The document discusses preformulation of sterile products. It covers key areas of preformulation including bulk characterization, solubility analysis, and stability analysis. Bulk characterization involves assessing properties like crystallinity, polymorphism, particle size, powder flow, and hygroscopicity. Solubility analysis includes studying aqueous solubility, drug ionization at physiological pH, partition coefficient, and thermal effects. Stability analysis focuses on stability in toxicology formulations, solution stability, and solid state stability under various conditions. The goal of preformulation is to characterize important physicochemical properties of drug substances to aid in developing appropriate formulations.

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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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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