Pharmaceutical Dosage Forms and Drug Delivery Ram I. Mahato CRC Press Taylor & Francis Group Boca Raton London NewYorV CRC Press is an imprint of the Taylor & Francis Group, an informa business
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PharmaceuticalDosage FormsandDrug Delivery
Ram I. Mahato
CRC PressTaylor & Francis Group
Boca Raton London NewYorV
CRC Press is an imprint of theTaylor & Francis Group, an informa business
Table of Contents
List of Illustrations xixList of Tables xxiiiForeword xxvPreface xxviiAcknowledgments xxixAbout the Author xxxi
Chapter 1 Drug Development and Regulatory Process 1
Learning Objectives 1I. Introduction 1II. Identification of New Therapeutic Molecules 2
A. Extraction from Plants 2B. Organic Synthesis 3C. Use of Animals 4D. Genetic Engineering 4E. Gene Therapy 4
III. Preclinical Research 4IV. Formulation Development 5V. Regulatory Issues 5
A. Investigational New Drug (IND) Application 5B. Clinical Trials 6
1. Phase I Clinical Trials 62. Phase II Clinical Trials 63. Phase III Clinical Trials 7
C. New Drug Application (NDA) 7D. Approval and Postmarketing Surveillance 7E. Abbreviated New Drug Application (ANDA) 8F. Role of FDA's Advisory Committees 8
Review Questions 8Bibliography 9
Chapter 2 Pharmaceutical and Formulation Considerations 11
Learning Objectives 11I. Introduction 11II. Advantages of Pharmaceutical Dosage Forms 11
viii Pharmaceutical Dosage Forms and Drug Delivery
III. Influential Factors in Dosage Form Design 12A. Molecular Size and Volume 13B. Drug Solubility and pH 14C. Lipophilicity and Partition Coefficient 16D. Polymorphism 17E. Stability 19F. pKa/Dissociation Constants 20G. Degree of lonization and pH-Partition Theory 24
1. Limitations of pH-Partition Theory 24Review Questions 25Bibliography 26
Chapter 3 Biopharmaceutical and Physiological Considerations 29
Learning Objectives 29I. Introduction 29II. Drug Transport across a Polymeric Barrier 30III. Fick's Laws of Diffusion 30
A. Fick's First Law of Diffusion 30B. Fick's Second Law of Diffusion 32
1. Steady-State Conditions 322. Lag Time 34
IV. Pore Diffusion 34V. Matrix (Monolithic)-Type Nondegradable Device 35VI. Biological Membranes and Drug Absorption 36
A. Passive Transport 371. Simple Diffusion 372. Carrier-Mediated Transport 373. Channel-Mediated Transport 37
B. Active Transport 37VII. Fick's Law of Diffusion and Drug Absorption 38VIII. Dissolution Rate and Noyes-Whitney Equation of Dissolution 40IX. Factors Influencing Dissolution Rate 41
A. Physicochemical Properties 41B. Thickness of Diffusion Layer 42C. Gastrointestinal Fluids 42D. Particle Size 42E. Crystallinity 42F. Porosity and Tortuosity of Solid Particles 43G. Temperature 43H. Surfactants 43
X. Drug Absorption and Bioavailability 43Review Questions 43Bibliography 45
Table of Contents
Chapter 4 Complexation and Protein Binding 47
Learning Objectives 47I. Introduction 47II. Types of Complexation 47
A. Coordination Complexes 48B. Molecular Complexes 48C. Drug Complexes 50D. Polymer Complexes 50E. Inclusion Complexes 50
III. Drug Interaction with Plasma Proteins 52IV. Binding Equilibria 52
A. Protein Binding 54V. Impact of Plasma Protein Binding on Dosing Regimens 55Review Questions 56Bibliography 57
Chapter 5 Chemical Kinetics and Stability 59
Learning Objectives 59I. Introduction 59II. Rates and Order of Reaction 59
A. Zero-Order Reactions 60B. First-Order Reactions 61C. Second-Order Kinetics 63
III. Factors Affecting Reaction Kinetics 65A. Catalysis 65B. Effect of Temperature 65C. Effect of Solvent 67D. Effect of pH 67E. Presence of Additives 67
IV. Pathways and Prevention of Chemical Decomposition of Drugs 68A. Hydrolysis 68
1. Control of Drug Hydrolysis 69B. Oxidation 70
1. Control of Drug Oxidation 72C. Photolysis 72
1. Control of Photodegradation of Drugs 72
Review Questions 73Bibliography 73
Chapter 6 Interfacial Phenomena 75
Learning Objectives 75I- Introduction 75
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II. Liquid Interfaces 75A. Surface and Interfacial Tensions 75B. Surface Free Energy 76
III. Adsorption at Solid-Gas Interfaces 77A. Physical Adsorption 77B. Chemical Adsorption 78C. Adsorption Isotherms 78
1. Freundlich Adsorption Isotherm 782. Langmuir Adsorption Isotherm 793. BET Adsorption Isotherm 804. Type of Isotherms 80
IV. Adsorption at Solid-Liquid Interface 81A. Factors Affecting Adsorption from Solution 81B. Application of Adsorption 82
V. Wettability and Wetting Agents 83A. Wetting Agents 83
VI. Protein Adsorption 84Review Questions 84Bibliography 85
Chapter 7 Rheology 87
Learning Objectives 87I. Introduction 87II. Newtonian Flow 87
A. Temperature Dependence and Viscosity of Liquids 88III. Non-Newtonian Flow 88
A. Plastic Flow 88B. Pseudoplastic Flow 90C. DilatantFlow 90
IV. Thixotropy 91A. Hysteresis Loop 91B. Negative Thixotropy 93
V. Pharmaceutical Applications of Rheology 93Review Questions 94Bibliography 94
Chapter 8 Disperse System Basics 95
Learning Objectives 95I. Introduction 95II. Types of Colloidal Systems 96
A. Lyophilic Colloids 96B. Lyophobic Colloids 96C. Association Colloids 97
Table of Contents xi
III. Kinetic Properties of Colloids 97A. Brownian Movement 97
1. Diffusion 962. Sedimentation 96
IV. Electrical Properties 99A. Ionization 99B. Ion Adsorption 100C. Ion Dissolution 100
V. Electrostatic Effect 100VI. Electrical Double Layer 100
A. Nerst and Zeta Potentials 102B. DLVO Theory 102C. Electrophoretic Phenomena 102
VII. Stability of Colloids 103A. Aggregation 104B. Coagulation 104C. Flocculation 104
Review Questions 104Bibliography 105
Chapter 9 Surfactants and Micelles 107
Learning Objectives 107I. Introduction 107II. Surfactants 107
A. Types of Surfactants 1081. Anionic Surfactants 1082. Cationic Surfactants 1093. Nonionic Surfactants 1094. Ampholytic Surfactants 109
III. HLB Systems 110IV Micelles 111
A. Types of Micelles 114B. CMC and Micellar Size 114
V. Micellar Solubilization 115A. Factors Affecting Solubilization 115
1. Nature of Surfactants 1152. Nature of Solubilizates 1163. Effect of Temperature 1164. Effect of pH 116
B. Pharmaceutical Applications of Micellar Solubilization 116C. Thermodynamics of Solubilization 117
VI. Krafft Point 118VII. Cloud Point 119
xii Pharmaceutical Dosage Forms and Drug Delivery
Review Questions 119Bibliography 120
Chapter 10 Pharmaceutical Suspensions 123
Learning Objectives 123I. Introduction 123II. Classification of Suspensions 123III. Characteristics of Pharmaceutical Suspensions 124IV. Formulation of Suspensions 125V. Flocculation and Deflocculation 126
A. Properties of Deflocculated (Dispersed) Particles 129B. Properties of Flocculated Particles 129
VI. Suspension Stability 130A. Adhesion of Suspension Particles to Containers 130B. Sedimentation Parameters 130C. Sedimentation and Stoke's Law 131
Review Questions 132Bibliography 133
Chapter 11 Pharmaceutical Emulsions 135
Learning Objectives 135I. Introduction 135II. Advantages of Emulsion Dosage Forms 135III. Types of Emulsions 135
A. Oil-in-Water Emulsions 136B. Water-in-Oil Emulsions 136C. Multiple Emulsions 137D. Microemulsions 137
IV. Roles of Interfacial Free Energy on Emulsification 137V. Formulations of Emulsions 138VI. Emulsifying Agents 138
A. Surfactants 140B. Hydrophilic Colloids 140C. Finely Divided Solid Particles 141
VII. Types of Instability in Emulsions 141A. Creaming and Sedimentation 141B. Breaking and Coalescence 142C. Phase Inversion 143D. Microbial Growth 143
Review Questions 143Bibliography 144
Table of Contents
Chapter 12 Pharmaceutical Solutions 145
Learning Objectives 145I. Introduction 145II. pH and Solubility 146III. Buffer and Buffer Capacity 146IV. Vehicles 148V. Types of Solutions 148
A. Syrups 148B. Elixirs 149C. Tinctures 149D. Miscellaneous Solutions 149
VI. Dry or Lyophilized Mixtures for Solution 150Review Questions 150Bibliography 150
Chapter 13 Tablets 153
Learning Objectives 153I. Introduction 153II. Types of Tablets 153
A. Swallowable Tablets 153B. Effervescent Tablets 154C. Chewable Tablets 154D. Buccal and Sublingual Tablets 154E. Lozenges 154F. Coated Tablets 154G. Controlled-Release Tablets 155H. Immediate-Release Tablets 156
III. Tablet Formulation 156A. Diluents 156B. Adsorbents 157C. Moistening Agents 157D. Binding Agents 157E. Glidants 158F. Lubricants 158G. Disintegrants 158H. Miscellaneous 159
IV Powder Flow and Compressibility 159V. Manufacturing of Tablets 159VI. Relationship among Disintegration. Dissolution, and Absorption 160VII. Evaluation of Tablets 161Review Questions 161Bibliography 163
xiv Pharmaceutical Dosage Forms and Drug Delivery
Chapter 14 Capsules 165
Learning Objectives 165I. Introduction 165II. Hard Gelatin Capsules 166
A. Advantages and Disadvantages of Hard Gelatin Capsules 166B. Formulation of Hard Gelatin Capsules 167
III. Soft Gelatin Capsules 168A. Formulation of Soft Gelatin Capsules 169
IV. Evaluation of Capsules 170Review Questions 171Bibliography 171
Chapter 15 Injectable Dosage Forms 173
Learning Objectives 173I. Introduction 173II. Isotonicity 174III. Parenteral Routes of Administration 174
A. Intravenous Route 174B. Intramuscular Route 175C. Subcutaneous Route 175D. Other Routes 175
IV. Formulation of Parenteral Products 176A. Physicochemical Properties of the Drug 176B. Excipients in Parenteral Formulations 176C. Vehicles 177
V. Sterilization of Parenteral Products 177A. Filtration 177B. Dry Heat Sterilization 178C. Steam Sterilization 178D. Radiation Sterilization 178
VI. Types of Parenteral Dosage Forms 178A. Solutions 178B. Suspensions 179C. Emulsions 179D. Dry Powders 179
VII. Evaluation of Injectable Products 179A. Sterility 180B. Pyrogens 180C. Paniculate Matters 180
Review Questions 181Bibliography 181
Table of Contents xv
Chapter 16 Semisolid Dosage Forms 183
Learning Objectives 183I. Introduction 183II. Ointments 183
A. Types of Ointment Bases 1831. Hydrocarbon Bases 1842. Absorption Bases 1843. Emulsion Bases 1844. Water-Soluble Bases 185
B. Incorporation of Drugs into Ointment 185III. Creams 185IV Gels 186V Lotions 187VI. Pastes 187Review Questions 187Bibliography 188
Chapter 17 Inserts, Implants, and Devices 189
Learning Objectives 189I. Introduction 189II. Inserts 189III. Implants 191IV. Suppositories 192V. Aerosol Products 193
A. Nebulizers 193B. Metered-Dose Inhalers (MDIs) 195C. Powder Inhalers 195
VI. Transdermal Patches 196Review Questions 197Bibliography 197
Chapter 18 Pharmaceutical Polymers 199
Learning Objectives 199I. Introduction 199II. Definitions and Architectures of Polymers 199HI. Polymer Molecular Weight and Weight Distribution 204IV. Biodegradablity and Biocompatibility 205V. Polymer Solubility 205VI. Block Copolymers 206VII. Intelligent or Stimuli-Sensitive Polymers 207VIII. Water-Soluble Polymers 208IX. Bioadhesive/Mucoadhesive Polymers 209
xvi Pharmaceutical Dosage Forms and Drug Delivery
Review Questions 209Bibliography 210
Chapter 19 Drug Delivery Systems 211
Learning Objectives 211I. Introduction 211II. Prodrugs 212III. Soluble Macromolecular Carriers 213IV. Particulate Carrier Systems 214
A. Liposomes 2151. Types of Liposomes 2152. Fabrication of Liposomes 216
B. Microparticles and Nanoparticles 2181. Fabrication of Microparticulates 219
C. Nanoparticles 223V. Oral Drug Delivery 224VI. Alternative Routes of Delivery 225
A. Buccal and Sublingual Drug Delivery 225B. Nasal Drug Delivery 226C. Pulmonary Drug Delivery 227D. Ocular Drug Delivery 227E. Rectal Drug Delivery 228F. Vaginal Drug Delivery 228
Review Questions 229Bibliography 229
Chapter 20 Protein- and Peptide-Based Dosage Forms 231
Learning Objectives 231I. Introduction 231II. Structure of Peptides and Proteins 232
A. Primary Structure 234B. Secondary Structure 235C. Tertiary Structure 235D. Quaternary Structures 235
III. Hydrophobicity of Peptides and Proteins 235IV. Solubility of Peptides and Proteins 236V. Instability of Peptides and Proteins 237
A. Physical Instability 2371. Denaturation 2372. Aggregation and Precipitation 2383. Surface Adsorption 238
Table of Contents xvii
B. Chemical Instability 2381. Hydrolysis 2392. Deamidation 2393. Oxidation 2394. Racemization 2405. Disulfide Exchange 240
VI. Formulation of Proteins and Peptides 240A. Additives 240B. Lyophilized Proteins 241C. Chemical Modification 242D. PEGylation 242
VII. Antibody-Based Therapy and Delivery 242VIII. Antigenicity and Immunogenicity 244Review Questions 244Bibliography 245
Chapter 21 Biotechnology-Based Dosage Forms 247
Learning Objectives 247I. Introduction 247II. Genes and Gene Expression 247III. Gene Silencing 248IV. Classification of Gene-Silencing Technologies 249
A. Antisense Oligonucleotides 249B. Triplex-Forming Oligonucleotides 250C. Peptide Nucleic Acids 250D. Antisense RNA 250E. Aptamers 250F. Ribozymes 251G. RNA Interference 251
V. Gene Therapy 251A. Retroviral Vector 252
1. Moloney Murine Leukemia Viruses 2532. Lentiviruses 253
B. Adenoviral Vectors 254C. Adeno-Associated Virus Vectors 254D. Herpes Simplex Virus Vectors 254E. Gene Expression Plasmid 254F. Gene Delivery Systems 255
1. Lipid-Based Gene Delivery 2562. Peptide-Based Gene Delivery 2573. Polymer-Based Gene Delivery 258
Review Questions 258Bibliography 259
xviii Pharmaceutical Dosage Forms and Drug Delivery
Chapter 22 Answers to Review Questions 261
Chapter 1: Drug Development and Regulatory Process 261Chapter 2: Pharmaceutical and Formulation Considerations 261Chapter 3: Biopharmaceutical and Physiological Considerations 266Chapter 4: Complexation and Protein Binding 267Chapter 5: Chemical Kinetics and Stability 269Chapter 6: Interfacial Phenomenon 270Chapter 7: Rheology 271Chapter 8: Disperse System Basics 272Chapter 9: Surfactants and Micelles 275Chapter 10: Pharmaceutical Suspensions 276Chapter 11: Pharmaceutical Emulsions 277Chapter 12: Pharmaceutical Solutions 279Chapter 13: Tablets 279Chapter 14: Capsules 280Chapter 15: Injectable Dosage Forms 280Chapter 16: Semisolid Dosage Forms 281Chapter 17: Inserts, Implants, and Devices 281Chapter 18: Pharmaceutical Polymers 281Chapter 19: Drug Delivery Systems 282Chapter 20: Protein- and Peptide-Based Dosage Forms 283Chapter 21: Biotechnology-Based Dosage Forms 283
Index 285
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