Pre formulation
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This document discusses preformulation studies for parenteral products. Preformulation testing provides important information for developing dosage forms and involves determining the physical and chemical properties of drug molecules. Key aspects of preformulation studies discussed include bulk characterization of properties like crystallinity and polymorphism. Solubility analysis looks at aqueous solubility, drug ionization, and partition coefficient. Stability studies evaluate stability in formulations, of solutions, and in the solid state under various temperature and humidity conditions. Additional analytical techniques discussed that are useful in preformulation include spectroscopy, microscopy, and chromatography. Thorough preformulation work lays the foundation for developing efficacious and stable dosage forms.
Pre formulation
- 1. P REFORMULATION OF P ARENTRAL P RODUCT BY, 11/03/13 Joan Vijetha.R M.Pharm(pharmacutices) 1
- 2. CONTENT Introduction. Definition. Pre-formulation 11/03/13 studies Bulk characterisation. Solubility analysis. Stability analysis. Spectroscopy. Microscopy. Chromatography . 2
- 3. INTRODUCTION Pre-formulation testing is the first step in the rational development of dosage forms. Pre-formulation study is done mainly to develop efficient dosage form. Gives information for design of dosage form. Used to identify molecular structure, formula, molecular weight, etc. Therapeutic identification. 11/03/13 3
- 4. Definition refers injectable route of administration. It derived from Greek words Para (Outside) and enter on (Intestine). So it is a route of administration other than the oral route. Parenteral is done prior to development of dosage form, it is essential that certain fundamental physical and chemical properties of the drug molecule and other derivative properties of the drug is 11/03/13 4 determined. Per-formulation
- 5. Bulk characterisation Bulk properties of the solid form such as Crystallinity, Polymorphism, Particle size, Powder flow property, and Surface characteristics are likely to change during process development. 11/03/13 5
- 6. 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. 11/03/13 6
- 7. 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 11/03/13 7 stability, compatibility, etc.
- 8. 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 . 11/03/13 8
- 9. 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. 11/03/13 9
- 10. 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 11/03/13 10 temperature.
- 11. SOLUBILITY ANALYSIS Aqueous Solubility Drug Pka / Ionization At Physiological Ph Partition Coefficient Thermal effect 11/03/13 11
- 12. Aqueous Solubility Solubilisation is increased by addition of cosolvent E.g.- propylene molecules by glycol disrupting solubilize the drug hydrophobic interactions of water. More non polar the solute 11/03/13 greater is the solubilisation 12
- 13. 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. 11/03/13 Where as, the ionized substances is 13
- 14. 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) 11/03/13 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. 14
- 15. 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, C o -organic phase concentration C w -aqueous phase concentration 11/03/13 15
- 16. THERMAL/HEAT EFFECTS Drugs which are unstable to heat requires refrigerate storage or lyophilisation (these products must be used within short periods) If it is endothermic ---> ∆H is +ve increase in temp ---> increase in drug solubility If it is exothermic ---> ∆H is – ve increase in temp ---> decrease in drug solubility For determining ∆H ln S= - ∆H /RT + C S=molar solubility at temperature, T=temperature in Kelvin, R= gas constant 11/03/13 16
- 17. Stability analysis Stability in toxicology formulation. Solution stability. Solid state stability. 11/03/13 17
- 18. 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. 11/03/13 18
- 19. 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 11/03/13 19
- 20. 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, temp, humidity for 12weeks. 11/03/13 20
- 21. STORAGE CONDITION 4WEEKS 8WEEKS 12WEEKS 5o C-REFRIGERATOR 22OC- ROOM TEMP 37OC-AMBIENT HUMIDITY 50OC-AMBIENT HUMIDITY 70OC-AMBIENT HUMIDITY 90OC-AMBIENT HUMIDITY 37OC/75%R.H 11/03/13 21
- 22. Hydrolysis Important factor in drug stability. Hydrolytic reaction involves nucleophilic attack. The condition catalysis the brake down as follows • • • 11/03/13 Presence of OH. Presence of divalent metal ion. Presence of light and heat. 22
- 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. 11/03/13 23
- 24. Spectroscopy UV and Visible Spectrophotometry: When organic molecules in solution, or as liquid, are exposed to light in the visible and ultraviolet light regions of spectrum, they absorb light of particular wavelengths depending on the type of electronic transition that is associated with the absorption. IR Spectrophotometer: The study of the interaction of electromagnetic radiation with vibrational and rotational resonances within a molecular structure is termed as IR Spectroscopy. X-Ray Diffraction: When a beam of non homogenous x-rays is allowed to pass through 24 11/03/13
- 25. Microscopy In this technique substances are examined under the microscope. It gives information about shape, thickness, particle size, etc. of drug molecules. By this method we can study crystal morphology, difference between polymorphic character of molecule. 11/03/13 25
- 26. Chromatography In the pre-formulation studies, chromatographic techniques such as TLC, HPLC,GC carrying a major role. Analytical data from TLC may be required to precisely determine the kinetics of decomposition. HPLC and GC are useful for solubility measurements 11/03/13 26
- 27. SUMMARY Preformulation studies on a new drug molecule provide useful information for subsequent formulation of a Physicochemically stable and Biopharmaceutically suitable dosage form. Thorough Preformulation work is the foundation of developing efficacious and economical formulations. 11/03/13 27
- 28. REFERENCE Remington, The Science And Practice Of Pharmacy, 20th Edition,pg.940-42. Leon Lachman, Herbert Al, Joseph Lk., The Theory And Practice Of Industrial Pharmacy, 3rd Ed.Pg. 171- 196. Bhatt Bhavik R, A SEMINAR ON PREFORMULATION STUDIES:PHYSICOCHEMICAL CHARACTERIZATION OF NEW DRUG MOLECULES. Manjul Pratap Singh & Anita Singh, Parenteral Products. 11/03/13 28