1. Phases in drug developments I: Pre-clinical studies
Kausar Ahmad
Department of Pharmaceutical Technology
Kulliyyah of Pharmacy
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2. 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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3. Preformulation Understanding physicochemical parameters of a drug
Characterization of drug molecule
Application of biopharmaceutical principles
Drug delivery system
Dosage form
drug has already been discovered.
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4. 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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5. 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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6. 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
Non-UV spectroscopy:
Vibrational spectroscopy IR
Raman spectrum
NMR spectrometry
1H-NMR and 13C-NMR
Mass spectrometry
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7. 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).
The Henderson-Hasselbalch equation provides an estimate of the ionized and un-ionized drug concentration at a particular pH.
For weak acids: pH = log10 (Conc Acids/ Conc Salts)
For weak bases: pH = log10 (Conc Salts/ Conc Bases)
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8. 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)
Done by placing product in basket, rotate at 100 rpm, 20 mm from bottom of a 1 L flat bottomed dissolution flask which contain 1L of fluid at 370C.
The amount of drug release is then monitored, usually by UV spectrometry, with time (eg. 0, 5, 15, 30, 45 mins)
Fluid used : 0.05M HCL (gastric, pH1), phosphate buffer (intestinal, pH7) and distilled water
Dissolution rate depends on : Intrinsic solubility, pKa and pH of surrounding (bulk dissolution medium or microenvironment created by the dissolving salts)
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9. 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
This balance has been shown to be a contributing factor for the rate and extent of drug absorption.
Drugs having values of P greater than 1 are classified as lipophilic, whereas those with partition coefficients less than 1 are indicative of a hydrophilic drug.
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10. Melting Point Affected by purity Affected by types of polymorphs
3 types of measuring MP:
– Capillary melting
– Hot stage microscopy
– Differential Thermal Analysis or Diff Scanning calorimetry
Capillary melting observe melting in a capillary tube
Only.
Hot stage microscopy used microscope with a heated and lagged sample stage; allowing 3 transition phases be observed
– 1st melt > 50% melt > complete melting
Differential thermal analysis allows all the various phase
changes be observed.
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11. 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
Critical issues in formulation:
No. of polymorphs exisiting for the substance
Identify pseudopolymorphism or true polymorphism
Stability of the different polymorphs
Is there an amorphous glass?
Can the metastable be stabilised?
What is the solubility and melting points of each forms?
Will the more soluble form be stable after processing and storage?
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12. 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.
Bulk flow, formulation homogeneity, dissolution and chemical reactivity are directly affected by size, shape & surface morphology of the drug particles as well as particle size distribution.
Size can also be a factor in stability of tablets; fine materials are relatively more prone to attack from atmospheric oxygen, humidity, and interacting excipients compared to coarse materials.
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13. 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
Assessing powder flow by:
Measuring bulk density/tapped density
Measuring angle of repose
Use of Carr’s index (%) for Bulk density = (Tapped density – Poured density) / Tapped density
Carr’s index of 5 – 16 show good flow
Use of Hausner ratio = Tapped density / Poured density
Hauser ratio of less than 1.25 show good flow
Assesing the angle of repose, the angle of a conical mound of powder to the horizontal (θ )
θ with less than 30 show good flowability
Powder Compression Properties
Crucial for tablet dosage forms.
Most drug has poor compression properties, thus requiring compression aids.
If dose < 50mg, tablets can be prepared by direct compression using modern direct compression excipients.
If dose is high and drug does not have good compressibility, use wet granulation method.
To form good tablet, materials should be plastic (capable of permanent deformation) while also exhibit a degree of brittleness (fragmenting)
If drug dose is high and behave plastically, then add excipient that fragments (lactose, calcium phosphate)
If drug is brittle or elastic, add excipients that are plastic
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14. 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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15. Excipient: Particle size distribution
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16. Excipient: Pore volume & pore diameter
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17. 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.
Usually the first quantitative assessment
Max shelf-life allowable is 5 years
Factors influencing chemical stability in dosage form:
Temperature & humidity
pH, ionic strength
Co-solvent, dosage form diluent.
Light
Oxygen
Stress conditions used:
Elevated temperature studies
Stability under High-Humidity Conditions
Photolytic Stability
Oxidative Stability
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18. 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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19. Incompatibility Chemical pH/dissociation pH/disperse systems
polyvalent cations
complexation
cationic and anionic compounds of high MW
reducing agents (cause fading of dyes)
Physical
Immiscibility
Insolubility
Packaging
Formulation and packaging materials
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20. Detection of Incompatibility
Cracked cream
Hydrolysis or oxidation
Discoloration
Precipitation
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21. Other factors to be considered in preformulation
Consumer’s preferences
Compatibility of packaging materials
Facility and equipment capabilities
Market needs
Child-resistance packaging
Security/Protection
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22. Route of administration
Dosage form design
Ailment
Route of administration
Enteral
Oral
tablets
Rectal
suppositories
Parenteral
Intravascular
vaccines
Subcutaneous
Creams
Bio
Pharmaceutics
Packaging
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23. Dosage form
Tablets, liquids, capsules, creams, ointments, vaccines
Optimise formulation (& processes)
Use required excipients
Surfactants
Anti-oxidants
Preservatives
Binders
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24. 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.
Every medicinal product is a combination of the drug substance and excipients. Knowledge of the composition, function, and behavior of excipients is a prerequisite to the successful design, development and manufacture of pharmaceutical dosage forms.
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25. Formulation requirement: efficacy, safety, and quality
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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26. 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
Excipients in creams:
Base
SAA
Anionic - SDS
Non-ionic – Span, Tween
Anti-oxidants – BHA, BHT
Preservatives: methyl and propyl paraben (potency, integrity, prevent microbial growth)
Stearic acid
Stearyl alcohol, cetyl alcohol
Glycerol monostearate
Lanolin
Glycerin
Zinc stearate
opacifying agent, dusting powder…..
Fragrance, dyes
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27. Choosing excipients
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
No single excipient would satisfy all the criteria; therefore, a compromise of the different requirements has to be made.
For example, although widely used in pharmaceutical tablet and capsule formulations as a diluent, lactose may not be suitable for patients who lack the intestinal enzyme lactase to break down the sugar, thus leading to the gastrointestinal tract symptoms such as cramps and diarrhea.
What about excipients in creams?
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28. Pharmaceutical evaluation
Product testing
Tablets
Hardness
Disintegration
Creams
Viscosity
Microbial
Diffusion
Animal study
Efficacy of product
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29. Example
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30. Summary
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31. 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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