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 RM-KAHS 1
Dec 18, 2015
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Phases in drug developments I: Pre-clinical studies
Kausar AhmadDepartment of Pharmaceutical Technology
Kulliyyah of [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 pointCrystal
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
spectroscopy
• for identifying the best salt to develop and for producing liquid dosage forms
solubility
• which reflects, for example, crystalline solubility
melting point
• necessary for drug stability studies, perhaps employing thin layer- or high pressure liquid- chromatography
assay development
• in solution and in the solid state, alone or with excipients
stability
• to determine crystal morphology and particle size and polymorphism
Microscopy
• necessary data for capsule & tablet formulation
powder flow & compression properties
• to ensure that dosage forms perform correctly
excipient compatibility
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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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Crystal Properties & Polymorphism
Need to determine crystal morphology and particle size
• Dissolution rate affects bioavailability• Tensile strength affects compression ability• Different stability at various temperature & pressure
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.
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.
• 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.
Particle size is critical in dose uniformity and dissolution rate of solid dosage forms.
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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10 m, porous
7 m, empty spheres
Polyamide: Carrier for insoluble ingredients; Protector for sensitive ingredients; Slow delivery & long lasting effect
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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
Incompatibility
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Chemical
pH/dissociation
pH/disperse systems
polyvalent cations
complexation
cationic and anionic compounds of high MW
reducing agents (cause fading of dyes)
Detection of Incompatibility
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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
Market needs
Security/ProtectionChild-resistance
packaging
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Dosage form design
Ailment
Route of administration
EnteralOraltablet
s
Rectalsupp
ositories
ParenteralIntrav
ascularvacci
nes
Subcutaneo
usCreams
BioPharmaceutics Packaging
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Dosage form
Tablets, liquids, capsules, creams, ointments, vaccines
Optimise formulation (& processes)
Use required excipients• Surfactants• Anti-oxidants• Preservatives• Binders
Formulation
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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
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Contain accurate dose Convenient to take or administer
Provide drug in a form for absorption or other
delivery to the target Retain quality throughout shelf life & usage period
Manufactured by a process that does not compromise
performance and that is reproducible and
economical
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Categories of excipients
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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
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physiological inertness
physical and chemical stability
conformance to regulatory agency
requirements
no interference with drug bioavailability
absence of pathogenic microbial
organisms
commercially available at low cost
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Pharmaceutical evaluation
Product testing
Tablets• Hardn
ess• Disint
egration
Animal study
Efficacy of product
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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.