PREFORMULATION

PREFORMULATION

1. PREFORMULATION Mr Nandakishor B Deshmukh Assistant Professor Department of Pharmaceutics Shraddha institute of Pharmacy, kondala zambre , washim 1 2-Jul-23 PROF N.B.DESHMUKH

2. Definition : Preformulation may be defined as a stage of the research and development process where the preformulation studies characterizes the physical and chemical properties of a new drug substance in order to develop stable safe and effective dosage form . 2 2-Jul-23 PROF N.B.DESHMUKH

3. Goals and Objectives The goals of pre-formulation are: 1) To establish the physicochemical parameters of a new drug substance. 2) To establish the physical characteristics of a new drug substance . 3) To establish the kinetic rate profile of a new drug substance. 4) To establish the compatibility of the new drug substance with the common excipients 5) To choose the correct dosage form of a drug substance. 3 2-Jul-23 PROF N.B.DESHMUKH

4. The objectives of Pre-formulation are : 1) To develop elegant, stable, effective, and safe dosage forms. 2) It is required to have an understanding of the physical description of a drug substance before the development of any dosage form. 3) Pre-formulation is the first step in rational development of a dosage form of a drug substance before the development of dosage form. 4 2-Jul-23 PROF N.B.DESHMUKH

5. Following are the major physicochemical characteristics of drug substances 1 ) Physical properties i ) Organoleptic Characters. ii) Bulk characterisation: a) Physical form b) Polymorphism c) Particle size d) Particle shape e) Flow properties.. 5 2-Jul-23 PROF N.B.DESHMUKH

6. ii) Solubility analysis : Ionisation constant – pKa b) pH solubility profile c) Partition coefficient. iii) Stability analysis: Stability in toxicology formulations Solution stability – pH rate profile Solid state stability: Bulk stability Compatibility 6 2-Jul-23 PROF N.B.DESHMUKH

7. 2 ) Chemical properties Hydrolysis Oxidation Reduction Racemisation Polymerisation. 7 2-Jul-23 PROF N.B.DESHMUKH

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9. ii) Bulk characterisation: Physical form Crystallinity Crystal habit & internal structure physicochemical property of molecule of drug can affect bulk . Crystal habit is description of outer appearance of crystal. The internal structure is molecular arrangement within the solid.Change with internal structure usually alters crystal habit. Eg. Conversion of sodium salt to its free acid form produce both change in internal structure & crystal habit. 9 2-Jul-23 PROF N.B.DESHMUKH

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11. Different shapes of crystals Depending on internal structure compounds is classified as Crystalline Amorphous Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional . In amorphous form atom or molecule are randomly placed. Solubility & dissolution rate are greater for amorphous form than crystalline, as amorphous form has higher thermodynamic energy. Eg. Amorphous form of Novobiocin is well absorbed where as crystalline form results in poor absorption. 11 2-Jul-23 PROF N.B.DESHMUKH

12. Polymorphism The ability of a substance to exist in more than one crystalline form is called as polymorphism . There are two types of Polymorphism. Enantiotropic Polymorphism By altering the temperature or pressure is and changed into another in a reversible manner called as enantiotropic Polymorphism. e.g sulphur. 2) Monotropic Polymorphism: Under all the conditions of temperature and pressure the monotropic Polymorphism remain unstable is called monotropic Polymorphism e.g glyceryl stearate. 12 2-Jul-23 PROF N.B.DESHMUKH

13. METHODS TO IDENTIFY POLYMORPHISM Optical crystallography Hot 0stage microscopy X-Ray Diffraction method NMR technique FTIR technique. Microcalorimetry Thermal methods Melting point determination 13 2-Jul-23 PROF N.B.DESHMUKH

14. c) Particle size Particle size is characterized using these terms: Very coarse, Coarse, Moderately coarse, Fine,Very fine. • Particle size can influence variety of important factors- Dissolution rate Suspendability Uniform distribution Penetrability- Lack of grittiness 14 2-Jul-23 PROF N.B.DESHMUKH

15. Methods to Determine Particle Size Sieving (5u-150µ) Microscopy(0.2μ-100μ) Sedimentation rate method(1μ-200μ) Light energy diffraction(0.5μ-500μ) Laser holography(1.4u-100µ ) 15 2-Jul-23 PROF N.B.DESHMUKH

16. Particle Shape The term particle shape is used to express the geometrical shape and surface regularity of the material particle shape affects the surface area flow packing properties of the particles. Equant Acicular   Flake Plate Columnar Lath 16 2-Jul-23 PROF N.B.DESHMUKH

17. Flow Properties The flow properties of powders are critical for an efficient tablet operation. During the preformulation evaluation of the drug substance, therefore its flow ability characteristic should be studied especially when the anticipated dose of the drug is large. Flow properties are affected by changes in particle size, density, shape, electrostatic charges, and adsorbed moisture. 17 2-Jul-23 PROF N.B.DESHMUKH

18. It is characterized by Angle Of Repose Carr‟s Index Hausner Ratio Rheology Thixotropy 18 2-Jul-23 PROF N.B.DESHMUKH

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23. Solubility analysis Ionization Constant (PKA ) Many drugs are either weakly acidic or basic compounds and, in solution, depending on the pH value, exist as ionized or un-ionized species. The un- ionized species are more lipid soluble and hence more readily absorbed. The factors that are important in [Un- ionized form] pH = pKa + log ----------------------------- ----------------------for bases [ionized form] [Ionized form] pH = pKa + log ---------------------------------------- for acids [un ionized form 23 2-Jul-23 PROF N.B.DESHMUKH

24. Determination of pka Potentiometric titration Spectrophotometric determination Dissolution rate method Liquid-Liquid partition method 24 2-Jul-23 PROF N.B.DESHMUKH

25. b) Partition coefficient The lipophilicity of an organic compound is usually described in terms of a partition coefficient log P which can be defined as the ratio of the concentration of the unionized compound at equilibrium between organic and aqueous phases This ratio is known as the partition coefficient or distribution coefficient and is essentially independent of concentration of dilute solutions of a given solute species. Log P = 0 means that the absorption of weakly acidic and basic compounds are the pH at the sit e of absorption 25 2-Jul-23 PROF N.B.DESHMUKH

26. Methods of finding Partition coefficient: 1 ) Shake-flask method 2) Chromatographic method. 3) Counter current and filter probe method. 4) Tomlinson‟s filter probe method. 5) Microelectrometrictitratation method 6) Automated instrument is now available 26 2-Jul-23 PROF N.B.DESHMUKH

27. Applications of partition coefficient Measure of Lipophilic character of Drugs molecules. Recovery of antibiotics from fermentation. Extraction of drug from biological fluid for therapeutic monitoring. Absorption of drug from dosage forms. (Ointments, Suppositories, Transdermal patches). Study of distribution of flavoring oil between oil & water in emulsion 27 2-Jul-23 PROF N.B.DESHMUKH

28. c ) Solubilization Solubility is defined as amount of solute that can be dispersed molecularly in the given amount of solvent under standard conditions of temperature pressure and pH . Terms Expression of solubility Part by volume of solvent required to dissolve 1 part by weight of solute Very soluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30 Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1000 Very slightly soluble From 1000 to 10,000 28 2-Jul-23 PROF N.B.DESHMUKH

29. Methods for increasing solubility pH Adjustments Co-solvency Complexation Surface active agent / Solubilization by Surfactant Solid Solutions. 6. Chemical Modification of drug. 29 2-Jul-23 PROF N.B.DESHMUKH

30. Chemical properties Chemical stability study includes the ways that cause instability of drug through chemical reactions resulting in a reduction of potency . The following chemical properties should be evaluated during a pre-formulation research: Hydrolysis Oxidation Reduction Racemisation Polymerisation . 30 2-Jul-23 PROF N.B.DESHMUKH

31. HYDROLYSIS Hydrolysis is the most common degradation pathway since water plays an important role in many processes especially in solution and also in solids (in which water may be present in low concentrations). Preventive Measures against Hydrolysis Hydrolysis reactions occurring due to the presence of moisture and catalytic species H + and OH– ions can be prevented as follows: 1) Buffer : It is used for product stabilisation . 2) Complexing Agent : It forms a complex with drug, prevents its hydrolysis and thus prolongs the shelf-life. 3) Suppression of Solubility: Less solubility reduces the drug concentration in solution phase and also reduces the hydrolysis rate. 4) Removal of Water : Presence of water should be avoided by storing the drug in dry form and by using water immiscible vehicle 31 2-Jul-23 PROF N.B.DESHMUKH

32. Oxidation The environmental phenomenon of oxidation requires oxygen If molecular oxygen is involved the reaction is rapid and termed auto-oxidation. Chemically oxidation involves loss of electrons which requires an electron acceptor or an oxidising agent for Anti- oxidising agent, light and trace metals that can used catalyse the reaction. example iron converting from ferric (Fe3+) to ferrous (Fe2+)]. 32 2-Jul-23 PROF N.B.DESHMUKH

33. Preventive Measures against oxidation Oxidation reaction occurs due to the presence of moisture, oxygen, trace metals, H + and OH− ions. Oxidation can be prevented by: Using antioxidants (e.g. tocopherol) chelating agents Buffers Preventing light exposure Maintaining oxygen free environment Storing the product at a low temperature . 33 2-Jul-23 PROF N.B.DESHMUKH

34. Reduction Reduction is a relatively common pathway of drug metabolic process. Hepatic microsomes catalyse diverse reductive chemical reactions with the use of NADPH. Cytochrome P450 catalyses the azo and nitro reduction reaction. The enzyme alcohol dehydrogenase catalyses the reduction of chloral hydrate into trichloroethanol (its active metabolite). Prednisolone and cortisone reduces to hydrocortisone (their active metabolites). The intestinal flora reduces the azo dyes (used as colouring agents in pharmaceutical or food products) into amines in the liver. 34 2-Jul-23 PROF N.B.DESHMUKH

35. Racemisation Racemisation involves the conversion of one enantiomer of a compound such as an L - amino acid into the other enantiomer. The compound then alternates between each form while the ratio between the (+) and ( –) groups approach es the ratio 1:1, at which it becomes optically inactive . 35 2-Jul-23 PROF N.B.DESHMUKH

36. Polymerization Polymerisation is a continuous reaction occurring between molecules. A polymer is formed by the reaction between more than one monomer. For example glucose solution darkens due to polymerisation of the breakdown product [5 -(hydroxyl methyl) furfural ] 36 2-Jul-23 PROF N.B.DESHMUKH

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