PHYSICOCHEMICAL PRINCIPLES OF PHARMACY PHYSICOCHEMICAL PRINCIPLES OF PHARMACY A.T.FLORENCE Department of Pharmaceutics, University of Strathclyde and D. ATTWOOD Department of Pharmacy, University of Manchester M ISBN 978-0-333-44996-7 ISBN 978-1-349-19480-3 (eBook) DOI 10.1007/978-1-349-19480-3 © A.T. Florence and D. Attwood 1981 Softcover reprint of the hardcover 1st edition 1981 978-0-333-44995-0 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission First published 1981 by THE MACMILLAN PRESS LTD London and Basingstoke Associated companies in Delhi Dublin Hong Kong Johannesburg Lagos Melbourne New York Singapore and Tokyo ISBN 978-0-333-23404-4 ISBN 978-0-333-23405-1 The paperback edition of this book is sold subject to the condition that it shall not, by way of trade or otherwise, be lent, resold, hired out, or otherwise circulated without the publisher's prior consent in any form of binding or cover other than that in which it is published and without a similar condition including this condition being imposed on the subsequent purchaser Contents Preface xi 1 Gases 1.1 Ideal and non-ideal gases I 1.2 Application of the gas laws in aerosol formulation 3 1 .3 Solubility of gases in liquids 6 1.3.1 Effect of temperature on solubility 7 1.3.2 Effect of pressure on solubility 7 1.3.3 Solubility of volatile anaesthetics in oil 8 1.3.4 Solubility of anaesthetic gases in blood and tissues 9 2 Properties of the Solid State 13 Introduction 2.1 Crystal form and polymorphism 13 2.2 Crystallisation and factors affecting crystal form 16 2 .3 Analytical implications of polymorphism 18 2.4 Thermomicroscopy 22 2.5 Relative stability of polymorphs and their bioavailability 22 2.6 Dissolution of solid drugs 25 2 .7 Biopharmaceutical importance of particle size 26 2.8 Wetting of powders 33 2.9 Solid solutions and eutectics 33 2.9 .1 Eutectics and drug identification 36 2 .10 Crystal growth in suspensions 37 2.11 Dissolution testing of solid dosage forms 38 3 Liquids 43 3 .1 The liquid state 43 3.2 Cohesive forces in polar and non-polar liquids 45 3.3 The structure of water 46 3.3.1 Hydrophobic bonding 47 3.4 Properties of liquids 49 3.4.1 Flow properties 49 3 .4 .2 Surface and interfacial tension 52 3 .4 .3 Dielectric properties 54 3.5 The liquid crystalline state 59 vi Contents 4 Solutions 65 Introduction 4.1 Concentration units 65 4.2 Thermodynamics - basic principles 66 4.2.1 Definitions 66 4.2.2 Laws of thermodynamics 67 4.2.3 Free energy 73 4.2.4 Partial molar quantities - chemical potential 82 4.3 Thermodynamics of ideal and non-ideal solutions 84 4.3.1 Raoult's law 84 4.3.2 Concepts of fugacity and activity 86 4.3.3 Chemical potential in solution 93 4.4 Colligative properties 95 4.4.1 Vapour pressure lowering 95 4.4.2 Elevation of boiling point 96 4.4.3 Depression of freezing point 97 4.4.4 Osmotic pressure 98 4.5 Dynamic properties of electrolyte and non-electrolyte solutions 102 4.5.1 Conductance of electrolyte solutions 102 4.5.2 Diffusion 106 4.5.3 Viscosity 109 4.6 Ionisation of drugs in solution 110 4.6.1 Dissociation of weak acids and bases and their salts 111 4.6.2 The effect of pH on the ionisation of weakly acidic or basic drugs and their salts 112 4.6.3 Amphoteric electrolytes 117 4.6.4 Ionisation of polyprotic drugs and microdissociation constants 118 4.7 Buffer solutions 119 5 Solubility of Drugs in Liquids 125 Introduction 5.1 Expressions of solubility 125 5.2 Determination of solubility 126 5.3 Factors affecting solubility 126 5 .3.1 Solubility of solutes in liquids 128 5.3.2 Molecular surface area approach 129 5.3.3 Structural features of simple molecules and aqueous solubility 130 5.4 Hydration and solvation 134 5.4.1 Hydration of non-electrolytes 134 5.4.2 Hydration of ionic species 135 5.4.3 Hydrophobic hydration 135 5.5 The solubility of inorganic materials in water 136 5.6 Solubility products 137 Contents vii 5.7 The effects of additives on solubility: the solubility coefficient 137 5.8 Influence of crystal size 139 5.9 Solubility of weak electrolytes 139 5.9.1 Acidic drugs 139 5.9 .2 Basic drugs 140 5.9.3 Amphoteric drugs 141 5 .10 Determination of solubility of organic electrolytes in aqueous solution 147 5.11 The solubility parameter 149 5 .11.1 Solubility parameters and biological processes 150 5 .12 Drug solubility and biological activity 152 5 .13 Solubility in mixed solvents 153 5.14 A recent formulation problem : Septrin infusion 154 5 .15 The choice of drug salt 15 5 5 .16 Partitioning phenomena 158 5 .16.1 Extraction 160 5.16.2 Partitioning of weak electrolytes 162 5.17 Uses oflog P 164 6 Surface Chemistry 173 Introduction 6.1 Amphipathic compounds 173 6.2 The liquid-gas and liquid-liquid interface 174 6.2.1 Effects of amphiphiles on surface and interfacial tension 174 6.2.2 Gibbs adsorption equation 175 6.2.3 Application of the Gibbs equation to surfactant solutions 177 6.2.4 Surface activity of drugs 179 6.2.5 Spreading 181 6.2.6 Insoluble monolayers 184 6.2.7 Pharmaceutical applications of surface ftlm studies 188 6.3 The solid-liquid interface 192 6.3 .1 Contact angle and wettability of solid surfaces 192 6.3.2 Wettability of powders 193 6.3 .3 Adsorption at the solid-liquid interface 196 6.4 Micellisation 205 6.5 Properties of some commonly used surfactants 213 6.5.1 Anionic surfactants 213 6.5.2 Cationic surfactants 213 6.5.3 Nonionic surfactants 214 6.6 Solubilisation 216 6.6.1 Determination of maximum additive concentration 216 6.6.2 Location of solubilisate 217 6.6.3 Factors affecting solubilisation 218 6.6.4 Pharmaceutical applications of solubilisation 220 viii Contents 7 Colloidal and Coarse Lyophobic Dispersions 223 Introduction 7 .1 Classification of colloidal systems 224 7.2 Colloid stability 224 7.3 Emulsions 233 7.3.1 Stability of emulsions 233 7.3 .2 HLB system 234 7 .3.3 Multiple emulsions 238 7.3 .4 Microemulsions 238 7 .3.5 Biopharmaceutical aspects of emulsion systems 238 7 .3.6 Preservative availability in emulsified systems 241 7.3 .7 Mass transport in oil-water emulsions 242 7.3 .8 Intravenous fat emulsions 24 7 7.4 Non-Newtonian flow 24 7 7.5 Pharmaceutical suspensions 251 7.5 .1 Settling of suspended particles 251 7.5 .2 Suspension stability 253 7.5 .3 Extemporaneous suspensions 259 7.5 .4 Rheology of suspensions of solid particles 259 7.5 .5 Adhesion of suspension particles to containers 262 7.5 .6 Crystal growth 265 7.6 Application of colloid theory to other systems 265 7 .6.1 Cell-cell interactions 265 7 .6.2 Sorption of microbial cells on surfaces 267 7 .6.3 Blood as a colloidal system 269 7.7 Foams 271 7.7.1 Foams: clinical considerations 272 8 Polymeric Systems 275 Introduction 8.1 Water-soluble polymers 278 8.2 General properties of polymer solutions 279 8.2 .1 Polydispersity 279 8.2.2 Viscosity 281 8.2.3 Gelling tendency 282 8 .2 .4 Heterogels 284 8 .2 .5 Syneresis 285 8.2 .6 Macromolecular complexation 286 8.2 .7 Binding of ions to macromolecules 288 8 .2 .8 Interaction of polymers with solvents including water 289 8.2.9 Adsorption of macromolecules 291 8.2.10 Polymer crystallinity 293 8.3 Water-insoluble polymers and polymer membranes 293 8.3 .1 Permeability of polymers 293 8.3.2 Ion-exchange resins 297 Contents ix 8 .4 Details of specific polymers used in pharmacy and medicine 301 8 .4 .1 Carboxypolymethylene ( carbomer, carbopol) 30 1 8.4.2 Cellulose derivatives 302 8.4.3 Hyaluronic acid, agarose and carrageenan 304 8.4.4 Natural gums and mucilages 305 8 .4.5 Dextran 309 8.4.6 Polyvinylpyrrolidone 310 8.4.7 Liquid polymers 312 8 .5 Some applications of polymeric systems in drug delivery 313 8.5 .1 Release of drugs from matrices 315 8.5 .2 Microencapsulation 317 8.5 .3 Rate-limiting membranes and devices 319 8.6 Mucus as a polymeric system 321 9 Principles of Drug Absorption and Routes of Administration 325 Introduction 9.1 Biological membranes and drug transport 325 9.2 Drug absorption from the gastro-intestinal tract 331 9.2 .1 Structural principles of the gastro-intestinal tract 333 9 .2.2 Permeability and the pH-partition hypothesis 334 9.2 .3 Problems in the quantitative application of the pH-partition hypothesis 337 9.2.4 Bile salts and fat absorption pathways 342 9.2.5 Gastric emptying, motility and volume of contents 344 9.3 Absorption of drugs from intramuscular and subcutaneous injections 345 9.4 Topical preparations 354 9 .4.1 Influence of drug 357 9.4.2 Influence ofvehicle 361 9 .4.3 Dilution of topical steroid preparations 366 9 .4.4 Transdermal medication 366 9.5 Medication of the eye 368 9.5.1 The eye 369 9.5 .2 Absorption of drugs 371 9.5 .3 Influence of formulations 3 72 9.5 .4 Systemic effects from eye-drops 3 77 9.6 Permeability of the oral mucosa; buccal absorption 377 9 .6.1 Mechanism of absorption 378 9.7 Inhalation therapy 379 9.7 .1 Physical factors of deposition of aerosols 381 9.7 .2 Experimental observations 383 9.7 .3 Analysis of particle size distribution in aerosols 388 9.8 The intranasal route 389 9.9 Rectal absorption of drugs 391 x Contents 10 Drug Interactions and Incompatibilities: a physicochemical viewpoint 401 Introduction 10.1 pH and other solvent effects 401 10.2 Cation-anion interactions 404 10.3 Simple electrolytes and their effect on drug solutions 406 10.4 Complex formation 406 10.5 Other complexes 412 10.6 Ion-exchange interactions 414 10.7 Adsorption of drugs 415 10.8 pH effects on drug behaviour in vivo 419 10.9 Protein binding 425 10.10 Interaction of drugs with (3-cyclodextrin 433 Appendix 10.1: Drug interactions based on physical mechanisms 436 11 Chemical Stability of Drugs 445 Introduction 11.1 The chemical decomposition of drugs 445 11.1.1 Hydrolysis 445 11.1.2 Oxidation 447 11.1.3 Isomerisation 449 11.1.4 Photochemical decomposition 451 11.1.5 Polymerisation 452 11.2 Kinetics of chemical decomposition in solution 453 11.2 .1 Order of reaction 453 11.2.2 Zero-order reactions 454 11.2.3 First-order reactions 455 11.2.4 Second-order reactions 457 11.2.5 Third-order reactions 458 11.2 .6 Determination of order of reaction 459 11.2.7 Complex reactions 461 11.3 Kinetics of chemical decomposition in solid dosage forms 465 11.4 Factors affecting the rate of chemical decomposition 469 11.4.1 Liquid dosage forms 469 11.4.2 Semisolid dosage forms 479 11.4.3 Solid dosage forms 480 11.5 Stability testing of drugs 483 11.5 .1 Effect of temperature on stability 484 11.5 .2 Other factors affecting stability 491 Index 495