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| Slide 1 of 39 April 2007

Training Workshop onPharmaceutical Development withfocus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

Pharmaceutical Development

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Physicochemical Properties of APIs

and their relevance to formulation

Presenter: Peter York

Professor of Physical Pharmaceutics

Institute of Pharmaceutical Innovation (IPI),

University of Bradford, UK

(www.ipi.ac.uk)

([email protected])
http://www.ipi.ac.uk/http://www.ipi.ac.uk/

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Sources of APIs - Procurement

Patented compoundsfrom originators or their licenced suppliers

Non-patented APIs and generic APIs

- transition from traditional supplying countries to other

emerging nations eg India, China

- consistency between tender samples and following supplies

from chosen supplier

- pressure regarding CoG issues; no compromise with APIs for

quality and safety

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Specifications and Standards for APIs

API suppliersfor patented compounds

Likely to be licenced manufacturing agreement with originator,

according to originators documentation

Drug Master File (submitted to registration authorities) containing

full details regarding synthesis, testing and analytical procedures,

impurities (sources and limits), storage requirements; drug source

will be originator or their licenced toll manufacturer

Certificate of Analysis provided by API supplier; details results of

routine tests applied to specified batches

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Specifications and Standards for APIs

Specific pharmacopoeial monographs for off-patent/generic APIs

Pharmacopoeias (eg BP) initiate new monographs for APIs

approaching end of patent life, with support/dialogue with originator

companies

USP, EP, Int Ph, and national pharmacopoeia (eg JP, BP)

Additional general guidance chapters and information provided in

pharmacopoeias (eg testing methods..)

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Generalised Content of API Monographs

Increasing awareness of need to monitor physical, crystallographic andfunctional properties some testing required by pharmacopoeial monographs

Such information can provide valuable aid to formulation design

Physical properties

- moisture content

- solid state/crystallography (eg polymorphism, level of solvation,crystalline/amorphous character)

- particle properties (eg particle size)

Storage recommendations

NB indication of availability of reference standards provided

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Pharmacopoeial Monographs for APIs

Assay

- often a precise, non-specific (eg volumetric assay) test detailed

- can use alternative assay method if known that alternative method willgive a result of equivalent accuracy

- purity figure related to reference substance

- local reference material can be used if calibrated against official referencematerial

- limits (range) based on data obtained in normal analytical practice, takinginto account normal analytical errors, and acceptance of some variation inmaterial

eg aspirin99.5101.5% (EP)

eg erythromycinsum of the contents of erythromycin A, B and C- 93.0 to102%, with erythromycin B - maximum 5%, erythromycin C - maximum 5%(EP)

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Erythromycin Molecules- Structure

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Pharmacopoeial Monographs for APIs

Storage recommendations

- to avoid/minimise degradation for sensitive materials

- to avoid/minimise any contamination

- possible vectors leading to degradation - elevated

temperatures, light, oxygen (free radicals), moisture/high

humidity, microorganisms

eg aspirinstore in an air tight container (EP)

eg erythromycin- protect from light (EP)

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API Routine TestingGood Practice

Provide assurance of quality and safety

Verification of CoA and magnitude of testing programme

Sampling programme/isolated quarantine storage areas

Retention/storage of batch samples

Training programmes for staff, SOPs, GLP and validationof methods

Confidence in consistent quality of supply from chosensuppliers

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API PropertiesFormulation Design

and Processing

50% of new APIs, and many others, have very low aqueous solubility which canconstrain drug dissolution (ie rate of solution) and thereby limit bioavailability

Many APIs exhibit polymorphism (also solvationhydration)alternativemolecular packing of the same chemical in crystalline material leading to differentproperties such as dissolution rate)

Moisture content controlhygroscopic material often difficult to process (egtabletting); change in hydration state (eg during wet granulation)

Respiratory drug deliveryDPIs and suspension MDIs require drug particle size(aerodynamic) of 15 microns

All above are also examples of QUALITY issues when formulating andprocessing APIs; may require additional testing and/or control procedures

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API Properties - Solubility

Descriptive solubilities

General rules Polar solutes dissolve in polar solvents Non-polar solutes dissolve in non-polar solvents

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API Properties - Solubility

Many drugs are weak acids or weak bases Dissociation (ionisation) constants and pea

Formulation and drug delivery issues pKa of aspirin (weak acid) = 3.5

Change in degree of ionisation and

relative solubility of weakly acidic

and weakly basic drugs as afunction of pH

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API Properties - Polymorphism

e.g carbamazepine, ritonavir

Representation of two

polymorphic forms of a

crystal consisting of a

molecule represented by ahockey-stick shape

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API PropertiesCrystallinity

The disruption of a crystal

(represented as a brick wall),

giving the possibility for water

vapour absorption in the

amorphous region

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API PropertiesCrystallinity

API pretreatment effects on crystallinity

The amorphous content of a model

drug substance following milling in a

ball mill and a micronizer (Ahmed et

al 1996).

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and Processing

Alternative pre-treatment and processing of APIs (egalternative final solvent used during final crystallisation

step during synthesis of API; use of crystallisation rather

than milling process for particle size reduction ) can lead

to different surface properties of particles, such as

interparticle cohesion and surface charge

These phenomena can lead to different secondary

processing behaviour and potentially variation in product

performance

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API PropertiesParticle Size Analysis

Microscopyequivalent diameters

Different equivalent diameters

constructed around the same particle.

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- eye-piece graticule: circles with diameters inprogression

- particle size distribution (number basis) over range

2200 microns

2

Frequency distribution curves corresponding to (a) a normal distribution, (b) a positively

skewed distribution and (c) a bimodal distribution.

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Sieve analysisequivalent diameters

- stack of sieves

- particle size distribution (weight basis) over range501000 microns

Sieve diameter dsfor various

shaped particles

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API PropertiesParticle size, drug dissolution and bioavailability

Dissolution is measure of rate of solution Dissolution related to particle size and particle surface area

(smaller particle size, larger surface area, faster dissolution)

= dissolution rate, A = surface area of solid, k = dissolution

rate constant, Cs= saturation of drug, C = concentration of drug insolution)

CCkA

dt

dm

s

dt

dm

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API PropertiesParticle Size Reduction

Examples of drugs where a reduction in particle size hasled to improvements in bioavailability

API P ti

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API Properties

Biopharmaceutical Classification Scheme

Valuable classification system to guide formulators in requirements for particleengineering of APIs

Consider aqueous solubility and permeability via oral route of delivery

Class Ihigh solubility, high permeability

- rapid absorption, good bioavailability

- eg propanolol, metaprolol

Class IIlow solubility, high permeability

- API controls absorption; potential for particle size effects onbioavailability

- eg ketoprofen, carbamazepine

API P ti

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API Properties

Biopharmaceutical Classification Scheme

Class III high solubility, low permeability

- APIs dissolve rapidly and poorly absorbed

- require fast API dissolution to maximise absorption

- potential benefits from particle size reduction

eg ranitidine, atenolol

Class IV low solubility, low permeability

- challenging molecules, likely to exhibit low bioavailability

eg hydrochlorothiazide, furosemide,

- option to increase permeability - modify APIs as prodrugs

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API PropertiesProdrugs with modified permeability and absorption

Examples of prodrugs with improved permeability andoral absorption

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API Properties and Design of Medicines

Wide range of dosage forms - liquids, semi-solids, solids

Range of administration routes

Medicines containing more than one API

Single unit dosage and multi unit dose systems

Device, administration and compliance issues

All these are issues that can impose requirements fordesired API properties, in addition to chemical qualityand safety assurance

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API PropertiesCharacteristics

to be considered when formulating medicines

API P t Cl ifi ti

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API Property Classification

inter-dependencies between groupings

API P ti F l ti D i

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and Processing

Formulation designdosage form and delivery route issues, and functionalitytests for guiding choice of processing route and conditions

API stability, solubility (dissolution) and particle size are key properties foreffective formulation design

For preparation of solutions, suspensions, granules for reconstitution

- NB attention to stability (chemical and physical) and storage requirements

For solid dosage formseg tablets and capsules

- NB biopharmaceutics classification

- potential for increasing drug dissolution rate

- potential for modifying drug solubility/permability (eg salts, prodrugs)

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Life-Time of APIs

Appropriate specifications must be met throughout life-time of APIto ensure quality and safety

Life-time = from - isolation of API

- API received by product manufacturer fromsupplier

- API processed into pharmaceutical product

- storage period of product (shelf life limit)

to - end of period of administration of product to

patientNB Alternative specifications will apply at the different stages

Challenges for API Procurement

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Challenges for API Procurement

and Evaluation

Compliance with CoA, and/or pharmacopoeial

monograph

Consistency within/between batches, sampling issues

Alternative suppliers and CoG issues

Building confidence in supplying agencies

Quality and safety, quality and safety, quality and safety!!

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their relevance to formulation

Summary and conclusion

Assurance of quality and safety of APIs

Spectrum of tests and specifications of criteria for APIs

Interdependency between categories of API properties

Functionality testing related to formulation design (and

processing route and conditions)

Summary of challenges in API procurement and in evaluatingAPIs for formulation design

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