| slide 1 of 39 april 2007 training workshop on pharmaceutical development with focus on paediatric...

| Slide 1 of 39 April 2007

Training Workshop on Pharmaceutical Development

with focus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

Pharmaceutical DevelopmentPharmaceutical Development


Physicochemical Properties of APIsand their relevance to formulation

Physicochemical Properties of APIsand 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])


Physicochemical Properties of APIs and their relevance to formulation

Physicochemical Properties of APIs and their relevance to formulation

Outline of presentation

Assurance of quality and safety of APIs

Spectrum of tests and criteria for specifications for APIs

Inter-dependency between ‘categories’ of properties

‘Functionality’ testing related to formulation design

Summary of ‘challenges’ in API procurement and in evaluating APIs for formulation design


Sources of APIs - ProcurementSources of APIs - Procurement

Patented compounds – from 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


Specifications and Standards for APIsSpecifications and Standards for APIs

API suppliers – for patented compounds

Likely to be ‘licenced’ manufacturing agreement with originator, according to originator’s 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


Specifications and Standards for APIsSpecifications 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…..)


Generalised Content of API MonographsGeneralised Content of API Monographs

Objective – to provide the standards required to ensure the quality and safety of API compounds; appropriate limitation of potential impurities rather than provide against all possible impurities

Monographs generally focus on chemical identification and purity assessment

Chemical properties –

- structure, molecular weight and chemical formula, melting point, moisture content

- identification tests

- solubility in common solvents

- impurities, related substances (resulting from synthesis, and potential of degredants from storage during shelf life of API), and limits for

their contents

- assay


Generalised Content of API MonographsGeneralised Content of API Monographs

Increasing awareness of need to monitor physical, crystallographic and ‘functional’ 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


Pharmacopoeial Monographs for APIsPharmacopoeial Monographs for APIs

Nomenclature/structure

- follow international agreed systems (eg rINN, BAN; CASRN))

Identification – means of verifying identity of API is as stated on the label

- often two tests detailed –(for EP first is used in all circumstances, second if API complies with all other aspects of monograph)

Impurities/related substances

- specific, discriminating analytic methods

- substances controlled related to synthetic route (eg reagents, catalysts)

- limits imposed by monographs (and general guidelines)

- additional limits for known degredation products if API unstable on storage


Pharmacopoeial Monographs for APIsPharmacopoeial Monographs for APIs Assay

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

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

- purity figure related to reference substance

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

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

eg aspirin – 99.5 – 101.5% (EP)

eg erythromycin – sum of the contents of erythromycin A, B and C- 93.0 to 102%, with erythromycin B - maximum 5%, erythromycin C - maximum 5% (EP)


Aspirin Molecule - StructureAspirin Molecule - Structure


Erythromycin Molecules- StructureErythromycin Molecules- Structure


Pharmacopoeial Monographs for APIsPharmacopoeial 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 aspirin – store in an air tight container (EP)

eg erythromycin- protect from light (EP)


API Routine Testing – ‘Good Practice’ API Routine Testing – ‘Good 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 validation of methods

‘Confidence’ in consistent quality of supply from chosen suppliers


API Properties – Formulation Design and Processing


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

Many APIs exhibit polymorphism (also solvation – hydration) – alternative molecular packing of the same chemical in crystalline material leading to different properties such as dissolution rate)

Moisture content control – hygroscopic material often difficult to process (eg tabletting); change in hydration state (eg during wet granulation)

Respiratory drug delivery – DPIs and suspension MDIs require drug particle size (aerodynamic) of 1 – 5 microns

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


API Properties – Formulation Designand Processing


Additional tests (sometimes specified in monograph, or testing methods detailed in pharmacopoeias)-

Examples –

- solubility/dissolution (ie rate of solution)

- polymorphism (eg IR analysis)

- chirality (pure chiral API compared with racemate – HPLC with chiral colomn, capillary electrophoresis (CE))

- particle sizing (eg microscopy, sieves) or particle surface area (eg gas adsorption, permeability)

- particle sizing for inhalation products (eg cascade impactors for aerodynamic particle size measurement


API Properties - SolubilityAPI Properties - Solubility

Descriptive solubilities

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


API Properties - SolubilityAPI Properties - Solubility

Many drugs are weak acids or weak basesDissociation (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 a function of pH


API Properties - PolymorphismAPI Properties - Polymorphism

e.g carbamazepine, ritonavir

Representation of two polymorphic forms of a crystal consisting of a molecule represented by a ‘hockey-stick’ shape


API Properties – CrystallinityAPI Properties – Crystallinity

The disruption of a crystal (represented as a brick wall), giving the possibility for water vapour absorption in the amorphous region


API Properties – CrystallinityAPI Properties – Crystallinity

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).




Alternative pre-treatment and processing of APIs (eg alternative 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


API Properties – Particle Size AnalysisAPI Properties – Particle Size Analysis

Microscopy – equivalent diameters

Different equivalent diameters constructed around the same particle.



- eye-piece graticule: circles with diameters in progression

- particle size distribution (number basis) over range 2 – 200 microns

2

Frequency distribution curves corresponding to (a) a normal distribution, (b) a positively skewed distribution and (c) a bimodal distribution.



Sieve analysis – equivalent diameters

- ‘stack’ of sieves

- particle size distribution (weight basis) over range 50 – 1000 microns

Sieve diameter ds for various shaped particles


API Properties Particle size, drug dissolution and bioavailability

API Properties Particle 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 in

solution)

CCkAdt

dms

dt

dm


API Properties – Particle Size ReductionAPI Properties – Particle Size Reduction

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


API Properties – Biopharmaceutical Classification Scheme


Valuable classification system to guide formulators in requirements for ‘particle engineering’ of APIs

Consider aqueous solubility and permeability via oral route of delivery

Class I – high solubility, high permeability

- rapid absorption, good bioavailability

- eg propanolol, metaprolol

Class II – low solubility, high permeability

- API controls absorption; potential for particle size effects on bioavailability

- eg ketoprofen, carbamazepine




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’


API Properties – Prodrugs with modified permeability and absorption

API Properties – Prodrugs with modified permeability and absorption

Examples of prodrugs with improved permeability and oral absorption


API Properties and Design of Medicines 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 for ‘desired’ API properties, in addition to chemical quality and safety assurance


API Properties – Characteristics to be considered when formulating medicines

API Properties – Characteristics to be considered when formulating medicines


API Property Classification – inter-dependencies between ‘groupings’

API Property Classification – inter-dependencies between ‘groupings’




Formulation design – dosage form and delivery route issues, and ‘functionality’ tests for guiding choice of processing route and conditions

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

For preparation of solutions, suspensions, granules for reconstitution

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

For solid dosage forms – eg tablets and capsules

- NB biopharmaceutics classification

- potential for increasing drug dissolution rate

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




Additional tests being considered for including in pharmacopoeias as tests for APIs (and solid particle excipients)

- these include ‘functionality’ based (to standardise ‘performance’ of API in formulation and secondary processing)

- characterisation of crystalline and partially crystalline solids (by X-ray powder diffraction)

- porosity and pore size distribution of solids (by mercury porosimetry)

- water-solid interactions (by sorption isotherms, hygroscopicity, water activity)

- particle size analysis (by laser light diffraction)

- calorimetric and thermal behaviour of powders


‘Life-Time’ of APIs‘Life-Time’ of APIs

Appropriate specifications must be met throughout ‘life-time’ of API to ensure quality and safety

Life-time = from - isolation of API

- API received by product manufacturer from supplier

- API processed into pharmaceutical product

- storage period of product (shelf life limit)

to - end of period of administration of product to patient

NB Alternative specifications will apply at the different stages


Challenges for API Procurement and Evaluation

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!!


Challenges for API Formulation and Processing

Challenges for API Formulation and Processing

Identify critical chemical, physical and ‘functional’ properties which are crucial for specific formulation requirements

Awareness of stability of API as pure substance, during formulation and processing, and through ‘shelf life’ of product

This information needs to be linked to the type of dosage form required, route of administration and desired ‘shelf life’ of product under ‘anticipated’ storage conditions


Physicochemical Properties of APIs their relevance to formulation

Physicochemical Properties of APIs 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 evaluating APIs for formulation design

| slide 1 of 39 april 2007 training workshop on pharmaceutical development with focus on paediatric...

Documents

safety slide

sources of apis

apis api suppliers

formulation design slide

specified batches slide

contents assay slide

generic apis transition

apis interdependency