracy of the proposed LEC HPLC method for the determination of escitalopram

oxalate in drug substance as pure isomer and in rac-citalopram

0.37

0.79

1.57

1.99

2.38

0.8

1.6

3.2

4

4.8

Escitalopram (pure isomer) Citalopram (Racemic mixture)

Taken conc.

(µg/mL)

Taken conc.

(µg/mL)

Found conc.

(µg/mL)

Found conc.

(µg/mL)

Recovery * (%) RSD% RSD%

Recovery * (%) of claimed amount

0.4

0.8

1.6

2

2.4

Mean RSD% 97.82 0.795 Mean RSD% 49.22 1.002

0.39

0.78

1.55

1.97

2.37

97.50

97.50

96.87

98.50

98.75

0.265

0.514

0.609

0.381

0.649

0.258

0.214

0.362

0.325

0.228

47.50

49.93

49.37

49.50

49.79

*Average of four different determinations

Table (2b): Accuracy of the proposed LEC HPLC method for the determination of escitalopram oxalate in drug products as pure isomer and in rac-citalopram

Taken conc.

(µg/mL)

Taken conc.

(µg/mL)

Found conc.

(µg/mL)

Found conc.

(µg/mL)



Mean RSD% Mean RSD%

Estikan tablet (20 mg Escitalopram/ tablet) ( Depram tablet) (20 mg Citalopram/ tablet)

2.4

0.4

0.8

1.6

2

0.4080.39 97.00 0.125 0.37 46.250.8

2.37

0.78

1.55

1.97

0.34997.25 0.243 1.6 0.79 49.37

97.91

96.25

97.50

0.2610.208 3.2 1.57 49.06

0.199

0.234 0.7614 1.99 49.75

0.9324.8 2.38 49.58

97.18 0.639 48.80 1.450

*Average of four different determinations

Table (3a): Accuracy of the proposed HPLC method for the determination of dexibuprofen in drug substance as pure isomer and in rac-ibuprofen

Ibuprofen (Racemic mixture)

Taken conc.

(µg/mL)

Taken conc.

(µg/mL)

Found conc.

(µg/mL)

Found conc.

(µg/mL)



Mean RSD% Mean RSD%

Dexibuprofen (Pure isomer)

80.0

1.0

10.0

20.0

40.0

0.1581.02 102.00 0.325 1.03 51.502.0

80.85

10.12

20.19

40.97

0.392101.20 0.492 20.0 10.25 51.25

101.06

100.95

102.42

0.4220.931 40.0 20.41 51.02

0.723

0.581 0.52580.0 41.91 52.38

0.528160.0 82.36 51.47

101.52 0.639 54.44 0.630

*Average of four different determinations.

ParametersSelectivity, á (NLT 1.0)

Resolution, Rs(NLT 1.5)

Tailing factor, T (NMT 3)

Column efficiency, N(NLT 1000)

RSD % of six replicate

injections

Flow rate0.9 ml/min1.1 ml/min

Buffer pH4.85.2

Column temperature8°C12°C

Organic modifier bvolume

19ml21ml

Organic modifier cvolume

9.8 ml10.2 ml

Organic modifier dvolume

0.58 ml0.62 ml

1.511.50

3.673.65

1.221.21

19011989

0.2300.154

1.501.50

3.663.67

1.211.20

21611921

0.2410.321

1.511.50

3.673.65

1.201.23

21482006

21482006

1.511.51

3.643.67

1.221.23

20272135

0.2850.225

1.501.50

3.643.65

1.211.24

21842972

21842972

1.511.50

3.673.65

1.201.22

21471938

0.1460.325

Flamotal topical gel(5 g Ibuprofen/100 g cream)

Taken conc.

(µg/mL)

Taken conc.

(µg/mL)

Found conc.

(µg/mL)

Found conc.

(µg/mL)



MeanRSD%

MeanRSD%

Brufen effervescent granules(600 mg ibuprofen/sachet)

160.0

2.0

20.0

40.0

80.0

0.6321.16 58.00 0.205 1.16 58.002.0

88.21

11.21

22.52

44.02

0.54256.05 0.425 20.0 11.23 56.15

55.13

56.30

55.02

0.4090.647 40.0 22.92 57.30

0.825

0.741 0.48780.0 44.15 55.18

0.321160.0 88.64 55.40

56.102.136

56.402.153





Table (3b): Accuracy of the proposed HPLC method for the determination of dexibuprofen in rac-ibuprofen drug product

*Average of four different determinations.

aTable 4: Summary of robustness data and system suitability parameters for separation of citalopram hydrobromide enantiomers

a. Values in parentheses are the system suitability acceptance criteria. NMT= not more than; NLT = not less than; á= selectivity; Rs = resolution between the adjacent peaks.b. Methanolc. Acetonotriled. Tetrahydrofuran




Print ISSN: 2454-3756DOI: 10.21276/UJPSR.2016.02.02.22aTable 5: Summary of robustness data and system suitability parameters for separation of ibuprofen

enantiomers

Selectivity, á (NLT 1.0)

6.966.92

1.161.16

80848089

0.2140.321

1.971.97

6.956.96

1.171.15

80788093

0.3050.411

Column temperature14.8 °C15.2 °C

1.951.97

6.966.94

1.171.18

80718079

0.2790.321

1.961.97

6.926.95

1.191.17

80868075

0.3090.401

Organic modifier cvolume

24 ml26 ml

1.971.95

6.966.95

1.161.18

82658055

0.4960.436

ParametersResolution, Rs

(NLT 1.5)Tailing factor,

T (NMT 3)

Column efficiency, N(NLT 1000)

RSD % of six replicate

injections

Flow rate2.4 ml/min2.6 ml/min

Buffer pH2.83.2

1.971.96

Organic modifier bvolume

74ml76ml

a Values in parentheses are the system suitability acceptance criteria. NMT= not more than; NLT = not less than; á= selectivity; Rs = resolution between the adjacent peaks. b Methanol.C Ethyl acetate

CONCLUSION

The paper describes improved, simple and inexpensive methods to analyze enantiomeric mixtures of citalopram hydrobromide and ibuprofen, suitable to be used routinely by any group working in quality control laboratories as well as to describe the importance of the chiral selector structure to the desired enantioseparations and its implications on the chromatographic parameters. The proposed methods are clearly superior to published methods being application inexpensive. The stereospecificity was achieved by CLEC and

mucopolysaccharide chiral selectors on conventional columns. The optimum HPLC methods were found to be sensitive and selective for identification and quantitative determination of enantiomeric purity of escitalopram oxalate and dexibuprofen in their drug substances and products. The methods can be useful to investigate adultration of pure isomers with cheap racemic forms. The proposed methods are clearly superior to published methods

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