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Workshop I
Chemical Principles Applicable to Active Pharmaceutical Ingredients
Shaukat Ali, Ph.D.
Technical Service Manager
Ledgewood, NJ 07852
ExcipientFest
San Juan, Puerto Rico
April 22, 2009
Chemistry 101 for Non-Chemists
Part I
Chemical Principles Applicable to Active Pharmaceutical Ingredients (API's) in solid oral dosage:
Basic chemical principles such as oxidation, hydrogen bonding, moisture absorption, and light and temperature sensitivity play a critical role in the stability of the API. Part I of this session will focus on developing a basic understanding of chemical interactions between the API's and the environment. In addition the inherent toxicological challenges and safety aspects surrounding the API world will be addressed with simple examples and pharmaceutical norms.
The Drug Formulation Balance
API
DeliveryForm
Excipients
Manuf.Processing
Safety &Efficacy
Highly Regulated
Environment
FDA
Active Pharmaceutical Ingredient (API)
“A compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active ingredient.”
(World Health Organization, Blue Book)
API Source Information
IntPh International Pharmaceutical Abstract
CA Chemical Abstract by ACS
PhEur European Pharmacopeia
USP United States Pharmacopeia
JPE Japanese Pharmacopeia
Merck The Merck Index
Apr Analytical Profiles of Drug Substances & Excipients
Codex Pharmaceutical Codex
Lit Literature search
Classification
Active Pharmaceutical Ingredient
FDA Approved
Pharmacopoeial Monograph
No PharmacopeialMonograph
New Chemical Entity (NCE)
Used in InnovatorProduct
Lower Risk High`
Dekker, WHO Workshop 2007
Presentation Scope
Structures
Specifications
Solubility
Stability
STRUCTURE
New Chemical Entity (NCE)
Proof of chemical structure with correct stereochemistry, if any
Spectrometric data (IR, 1H & 13C NMR, MS, etc.)
Stereochemistry and Optical rotation
Single crystal X-ray structure
Structure assignments against the structure from peer reviewed literature
Strongly recommended methodologies
» 1H & 13C NMR, IR, Mass Spectroscopy, and Stereochemistry
Physico-chemical properties
SPECIFICATION
Typical Parameters
Appearance/descriptionIdentification (at least one specific, e.g. infrared spectrum)Moisture content or LOD (moisture/water)Impurities
Related organic substances Specified (identified and unidentified), including stereo-isomers
Unspecified andTotal organic impurities
Inorganic impurities, including catalysts/heavy metalsResidual solvent(s)
AssayParticle size, polymorphic form, microbial limits
Typical Parameters…contd.
Storage recommendations
to avoid/minimize degradation for sensitive materials
to avoid/minimize any contamination
possible vectors leading to degradation - elevated temperatures, light, oxygen (free radicals), moisture/high humidity, microorganisms
e.g. aspirin – store in an air tight container (EP)
e.g. erythromycin- protect from light (EP)
Manufacturer retest date
- Shelf life of the API and qualifying criteria after retesting
SOLUBILITY
Rules
Description
Polar solutes dissolve in polar solventsNon-polar solutes dissolve in non-polar solvents
Some Examples
EthanolCHCl3WaterAPI
SlightlyFreelyWater: Slightly pH 7.5: 0.3% pH 5.3: 0.4% pH 2.0: 10%
Rifampicin
20%0.1%50%Ethambutol 2HCl
ModerateVerySparinglyEthambutol base
2%0.1%14%Isoniazid
0.6%0.7%1.5%Pyrazinamide
Ibuprofen
2333.447.4
2373.376.8
11680.6855.5
95240.0844.5
186050.0433
210530.0381
Volume to dissolve 800 mg Ibuprofen (ml)
Solubility at 37 oC(mg/ml)
pH
Potthast et al., J. Pharm. Sci., 2005, 94, 2121
Type II
70%
Type IV
20%
Type I
5%
Type III
5%
Solubility/PermeabilitySo
lubi
lity
Permeability Benet, EDAN, Leuven, March 18-20 2007
LSLP
LSHP
HSHP
HSLP
STABILITY
Environmental Susceptibility
Rifampicin
Quinone
Dekker, North West University, South Africa
Light SensitiveOxygen SensitiveMoisture Sensitive
Hydrolysis (to 25-desacetyl)
Oxidation(to quinone)
Oxidation(to N-oxide)
Hydrolysis(to 3-formyl Rifamycin)
Factors
Particle size/surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Oxidation
Examples:Amine Oxidation
Alcohol Oxidation
Aldehyde Oxidation
Chemical Induced
Oxidations
Examples:Aromatic hydroxylation
Aliphatic oxidation
Epoxidation
N-Oxidation
S-Oxidation
Microsomal mediated
Oxidations
Oxidation
Benzylic carbon
Benzylic carbon
Metoprolol-Lopressor®Beta adrenergic blocker
Tolmetin - Tolectin®Anti-inflammatory analgesic
Oxidation
Oxidation
Factors
Particle size/surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Hydrolysis
Paclitaxel
Paclitaxel Baccatin III
(Anti-tumor activity) (Inactive)
H
Hydrolysis
pH dependent
Factors
Particle size/surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Hygroscopicity
Cefixime trihydrate
Kitamura et al. Int. J. Pharm. 1990, 59, 217-224
Cefixime tihydrate is unstable below the critical relative humidity
Rate of decomposition usually increases with %RH
Dehydration creates disorderand instability
Faster rate of degradation atlow %RH
Some compounds may need lattice water for stability
COOH Lactone
Factors
Particle size/surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Stereochemistry
(R)- and (S)- Enantiomers*
Beta blockerInactivePropranolol
Convulsant effectAnesthetic activityMethylphenylpropylbarbituric acid
ToxicAntibioticPenicillamine
PsoriasisPsoriasisFlecainide
AllergyAllergyPromethazine
(S)-Enantiomer(R)-Enantiomer
API Biological Activity
*Enantiomers - Mirror image but not super-imposablee.g. left and right hands
Stereochemistry.. Contd.
(R)-Ibuprofen to (S)-Ibuprofen
Only (S)-(+)-enantiomer of the racemic (R,S) Ibuprofen is active
(R)-(-)-enantiomer is converted in VIVO irreversibly to (S)-(+)-Ibuprofen
No apparent therapeutic advantage of (R)-(-)-enantiomer.
Interest in marketing (S)-(+)-ibuprofen has been very limited!!
Racemic (R,S)-(+)-Ibuprofen Enantiomers
(R,S)
Achiral
Factors
Particle size/surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Photo-degradation
MOLECULE
Photo-degradation
Aclovir
Iqbal et al., Chem. Pharm. Bull., 2006, 54, 519-521
Factors
Particle size/surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Light and Temperature Sensitivities
Co-enzyme Form Vitamin B12
Haleblian JK. J. Pharm. Sci. 1975, 64, 1269-88
0
20
40
60
80
100
% R
emai
ning
Crystal Hydrate Form A Hydrate Form B
Sun light, 3HrTemp. 85 oC, 1Hr
Factors
Particle size/Surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Polymorphism or Crystal Packing
Polymorphism May Lead to:
Definition
A compound with at least two different orientations of the molecules in the crystalline state.
Polymorphism or Crystal Packing…contd.
Different melting temperatures (MP) and enthalpy of melting (ΔH)
Different hygroscopicity
Different solubility
Different stability
Different toxicology and safety
Different dissolution, efficacy and bioavailability
Transformation from the least stable to most stable polymorph
Undesired Interaction with the excipients in the formulations
Manufacturing issues
Polymorphism….contd.
Single and two component packings
Single component crystal packing Two components crystal
packing
Example Example
Butterflies
Fish and Boats
Polymorphism….contd.
Dissolution of Carbamazepine (CBZ)
Kabayashi et al. Int. J. Pharm. 2000, 193:137-146
CBZ dissolution rate decreased in the order: Form III > Form I > Dihydrate
Form III is transformed to dihydratemore readily than Form I, and thus lowers the dissolution rate
Determined by the static disk method in JP13 1st fluid at 37°C,(0–10 min)
Form III
Form I
Dihydrate
(Stable at RT)(Stable at high temp.)
Factors
Particle size/surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Isomerization
Vitamin A
13-Z-Retinoic acid(13-cis-Retinoic acid)
Isotretinoin
Tretinoin
All-trans-retinoic acid(all-E Vitamin A acid)
Light Sensitive
Chemical Formula:C20H28O2
Mol. Wt.:300.4
Factors
Particle size/Surface areaPhoto-degradation
IsomerizationStereochemistry
PolymorphismHygroscopicity
Temperature Sensitivity Hydrolysis
Light SensitivityOxidation
Particle size/Surface area
Molecule Particle Powder
Chemistry Physics Functional
Structure Particle Size Surface area
• Molecular weight Surface properties Flowability• Melting point• pKa• clogP Crystallinity• Assay Porosity• Impurity Hygroscopicity
Mechanical MillingCompressibility
Solubility Dissolution
Particle size/Surface area…contd.
Cephalexin
0
2
4
6
8
10Su
rfac
e ar
ea (m
2/g)
Crystalline Spray Dried Ball Milled Freeze Dried
Physical StateParticle size decreased in the order:
Freeze dried > Ball milled > Spray dried > Crystalline
Hydration state is different under different relative pressure and temperatureconditions
Hendriksen and York, Int. J. Pharm. 1995, 118, 1-10
Presentation Scope
Structures
Specifications
Solubility
Stability
Stability Testing
Process Methodology
STABILITY TESTING
ICH Conditions
1260±5Long term: 25±2
1265±5Intermediate: 30±2
675±5Accelerated: 40±2
Minimum time period covered by data at submission (months)
Relative
Humidity(%)
Storage temperature(°C)
Shelf Life
Carstensen, J.T., Drug Dev. Indus. Pharm 1988; 14,1927-69.
PROCESSING METHODOLOGY
Selection
Understanding of degradation
pathways of API
Understanding of Physico-chemicalproperties of API
APIs sensitive to moisture mediated degradation,choose direct compression or dry granulation over wet granulation
APIs sensitive to hydrolysis (e.g. ester pro-drugs), choose alcoholic and semi-solid vehicles, or lyophilization, hot melt, or spray drying process
For APIs with poor flowability, choose a granulation approach (wet or dry granulation)
For APIs with reduced crystallinity after processinge.g. milling, micronization, etc., choose wet granulation(presence of water will anneal (crystallise) amorphous API)
For APIs with low melting point, choose an encapsulation approach (high speed rotary presses will generate heat that could melt API)
Summary
Chemical StructuresSpecificationSolubility Stability Safety and ToxicologyPhysical and chemical propertiesMorphologyParticle size and surface area
Summary…contd.
Degradants and their toxicologies
Structural changes (chirality, racemization and isomerization)
Crystal packing (polymorphs and co-crystals)
Hygroscopicity
Susceptibility to oxidation and photo-degradation
Manufacturer’s CoA, test methods, and retest date
Let’s Discuss
Thank You For Your Attention!