chemical principles applicable to active pharmaceutical ...proof of chemical structure with correct...

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






Hydrolysis

Paclitaxel

Paclitaxel Baccatin III

(Anti-tumor activity) (Inactive)

H

Hydrolysis

pH dependent

Factors






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






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






Photo-degradation

MOLECULE

Photo-degradation

Aclovir

Iqbal et al., Chem. Pharm. Bull., 2006, 54, 519-521

Factors






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





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






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





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!

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