umesh bhandari

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Preformulation Study: for solids Presented By :- Mr. BHANDARI UMESH M. 1 st yr M - Pharm. Department of Pharmaceutics. RCPIPER, SHIPUR 1

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INTRODUCTION 3 Preformulation testing is the first step in the rational development of dosage forms. If an organic compound shows sufficient desirable pharmacological activity, next step is to incorporate the compound in dosage form. Preformulation may be defined as phase of research and development where the preformulation scientific charecterises the physical, chemical , mechanical and medicinal properties of a new drug subject to in order to develop ,safer , and effective dosage form. 21-Apr-16

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OBJECTIVES 4 To develop the most stable , safe and effective dosage form with maximum bioavailability. To confirms absence of barrier for the development of compound into safe and marketable drug To study the physicochemical characterization of drug To select the most suitable excipients. Establish its compatibility with common excipients 21-Apr-16


21-Apr-16 5 WHY PREFORMULATION IS IMPORTANT ? 5 It describes the process of optimizing the delivery of drug thorough determination of physical, chemical properties of new drug molecule that affect drug performance and development of an efficacious stable and safe dosage form. Preformulation studies on a new drug molecule provide useful information for subsequent formulation of a physicochemically stable and Biopharmaceutically suitable dosage form.


1. BULK CHARACTERIZATION : 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. Crystallinity The crystal habit and internal structure of drug can affect the bulk and physicochemical properties, but sometime same internal structure but different habit. Compounds have several different habits ( platy, equant, needle, bladed, and prismic etc.) eg. Novobiosin (antibiotic) 6 PHYSICOCHEMICAL PROPERTIES 21-Apr-16

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POLYMORPHISM When a substance exist in more than one crystaline species with a different internal structure thus various forms called as polymorphism 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 Two types of polymer Enantiotropic eg. Sulphur Monotropic eg. Glyceryl sterate 7 21-Apr-16

Pseudo-polymorphism :

Pseudo-polymorphism 8 The molecular complex is incorporated in crystallizing solvents molecules, at specific site with in crystaline lattice and has steriometric number of solvent molecule complex Two types Hydrates incorporated solvent is water Solvates incorporated solvent other than water 21-Apr-16

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Particle size Study of particle size give an information about solubility, dissolution rate, absorption etc. Smaller the particle size and greater surface area and faster the dissolution rate better will be the absorption rate and get higher bioavability of drug eg. 1. Hydrophilic drug : Griseofulvin and spironolactone 2. Hydrophobic drug : Aspirin 9 21-Apr-16

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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. Most flow property significantly affected by change in partical size, density, shape , electrostatic charge and adsorbed moisture. Flow property of powder is not good then weight variation hardness and thickness variation occur Method for measurement of flow property Angle of repose Bulk density 21-Apr-16


ANGLE OF REPOSE 11 Angle of repose Flow property <20 20-30 30-34 >40 Excellent Good Passable Very poor 21-Apr-16 Angle of repose of the granules was determined by the height cone method . A funnel was fixed to a desired height and granules were filled in it. They were allowed to flow down on a graph paper fixed on a horizontal surface’

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21-Apr-16 12 Bulk density Carr’s index = ( tapped density – poured density) poured density Hausner’s Ratio = tapped density poured density A. Carr’s Index : B. Hausner’s Ratio : X 100 X 100

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13 HYGROSCOPICIT Y Many pharmaceutical materials have the tendency to adsorb atmospheric moisture (specially water soluble salt ) they called as hygroscopic and this phenomenon know as hygroscopicity Hygroscopicity determine by Thermo gravimetric analysis Gas chromatography Karl Fischer titration 21-Apr-16


1. INTRINSIC SOLUBILITY It is equilibrium solubility of the free acids or free bases form of an ionisable compound at a pH where it fully unionised Orally administered drug must dissolve in the aqueous fluid of the GIT prior to absorption. Solubility can be improved by addition of cosolvents. It can be determine by adding excess amount of drug to fixed volume of a solvent till saturation , and then filter then determine the concentration of drug 14 SOLUBILITY ANALYSIS 21-Apr-16

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2. Drug pKa / Ionization at physiological pH pKa is the dissociation constant of a drug. The nonionized 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 is slow. 15 21-Apr-16

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The percentage of ionization can be calculated by Henderson Hasselbalch equation … For Acidic compounds: For Basic compounds: 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. pH = pKa + log(unionized drug/ionized drug) pH = pKa + log(ionized drug/unionized drug) 16 21-Apr-16

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3. PARTITION COEFFICIENT Partition coefficient is a ratio of equilibrium concentration of drug in oil phase to equilibrium concentration of drug in aqueous phase . where, C o -organic phase concentration C w -aqueous phase concentration It useful for the measuring liphophilic charecter of drug. K=C o /C w 17 21-Apr-16

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18 Eg. n- octanol Chloroform Ether etc. various organic solvents used 4. SOLUBILITY ENHANCEMENT solubility of poorly water soluble drug can be enhanced by one of the following method. Co-solvency eg. Ethanol, PEG, glycerin Solubilisation eg. Tween, SLS 21-Apr-16

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19 5. DISSOLUTION To know the gastrointestinal absorption & other physicochemical properties. The intrinsic dissolution rate is determined by the rotating disc method. The dissolution rate is described by Noyes- Whiteny equation. = 21-Apr-16 dc DA dt = h (Cs – C)


DRUG STABILITY In this study includes both solutions and solid-state experiments under various conditions for handling, formulation, storage, and in vivo administration. Stability is important part of drug development program Acid sensitive drugs protected from highly acidic environment of the stomach by coating it with suitable polymers. Solid phase stability depends on several factors like temperature, pH, humidity, hydrolysis, oxidation, etc… STABILITY ANALYSIS 20 21-Apr-16

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COMPATIBILITY Compatibility test play a very important role in the preformulation studies of oral dosage forms. Problems arise because of the interaction with other drug substances and with preservatives, stabilizers, dyes, and flavors. It is important for the formulator of a new drug substance to know with which excipients he can work and which he cannot. 21 21-Apr-16

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ANALYTICAL MEASURES Various analytical techniques are available for the investigation of the physicochemical properties and determination of impurity of new drug molecules. These includes: Microscopy Spectroscopy Chromatography Thermal method 23 21-Apr-16

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A. 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. Following microscopic tech Electron microscope Optical microscope SEM TEM     24 21-Apr-16

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B. SPECTROSCOPY 1.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. The electronic transitions depends on the electron bonding with in the molecule. Detection of impurity. UV study of compounds gives information regarding unsaturation of compounds. 25 21-Apr-16

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2. IR Spectroscopy The study of the interaction of electromagnetic radiation with vibrational and rotational resonances within a molecular structure is termed as IR Spectroscopy. Gives an information regarding functional group present in new drug molecule. FT-IR use for both qualitative and quantitative analysis of sample. IR has the ability to differentiate isomers groups such as Cis -trans double bond compound.   26 21-Apr-16

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3. X-RAY DIFFRACTION When a beam of non homogenous x-rays is allowed to pass through a sample the x-ray beam is diffracted & it is recorded by means of photographic plates . Single Crystal X-ray provides the most complete information about the solid state. It is used to differentiate the amophous and crystalline forms. This method is tedious, time consuming & hence unsuitable for routine use. 27 21-Apr-16

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C. CHROMATOGRAPHY In the preformulation studies, chromatographic techniques such as TLC HPTLC HPLC GC FLASH CHROMATOGRAPH The major advantages are direct analysis of aqueous samples , high sensitivity , and specific determination of drug concentration , separation of drug from impurities or degradation products . 28 21-Apr-16

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29 Analytical data from TLC may be required to precisely determine the kinetics of decomposition. HPLC and GC are useful for solubility measurements. GC has strong separation power. 21-Apr-16

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D. THERMAL ANALYSIS In the preformulation studies, Thermal analysis techniques such AS DTA DSC TGA These following method are particularly useful in preformulation studies including purity, polymorphism, solvation, degradation, and excipient compatibility. It measures physical or chemical changes of drug molecule 30 21-Apr-16

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CONCLUSION 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 effective and economical formulations. 31 21-Apr-16

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32 Leon Lachman, Herbert A.L, The theory and practice of industrial pharmacy, special Indian edition 2009: CBS publishers and distributors. Pg no.. 171- 196 Banker GS, Rhodes CT., Modern pharmaceutics, 4 th ed. New York: Marcel Dekker; 2002. p.167-184 Alfred Martin., Physical pharmacy. 4 th ed. New York: Lippincott Williams & Wilkins; 2001. p. 77-100 Michael E. Aulton, Aulton’s pharmaceutics, 3 rd ed Elsevier Ltd 2007, page no. 336-370 REFERENCES 21-Apr-16

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33 5) D.A. Skoog, F.J Holler, S.R. Crouch, Instrumental analysis Indian edition New Delhi, 2011, page no.191,836,865-867,893-896,976-988 6) A.H. Nathani, Ready retrive, Pharmaceutical formulation, 1 st ed Carrier publication Nashik, page no. 1-22 7) Chatwal G.R, Anand S.K, Instrumental method of chemical analysis, 5 th ed Himalaya publication, Mumbai 2013, page no. 2.177, 21-Apr-16

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34 21-Apr-16 Thank you 34 21-Apr-16 Thank you Email. : [email protected]

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