TP. Ss "Textbook" Technical Pharmacy Series Strictly Based On PCI Syllabus INDUSTRIAL PHARMACY - I a F IFTH SEM. B. PHARM > Yogesh N. Gholse Re kn » Dr. Rahul H. Kasliwal vbdpublications.com OR amazonin » Dr. Dinesh R. ChapleSYLLABUS UNIT -I Preformulation Studies: Introduction to preformulation, goals and objectives, study of physicochemical characteristics of drug substances. (a) Physical properties: Physical form (crystal and amorphous), particle size, shape, flow properties, solubility profile (pKa, pH, partition coefficient), polymorphism (b) Chemical Properties: Hydrolysis, oxidation, reduction, racemisation, polymerization BCS classification of drugs and its significance. Application of preformulation considerations in the development of solid, liquid oral and parenteral dosage forms and its impact on stability of dosage forms. UNIT - I Tablets: (a) Introduction, ideal characteristics of tablets, classification of tablets. Excipients, Formulation of tablets, granulation methods, compression and processing problems. Equipments and tablet tooling. (b) Tablet coating: Types of coating, coating materials, formulation of coating composition, methods of coating, equipment employed and defects in coating. (c) Quality control tests: In process and finished product tests Liquid orals : Formulation and manufacturing consideration of syrups and elixirs suspensions and emulsions; Filling and packaging; evaluation of liquid orals official in pharmacopoeia. UNIT - II Capsules: (a) Hard gelatin capsules : Introduction, Production of hard gelatin capsule shells. size of capsules, Filling, finishing and special techniques of formulation of hard gelatin capsules, manufacturing defects. In process and final product quality control tests for capsules. INDUSTRIAL PHARMACY.I(B.Pharm. V SEM.)(b) Soft gelatin capsules: Nature of shell and capsule content, size of capsules,importance of base adsorption and minim/gram factors, production, in process and final product quality control tests. Packing, storage and stability testing of soft gelatin capsules and their applications. Pellets: Introduction, formulation requirements, pelletization process, equipments for manufacture of pellets UNIT - IV Parenteral Products: (a) Definition, types, advantages and limitations. Preformulation factors and essential requirements, vehicles, additives, importance of isotonicity. (b) Production procedure, production facilities and controls, aseptic processing (c) Formulation of injections, sterile powders, large volume parenterals and lyophilized products. (d) Containers and closures selection, filling and sealing of ampoules, vials and infusion fluids. Quality control tests of parenteral products. Ophthalmic Preparations : Introduction, formulation conside- rations, formulation of eye drops, eye ointments and eye lotions; methods of preparation; labeling, containers; evaluation of ophthalmic preparations : Formulation and preparation of the following cosmetic preparations: lipsticks, shampoos, cold cream and vanishing cream, tooth pastes, hair dyes and sunscreens. Pharmaceutical Aerosols: Definition, propellants, containers, valves, types of aerosol systems; formulation and manufacture of aerosols; Evaluation of aerosols; Quality control and stability studies. Packaging Materials Science: Materials used for packaging of pharmaceutical products, factors influencing choice of containers, legal and official requirements for containers, stability aspects of packaging materials, quality control tests. INDUSTRIAL PHARMACY-| (B.Pharm. V SEM.)CONTENTS OF PARTI UNIT -I 11 Introduction 1.2 Goals and objectives 2 1.3 Study of physicochemical characteristics of drug substances 3 1.4 Physical properties 4 1.5 Chemical properties 19 1.6 BCS classification of drugs and its significance 23 1.7 Application of preformulation considerations in the development of solid dosage forms and its impact on stability 33 1.8 Application of preformulation considerations in the development of liquid oral dosage forms and its impact on stability 36 1.9 Application of preformulation considerations in the development of parenteral dosage forms and its impact on stability 38 1.10 Points to remember 43 1.11 Exercise UNIT - II Tablets : 2.1 2.2 2.3 Ideal characteristics of tablets 51 2.4 Classification of tablets 52 2.5 Excipients 55 2.6 Formulation of tablets 62 Introduction Definition INDUSTRIAL PHARMACY-| (B.Pharm. V SEM.)2.7. Granulation methods 2.8 Compressions 2.9 Processing problems 2.10 Equipments and tablet tooling 2.11 Tablet coating 2.12 Types of coating 2.13 Coating materials 2.14 Formulation of coating composition 2.15 Methods of coating 2.16 Equipment employed 2.17 Quality control tests 2.17.1 In process and finished product tests 2.17.2 IPQC and FPQC test for pharmaceutical tablets according to pharmacopoeias are listed below Liquid orals : 2.18 Introduction 2.18.1 Formulation and manufacturing consideration of syrups 2.19 Formulation and manufacturing consideration of elixirs 2.20 Formulation and manufacturing consideration of suspensions 2.21 Formulation and manufacturing consideration of emulsions 2.22 Filling and packaging 2.23. Evaluation of liquid orals official in pharmacopoeia 2.24 Points to remember 2.25 Exercise INDUSTRIAL PHARMACY-|(B.Pharm. V SEM.)UNIT - III Capsule : 3.1 Introduction 3.2 Definition 3.3 Hard gelatin capsules 3.3.1 Production of hard gelatin capsule shells 3.3.2 Size of capsules 3.3.3 Filling and finishing 3.3.4 Special techniques of formulation of hard gelatin capsules 3.3.5 Manufacturing defects 3.3.6 In-process and final product quality control tests for capsules 3.4 Soft gelatin capsules 3.4.1 Nature of shell 3.4.2 Capsule content 3.4.3 Size of capsules 3.4.4 Importance of base adsorption and minim /gram factors 3.4.5 Production 3.4.6 In-process and final product quality control tests 3.4.7 Packing and storage 3.4.8 stability testing of soft gelatin capsules 3.4.9 Applications Pellets : 3.5 Introduction 3.6 Formulation requirements 3.7 Pelletization process 3.8 Equipments for manufacture of pellets 3.9 Points to remember 3.10 Exercise INDUSTRIAL PHARMACY-| (B.Pharm. V SEM.)CONTENTS OF PART II UNIT - IV Parenteral products : 4.1 Introduction 4.2 Definition, types, advantages and limitations of parenteral product 4.3. Preformulation factors 4.4 Essential requirements, vehicles and additives 4.5 Importance of isotonicity 4.6 Production procedure, production facilities, controls and aseptic processing 4.7 Formulation of injections 4.8 Formulation of sterile powders 4.9 Formulation of large volume parenterals 4.10 Formulation of lyophilized products 4.11 Containers and closures selection, filling and sealing of ampoules 4.12 Containers and closures selection, filling and sealing of vials 4.13 Containers and closures selection, filling and sealing of infusion fluids 4.14 Quality control tests of parenteral products, ophthalmic preparations Ophthalmic Preparations : 4.15 Introduction 4.16 Definition, properties, characteristics, types of ophthalmic dosage forms 4.17 Formulation considerations 4.18 Eye drops INDUSTRIAL PHARMACY-| (B.Pharm. V SEM.)4.19 Eye lotions 4.20 Eye ointments 4.21 Evaluation of ophthalmic preparations 4.22 Points to remember 4.23 Exercise UNIT-V Cosmetics : 5.1 Introduction 5.2 Formulation and preparation of the lipsticks 5.3 Formulation and preparation of the shampoos 5.4 Formulation and preparation of the cold cream 5.5 Formulation and preparation of the vanishing cream 5.6 Formulation and preparation of the tooth pastes 5.7 Formulation and preparation of the hair dyes 5.8 Formulation and preparation of the sunscreens Pharmaceutical aerosols : 5.9 Introduction 5.10 Propellants 5.11 Containers 5.12 Valves 5.13 Actuators 5.14 Types of aerosol systems 5.15 Formulation of aerosols 5.16 Manufacture of aerosols 5.17 Evaluation of aerosols 5.18 Quality control 5.19 Stability studies INDUSTRIAL PHARMACY-| (B.Pharm. V SEM.)Packaging material science : 5.20 5.21 5.22 5.23 5.24 5.25 5.26 5.27 Introduction Materials used for packaging of pharmaceutical products Factors influencing choice of containers Legal and official requirements for containers Stability aspects of packaging materials Quality contro! tests Points to remember Exercise VIVA-VOCE Glossary Index INDUSTRIAL PHARMACY-| (B.Pharm. V SEM.)TPS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) 1 UNIT -I PREFORMULATION STUDIES SYLLABUS Preformulation Studies : Introduction to preformulation, goals and objectives, study of physicochemical characteristics of drug substances. (a) Physical properties : Physical form (crystal and amorphous), particle size, shape, flow properties, solubility profile (pKa, pH, partition coefficient), polymorphism. (b) Chemical Properties : Hydrolysis, oxidation, reduction, racemisation, polymerization BCS classification of drugs and its significant. Application of preformulation considerations in the development of solid, liquid oral and parenteral dosage forms and its impact on stability of dosage forms. 1.1 INTRODUCTION: . Preformulation is a first learning phase of the dosage form development. It is considered as a first step in the rational development of dosage forms of a drug substance since 1950 and early 1960. «The fundamental, physical and chemical properties of the drug molecule and other properties of the drug are necessary to determine before development of any kind of dosage form. e It involves the application of biopharmaceutical principles of the physicochemical property of the drug with the goal of designing effective drug delivery system.1.2 (i) (ii) (iii) (iv) TPS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) The pharmacokinetic and pharmacodynamic properties of the drug is characterized and established during this develop- mental stage. Definition : It is a development stage during which the physicochemical properties of the drug substance alone and when combined with excipients is characterized and established. It may be described as the process of optimizing a drug through determination of those physical and chemical properties considered important in the formulation of a stable, effective and safe dosage form. Preformulation influences : Selection of the drug candidate itself. Selection of formulation components. API and drug product manufacturing processes. Determination of the most appropriate container closure system. Development of analytical methods. Assignment of API retest periods. The synthetic route of the API. Toxicological strategy. GOALS AND OBJECTIVES : Goals : Following are the goals of performulation studies : To establish the physico-chemical parameters of new drug substance. To establish the kinetic rate profile. To establish the compatibility with the common excipient. To choose the correct form of a drug substance.‘TPS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) 3 vy) (vi) 1.3 qd) Q) @) To generate a thorough understanding of the materials stability under the conditions that will lead to development of an optimal drug delivery system. To provide a scientific data to support the dosage form design and evaluation of the product efficiency and stability. Objectives : Following are the objectives of performalation studies : To generate information useful to the formulator in developing stable and bioavailable dosage forms that can be mass produced. To develop the elegant dosage forms (stable, effective and safe). To understand the physical description of a drug substance before dosage form development. To generates useful information to the formulator to design an optimum drug delivery system. STUDY OF PHYSICOCHEMICAL CHARACTERISTICS OF DRUG SUBSTANCES : ———— aera Various physical and chemical properties consider for preformulation study of drug substances such as : Physical Properties : Organoleptic properties. Bulk characteristics : (a) Solid state characteristics. (b) Flow properties. (c) Densities. (d) Compressibility. (e) Crystalline. (f) Polymorphism. (g) Hygroscopicity. Solubility analysis : (a) Ionization constant (Pka). TPS(4) 1.4 ay (a) TRS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) (b) Partition co-efficient. (c) Solubilization (d) Thermal effect. (e) Common ion effect (Ksp). (f) Dissolution. Stability analysis : (a) Solution-state stability (b) Solid-state stability (c) Drug-excipients compatibility Chemical Properties : (1) Hydrolysis (2) Oxidation (3) Photolysis (4) Recemization (5) Polymerization (6) Isomerization PHYSICAL PROPERTIES : In the dosage form development, the acceptable stability of the drug substance and drug product is one of the basic requirements for clinical studies, regulatory approval, and marketing. The stability of a drug product is related not only to the intrinsic chemical stability of the drug molecule, but also to the physical forms and various physical properties of drug. Physical properties mainly affect dosage form dis- integration, dissolution, solubility, permeability, absorption and finally bioavailability of drug. Physical form (crystal and amorphous) : Amorphous drugs : Amorphous drugs have randomly arranged atoms or molecules same as ina liquid.PS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) 6 (b) Amorphous forms are prepared by rapid precipitation, lyophilization, or rapid cooling of liquid melts. They are highly soluble and have higher dissolution rate as they have higher thermodynamic energy. It is converted in to more stable form on storage. Example : Novobiocin : It is inactive when administered in crystalline form, but when they are administered in the amorphous form, absorption from the gastrointestinal tract proceeds rapidly with good therapeutic response. Advantage : Amorphous forms have higher solubility as well as dissolution rates as compared to crystalline forms. Disadvantage : As it converts in to more stable forms the thermodynamic instability can occur during bulk processing or within dosage forms. Crystalline drugs : Crystals are characterized by repetitious spacing of constituent atoms or molecules in a three dimensional array. A crystal structure is a unique arrangement of atoms in a crystal. A crystalline particle is characterized by definite external and internal structures. Example : Penicillin : the crystalline forms of penicillin as potassium or sodium salt is considerably more stable and result in excellent therapeutic response than amorphous forms. It can be classifies as Internal structures (cubic, tetragonal, hexagonal, rhombic, etc.), Solid habits (platy, needle, tabular, prismatic, bladed, etc.), Changing the internal structures alter the crystal habits, Changing the chemical form (e.g. salt formation) alter both the internal structure and crystal habit. Crystal habit describes the external shape of a crystal.a) Q) GB) (4) ‘PPS INDUSTRIAL PHARMACY- | (B.Pharm. v SEM) Different polymorphs are obtained by crystallization from different solvents and by solidification after melting. Solvate : It is a crystalline compound in which crystallizing Organic solvent get incorporated within the crystal lattice. It is undesirable to use solvates for drugs and pharmaceuticals, as the presence of organic solvent residues may be toxic; regulations for all the organic solvents in products for human use establish specific limits to how much daily exposure to residual solvent in the formulated preparation is allowed. The solubility and dissolution rate of a drug can significantly differ for different solvates, and in particular hydrates. Hydrate : It is a crystalline compound in which water get incorporated within the crystal lattice. On the basis of numbers of water molecules incorporated, hydrate are of following types : Hemihydrate : It is a crystalline compound in which half molecule of water get incorporated within the crystal lattice. Monohydrate : It is a crystalline compound in which one molecule of water get incorporated within the crystal lattice. Dihydrate : It is a crystalline compound in which two molecule of water get incorporated within the crystal lattice. Anhydrous : It is a crystalline compound which Not containing any molecule of water get incorporated within the crystal lattice. Hydrates may have a faster or slower dissolution rate than the Corresponding anhydrous form, though more frequently, the former are slower than the latter, perhaps because there are fewer sites of the drug molecule available for interaction with water during dissolution,Q) TPS INDUSTRIAL PHARMACY. | (B.Pharm. V SEM.) 7 SS em Example : Theophylline Anhydrate, which dissolves faster than its hydrate form. In other cases, the hydrate form exhibits a more rapid dissolution rate than its anhydrous form Example : Erythromycin Dihydrate was found to exhibit a significantly faster dissolution rate than that of monohydrate and anhydrous forms. Particle size and shape : Before the preformulation, each new drug should be tested with the smallest particle size as is practical facilitate prepa- ration of homogeneous samples and maximize the drug’s surface area for interactions. Certain physical and chemical properties of drug substances are affected by the particle size distribution, including flow characteristics, sedimentation rates, drug dissolution rate, bioavailability, content uniformity, taste, texture color, and stability. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. Example : The bioavailability of griseofulvin and phenacetin is directly related to the particle size distributions of these drug. In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability, fine materials are relatively more open to attack from atmospheric oxygen, the humidity and interacting excipients than are coarse materials. When large differences in size exist between the active com- ponents and excipients, mutual sieving (de-mixing) effects can occur making thorough mixing difficult or if attained difficult to maintain during the subsequent processing steps.8 ‘TRS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) Sr. No. Technique Particle size (am) (1) _ | Microscopic method 1-100 (2) _| Sieve analysis method >5 (3) Sedimentation method >I | (4 __| Elutriation method 1-50 (5) Centrifugal method <50 (6) Permeability method >I (7) Light scattering method 0.5 - 50 Table 1; Common techniques for measuring fine particles of various sizes (3) Flow properties During the preformulation of the drug substance, its flowability 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. The flow properties of powders are critical for an efficient tableting operation. A good flow of the powder or granulation to be compressed is necessary to assure efficient mixing and acceptable weight uniformity for the compressed tablets. Flow properties of powder can be determine by the parameters like angle of repose, Hausner’s ratio, Carr’s index and com- pressibility of any powdered sample. . Changes in particles size and shape are generally very important an increase in crystal size or a more uniform shape will lead to a small angle of repose and a smaller Carr’s index. (a) Angle of repose : © The angle of repose can be defined as the constant three dimensional angle measured relatively to the horizontal base, assumed by a cone-like pile of material formed when the powder is passed through a funnel-like container. HoTPS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) 9 (b) The maximum angle which is formed between the surface of pile of powder and horizontal surface is called the angle of repose. Angle of repose has been used in the several branches of science to characterize the flow properties of solids. Angle of repose is a characteristic related to inter particulate friction or resistance to movement between particles. For most pharmaceutical powders, the angle-of repose values range from 25 to 45°, with lower values indicating better flow characteristics. It can be calculated by formula : Tan 0=h/r Where, h = height of heap of pile, r= radius of base of pile This method is very simple but has some disadvantages. The powder experiences segregation, consolidation or aeration, which influence the cone formation. Compressibility index : In recent years the compressibility index has become the simple, fast and popular methods of predicting powder flow characteristics. This index measures the tendency of a powder to consolidate. The compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content and cohesiveness of materials influence the observed compressibility index. The compressibility index has an inverse relation with flowability, i.e. the more compressible is the material the less flowable it will be.10 ‘TRS INDUSTRIAL PHARMACY. | (B.Pharm. V SEM) . The compressibility index calculated using measured value for bulk density and tapped density as follows : Tapped density — Bulk density Compressibility index = —“PP&E CCDS ~ Suk Censity 49 Tapped density Angle of Carr’s Ha usner’: ae Flow ngie o | Compressibility eee No. repose E ratio index (1) | Excellent <25 5-15 1.00-1.11 (2) [Good 25-30 12-16 112-118 (3) | Fair 30-40 18-21 1.19- 1.25 (4) | Poor >40 23 - 35 1.35 - 1.45 (5) | Very poor 56 - 65 33-38 1.46 - 1.59 (6) |Extremely poor} >66 >40 >1.60 Table 2 : Relationship between Flow, Angle of repose, Carr’s index and Hausner’s Ratio. (c) Hausner’s ratio : ¢ The Hausner ratio is defined as the ratio between the tapped density and the bulk density. * This ratio is a useful measure of cohesion reflecting particle friction. * It become the simple, fast, and popular methods of predicting powder flow characteristics, * Hausner’s ratio may be calculated using measured value for bulk density and tapped density as follows : Tapped density "Bulk density (4) Solubility profile (pKa, pH and Partition coefficient) : ° A drug must possess some aqueous solubility for therapeutic efficacy. Hausner’s ratio =‘TPS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) a TRS INDUSTRIAL PHARMACY-1(B.Pharm.VSEM) 17 a) In order for a drug to enter the systemic circulation to exert a therapeutic effect, it must first be in solution. We need to perform solubility analysis of a new drug to provide a basis for later formulation work and can affect drug performance. Drugs with an aqueous solubility less than 1 % (10 mg/ml) will suffer from bioabsorption problems. Relatively insoluble compounds often exhibit incomplete absorption. The approximate solubilities of pharmacopeial and national formulary substances are indicated by the descriptive terms in accompanying table. or Solubility Part of solvent require No. to soluble part of solute (1) | Very soluble Less than ] (2) |Freely soluble From | to 10 (3) |Soluble From 10 to 30 (4) | Sparingly soluble From 32 to 100 (5) | Slightly soluble From 100 to 1000 (6) | Very slightly soluble | From 1000 to 10000 (7) {Insoluble From 10000 to Over Table 3 : Solubility parameters Common solvents used for solubility determination are : Water, Polyethylene Glycols, Propylene Glycol, Glycerin, Sorbitol, Ethyl Alcohol, Methanol, Benzyl Alcohol, Isopropyl Alcohol, Tweens, Polysorbates, Castor Oil, Peanut Oil, Sesame Oil, Buffer at various pHs Factors affecting the solubility of a drug are : Temperature,2 (2) @) (4) (5) (6) (a) TPS INDUSTRIAL PHARMACY- 1(B.Pharm. V SEM.) Chemical and physical properties of both the solute and the solvent, Pressure, Acidity or basicity of the solution, State of subdivision of the solute and solvent, Physical agitation applied to the solution durin g the dissolving process etc. Methods of solubility analysis include : (1) Solubility determination. (2) pKa determination. (3) Partition coefficient. (4) Dissolution behavior. (5) Common ion effect. (6) Membrane permeability. Methods to improve drug solubility are : (1) Chemical modification of the drug into salt or ester forms, (2) Use of a different solubilizing agent, (3) Use of co-solvents, (4) Micronization, (5) Solid dispersion, (6) Adjustment of the pH of the solvent in which the drug is to be dissolved etc. Intrinsic solubility (Co) : When the purity of the drug sample can be assured the solubility obtained in acid for a weak acid or alkali for a weak base can be assured to be the intrinsic solubility (Co) i.e. the fundamental solubility when completely unionized. An increase in solubility in acid compared to aqueous solubility suggests a weak base and an increase in alkali, a weak acid. An increase in acidic and alkaline solubility suggests either impotence or zwitter ion behaviour. TPS‘TPS INDUSTRIAL PHARMACY. | (B.Pharm. V SEM.) 13 Q) Q) (b) In this case there will be two pKa’s, one acidic and one basic. The intrinsic solubility should be measured at two temperature : 4 to 5°Cto ensure good physical stability and to extend short term storage and chemical stability until more definite data is available. 37° Cto support biopharmaceutical evaluation. The solubility of weakly acidic and weakly basic drug as function of pH can be predicted with help of equation. S =So {1 + (K1/[H+])} For weak acids. S = So {1 + ({H+]/K2)} For weak base. Where, S = solubility at given pH. So = intrinsic solubility of neutral form. K1 = dissociation constant for the weak acid. K2 = dissociation constant for weak base. pH and Ionization Constant (pKa) : Determination of dissociation constant for a drug capable of ionization with in a pH range of 1 to 10 is important since solubility, consequently absorption, can be changed by changing in pH. Many drugs are either weakly acidic or basic compounds and in solution, depending on the pH value, exist as ionized or un-ionized species. Knowledge of their individual ionization or dissociation characteristics is important, because their absorption is governed to a large extent by their degrees of ionization as they are presented to the membrane barriers. The degree of a drug's ionization depends both on the pH of the solution in which it is presented to the biologic membrane and on the pKa, or dissociation constant of the drug (whether an acid or base). vex}14 qd) Q) G3) TPS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM) The unionized species are more lipid soluble and hence more readily absorbed. The gastrointestinal absorption of weakly acidic or basic drugs is thus related to the fraction of the drug in solution that is unionized. The conditions that suppress ionization favor absorption. The factors that are important in the absorption of weakly acidic and basic compounds are : The pH at the site of absorption, The ionization constant and The lipid solubility of the unionized species. These factors together constitute the widely accepted pH partition theory. The relative concentrations of un-ionized and ionized forms of a weakly acidic or basic drug in a solution at a given pH can be readily calculated using the Henderson-Hasselbalch equations. For Bases, pH = pKa + log [Wnionized form] [lonized form] For Acids, pH = pKa + log _Llonized form] _ Unionized form] Weakly acidic compounds (pKa < 4.3) were absorbed relatively rapidly. Those with pKa values ranging between 2.0 and 4.3 were absorbed more slowly; and strong acids (pKa > 2.4) were hardly absorbed. For bases, those with pKa values smaller than 8.5 were absorbed relatively rapidly; those with a pK a between 9 and 12 were absorbed more slowly; and completely ionized quaternary ammonium compounds were not absorbed.qa) 2) GB) (4) qd) Q) @) (4) ‘FPS INDUSTRIAL PHARMACY- | (B.Pharm. V SEM.) 15 NB Pharm VSEM) The pKa value is the PH at which acidic or basic groups attached to molecules exist as 50% ionized and 50% nonionized in aqueous solution. The pKa value provides valuable data on the interaction of an ionizable drug with charged biological membranes and Teceptor sites and information on where the drug may be absorbed in the digestive tract. Knowing the pKa also enables the scientist to know how much to alter the pH to drive a compound to its fully ionized or nonionized form for analytical and other purposes, such as formulation, solubility and stability. If the drug dissolves too early, it may reprecipitate in a form that is poorly absorbed. Determination of the dissociation content for a drug capable of ionization within a pH rang of 1 to 10 is important since solubility and consequently absorption, cab be altered by orders of magnitude with changing pH. Determination of pKa : Potentiometric titration. Spectrophotometric determination. Dissolution rate method. Liquid-Liquid partition method. Significances : Provided that the intrinsic solubility and pKa are known, the solubility at any pH can be predicted. Henderson equations can facilitate the selection of suitable salt forming compounds and predict salt’s solubility. Determination of the ratio of the ionized to the unionized form of a drug molecule. This is useful to predict which form will predominate at different Physiologic pH. va AY16 (5) (c) TRS INDUSTRIAL PHARMACY. | (B.Pharm. V SEM) The pKa will determine the species of molecules, which is likely to be present at the site of action and how quickly or completely would the species cross a large number of transport barriers in the body, regardless of the route of administration, Partition coefficient : It is also known as distribution coefficient and is essentially independent of concentration of dilute solutions of a given solute species. The oil/water partition coefficient is a measure of a molecule’s lipophilic characters that is, its preference for the hydrophilic or lipophilic phase. Ifa solute is added to a mixture of two immiscible liquids, it will distribute between the two phases and reach equilibrium at a constant temperature. The distribution of the solute (un-aggregated and un-dissociated) between the two immiscible layers can be described as follows : it is the ratio of the unionized drug distributed between the organic (upper phase) and aqueous (lower) phases at equilibrium. 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 : Log P= [Unionized compound] Org. (Unionized compound] Ags. Log P = 0 means that the compound is equally soluble in water and in the partitioning solvent. If the compound has a log P = 5, then the compound is 100,000 times more soluble in the partitioning solvent. Deny‘TPS INDUSTRIAL PHARMACY. | (B.Pharm. V SEM.) aL FES INDUSTRIAL PHARMACY-I(B.Pharm.VSEM) 17. qa) Q) @) (4) 6) (6) a) Q) (3) (4) 6) (6) ) A log P = — 2 means that the compound is 100 times more soluble in water, i.e., it is quite hydrophilic. Drugs having values of P much greater than | are classified as lipophilic, whereas those with partition coefficients much less than 1 are indicative of a hydrophilic drug. Although it appears that the partition coefficient may be the best predictor of absorption rate, the effect of dissolution rate. Various organic solvents such as chloroform, ether, amyl acetate, isopropylmyristate, carbon tetrachloride, and n - Octanol can be used in the determination of the partition coefficient, with the latter gaining increasing acceptance. Determination of partition coefficient : Shake-flask method Chromatographic method. Countercurrent and filter probe method. Tomlinson’s filter probe method. Micro electrometric titration method. Automated instrument is now available. Applications of partition coefficient : Recovery of antibiotics from fermentation broth. Extraction of drug from biological fluid for therapeutic monitoring. Absorption of drug from dosage forms. (Ointments, Supp- ositories, Transdermal patches). Study of distribution of flavoring oil between oil and water in emulsion. It does provide a means of characterizing the lipophilic / hydrophilic nature of the drug. It is a contributing factor for the rate and extent of drug absorption. Measure of Lipophilic character of molecules. e-Ay(i) (ii) ‘TRS INDUSTRIAL PHARMACY: I (B.Pharm. V SEM, Polymorphism : Polymorphism is the ability of a compound to crystallize ag more than one distinct crystalline species with different internal lattices or crystal packing arrangement even they are chemically identical depending on the variation in; (a) Temperature (b) Solvent (c) Time They have different physicochemical properties (melting point, density, vapor pressure, X-ray, color, crystal shape, hardness, solubility, dissolution rate and bioavailability). Differences in the dissolution rates and solubilities of different polymorphic forms of a given drug are very commonly observed. When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving from may be utilized to improve the rate and extent of bioavailability. During preformulation, it is important to identify the polymorph that is stable at room temperature. For Ex. Chloromphenicol exist in A, B and C forms, of these B form is more stable and most preferable. For Ex. Riboflavin has I, II and III forms and the III form shows 20 times more water solubility than form I. Polymorphisms are of two types : Enantiotropic : Enantiotropic polymorphisms can be reversely changed into another by varying temperature and pressure. E.g. Sulphur, Carbon, Nitrogen and Oxygen. Monotropic polymorphism : polymorph is unstable at all temperature and pressure. E.g. Glyceryl stearate. pak