Transcript Phases in drug developments I: Pre

Phases in drug developments I:
Pre-clinical studies
Kausar Ahmad
Department of Pharmaceutical Technology
Kulliyyah of Pharmacy
[email protected]
http://staff.iium.edu.my/akausar
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Phases in drug development
Preformulation
• Chemical evaluations
Dosage form design
• Determination of dosage forms & product formulation
Early stage development
• Pharmaceutical, animal study and in-vitro evaluation
Late stage development
• In-vivo and clinical evaluations
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Preformulation
Understanding physicochemical parameters of a
drug
• Characterization of drug molecule
Application of biopharmaceutical principles
Drug delivery system
• Dosage form
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Physicochemical properties
Spectroscopy
Solubility
pKa
Partition
coefficient
Melting point
Crystal
properties and
Polymorphism
Particle size
shape
surface area
microscopy
Powder flow
Compression
properties
Stability
studies
Excipient
compatibility
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Physicochemical properties
• to produce a simple
method for analysing
the drug
• for identifying the
best salt to develop
and for producing
liquid dosage forms
• which reflects, for
example, crystalline
solubility
spectroscopy
solubility
melting point
assay
development
• in solution and in the
solid state, alone or
with excipients
• to determine crystal
morphology and
particle size and
polymorphism
• necessary data for
capsule & tablet
formulation
• to ensure that dosage
forms perform
correctly
powder flow &
compression
properties
excipient
compatibility
stability
Microscopy
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• necessary for drug
stability studies,
perhaps employing
thin layer- or high
pressure liquidchromatography
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Spectroscopy
To confirm drug structure and functional groups
• Usually by UV.
to quantify amount of drug in a particular solution
• use wavelength at λmax
• the amount of light absorbed is proportional to concentration
(C) and the path length of the solution (L) through which the
UV light has passed.
• Beer-Lambert’s Law
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pKa
• Determination of the dissociation constant for
a drug - capable of ionization within a pH
range of 1 to 10
• This is important since solubility, and
consequently absorption, can be altered by
changing pH (buffer).
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Rate of dissolution
• Determination of the rate is important when it
is the rate limiting step in the drug absorption
process.
• If solubility of drug > 10 mg/ml, at pH7, there
will be no problem of bioavailability or
dissolution (Kaplan,1972)
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Partition coefficient
Partition coefficient (oil/water) indicates ability of a drug to cross cell
membranes.
It is defined as the ratio of un-ionized drug distributed between the organic and
aqueous phases at equilibrium.
Biological membranes are lipoidal in nature. Thus, the rate of drug transfer for
passively absorbed drugs is directly related to the lipophilicity of the molecule.
Po/w = (Coil/Cwater) equilibrium
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Melting Point
• Affected by purity
• Affected by types of polymorphs
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Crystal Properties & Polymorphism
Need to determine crystal morphology and particle size
A polymorph is a solid material with two or more different molecular arrangements and
having a distinct crystal shape. These differences disappear in the liquid or vapour state.
Polymorphs generally have different melting points, x-ray diffraction patterns, and
solubilities, even though they are chemically identical.
• Dissolution rate affects bioavailability
• Tensile strength affects compression ability
• Different stability at various temperature & pressure
In general, the stable polymorph exhibits the highest melting point, the lowest solubility,
and the maximum chemical stability
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Particle properties
Properties of drugs are affected by particle size and shape.
Particle size is critical in dose uniformity and dissolution
rate of solid dosage forms.
• poorly soluble drugs have low dissolution rate & hence low
bioavailability.
• But bioavailable when administered in a finely subdivided state rather
than as a coarse material.
Suspensions and creams are more uniform if the
ingredients used are in micronised form.
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Powder Flow & Compression Properties
necessary data for capsule & tablet formulation
• Ease of operation
• Homogeneity
• Uniform unit dose
Factors
•
•
•
•
•
Particles sizes distribution
Chemical characteristics of substances
Differences in polymorphs
Drug-excipient interactions
Drug-environmental & excipient-environmental interactions
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Polyamide: Carrier for insoluble ingredients; Protector for sensitive
ingredients; Slow delivery & long lasting effect
7 m, empty spheres
10 m, porous
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Excipient: Particle size distribution
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Excipient: Pore volume & pore diameter
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Chemical Stability of Active Compounds
Study of intrinsic stability of the active components
allow better approaches to formulation, selection of
excipients, use of protective additives and accurate
selection of suitable materials and design of packaging.
Include both solution and solid state experiments under
conditions typical for the handling, formulation, storage,
and administration of a drug candidate as well as
stability in presence of other excipients.
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Excipients & Product Stability
• Excipients are important for processing and
efficacy
– For tablets: binders, disintegrants, lubricants, and
fillers.
– For liquids: preservatives, thickener, colorants,
flavours, sweeteners, buffer and water
• Techniques to screen drug-excipient
compatibility:
– Thin-layer chromatography
– Differential thermal analysis
– Diffuse reflectance spectroscopy
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Incompatibility
Chemical
Physical
pH/dissociation
Immiscibility
pH/disperse
systems
Insolubility
Packaging
Formulation and
packaging materials
polyvalent cations
complexation
cationic and anionic
compounds of high MW
reducing agents (cause fading
of dyes)
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Detection of Incompatibility
Cracked
cream
Hydrolysis or
oxidation
Discoloration
Precipitation
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Other factors to be considered in
preformulation
Consumer’s
preferences
Compatibility of
packaging materials
Facility and
equipment
capabilities
Security/Protection
Market needs
Child-resistance
packaging
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Dosage form design
Ailment
Bio
Route of administration
Enteral
Pharmaceutics
Packaging
Parenteral
Oral
Rectal
Intravascular
Subcutaneous
tablets
suppositories
vaccines
Creams
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Dosage form
Tablets, liquids, capsules, creams, ointments, vaccines
Optimise formulation (& processes)
Use required excipients
• Surfactants
• Anti-oxidants
• Preservatives
• Binders
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Formulation
Process whereby drugs are combined with other
substances (excipients)
• e.g. preservative
to produce dosage forms
• e.g. cream
suitable for administration to or by patients.
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Formulation requirement: efficacy, safety, and quality
Contain accurate
dose
Convenient to
take or administer
Retain quality
throughout shelf life
& usage period
Provide drug in a
form for absorption
or other delivery to
the target
Manufactured by a
process that does not
compromise performance
and that is reproducible
and economical
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Categories of excipients
Provide essential parts of dosage form & enhance bioavailability
• Emulsifiers
• Viscosity modifier
Prevent degradation of the formulation: protect, improve safety & enhance
stability
• Anti-oxidants
• Anti-bacterials
• Preservatives
• UV absorbers
Aid processing during manufacturing
Assist product identification  colour
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Choosing excipients
physiological
inertness
commercially
available at
low cost
physical and
chemical
stability
absence of
pathogenic
microbial
organisms
conformance
to regulatory
agency
requirements
no interference
with drug
bioavailability
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Pharmaceutical evaluation
Product testing
Tablets
• Hardness
• Disintegration
Creams
• Viscosity
• Microbial
• Diffusion
Animal study
Efficacy of product
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Example
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Summary
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References
Aulton, M.E. (2002). Pharmaceutics – The Science of Dosage Form Design (2nd Ed.). Churchill
Livingstone.
Bugay, D. E. (1999). Pharmaceutical excipients : characterization by IR, Raman, and NMR spectroscopy.
Kibbe, A. H. (2000). Handbook of pharmaceutical excipients.
Rowe, R. C., Sheskey, P. J. & Owen, S. C. (2006). Handbook of pharmaceutical excipients
Rowe, R. C. (2009). Handbook of pharmaceutical excipients.
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