Pharmaceutical Dosage Forms and Drug Delivery SECOND EDITION

Ram I. jit S. Narang

CRC Press Taylor Francis Croup Boca Raton London York

CRC Press is an imprint of the Taylor Francis Croup, an informa business

Contents List of Figures xxv List of Tables xxxi Foreword xxxiii Preface xxxv Acknowledgments xxxvii Authors xxxix

PART Introduction

Chapter 1 Drug Development and Regulatory Process 3

Learning Objectives 3 1.1 Introduction 3 1.2 Identification of New Therapeutic Moieties 5

1.2.1 Plant Sources 6 1.2.2 Organic Synthesis 6 1.2.3 Use of Animals 6 1.2.4 Genetic Engineering 6 1.2.5 Gene Therapy 7

1.3 Preclinical Development 7 1.4 Clinical Development 8

1.4.1 Phase I Clinical Trials 8 1.4.2 Phase II Clinical Trials 8 1.4.3 Phase III Clinical Trials 9

1.5 Formulation Development 9 1.6 Regulatory Interface 10

1.6.1 Investigational New Drug Application 10 1.6.2 New Drug Application 11 1.6.3 Approval and Post-Marketing Surveillance 11 1.6.4 Abbreviated New Drug Application 12 1.6.5 Accelerated Development/Review 12 1.6.6 Role of FDA's Advisory Committees 12

Review Questions 13 Further Reading 13

Chapter 2 Pharmaceutical Considerations 15

Learning Objectives 15 2.1 Introduction 15 2.2 Advantages of Pharmaceutical Dosage Forms 15

VII

viii Contents

2.3 Influential Factors in Dosage Form Design 16 2.3.1 Molecular Size and Volume 17 2.3.2 Drug Solubility and 18 2.3.3 Lipophilicity and Partition 20 2.3.4 Polymorphism 21 2.3.5 Stability 23 2.3.6 Constants 24 2.3.7 Degree of Ionization and pH-Partition Theory 28

2.3.7.1 Limitations pH-Partition Theory 28 Review Questions 29 Further Reading 30

Chapter 3 Considerations 33

Learning Objectives 33 3.1 Introduction 33 3.2 Diffusion 34

3.2.1 Drug Transport across a Polymeric Barrier 34 3.2.1.1 Molecular Diffusion 34 3.2.1.2 Pore Diffusion 35 3.2.1.3 Matrix Erosion 35

3.2.2 Principles of Diffusion 35 3.2.2.1 Fick's First Law 35 3.2.2.2 Fick's Second Law 36

3.2.3 Diffusion Rate 37 3.2.3.1 Diffusion Cell 37 3.2.3.2 Spherical Membrane-Controlled Drug

Delivery System 39 3.2.3.3 Pore Diffusion 39 3.2.3.4 Determining Permeability Coefficient 40 3.2.3.5 Lag Time in Nonsteady State Diffusion 40 3.2.3.6 Matrix (Monolithic)-Type

Nondegradable System 41 3.2.3.7 Calculation Examples 41

3.3 Dissolution 42 3.3.1 Noyes-Whitney Equation 43

3.3.1.1 Calculation Example 43 3.3.2 Factors Influencing Dissolution Rate 44

3.4 Absorption 46 3.4.1 Passive Transport 48

3.4.1.1 Simple Diffusion 48 3.4.1.2 Carrier-Mediated Transport 48 3.4.1.3 Channel-Mediated Transport 48

3.4.2 Fick's Laws of Diffusion in Drug Absorption 49 3.4.3 Active Transport 50

Contents ix

Review Questions 50 Further Reading 52

Chapter 4 Pharmacy Math and Statistics 53

Learning Objectives 53 4.1 Introduction 53 4.2 Systems of Measure 53

4.2.1 Volume and Weight Interconversions 54 4.2.2 Temperature Interconversions 55 4.2.3 Accuracy, Precision, and Significant Figures 55

4.3 Ratio and Proportion 56 4.4 Concentration Calculations 57

4.4.1 Percentage Solutions 57 4.4.2 Concentrations Based on Moles and Equivalents 57 4.4.3 Parts per Unit Concentrations 58 4.4.4 Dilution of Stock Solutions 59 4.4.5 Mixing Solutions of Different Concentrations 60

4.4.5.1 Alligation Medial 60 4.4.5.2 Alligation Alternate 60

4.4.6 Tonicity, Osmolarity, and Preparation of Isotonic Solutions 63

4.5 Clinical Dose Calculations 66 4.5.1 Dosage Adjustment Based on Body Weight or

Surface Area 67 4.5.2 Calculation of Children's Dose 67 4.5.3 Dose Adjustment for Toxic Compounds 69 4.5.4 Dose Adjustment Based on Creatinine Clearance 71

4.6 Statistical Measures 73 4.6.1 Measures of Central Tendency 73 4.6.2 Measures of Dispersion 74 4.6.3 Sample Probability Distributions 75

4.6.3.1 Normal Distribution 76 4.6.3.2 Log-Normal Distribution 76 4.6.3.3 Binomial Distribution 76 4.6.3.4 Poisson Distribution 76 4.6.3.5 Student's 76 4.6.3.6 Chi-Square Distribution 78

4.7 Tests of Statistical Significance 78 4.7.1 Parametric and Nonparametric Tests 79 4.7.2 Null and Alternate Hypothesis 80 4.7.3 Steps of Hypothesis Testing 80 4.7.4 One-Tailed and Two-Tailed Hypothesis Tests 81 4.7.5 Regions of Acceptance and Rejection 81 4.7.6 Probability Value and Power of a Test 82

Contents

4.7.7 Types of Error 83 4.7.8 Questions Addressed by Tests of Significance 83 4.7.9 Analysis of Variance 87

4.7.9.1 One-Way ANOVA 87 4.7.9.2 Two-Way ANOVA: Design of

Experiments 93 Review Questions 98 References 100

PART II Physicochemical Principles

Chapter 5 Complexation and Protein Binding 103

Learning Objectives 103 5.1 Introduction 103 5.2 Types of Complexes 104

5.2.1 Coordination Complexes 104 5.2.2 Molecular Complexes 107

Small Molecule-Small Molecule Complexes 108

5.2.2.2 Small Molecule-Large Molecule Complexes 108

5.2.2.3 Large Molecule-Large Molecule Complexes 109

5.3 Protein Binding 110 5.3.1 Kinetics of Ligand-Protein Binding

5.3.1.1 Parameters of Interest 5.3.1.2 Experimental Setup 5.3.1.3 Determining 112

5.3.2 Thermodynamics of Ligand-Protein Binding 115 5.3.3 Factors Influencing Protein Binding 117

5.3.3.1 Physicochemical Characteristics and Concentration of the Drug 117

5.3.3.2 Physicochemical Characteristics and Concentration of the Protein 117

5.3.3.3 Physicochemical Characteristics of the Medium 118

5.3.4 Plasma Protein Binding 118 5.3.4.1 Plasma Proteins Involved in Binding 118 5.3.4.2 Factors Affecting Plasma

Protein Binding 118 5.3.4.3 Consequences of Plasma

Protein Binding 119 5.3.5 Drug-Receptor Binding 120 5.3.6 Substrate-Enzyme Binding 120

Contents xi

Review Questions 121 Further Reading 122

Chapter 6 Chemical Kinetics and Stability 123

Learning Objectives 123 6.1 Introduction 123 6.2 Reaction Rate and Order 123

6.2.1 Order Reactions 125 6.2.2 Determination of Reaction Order 125 6.2.3 Zero-Order Reactions 126

6.2.3.1 Rate Equation 126 6.2.3.2 Half-Life 127

6.2.4 First-Order Reactions 127 6.2.4.1 Rate Equation 128 6.2.4.2 Half-Life 129

6.2.5 Second-Order Reactions 130 6.2.5.1 Rate Equation 130 6.2.5.2 Half-Life 131

6.2.6 Complex Reactions 132 6.2.6.1 Reversible Reactions 132 6.2.6.2 Parallel Reactions 132 6.2.6.3 Consecutive Reactions 133

6.3 Factors Affecting Reaction Kinetics 133 6.3.1 Temperature 133

6.3.1.1 Arrhenius Equation 133 6.3.1.2 Shelf Life 135 6.3.1.3 Thermodynamics of Reactions 135

6.3.2 Humidity 135 6.3.2.1 Water as a Reactant 136 6.3.2.2 Water as a Plasticizer 136 6.3.2.3 Water as a Solvent 136 6.3.2.4 Determination and Modeling the

Effect of Water/Humidity 136 6.3.3 pH 137

6.3.3.1 Disproportionation Effect 137 6.3.3.2 Acid-Base Catalysis 137 6.3.3.3 pH Rate Profile 137

6.3.4 Cosolvents and Additives 138 6.3.4.1 Drug-Excipient Interactions 139 6.3.4.2 Catalysis 139

6.4 Drug Degradation Pathways 140 6.4.1 Hydrolysis 140

6.4.1.1 Ester Hydrolysis 140 6.4.1.2 Amide Hydrolysis 141 6.4.1.3 Control of Drug Hydrolysis 142

Contents

6.4.2 Oxidation 143 6.4.2.1 Control of Drug Oxidation 145

6.4.3 Photolysis 146 6.4.3.1 Control of Photodegradation of Drugs 147

Review Questions 147 Further Reading 148

Chapter 7 Interfacial Phenomena 151

Learning Objectives 151 7.1 Introduction 151 7.2 Liquid-Liquid and Liquid-Gas Interface 151

7.2.1 Surface Tension 152 7.2.2 Interfacial Tension 153 7.2.3 Factors Affecting Surface Tension 153 7.2.4 Surface Free Energy 154

7.3 Solid-Gas Interface 155 7.3.1 Adsorption 155 7.3.2 Factors Affecting Adsorption 155 7.3.3 Types of Adsorption 155

7.3.3.1 Physical Adsorption 156 7.3.3.2 Chemical Adsorption (Chemisorption) 156

7.3.4 Adsorption Isotherms 157 7.3.4.1 Types of Isotherms 157 7.3.4.2 Modeling Isothermal Adsorption 157

7.4 Solid-Liquid Interface 160 7.4.1 Modeling Solute Adsorption 160 7.4.2 Factors Affecting Adsorption from Solution 160 7.4.3 Wettability and Wetting Agents 161

7.5 Biological and Pharmaceutical Applications 162 Review Questions 163 Further Reading 163

Chapter 8 Disperse Systems 165

Learning Objectives 165 8.1 Introduction 165 8.2 Types of Colloidal Systems 166

8.2.1 Lyophilic Colloids 166 8.2.2 Lyophobic Colloids 166 8.2.3 Association Colloids 166

8.3 Preparation of Colloidal Solutions 167 8.4 Properties of Colloidal Solutions 168

8.4.1 Kinetic Properties 168 8.4.1.1 Brownian Movement 168 8.4.1.2 Diffusion 168 8.4.1.3 Sedimentation 169

Contents xiii

8.4.2 Electrical Properties 170 8.4.2.1 Surface Charge 170 8.4.2.2 Electrical Double Layer 171

8.4.3 Colligative Properties 173 8.4.3.1 Lowering of Vapor Pressure 173 8.4.3.2 Elevation of Boiling Point 173 8.4.3.3 Depression of Freezing Point 174 8.4.3.4 Osmotic Pressure 174

8.4.4 Optical Properties 174 8.5 Physical Stability of Colloids 175

8.5.1 Stabilization of Hydrophilic Colloids 175 8.5.2 Stabilization of Hydrophobic Colloids 175

Review Questions 176 Further Reading 177

Chapter 9 Surfactants and Micelles 179

Learning Objectives 179 9.1 Introduction 179 9.2 Surfactants 180

9.2.1 Types of Surfactants 180 9.2.1.1 Anionic Surfactants 181 9.2.1.2 Cationic Surfactants 181 9.2.1.3 Nonionic Surfactants 182 9.2.1.4 Surfactants 182

9.2.2 HLB System 182 9.2.2.1 Type of Emulsion Formed 183 9.2.2.2 Required HLB of a Lipid 184 9.2.2.3 Required HLB of a Formulation 184 9.2.2.4 Assigning an HLB Value to a Surfactant.... 186 9.2.2.5 Selection of Surfactant Combination

for a Target HLB Value 186 9.3 Micelles 186

9.3.1 Types of Micelles 186 9.3.2 Micelles versus Liposomes 187 9.3.3 Colloidal Properties of Micellar Solutions 187 9.3.4 Factors Affecting CMC and Micellar Size 189 9.3.5 Krafft Point 190 9.3.6 Cloud Point 191 9.3.7 Micellar Solubilization 191

Factors Affecting the Extent of Solubilization 191

9.3.7.2 Pharmaceutical Applications 192 9.3.7.3 Thermodynamics/Spontaneity 192

Review Questions 194 Further Reading 195

XIV Contents

Chapter 10 Pharmaceutical Polymers 197

Learning Objectives 10.1 Introduction 197 10.2 Definitions and Architectures of Polymers 197

Polymer Molecular Weight and Weight Distribution 201 10.4 Biodegradability and Biocompatibility 202 10.5 Polymer Solubility 202 10.6 Block Copolymers 203 10.7 Intelligent or Stimuli-Sensitive Polymers 204 10.8 Water-Soluble Polymers 204

10.8.1 Carbopol) 205 10.8.2 Cellulose Derivatives 205 10.8.3 Natural Gum (Acacia) 205 10.8.4 Alginates 206 10.8.5 Dextran 206 10.8.6 Polyvinylpyrrolidone 206 10.8.7 Polyethylene Glycol 206

10.9 Bioadhesive/Mucoadhesive Polymers 206 Review Questions 207 Further Reading 207

Chapter 11 Rheology 209

Learning Objectives 209 11.1 Introduction 209

Newtonian Flow 209 Temperature Dependence and Viscosity

of Liquids 210 11.3 Non-Newtonian Flow 211

11.3.1 Plastic Flow 211 11.3.2 Flow 211 11.3.3 212

11.4 Thixotropy 212 11.4.1 Hysteresis Loop 213 11.4.2 Negative Thixotropy 214

11.5 Pharmaceutical Applications of Rheology 214 Review Questions 215 Further Reading 215

Chapter 12 Drug Delivery Systems 217

Learning Objectives 217 12.1 Introduction 217 12.2 Prodrugs 218 12.3 Soluble Carriers 218

Contents

12.4 Particulate Carrier Systems 220 12.4.1 Liposomes 221

12.4.1.1 Types of Liposomes 221 12.4.1.2 Fabrication of Liposomes 222

Microparticles and Nanoparticles 224 12.4.2.1 Fabrication of Microparticulates 224

12.4.3 Nanoparticles 229 12.5 Oral Drug Delivery 230 12.6 Alternative Routes of Delivery 230

12.6.1 Buccal and Sublingual Drug Delivery 231 12.6.2 Nasal Drug Delivery 232 12.6.3 Pulmonary Drug Delivery 232 12.6.4 Ocular Drug Delivery 233 12.6.5 Rectal Drug Delivery 234 12.6.6 Vaginal Drug Delivery 234

Review Questions 234 Further Reading 235

SECTION III Dosage Forms

Chapter 13 Suspensions 239

Learning Objectives 239 13.1 Introduction 239 13.2 Types of Suspensions 239 13.3 Powder for Suspension 240

13.3.1 Unit-Dose PFS 241 13.3.2 Multidose PFS 241

13.4 Quality Attributes 241 13.5 Formulation 243

13.5.1 Flocculation 245 13.5.2 Sedimentation Parameters 249 13.5.3 250

13.6 Manufacturing Process 251 Review Questions 251 Further Reading 252

Chapter 14 Emulsions 255

Learning Objectives 255 14.1 Introduction 255 14.2 Types of Emulsions 256

14.2.1 Emulsion 256 14.2.2 Emulsion 257 14.2.3 Multiple Emulsions 257

Contents

14.2.4 Microemulsions 257 14.2.5 Self-Emulsifying Drug Delivery Systems and

Drug Delivery Systems 257 14.3 Quality Attributes 258 14.4 Formulation 259

14.4.1 Interfacial Free Energy 260 14.4.2 Phase Ratio 260 14.4.3 260 14.4.4 Zeta Potential 261

14.5 Emulsification 261 14.5.1 Surfactants 262

14.5.1.1 Ionic Surfactants 262 14.5.1.2 HLB Value 263

14.5.2 Hydrophilic Colloids 263 14.5.3 Finely Divided Solid Particles 263

14.6 Manufacturing Process 264 14.7 Stability 264

14.7.1 Physical Instability 264 14.7.1.1 Creaming and Sedimentation 264 14.7.1.2 Aggregation, Coalescence, and

Breaking 265 14.7.1.3 Phase Inversion 266

14.7.2 Chemical Instability 266 14.7.3 Microbial Growth 266

Review Questions 266 Further Reading 267

Chapter 15 Pharmaceutical Solutions 269

Learning Objectives 269 15.1 Introduction 269 15.2 Types of Solutions 270

15.2.1 Syrup 270 15.2.2 Elixir 270 15.2.3 Tincture 271 15.2.4 Oil-Based Solutions 271 15.2.5 Miscellaneous Solutions 271 15.2.6 Dry or Lyophilized Mixtures for Solution 271

15.3 Quality Attributes 272 15.4 Formulation Components and Manufacturing Process 272 15.5 Solubility 273

15.5.1 pH and Buffer Capacity 273 15.5.2 Surfactants and Cosolvents 275

15.6 Stability 275 15.6.1 Physical Stability 275

Contents xvii

15.6.2 Chemical Stability 276 15.6.3 Microbial Stability 276

Review Questions 277 Further Reading 277

Chapter 16 Powders and Granules 279

Learning Objectives 279 16.1 Introduction 279 16.2 Production of Powders and Granules 280

16.2.1 Origin of Powdered Excipients 280 16.2.2 Amorphous and Crystalline Powders 281 16.2.3 Production of Crystalline Powders 281

16.2.3.1 Crystallization versus Dissolution 282 16.2.3.2 Polymorphism 282

16.2.4 Production of Amorphous Powders 283 16.3 Analyses of Powders 283

16.3.1 Particle Shape and Size 284 16.3.1.1 Defining Particle Shape and Size 284 16.3.1.2 Defining Particle Size Distribution 285 16.3.1.3 Desired Particle Shape and Size 285 16.3.1.4 Factors Determining Particle Shape 288 16.3.1.5 Techniques for Quantifying Particle

Shape and Size 288 16.3.1.6 Changing Particle Shape and Size 289

16.3.2 Surface Area 292 16.3.2.1 Significance of Surface Area 292 16.3.2.2 Defining Surface Area 292 16.3.2.3 Quantitation of Surface Area by Gas

Adsorption 292 16.3.2.4 Altering Powder Surface Area 294

16.3.3 Density and Porosity 294 16.3.3.1 Significance of Density Determination .... 294 16.3.3.2 Defining Powder Density 294 16.3.3.3 Methods for Quantifying Powder

Density and Porosity 295 16.3.3.4 Changing Powder Density and 296

16.3.4 Flow 297 16.3.4.1 Importance of Flowability of Powders 297 16.3.4.2 Factors Influencing Flow of Powders 297 16.3.4.3 Quantitation of Powder Flow 297 16.3.4.4 Manipulation of Flow Properties of

Powders 298 16.3.5 Compactibility 298

16.3.5.1 Compactibility, Compressibility, and Tabletability 298

Contents

16.3.5.2 Importance of Compactibility 299 16.3.5.3 Determination of Compaction

Characteristics 299 16.3.5.4 Factors Affecting Compactibility 299

16.3.6 Content Uniformity 300 16.3.6.1 Importance of Uniform Mixing 300 16.3.6.2 Factors Affecting Mixing Uniformity 300 16.3.6.3 Assessment of Content Uniformity 301 16.3.6.4 Addressing Content Nonuniformity

Issues 301 16.4 Powder Processing 302

16.4.1 Increasing Particle Size: Granulation 302 16.4.1.1 Dry Granulation 302 16.4.1.2 Wet Granulation 303

16.4.2 Decreasing Particle Size: 306 Techniques for Particle Size 306

16.4.2.2 Selection of Size Reduction Technique .... 307 16.5 Powders as Dosage Forms 307

16.5.1 Types of Powder Dosage Forms 307 16.5.1.1 Oral Powders in Unit Dose Sachets 308 16.5.1.2 Powders for Oral Solution or

Suspension 308 16.5.1.3 Bulk Powders for Oral Administration 308 16.5.1.4 Effervescent Granules 308 16.5.1.5 Dusting Powders 308 16.5.1.6 Dry Powder Inhalers 309

16.5.2 Advantages of Extemporaneous Compounding of Powders 309 16.5.2.1 Extemporaneous Compounding

Techniques 309 Review Questions 310 Further Reading 311

Chapter 17 Tablets 313

Learning Objectives 313 17.1 Introduction 313 17.2 Types of Tablets 313

17.2.1 Swallowable Tablets 320 17.2.2 Effervescent Tablets 320 17.2.3 Chewable Tablets 320 17.2.4 Buccal and Sublingual Tablets 320 17.2.5 Lozenges 320 17.2.6 Coated Tablets 321 17.2.7 Controlled-Release Tablets 322 17.2.8 Immediate Release Tablets 323

Contents xix

17.3 Tablet Formulation 323 17.3.1 Diluents 324 17.3.2 Adsorbents 325 17.3.3 Moistening Agents 325 17.3.4 Binding Agents 326 17.3.5 Glidants 326 17.3.6 Lubricants 327 17.3.7 Disintegrants 327 17.3.8 Miscellaneous 327

17.4 Manufacturing of Tablets 327 17.4.1 Requirements 327 17.4.2 Powder Flow and Compressibility 328 17.4.3 Types of Manufacturing Processes 329 17.4.4 Packaging and Handling Considerations 331

17.5 Evaluation of Tablets 331 17.5.1 General Appearances 331 17.5.2 Uniformity of Content 331 17.5.3 Hardness 331 17.5.4 Friability 332 17.5.5 Weight and Content Uniformity 332 17.5.6 Disintegration 332 17.5.7 Dissolution 332

17.6 Relationship between Disintegration, Dissolution, and Absorption 333

Review Questions 334 Further Reading 335

Chapter 18 Capsules 337

Learning Objectives 337 18.1 Introduction 337 18.2 Hard Gelatin Capsules 338

18.2.1 Advantages and Disadvantages of Hard Gelatin Capsules 340 18.2.1.1 Comparison with Tablets 340 18.2.1.2 Comparison with Soft Gelatin Capsules 340

18.2.2 Solid Filled Hard Gelatin Capsules 341 18.2.2.1 Main Applications 341 18.2.2.2 Formulation Considerations 341 18.2.2.3 Formulation Components 342 18.2.2.4 Manufacturing Process 343

18.2.3 Liquid and Semisolid Filled Hard Gelatin Capsules.... 345 18.2.3.1 Main Applications 345 18.2.3.2 Formulation Considerations 345 18.2.3.3 Formulation Components 346 18.2.3.4 Manufacturing Process 346

XX Contents

18.3 Soft Gelatin Capsules 347 Advantages and Disadvantages of Soft Gelatin

Capsules 347 Drivers for Development of Soft Gelatin Capsules 348

18.3.3 Formulation of Soft Gelatin Capsule Shell 348 18.3.3.1 Gelatin 349 18.3.3.2 Plasticizer 349 18.3.3.3 Water 349 18.3.3.4 Preservative 350 18.3.3.5 Colorant and/or Opacifier 350 18.3.3.6 Other Excipients 350

18.3.4 Drug Formulation for Encapsulation in Soft Gelatin Capsules 350

18.3.5 Manufacturing Process 351 18.3.6 Nongelatin Soft Capsules 352

18.4 Evaluation of Capsules 352 18.4.1 In-Process Tests 353 18.4.2 Finished Product Quality Control Tests 353

18.4.2.1 Permeability and Sealing 353 18.4.2.2 Potency and Impurity Content 353 18.4.2.3 Average Weight and Weight Variation 353 18.4.2.4 Uniformity of Content 354 18.4.2.5 Disintegration 354 18.4.2.6 Dissolution 354 18.4.2.7 Moisture Content 354 18.4.2.8 Microbial Content 354

18.5 Shelf Life Tests 354 Review Questions 355 Further Reading 356

Chapter 19 Parenteral Drug Products 357

Learning Objectives 357 19.1 Introduction 357 19.2 Parenteral Routes of Administration 358

19.2.1 Intravenous Route 358 19.2.2 Intramuscular Route 358 19.2.3 Subcutaneous Route 359 19.2.4 Other Routes 359 19.2.5 and Extent of Absorption 359 19.2.6 Factors Affecting Selection of Route 360

19.3 Types of Parenteral Dosage Forms 360 19.3.1 SVPs versus LVPs 360 19.3.2 Injections versus Infusions 361 19.3.3 Types of Formulations 361

19.3.3.1 Solutions 361

Contents xxi

19.3.3.2 Suspensions 361 19.3.3.3 Emulsions 362

19.4 Quality Attributes and Evaluation 362 19.4.1 Sterility 362 19.4.2 Pyrogens 363

19.4.2.1 Endotoxins, Exotoxins, and Pyrogens 363 19.4.2.2 Endotoxin Components and Tolerance

Limits 363 19.4.2.3 Sources 363 19.4.2.4 Depyrogenation 363 19.4.2.5 Detection 364

19.4.3 Particulate Matters 364 19.5 Formulation Components 364 19.6 Sterilization 365

19.6.1 Filtration 365 19.6.2 Dry Heat Sterilization 366 19.6.3 Steam Sterilization (Autoclaving) 366 19.6.4 Radiation Sterilization 366

Review Questions 366 Further Reading 367

Chapter 20 Semisolid Dosage Forms 369

Learning Objectives 369 20.1 Introduction 369 20.2 Ointments 369

20.2.1 Types of Ointment Bases 370 20.2.1.1 Hydrocarbon Bases 370 20.2.1.2 Absorption Bases 371 20.2.1.3 Emulsion or Water-Removable Bases 372 20.2.1.4 Water-Soluble Bases 373

20.2.2 Selection of Ointment Bases 374 20.2.3 Methods of Incorporation of Drugs into

Ointment Bases 374 20.3 Creams 375 20.4 Gels and Jellies 376

20.4.1 Gels 376 20.4.2 Jellies 377

20.5 Lotions 377 20.6 Pastes 377 20.7 Foams 378 20.8 Manufacturing Processes 378

20.8.1 Laboratory Scale 378 20.8.2 Industrial Scale 379

20.9 Evaluation of Semisolid Dosage Forms 379

Contents

Review Questions 380 Further Reading 381

Chapter 21 Inserts, Implants, and Devices 383

Learning Objectives 383 21.1 Introduction 383 21.2 Inserts 384

21.2.1 Ocular Inserts 384 21.2.2 Suppositories 385

21.2.2.1 Types of Suppositories 385 21.2.2.2 Suppository Bases 386 21.2.2.3 Manufacturing Process and

Formulation Considerations 386 21.2.3 Vaginal Rings 387

21.3 Implants 387 21.3.1 Types of Drug-Containing Implants 388

21.3.1.1 Diffusion-Controlled Implants 388 21.3.1.2 Osmotic 388

21.3.2 Types of Implants Based on Clinical Use 389 21.3.2.1 Cardiac Implants 389 21.3.2.2 Dental Implants 391

Urological and Penile Implants 391 21.3.2.4 Breast Implants 391 21.3.2.5 Ophthalmic Implants 391 21.3.2.6 Dermal or Tissue Implants 392

21.4 Devices 392 Inhaler Devices for Pulmonary Drug Delivery 392

21.4.1.1 Nebulizers 394 21.4.1.2 Metered-Dose Inhalers 394 21.4.1.3 Dry Powder Inhalers 395

21.4.2 Transdermal Patches 396 21.4.3 Intrauterine Devices 396

Review Questions 397 Further Reading 397

Chapter 22 Protein and Peptide Drug Delivery 399

Learning Objectives 399 22.1 Introduction 399 22.2 Structure 401

22.2.1 Amino Acids 403 22.2.2 Primary Structure 406 22.2.3 Secondary Structure 406 22.2.4 Tertiary Structure 406 22.2.5 Quaternary Structure 407

Contents xxiii

22.3 Types of Proteins and Peptides Therapeutics 407 22.3.1 Antibodies 407 22.3.2 Hormones and Physiological Proteins 409 22.3.3 Chemically Modified Proteins and Peptides 409

22.3.3.1 PEGylation 410 22.3.3.2 Other Protein Conjugation Approaches....

22.4 Protein Characterization 411 22.4.1 Biophysical Characterization 411 22.4.2 Physicochemical Characterization 412

22.4.2.1 Solubility 412 22.4.2.2 Hydrophobicity 413

22.5 Instability 414 22.5.1 Physical Instability 414

22.5.1.1 Denaturation 414 22.5.1.2 Aggregation and Precipitation 415 22.5.1.3 Surface Adsorption 415

22.5.2 Chemical Instability 416 22.5.2.1 Hydrolysis 416 22.5.2.2 416 22.5.2.3 Oxidation 416 22.5.2.4 418 22.5.2.5 Disulfide Exchange 418 22.5.2.6 Maillard Reaction 418

22.6 Antigenicity and Immunogenicity 419 22.7 Formulation and Process 420

22.7.1 Route of Administration 420 22.7.2 of Formulation 421 22.7.3 Formulation Components 421 22.7.4 Manufacturing Processes 422

22.7.4.1 Protein Solution 422 22.7.4.2 Lyophilization 423

Review Questions 424 Further Reading 426

Chapter 23 Biotechnology-Based Dosage Forms 427

Learning Objectives 427 23.1 Introduction 427 23.2 Genes and Gene Expression 427 23.3 Gene Silencing 428 23.4 Classification of Gene Silencing Technologies 429

23.4.1 Antisense Oligonucleotides 429 23.4.2 Triplex-Forming Oligonucleotides 429 23.4.3 Peptide Nucleic Acids 430 23.4.4 Antisense RNA 430 23.4.5 430

xxiv Contents

23.4.6 430 23.4.7 RNA Interference 431

23.5 Gene Therapy 432 23.5.1 Retroviral Vector 433

23.5.1.1 MuLV 433 23.5.1.2 Lentiviruses 433

23.5.2 Adenoviral Vectors 433 23.5.3 Adeno-Associated Virus Vectors 434 23.5.4 Herpes Simplex Virus Vectors 434 23.5.5 Gene Expression Plasmid 434 23.5.6 Gene Delivery Systems 435

23.5.6.1 Lipid-Based Gene Delivery 436 23.5.6.2 Peptide-Based Gene Delivery 437 23.5.6.3 Polymer-Based Gene Delivery 437

Review Questions 438 Further Reading 438

Answers to Review Questions 439

Index 465