incompatibility of ibuprofen
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Workshop V
Chemical Principles Applicable to Formulation Developments
Shaukat Ali, Ph.D.Technical Service Manager
Ledgewood, NJ 07852
ExcipientFestSan Juan, Puerto Rico
April 23, 2009
Chemistry 101 for Non-Chemists
Part II
Chemical Principles Applicable to Formulation Developments (primarily Solid Oral Dosage Forms):
Formulation development requires a balance between physical andchemical properties. This session will continue to elaborate on basic chemical principles that need to be taken into consideration to achievewhat is normally referred to in the industry as a robust formulation. Concepts such as excipient selection (binders and disintegrants), possible API and excipient interactions, and how to achieve the desired physical and bioequivalent results will be addressed. A basic explanation on pharmaceutical coatings, their chemistry and corresponding functionality will also be covered.
The Drug Formulation Balance
API
DeliveryForm
Excipients
Manuf.Processing
Safety &Efficacy
Highly Regulated
Environment
FDA
Excipient Role
FORMULATION IS A BALANCING ACT!No one right answer - it depends (balancing tradeoffs)!
INPUT + Formulation & Processing = OUTPUTPhysicalChemicalFunctional
Excipients:a) Fillersb) Bindersc) Disintegrantsd) Lubricantse) Glidantsf) Solubilizers
Physical Tablet Characteristics:a) Weight (running weight variability)b) Dimensionsc) Hardness (breaking strength)d) Friabilitye) Disintegration Time
Manuf. Process / Operations: - Weighing - Sizing - Blending / Granulation - Compression / Encapsulation - Coating - Packaging
Delivery Form:
API
Excipients
Characteristics
Chemically inert carriers in the formulation
Present in significantly large quantity in a dosage
Properties dependent upon formulation or delivery systems
Enhance the functions to the dosages
Requires less stringent qualification criteria
Safety and toxicological profiles well understood
Robust methods to characterize them
Meet Pharmacopeial specifications (USP, EP, or JPE)
Type of Excipients
SweetenersBinders
Disintegrants
Lubricants
Glidants
Preservatives
Suspending agents
Film formers/coatings
Pigments
Print Inks
Fillers
Flavors
Compression aids Opacifiers
IPEC brings the transparency between suppliers and drug manufacturers
Role in Pharmaceutical Dosage
Tablets and Pellets
Fillers, binders, superdisintegrants, glidants, and solubilizers
Functional coatings
Instant release, sustained release or enteric release
Moisture barrier
Influence dissolution and release profile
Influence stability of the dosage form
Characterization
Density (bulk, tapped, true)
Viscosity
Degree of substitution
Molecular weight
Peroxides
Others
Particle Size distribution
Porosity
Moisture level
Surface area
Flowability
API-Excipient Interactions
ComplexationMetalsPhOH (Phenol)
DimerizationOxygenRCH2SH (Sulfhydryl)
OxidationOxygenRCH2OH (alcohol)
Salt formationBasesR-CO2H (carboxylic acid)
Aldehyde-amine, Schiff baseAmine, carbohydrates
R-C(O)H (aldehyde)
Hydrogen bondingSilanolR-C(O)R (carbonyl)
Hydrolysis, ring openingBasic pHR-COOR’ (esters, lactones)
Amine-aldehyde, amine-acetal
Mono- and disaccharides
R-NH2 (amine)
Possible InteractionIncompatibilityFunctional group
API-Excipient Interactions…contd.
Epinephrine/sod. Bisulfite, isomerization of Vit. B12
Undesirable pH conditionsDrug-buffer interaction
Benzocain/Polyvinylacetate phthalate, Norfloxacin/Mg stearate amide
Enzymetic condition, pH controlled
Trans-esterification
Gelatin capsules/PEG400 cross-linkage with aldehyde
Amines react with aldehydesSchiff base formation
Ceronapril/lactose, Isoniazid/lactose, Fluoxetine HCl/lactose
Amines with reducing sugars, alkaline microenvironment
Maillard reaction
Ceronapril/Dicalcium Phosphate,
Raloxifen/PVP/crospovidone
Peroxides, dye excipients, metal ions
Oxidation
Aspirin/excipients, Lansoprazole/excipients
Changes in the microenvironmentHydrolysis
CaCO3/tetracycline, Diclofenacsodium/polymethacrylic acid copolymer, Oxazolam/MCC, Ibuprofen or Aspirin/Mg stearate
Capable of interacting each other through H-bondings or ionization
Complexation
Indomethacin/NaHCO3, Citric acid or tartaric acid/NaHCO3
Capable of donating protons and hydroxyl ions
Acid/base
ExampleConditionType of reaction
Excipient Selection Criteria
Prior knowledge on the function of excipients
Expert systems, predictive tools and analytical methods
Formulation dosages or delivery system
Drug-excipient compatibility by selecting the “smart excipients”in the prototype formulation to alleviate interactions with API
Important to assess certain risks in early stage of formulationdevelopment to avoid any surprises
Process Flow Chart
Formulation Optimization
Stability Evaluation
Scale up andValidation
API Excipients
YesPrototype
Formulation,Processing and Characterization
No
No
No
Manufacturing
QbD
Factors Affecting the Formulation Stability
Drug & Excipient
Chemical structureImpurity profilePhysical formMoisture contentParticle sizeSurface areaMorphologyCrystal defects
Drug : Excipient ratio
Processing methodPhysical mixing/
milling or granulationPowder mixing and
packingProbability of
chemical interaction with API
Formulation
TemperatureRelative humidityPackagingLightOxygen
Environment
Stabilization of Formulation
Dosages Instability and Solutions
MoexiprilCaptoprilDrug : Excipient ratio
Study showed decomposition in the present of Mg stearate
High strength (100 mg) tablets with Mg stearate are stable
Low strength (12.5 mg) tablets showed a significant oxidative decomposition
Stabilizes N-Carboxylalkyl dipeptide via aminolysis at pH < 4.5 and ester hydrolysis at pH >10
Excipients are incompatible in dry state, but in wet granulations, alkaline agents retards API degradation due to presence of moisture
Stabilization by salt formation
Stabilization of Formulation…contd.
Dosages Instability and Solutions
Enalapril Ibuprofen
MCC incompatible with API due to adsorption and dissociation of amine maleate of drug
Ca-Phosphate compatible with API, no adsorption
Forms eutectic in presence of Mg stearatewhich vaporizes
Film coating of tablets eliminates this problem
Stabilization of Formulation
Basic Requirements and Solutions
Minimizing the level of moisture in formulation
Altering the properties of solid drug
SOLUTIONS
Increasing melting point
Choosing a non-hygroscopic form (crystal or salt form)
Reducing solubility by choosing a less soluble salt
Micellar inclusion
Complexation
Engineering of the particles (shape)
SOLUTIONS
Choice of excipients
Co-solvents
Manufacturing conditions
Storage conditions
Packaging
Stabilization of Formulation…contd.
Basic Requirements and Solutions
Changing the micro-environment in formulation
Minimizing contact between API & Excipients, and water
SOLUTIONS
Adjusting the pH by using acids, bases, or buffer salts
Incorporating complexation agents to inactivate trace metal ions
Displacing oxygen with nitrogen or argon
Incorporating antioxidants
SOLUTIONS
Coating with polymers/ microencapsulation
Multi-layer particles in capsule/tablet
Tablet in a tablet or capsule
Excipient and API Incompatibility
Excipients under different %RH
Gonnissen et la., Eur. J. Pharm. Biopharm. 2007, 67, 220-226
0
2
4
6
8
10
Moi
stur
e U
ptak
e, %
(w/w
)
32 52 65 75 85
Relative Humidity (% w/w)
MaltodextrinLactoseMannitol
Maltodextrin poses a compressibility challengeLactose is often used in the formulations (eg. Zyrtec OTC, etc.)Mannitol is low hygroscopic of all three (e.g. ODT)
Formulation Dosage Stability
Aspirin: Impact of moisture absorption
Moisture absorption decreases in the order:
Dicalcium phosphate > MCC > Lactose
DCP has more impact on instability of drug due to increase in internal pH resulting from moisture uptake
0
20
40
60
80
100
Deg
rada
tion,
%
Avicel Calc. Phos. HPMC Lactose MgStearate
PVP K-30 Primojel
Excipient
10 %RH
75 %RH
Wyttenbach et al., Pharm Dev and Tech., 2005, 10, 499.
Aspirin degradation @ Varied %RH
Formulation Dosage Stability…contd.
Indomethacin: Impact of moisture absorption
Water acts as a plasticizer and lower Tg of the excipient and alters the physico- chemical properties of API by increasing the molecular mobility that leads to phase separation and crystallization
0
30
60
90
120
150
180
Tg (o
C)
0 15 35 45 55 65 70
Relative Humidity (%)
Stubberud et al., Int. J. Pharm., 1996, 134, 79-88.0
2
4
6
8
10
kobs
x10
4
50 70 80 90
Relative Humidity (%)
IND decomposition
Stubberud et al., Int. J. Pharm., 1996, 134, 79-88.
Rate constant is correlated with amount of moisture
IND crystallizes under high %RH
Cartensen and Rhodes, Drug Stability, 3rd, Ed.
PVP K-25
30%
Moisture Uptake5%
Influence of Excipients on the Dissolution of an APICarbamazepine (CBZ) and PVP w/wo Solubilizers
0
0.04
0.08
0.12
0.16
0.2
Intr
insi
c D
isso
lutio
nra
te (m
g/m
in/c
m2)
CBZ CBZ-K30 (1:5) CBZ-K-30-Gelucire 44/14
(1:4:1)
CBZ-K-30-TPGS (1:4:1)
CBZ/Excipient
Sethia and Sequillante, Int. J. Pharm. 2004, 272, 1-10
Dissolution rate:
PVP K-30 > Vit. E-TPGS > Gellucire 44/14
Influence of Excipients on the Dissolution of an APICBZ in Different Dissolution Media
Tian et al., J. Pharm. Sci., 2007, 96, 584-594
Rate of CBZ dissolution: Water > PEG > HPMC
Faster dissolution of CBZ Dihydrate was due to increased surface area
CBZ
500 μm
H2O
PEG
H2O
HPMC
150 min
Excipient-API Incompatibility
Excipient’s Particle size on Aspirin Stability
Ahlneck et al (1988)
Aspirin degradation in presence of microcrystalline and microfine-cellulose (55°C/75% RH)
Stability decreased with increasing amount of cellulose presumably due to the catalytic effect
Dosages Stability – Functional Coating
Aspirin Stability (6 months)Tablet wt. 301.5 mg, API 100 mg, Coating level 3.7 wt%
0
0.4
0.8
1.2
Salic
ylic
aci
d, %
KollicoatProtect:Kaolin:Talc
(60:25:15)
KollicoatProtect:Kaolin:Talc
(40:40:20)
PVA based Competitor Product
Coated Aspirin Tablets
25 oC/60%RH
PVA-co-PEG is an effective moisture barrier polymer
Effect of Binders on Dissolution of API
Ibuprofen
Dissolution properties dependent on the binder selectionPossible interaction of Ibuprofen with DCP
Superdisintegrants in Performance of Phenacetin TabletsDisintegrant @5%
0
20
40
60
80
100
Dis
solu
tion,
%
Crospovidone CroscarmelloseSodium
Carboxymethystarch L-HPC
Superdisintegrants
Dissolution @15 min
Crospovidone ≥ Croscarmellose Sodium > Carboxymethylstarch > L-HPC
Functional coating with Polyvinylacetate dispersion 30%Effects of pore formers on Theophylline release
30% PVP K-90
30% PVA-co-PEG
30% PVP K-30
15% PVP K-90
15% PVA-co-PEG
no pore former
30% PVP K-90
30% PVA-co-PEG
30% PVP K-30
Theophylline release from the pellets coated with Kollicoat SR 30D with and without pore-formers
Far less porous
Less porous
Far more porous
FASTERDissolution
SLOWERDissolution
Coating Excipients in the Performance of ProductsTablets versus Pellets
0
20
40
60
80
100
0 1 2 3 4 5
Time, Hr
Rel
ease
d, %
Aspirin TabletAscorbic Acid Pellets
Enteric Effect
Achieve a similar release (0-2 Hr) from both coatings Provide more flexibilityEasy manufacturing
Multi-layeredpellets
Enteric coated tablets
Enteric Copolymer
Methylacrylic acid-ethyl acrylate co-polymer
Sustained release
Polyvinylacetate 30%
Drug Approval Process
Brand Rx vs. Generic Rx
Years
Bioequivalency of a Drug Product
Definition
Brand Rx Generic Rx
Pharmaceutical EquivalentProducts
Therapeutic Equivalence(Same dissolution spec., PK profile)
Possible Differences
Drug particle size,
Flowability..
Excipients
Manufacturing process
Equipments
Site of manufacturing
Batch size ….
Same Active
Conc
entra
tion
Time
Determine the Bioequivalency
Comparison of PK Profiles in Plasma
Food and Drug Administration Web site.
Generic Rx
Brand Rx The AUC and Cmax of the generic Rx must meet 80% - 125% of the brand Rx in order to be deemed BE
Tmax
Cmax
AUC
Bioequivalency of Brand Rx vs. Generic RxFDA Requirements
125%100%80%
Product ABioequivalent
Brand Rx (Reference Drug)
Product BNot Bioequivalent
Pharmacokinetic (PK)Reference Range
Food and Drug Administration Web site
Product A is BE to Brand RxProduct B is not BE
Achieving the Bioequivalency
Dissolution profiles of Generic Rx to Brand Rx
0
20
40
60
80
100
120
0 4 8 12 16 20 24
Time, hr
Rel
ease
d, %
Brand RxGeneric Rx
Dissolution profiles of brand Rx and generic Rx very close
Achieving the Bioequivalency
PK profiles of Brand Rx and Generic Rx
SRx-502 meets bioequivalencecriteria of Topamax forboth Cmaxand AUC
The PK data of SRx-502 supports approval based on bioequivalence
Source: Spherics
SRx-501(Levodopa-Carbidopa XR)
The fluctuationindex is identicalin both Brand Rx and Generic Rx
Efficacy and Bioavailability-PK Profiles
Effects of excipients on highly and poorly permeable drugs
Theophylline serum concentration profiles
Fassihi et al., Int. J. Pharm. 1991, 72, 175-178
Highly Permeable Drug
About 10 grams of sorbitol had no (minimal) effect on bioavailability (Cmax and AUC) of theophylline
WaterSorbitol
Efficacy and Bioavailability-PK Profiles…contd.Effects of excipients on highly and poorly permeable drugs
Adkin et al., J. Pharm. Sci. 1995, 84, 1405-1409
Sucrose solution
Chewable Sucrose tablet
Mannitol SolutionChewable mannitol tablet
Cimetidine serum concentration profile
Poorly Permeable Drug
2.3 grams of mannitol in a chewable tablet reduced bioavailability of cimetidine compared to a tablet containing the same amount of sucrose
Bioavailability of a Class III Drug
PK profiles of Ranitidine
Time (hours)0 2 4 6 8 10 12
Plas
ma
Con
c. (n
g/m
L)
0
100
200
300
400
500
Sucrose Sorbitol
Ranitidine: 150 mgSucrose: 5 gSorbitol: 5 g
Hussain, A., AAPS 2000
Sucrose metabolizes to glucose and fructose, and both show complete absorption
Ranitidine (poorly permeable drug)
LnCmax 44%-54%
LnAUCi 53%-62%
Concluding Remarks
Selection of the API
Selection of the excipients and compatibility in formulation
Development of analytical methods, method validation and testing
Product manufacturing processes and robustness
Stability, storage and packaging conditions
Safety and toxicological profiles
A comprehensive knowledge of APIs and Excipients is required to minimize any late stage development surprises!!
Success in Formulation Design
Thomas Edison
Many of life's failures are people who did not realize how close they were to success when they gave up.
Perseverance…
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