1. Dr. Prashant L. Pingale
Associate Professor-Pharmaceutics
GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research,
Nashik
Preformulation of Sterile Products

2. Learning outcomes
 On successful completion of this unit learners shall able to:
 Know about pre-formulation of sterile products,
 Discuss a physicochemical properties of drug substances.
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3. Preformulation
 Preformulation is a stage of development during which the physicochemical
properties of drug substance are characterized and established.
 The knowledge of relevant physicochemical and biopharmaceutical
properties determines the appropriate formulation and delivery method for
preclinical and Phase-I studies.
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4. Preformulation and Need
 To establish the necessary physicochemical parameters of drug ubstances
 To determine kinetic rate profile
 To establish physical characteristics
 To establish compatibility with common excipients.
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5. 5
Bulk characterization Solubility Analysis Stability Analysis
Principle areas of Preformulation

6. Bulk Characterization
 Crystallinity
 Polymorphism
 Particle size
 Powder flow property
 Hygroscopicity
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7. Crystallinity
 Crystal habit and internal structure of a drug can affect bulk and
physicochemical properties, which range form flow ability to chemical
stability.
 The crystal habit describes the outer appearance of crystals( plate,
equate, needle, bladed, etc.) and internal structure arrangement.
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8. Polymorphism
 Polymorphism is the ability of the compound to
crystallize as more than one distinct crystalline species
with different internal structure.
 Formation of different polymorphs depends on solvents,
temperature, pressure, rate of cooling, etc.
 Polymorphic transitions can also occur during milling,
granulating, drying and compressing operations
 Different polymorphs vary in physical properties such as
dissolution, solid-state stability, compatibility, etc.
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9. Particle size
 Study of particle size give an information about solubility, dissolution rate, absorption, etc.
 Fine particle characterization very important property and here smallest particle should be
tested to facilitate homogeneous sample preparation.
 Counter current Technique-To check particle size and particle volume
 BET (Brunauer, Emmet, Teller) Nitrogen Adsorption Apparatus-Measurement of surface area
 SEM( Scanning Electron Microscopy)- to check surface morphology.
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10. Powder flow property
 The flow properties of a powder will determine the nature and quantity of excipients
needed to prepare a compressed or a powder dosage form.
 This refers mainly to factors such as the ability to process the powder through
machines.
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11. Hygroscopicity
 The tendency of a solid to take up water from the atmosphere, as it is subjected to a
controlled RH program under isothermal condition i.e. hygroscopicity.
 Classified based on the amount of rate of water uptake when a solid is exposed to
controlled RH value at a specified temperature.
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12. Solubility Analysis
 Aqueous Solubility
 Drug pKa / Ionization at Physiological pH
 Partition Coefficient
 Thermal effect
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13. Aqueous Solubility
 Solubilization is increased by addition of cosolvent
 Example: propylene glycol solubilize drug molecules by disrupting the
hydrophobic interactions of water.
More non polar the solute
Greater is the solubilisation
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14. Drug pKa / Ionization at physiological pH
 pKa is the dissociation constant of a drug.
 The non ionized substances is lipid soluble thus dissolve in lipid material
of the membrane and transported by passive diffusion.
 Where as, the ionized substances is a lipid insoluble therefore
permeation takes place.
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15. Drug pKa / Ionization at physiological pH
 The percentage of ionization can be calculated as:
 For Acidic compounds:
% ionized = 100/ 1+ antilog (pKa – pH)
 For Basic compounds:
% ionized = 100/ 1+ antilog (pH – pKa)
 Degree of ionization depends up on the pH.
 For acidic drugs pKa ranges from 3-7.5.
 For basic drugs pKa ranges from 7-11
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16. Partition Coefficient
 Partition coefficient influence permeation of a drug across biological
membrane.
 Partition coefficient is a ratio of equilibrium concentration of drug in
oil phase to equilibrium concentration of drug in aqueous phase.
K=Co/Cw
 where, Co is organic phase concentration and Cw is aqueous phase
concentration
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17. Thermal/Heat Effects
 Drugs which are unstable to heat requires refrigerate storage or lyophilization
(these products must be used within short periods)
 If it is endothermic ---> ΔH is +ve, increase in temp ---> increase in drug solubility
 If it is exothermic ---> ΔH is –ve increase in temp ---> decrease in drug solubility
 For determining ΔH
ln S= - ΔH /RT + C
where S is molar solubility at temperature, T is temperature in Kelvin, R is gas constant, C is constant.
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van 't Hoff equation

18. Stability analysis
 Stability in toxicology formulation
 Solution stability
 Solid state stability
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19. Stability in toxicology formulation
 Toxicology studies typically commence early in development, it is often
advisable to evaluate samples of the toxicology preparation for stability
and potential homogeneity problems.
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20. Solution stability
 The primary objective of this phase of pre-formulation research
is identification of condition necessary to form a stable solution.
 This study include-effect of pH, ionic strength, light, temperature
and oxygen.
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21. Solid state stability
 Solid phase stability depends on several factors like temperature, pH,
humidity, hydrolysis, oxidation, etc
 For a new drug compound
Weighed sample are place in open screw cap vials and are exposed directly
to light, temperature, humidity for 12 weeks.
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22. Hydrolysis
 Important factor in drug stability.
 Hydrolytic reaction involves nucleophilic attack.
 The condition catalysis the brake down as follows:
Presence of OH.
Presence of divalent metal ion.
Presence of light and heat.
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23. Oxidation and Reduction
 Oxidation is controlled by environment (i.e.) light, oxygen & oxidizing
agent.
 Reduction is based on redox reaction where there is mutual change in
electrons.
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