Pharmaceutical Development
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
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Slide 1 of 39
April 2007
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)
(p.york@bradford.ac.uk)
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Slide 2 of 39
April 2007
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
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Slide 3 of 39
April 2007
Sources 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
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Slide 4 of 39
April 2007
Specifications 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
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Slide 5 of 39
April 2007
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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Slide 6 of 39
April 2007
Generalised 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
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Slide 7 of 39
April 2007
Generalised 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
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Slide 8 of 39
April 2007
Pharmacopoeial 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
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Slide 9 of 39
April 2007
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 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)
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Slide 10 of 39
April 2007
Aspirin Molecule - Structure
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Slide 11 of 39
April 2007
Erythromycin Molecules- Structure
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Slide 12 of 39
April 2007
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 aspirin – store in an air tight container (EP)
eg erythromycin- protect from light (EP)
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Slide 13 of 39
April 2007
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
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Slide 14 of 39
April 2007
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
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Slide 15 of 39
April 2007
API Properties – Formulation Design
and 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
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Slide 16 of 39
April 2007
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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Slide 17 of 39
April 2007
API Properties - Solubility
 Many drugs are weak acids or weak bases
 Dissociation (ionisation) constants and pea
Change in degree of ionisation and
relative solubility of weakly acidic
and weakly basic drugs as a
function of pH
 Formulation and drug delivery issues
 pKa of aspirin (weak acid) = 3.5
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Slide 18 of 39
April 2007
API Properties - Polymorphism
Representation of two
polymorphic forms of a
crystal consisting of a
molecule represented by a
‘hockey-stick’ shape
 e.g carbamazepine, ritonavir
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Slide 19 of 39
April 2007
API Properties – Crystallinity
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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Slide 20 of 39
April 2007
API 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).
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Slide 21 of 39
April 2007
API Properties – Formulation Design
and Processing
 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
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Slide 22 of 39
April 2007
API Properties – Particle Size Analysis
 Microscopy – equivalent diameters
Different equivalent diameters
constructed around the same particle.
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Slide 23 of 39
April 2007
API Properties – Particle Size Analysis
 - eye-piece graticule: circles with diameters in 2
progression
 - particle size distribution (number basis) over range
2 – 200 microns
Frequency distribution curves corresponding to (a) a normal distribution, (b) a positively
skewed distribution and (c) a bimodal distribution.
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Slide 24 of 39
April 2007
API Properties – Particle Size Analysis
 Sieve analysis – equivalent diameters
Sieve diameter ds for various
shaped particles
 - ‘stack’ of sieves
 - particle size distribution (weight basis) over range
50 – 1000 microns
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Slide 25 of 39
April 2007
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)
dm
 kA C s  C 
dt
 dm

 dt
= dissolution rate, A = surface area of solid, k = dissolution
rate constant, Cs = saturation of drug, C = concentration of drug in
solution)
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Slide 26 of 39
April 2007
API Properties – Particle Size Reduction
 Examples of drugs where a reduction in particle size has
led to improvements in bioavailability
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Slide 27 of 39
April 2007
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
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Slide 28 of 39
April 2007
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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Slide 29 of 39
April 2007
API Properties –
Prodrugs with modified permeability and absorption
 Examples of prodrugs with improved permeability and
oral absorption
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Slide 30 of 39
April 2007
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
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Slide 31 of 39
April 2007
API Properties – Characteristics
to be considered when formulating medicines
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Slide 32 of 39
April 2007
API Property Classification –
inter-dependencies between ‘groupings’
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Slide 33 of 39
April 2007
API Properties – Formulation Design
and Processing
 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)
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Slide 34 of 39
April 2007
API Properties – Formulation Design
and Processing
 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
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Slide 35 of 39
April 2007
‘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
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Slide 36 of 39
April 2007
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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Slide 37 of 39
April 2007
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
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Slide 38 of 39
April 2007
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
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Slide 39 of 39
April 2007