Transcript Physicochemical properties of APIs and their relevance to formulation

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)
([email protected])
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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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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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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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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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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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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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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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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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April 2007
Aspirin Molecule - Structure
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April 2007
Erythromycin Molecules- Structure
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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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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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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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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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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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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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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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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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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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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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April 2007
API Properties – Particle Size Analysis
 Microscopy – equivalent diameters
Different equivalent diameters
constructed around the same particle.
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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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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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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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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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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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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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April 2007
API Properties –
Prodrugs with modified permeability and absorption
 Examples of prodrugs with improved permeability and
oral absorption
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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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April 2007
API Properties – Characteristics
to be considered when formulating medicines
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April 2007
API Property Classification –
inter-dependencies between ‘groupings’
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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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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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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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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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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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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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April 2007