Applied Physical Pharmacy Second Edition Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsi- bility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Applied Physical Pharmacy Second Edition Editors Mansoor M. Amiji, PhD, RPh Distinguished Professor and Chairman Department of Pharmaceutical Sciences Director, Laboratory of Biomaterials and Advanced Nano-Delivery Systems (BANDS) School of Pharmacy Bouve College of Health Sciences Northeastern University Boston, Massachusetts Thomas J. Cook, PhD, RPh Director of Program Assessment Associate Professor Department of Pharmaceutical and Biomedical Sciences Touro College of Pharmacy New York, New York W. Cary Mobley, PhD, RPh Clinical Associate Professor Department of Pharmaceutics University of Florida College of Pharmacy Gainesville, Florida New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto Copyright © 2014 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-180442-4 MHID: 0-07-180442-0 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-174750-9, MHID: 0-07-174750-8. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. 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THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT IMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise. Brief Contents Contributors ix 7. Complexation and Protein Preface xi Binding 135 Mansoor M. Amiji 1. Introduction to Biopharmaceutics 1 8. Dispersed Systems 157 W. Cary Mobley W. Cary Mobley 2. States of Matter Related to Pharmaceutical Formulations 15 9. Interfacial Phenomena 173 Beverly J. Sandmann Maria Polikandritou Lambros and Edited by Ann Newman and Gregory T. Knipp Shihong Li Nicolaou 10. Rheology 197 3. Physical Properties of Solutions 41 Maria Polikandritou Lambros Beverly J. Sandmann, Antoine Al-Achi, and Robert Greenwood 11. Chemical Kinetics of Pharmaceuticals 221 4. Ionic Equilibria and Buffers 61 Thomas J. Cook Beverly J. Sandmann, Alekha K. Dash, Antoine Al-Achi, and Robert Greenwood Appendix Basic Mathematical 5. Solubility, Dissolution, and Concepts 245 Partitioning 87 Endnotes 251 Beverly J. Sandmann and Mansoor M. Amiji Index 257 6. Mass Transport 117 Mansoor M. Amiji This page intentionally left blank Contents Contributors ix Preface xi 4. Ionic Equilibria and Buffers 61 1. Introduction to Biopharmaceutics 1 Beverly J. Sandmann, Alekha K. Dash, W. Cary Mobley Antoine Al-Achi, and Robert Greenwood Introduction 1 Electrolytes versus Nonelectrolytes 61 Drug Disposition—The Fate of the Drug After Importance of Ionization in Pharmacy 61 Administration 3 Acids and Bases 62 LADME 8 Ionization of Water 63 Conclusion 13 Ionization of Electrolytes 65 Key Points 14 Ionization of Salts 70 Clinical Questions 14 Buffers 72 Ionization of Amphoteric Electrolytes 74 2. States of Matter Related to Ionization of Polyprotic Acids 75 Activity and Activity Coefficient 75 Pharmaceutical Formulations 15 Acid-Base Titration and Titration Curve 76 Beverly J. Sandmann Case Studies 77 Edited by Ann Newman and Gregory T. Knipp Problems 78 Answers 79 Intermolecular Forces 15 Key Points 80 States of Matter 19 Appendix 80 Stability of Solids 34 Suggested Readings 85 Acknowledgment 37 Problems 37 Answers 38 5. Solubility, Dissolution, and Key Points 39 Partitioning 87 Clinical Questions 39 Beverly J. Sandmann and Mansoor M. Amiji 3. Physical Properties of Solutions 41 Solubility 87 Dissolution 97 Beverly J. Sandmann, Antoine Al-Achi, Dissolution of Particles 97 and Robert Greenwood USP Dissolution Testing 99 General Considerations 41 Significance of Dissolution Studies 102 Concentration Expressions 42 Factors Affecting Drug Dissolution 103 Classification of Aqueous Solution Systems 45 Partitioning 106 Physical Properties of Solutions 46 Solubility Problems 110 Physiologic Applications of Answers 111 Colligative Properties 47 Dissolution Problems 113 Isotonic Solutions 50 Answers 113 Sodium Chloride Equivalent Values (E) 52 Partitioning Problems 114 Problems 54 Answers 114 Answers 57 Key Points 114 Key Points 59 Clinical Questions 115 Clinical Questions 59 vii viii CONTENTS 6. Mass Transport 117 Problems 190 Answers 190 Mansoor M. Amiji Key Points 191 Introduction 117 Clinical Questions 192 Transport Systems 118 Appendix 192 Diffusion Through a Membrane 121 Significance of Diffusion 125 10. Rheology 197 Significance of Osmosis 131 Maria Polikandritou Lambros Problems 132 Answers 133 Introduction 197 Key Points 134 Newtonian Flow 198 Clinical Questions 134 Viscosity of Newtonian Fluids 200 Effect of Temperature on Viscosity 201 7. Complexation and Protein Non-Newtonian Flow 202 Thixotropy 205 Binding 135 Viscoelasticity 206 Mansoor M. Amiji Significance of Rheology 206 Viscosity Modifiers 210 Introduction 135 Problems 215 Types of Complexes 136 Answers 216 Metal-Ion Coordinate Complexes 137 Key Points 216 Cyclodextrin Complexes 140 Clinical Questions 217 Ion-Exchange Resins 141 Appendix 217 Protein-Ligand Interaction 143 Plasma Protein Binding 146 11. Chemical Kinetics of Problems 148 Answers 149 Pharmaceuticals 221 Key Points 150 Thomas J. Cook Clinical Questions 151 Appendix 151 Common Drug Degradation Reactions 222 Order of Reaction 223 Determination of the Order of a Reaction 227 8. Dispersed Systems 157 Stability and Shelf Life of Drugs 229 W. Cary Mobley Enzyme Catalysis Reactions 234 Pharmacokinetics: An Extension Dispersed Systems Classified of Reaction Kinetics 236 by their Phases 157 Problems 238 Dispersed Systems Classified Answers 241 by their Particle Size 159 Clinical Questions 243 Physical Stability of Suggested Readings 243 Dispersed Systems 162 Summary 169 Problems 169 Appendix Basic Mathematical Answers 169 Concepts 245 Key Points 170 Clinical Questions 171 Equations 245 Suggested Readings 171 Logarithmic Function 245 Exponential Function 246 Differentiation and Integration Functions 246 9. Interfacial Phenomena 173 Bibliography 247 Maria Polikandritou Lambros and Mathematical Tables 248 Shihong Li Nicolaou Endnotes 251 Surface Tension 173 Electrical Double Layer 179 Index 257 Adsorption 180 Contributors Mansoor M. Amiji, PhD, RPh Robert Greenwood, RPh, PhD (Chapters 3, 4) (Chapters 5, 6 and 7) Associate Dean of Academic Affairs Distinguished Professor and Chairman Professor of Pharmaceutical Sciences Department of Pharmaceutical Sciences Campbell University College of Pharmacy & Director, Laboratory of Biomaterials and Advanced Health Sciences Nano-Delivery Systems (BANDS) Buies Creek, NC School of Pharmacy Bouve College of Health Sciences Gregory T. Knipp, PhD (Chapter 2) Northeastern University Associate Professor of Industrial and Physical Boston, MA Pharmacy Associate Director, Dane O. Kildsig Center for Antoine Al-Achi, PhD, (Chapter 4) Pharmaceutical Processing Research Associate Professor of Pharmaceutical Sciences Purdue University, Department of Industrial and Campbell University College of Pharmacy & Physical Pharmacy Health Sciences West Lafayette, IN Buies Creek, NC Maria Polikandritou Lambros, PhD Thomas J. Cook, PhD, RPh (Chapter 11) (Chapters 9 and 10) Director of Program Assessment Associate Professor of Pharmaceutical Sciences Associate Professor College of Pharmacy Department of Pharmaceutical and Biomedical Western University of Health Sciences Science Pomona, CA Touro College of Pharmacy New York, NY W. Cary Mobley, PhD, RPh (Chapters 1 and 8) Clinical Associate Professor Alekha K. Dash, RPh, PhD (Chapter 4) Department of Pharmaceutics Professor University of Florida Department of Pharmacy Sciences College of Pharmacy School of Pharmacy & Health Professions Gainesville, Florida Creighton University Medical Center Omaha, NE ix