Developing Solid Oral Dosage Forms (eBook)

Front Cover 1
Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice 4
Copyright Page 5
Contents 6
List of Contributors 30
Foreword 32
PART I: THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS 34
Chapter 1. Solubility of Pharmaceutical Solids 36
1.1 Introduction 36
1.1.1 Implication of Solubility in Dosage Form Development 36
1.1.2 Basic Concepts of Solubility and Dissolution 37
1.2 Thermodynamics of Solutions 38
1.2.1 Volume of Mixing 38
1.2.2 Enthalpy of Mixing 38
1.2.3 Entropy of Mixing 39
1.2.4 Free Energy of Mixing 39
1.3 Theoretical Estimation of Solubility 39
1.3.1 Ideal Solutions 39
1.3.2 Effect of Crystallinity 40
1.3.3 Non-ideal Solutions 41
1.3.4 Regular Solution Theory 41
1.3.5 Aqueous Solution Theory 42
1.3.6 The General Solubility Equation (GSE) 43
1.4 Solubilization of Drug Candidates 44
1.4.1 Solubility Enhancement by pH Control and Salt Formation 44
1.4.2 Solubilization Using Complexation 46
1.4.3 Solubilization by Cosolvents 48
1.4.4 Solubilization by Surfactants (Micellar Solubilization) 49
1.4.5 Solubilization by Combination of Approaches 49
1.5 Experimental Determination of Solubility 52
1.5.1 Stability of Solute and Solvent 53
1.5.2 Shakers and Containers 53
1.5.3 Presence of Excess Undissolved Solute 53
1.5.4 Determination of Equilibrium 54
1.5.5 Phase-separation 54
1.5.6 Determination of Solute Content in the Dissolved Phase 54
1.5.7 Experimental Conditions 55
Chapter 2. Crystalline and Amorphous Solids 58
2.1 Introduction 58
2.2 Definitions and Categorization of Solids 58
2.3 Thermodynamics and Phase Diagrams 60
2.3.1 Polymorphs 60
2.3.2 Solvates/Hydrates 65
2.3.3 Cocrystals 67
2.3.4 Amorphous Solids 68
2.4 Pharmaceutical Relevance and Implications 69
2.4.1 Solubility 70
2.4.2 Dissolution Rate and Bioavailability 71
2.4.3 Hygroscopicity 71
2.4.4 Reactivity and Chemical Stability 72
2.4.5 Mechanical Properties 73
2.5 Transformations Among Solids 73
2.5.1 Induced by Heat 73
2.5.2 Induced by Vapor 75
2.5.3 Induced by Solvents 76
2.5.4 Induced by Mechanical Stresses 77
2.6 Methods of Generating the Solids 77
2.6.1 Through Gas 77
2.6.2 Through Liquid 78
2.6.3 Through Solid 79
2.7 Amorphous Drugs and Solid Dispersions 79
2.7.1 Characteristics of Amorphous Phases 79
2.7.2 Characteristics of Amorphous Solid Dispersions 81
2.7.3 Crystallization of Amorphous Drug and Dispersions 84
2.8 Special Topics 87
2.8.1 Polymorph Screening and Stable Form Screening 87
2.8.2 High Throughput Crystallization 88
2.8.3 Miniaturization in Crystallization 88
Chapter 3. Analytical Techniques in Solid-state Characterization 94
3.1 Introduction 94
3.2 Review of Analytical Techniques and Methods 95
3.3 Microscopic Methods 95
3.3.1 Optical Microscopy 95
3.3.2 Electron Microscopy 96
3.4 Thermal Analysis 96
3.4.1 Differential Scanning Calorimetry 97
3.4.2 Thermogravimetric Analysis 98
3.4.3 Microcalorimetry 98
3.5 Diffraction Methods 98
3.5.1 Single-crystal X-ray Diffraction 98
3.5.2 Powder X-ray Diffraction 99
3.6 Vibrational Spectroscopy 100
3.6.1 Infrared Spectroscopy 100
3.6.2 Raman Spectroscopy 101
3.6.3 Near-infrared 101
3.7 Solid-State Nuclear Magnetic Resonance Spectroscopy 101
3.8 Sorption Techniques 103
3.9 Other Techniques 104
3.10 Characterization of Solids Using Complementary Analytical Techniques 104
3.11 Conclusion 106
Chapter 4. Salt Screening and Selection: New Challenges and Considerations in the Modern Pharmaceutical Research and Development Paradigm 108
4.1 Introduction 108
4.2 Theoretical Considerations 109
4.2.1 pH-Solubility Profiles and the Role of pK[sub(a)] 109
4.2.2 Prediction of Salt Solubility and In Situ Salt Screening 110
4.2.3 Solubility and Dissolution Rate of Salts 110
4.2.4 Dissolution of Salts in GI Fluids 111
4.2.5 Impact of Salt Form on Other Solubilization Techniques 113
4.2.6 Effect of Salts on Chemical Stability 114
4.2.7 Potential Disadvantages of Salts 114
4.3 Practical Considerations 114
4.3.1 Drug Substance Considerations 114
4.3.2 Dosage Form Considerations 114
4.3.3 Toxicity Considerations 115
4.3.4 Salt and Form Screening and Selection Strategies 115
4.3.5 The Role of Automation and High Throughput Designs in Salt Screening 117
4.4 Conclusions 118
Chapter 5. Drug Stability and Degradation Studies 120
5.1 Introduction 120
5.2 Chemical Stability 120
5.2.1 Solution Kinetics 121
5.2.2 Rate Equations 121
5.2.3 Elemental Reactions and Reaction Mechanism 121
5.2.4 Typical Simple Order Kinetics 122
5.2.5 Complex Reactions 124
5.2.6 Arrhenius Equation, Collision Theory, and Transition State Theory 125
5.2.7 Catalysts and Catalysis 127
5.2.8 pH-rate Profiles 128
5.2.9 Solid-state Reaction Kinetics 131
5.2.10 Solid-state Kinetic Models 132
5.2.11 Physical Parameters Affecting Solid-state Kinetics 134
5.2.12 The Role of Moisture 135
5.2.13 Topochemical Reactions 136
5.3 Common Pathways of Drug Degradation 136
5.3.1 Hydrolysis 136
5.3.2 Oxidative Degradation 138
5.3.3 Photochemical Degradation 140
5.3.4 Other Degradation Pathways 142
5.4 Experimental Approaches to Studying the Chemical Degradation of Drugs 142
5.4.1 Solution Thermal Degradation Studies 142
5.4.2 Solid-state Thermal Degradation Studies 145
5.4.3 Oxidative Degradation Studies 146
5.4.4 Photodegradation Studies 147
5.5 Physical Stability and Phase Transformations 148
5.5.1 Types of Phase Transformations 148
5.5.2 Mechanisms of Phase Transformations 148
5.6 Phase Transformations during Pharmaceutical Processing 150
5.6.1 Processes for Preparing Solid Dosage Forms and Associated Potential Phase Transformations 150
5.6.2 Anticipating and Preventing Phase Transformations in Process Development 154
Chapter 6. Excipient Compatibility 158
6.1 Introduction 158
6.2 Chemistry of Drug–Excipient Interactions 159
6.2.1 Influence of Water and Microenvironmental pH 159
6.2.2 Reactions with Excipients and their Impurities 160
6.2.3 Stabilizing Excipients 165
6.3 Current Practices 166
6.3.1 Experimental Design 167
6.3.2 Sample Preparation and Storage 168
6.3.3 Sample Analysis and Data Interpretation 171
6.4 Conclusions 176
Chapter 7. Theory of Diffusion and Pharmaceutical Applications 180
7.1 Introduction 180
7.1.1 Basic Equations of Diffusion 180
7.1.2 Solutions for Diffusion Equations 181
7.2 The Diffusion Coefficient and Its Determination 186
7.2.1 Steady State Flux Method 187
7.2.2 Lag Time Method 188
7.2.3 Sorption and Desorption Methods 188
7.3 Pharmaceutical Applications 189
7.3.1 Controlled Release 189
7.3.2 Particle Dissolution 191
7.3.3 Packaging Study 192
7.4 Appendix 193
7.4.1 The Error Function and Its Application 193
7.4.2 Derivation of Solution by Separation of Variables 193
Chapter 8. Particle, Powder, and Compact Characterization 196
8.1 Introduction 196
8.2 Particle Size Characterization 196
8.2.1 Light Microscopy 197
8.2.2 Scanning Electron Microscopy 198
8.2.3 Sieving 199
8.2.4 Light Diffraction 199
8.2.5 Importance/Impact of Particle Size Characterization 200
8.3 Powder Characterization 200
8.3.1 Density 200
8.3.2 Flow 202
8.4 Compact (Mechanical Property) Characterization 206
8.4.1 Important Mechanical Properties 207
8.4.2 Overview of Methods 208
8.4.3 Quasi-static Testing 209
8.4.4 Dynamic Testing 212
8.5 Conclusions 216
Chapter 9. Polymer Properties and Characterization 220
9.1 Introduction 220
9.1.1 Definition, Structure, and Nomenclature 221
9.1.2 Types of Homopolymers and Copolymers 223
9.2 Commonly Used Cellulose Derivatives in Solid Oral Products 224
9.3 Basic Concepts and Characterization of Polymeric Materials 228
9.3.1 Polymer Composition 230
9.3.2 Molecular Weight 231
9.3.3 Polymers in Solution 238
9.3.4 Structure–Property Relationships 240
9.4 Conclusion 249
Chapter 10. Applied Statistics in Product Development 252
10.1 Introduction 252
10.1.1 Statistics: A Tool for Decision Making and Risk Assessment 252
10.1.2 Sources of Uncertainty 253
10.1.3 Natural (Random) Variation 253
10.1.4 Systematic Error (Bias) and Blunders 254
10.2 Exploring Data: Types of Data 254
10.2.1 Nominal (Categorical) Data 254
10.2.2 Ordinal Data 255
10.2.3 Numerical Data 256
10.2.4 Continuously Variable Data and Digitization Pitfalls 256
10.3 Exploring Data: Graphical Techniques 257
10.3.1 Graphing Nominal Data 257
10.3.2 Bar Charts 257
10.3.3 Pie Charts 257
10.3.4 Graphing Univariate Numerical Data 257
10.3.5 Histograms 258
10.3.6 Quantile Plots 259
10.3.7 Box Plots 259
10.3.8 Graphing Bivariate Data 259
10.3.9 One Variable Nominal: Bar Graphs, Dot Plots, and Line Plots 260
10.3.10 One Variable Nominal: Box Plots 260
10.3.11 Both Variables Numeric and Random: Quantile–Quantile Plots 260
10.3.12 Both Variables Numeric: Scatterplots 261
10.3.13 Multivariate Data 261
10.3.14 Scatterplot Matrices 262
10.4 Data Distributions 262
10.4.1 Binomial Distribution 262
10.4.2 Poisson Distribution 263
10.4.3 Normal (Gaussian) Distribution 263
10.4.4 Other Useful Distributions 263
10.5 Location: Central Tendencies 263
10.5.1 Data for Central Value and Dispersion Examples 264
10.5.2 Arithmetic Mean 264
10.5.3 Median 264
10.6 Dispersion 265
10.6.1 Range 265
10.6.2 Interquartile Range and Median Absolute Deviation from the Median 265
10.6.3 Variance and Standard Deviation 265
10.6.4 Coefficient of Variation 267
10.6.5 Multivariate Covariance and Correlation 267
10.6.6 Correlation and Causality 267
10.6.7 Error Propagation 267
10.7 Probability 268
10.7.1 Chebyshev's Inequality 269
10.7.2 The Normal Probability Assumption 270
10.8 Interval Estimation 271
10.8.1 Confidence Intervals 271
10.8.2 Prediction Intervals 274
10.8.3 Tolerance Intervals 274
10.8.4 Rounding 275
10.9 Process Modeling and Experimental Design 276
10.9.1 Models, Parameters, and Hypotheses 277
10.9.2 Confidence Interval Estimation and Hypothesis Testing 277
10.9.3 Are Two Processes Different or the Same? 278
10.9.4 More Complex Models 278
10.9.5 Regression Models and the Analysis of Variance 279
10.9.6 One-way ANOVA with One Nominal Factor 279
10.9.7 Two-way ANOVA with Two Nominal Factors 279
10.9.8 Regression Analysis with One Continuous Factor 280
10.9.9 Regression Analysis with Multiple Continuous Factors 280
10.9.10 Regression with Nominal and Continuous Variables (ANCOVA) 280
10.9.11 Nonlinear Models 280
10.9.12 Data Snooping (Data Mining) 280
10.9.13 Outliers 281
10.10 The Measurement Process 282
10.10.1 Models and Assay Design in Analytical Chemistry 282
10.10.2 Direct Assays (Titrations) 282
10.10.3 Slope–Ratio Assays 282
10.10.4 Parallel Line and Ligand-binding Assays 283
10.10.5 Calibration Lines and Curves 283
10.10.6 Accuracy, Precision, Bias, and Blunders 284
10.10.7 Detecting and Eliminating Bias 284
10.10.8 Precision 285
10.10.9 Short-term Repeatability 285
10.10.10 Long-term Reproducibility 286
10.10.11 Measurement Reliability Analysis Based on ANOVA with Random Factors 286
10.10.12 Measurement Reliability Analysis Based on Prior Information and In-Process Standards 287
10.10.13 Reporting Measurement Reliability 287
10.10.14 Multivariate Methods 287
10.11 The Production Process 288
10.11.1 Controlled and Uncontrolled Factors 288
10.11.2 Response Surface Modeling: The Design Space 288
10.11.3 Classical Factorial Designs 289
10.11.4 Confounding Variables: Fractional Factorials 289
10.11.5 Screening Designs 289
10.11.6 Taguchi Designs 289
10.11.7 Model Assumptions 289
10.11.8 Choosing an Experimental Design 290
10.11.9 Data Analysis and Model Simplification 290
10.11.10 Evolutionary Operation 291
10.11.11 Process Stability and Capability 291
10.11.12 Statistical Process Control Revisited 291
10.11.13 In-process Monitoring and Control Using Process Analytical Technology 292
10.11.14 Process "Wellness" 292
10.12 Software 292
10.13 Summary 292
PART II: BIOPHARMACEUTICAL AND PHARMACOKINETIC EVALUATIONS OF DRUG MOLECULES AND DOSAGE FORMS 296
Chapter 11. Oral Absorption Basics: Pathways, Physico-chemical and Biological Factors Affecting Absorption 298
11.1 Barriers to Oral Drug Delivery 298
11.1.1 Intestinal Barrier 299
11.1.2 Hepatic Barrier 299
11.2 Pathways of Drug Absorption 299
11.2.1 Paracellular Diffusion 300
11.2.2 Passive Diffusion 300
11.2.3 Carrier-mediated Transport 301
11.2.4 Active Transport 302
11.2.5 Facilitated Transport 306
11.3 Pathways of Drug Metabolism 307
11.3.1 Phase I Metabolism 308
11.3.2 Phase II Enzymes 309
11.4 Pathways of Drug Elimination 310
11.4.1 P-glycoprotein (P-gp) 310
11.4.2 Multidrug-resistance Associated Proteins (MRPs) 311
11.4.3 Organic Anion Transporters 312
11.5 Coupling of Enzymes and Efflux Transporters 312
11.5.1 Double Jeopardy Theorem 312
11.5.2 Revolving Door Theorem 313
11.6 Physico-Chemical Factors Affecting Drug Absorption 314
11.6.1 Lipophilicity 315
11.6.2 Size 315
11.6.3 Charge 315
11.6.4 Solubility 315
11.6.5 Dissolution 315
11.7 Biological Factors Affecting Drug Absorption 315
11.7.1 Transit Time 316
11.7.2 pH 316
11.7.3 Food 317
11.7.4 Luminal Enzymes 317
11.8 Summary 317
Chapter 12. Oral Drug Absorption, Evaluation, and Prediction 322
12.1 Introduction 322
12.2 Biopharmaceutics Classification System (BCS) 322
12.2.1 FDA Guidance on Biowaivers 323
12.2.2 Scientific Basis for BCS 325
12.3 Intestinal Permeability Evaluation: Cultured Cells 326
12.3.1 Caco-2 Cells 327
12.3.2 Madin–Darby Canine Kidney Cells (MDCK) 328
12.3.3 Other Cells 329
12.3.4 Limitations of Cultured Cell Models 329
12.4 Intestinal Permeability Evaluation: Ex-In Vivo 330
12.4.1 The Everted Gut Sac Technique 330
12.4.2 Ussing Chamber 331
12.4.3 In Situ Method 332
12.4.4 Intestinal Perfusion in Man 333
12.5 In Silico Methods 334
12.5.1 CAT Model 335
12.5.2 Quantitative Structure Bioavailability Relationships (QSBR) 335
12.5.3 Quantitative Structure Permeability Relationships (QSPR) 336
12.6 Future Trends 337
12.7 Conclusion 338
Chapter 13. Fundamentals of Dissolution 342
13.1 Introduction 342
13.2 Mechanism and Theories of Solid Dissolution 342
13.2.1 Thermodynamic Considerations 342
13.2.2 Dissolution by Pure Diffusion 343
13.2.3 Diffusion Layer Model 343
13.2.4 Convective Diffusion Model 344
13.3 Planar Surface Dissolution 345
13.3.1 Intrinsic Dissolution Rate 345
13.3.2 Convective Diffusion Model for Flow Past a Planar Surface 345
13.4 Particulate Dissolution 346
13.4.1 Diffusion Layer-based Dissolution Models 346
13.4.2 Convective Diffusion-based Particulate Dissolution Model 348
13.4.3 Dissolution Under Non-sink Conditions 348
13.4.4 Effects of Particle Shape 349
13.4.5 Polydispersity Effects 349
Chapter 14. Dissolution Testing of Solid Products 352
14.1 Introduction 352
14.2 Components of Dissolution Test Method Development 353
14.2.1 Dissolution Apparatuses 353
14.2.2 Analytical Assay 355
14.2.3 Medium Selection 356
14.3 Dissolution Tests for Immediate-Release Products 360
14.3.1 Dissolution Tests for Tablets or Solid-Filled Capsule Products 360
14.3.2 Dissolution Tests for Liquid-filled Capsule Products 362
14.3.3 Method Development for Quality Control of Immediate-release Products 363
14.4 Drug Release Test Methods for Modified-Release Products 363
14.4.1 Drug Release Test Methods for Enteric Coated Products 364
14.4.2 Drug Release Test Methods for Extended-release Products 364
14.5 Statistical Comparison of Dissolution Profiles 365
14.6 Specifications 366
14.6.1 Method Validation 366
14.6.2 Acceptance Criteria 367
14.7 In Vitro–In Vivo Correlation (IVIVC) 368
14.7.1 Developing an IVIVC 368
14.7.2 Setting Specifications Using an IVIVC 369
14.8 Summary and Future State 370
Chapter 15. Bioavailability and Bioequivalence 374
15.1 General Background 374
15.2 Definitions and Key Concepts 375
15.2.1 Bioavailability 375
15.2.2 Bioequivalence 376
15.2.3 Pharmaceutical Equivalence and Therapeutic Equivalence 376
15.3 Statistical Concepts in Bioequivalence Studies 377
15.3.1 Selection and Transformation of Pharmacokinetic Measures 377
15.3.2 Variability in Pharmacokinetic Measures of Bioavailability 378
15.3.3 Statistical Criteria for Evaluating Bioequivalence 378
15.3.4 Bioequivalence Study Designs and Other Statistical Considerations 384
15.4 Other General Components of Bioequivalence Studies 385
15.4.1 Study Populations 385
15.4.2 Biofluid Matrices 385
15.4.3 Bioanalytical Methods 385
15.4.4 Drug Moieties 386
15.5 International Regulatory Perspectives 386
15.5.1 US Food and Drug Administration 386
15.5.2 European Agency for the Evaluation of Medicinal Products 389
15.5.3 Health Canada 390
15.5.4 Japanese Ministry of Health, Labour and Welfare 392
15.6 Waivers Based on the Biopharmaceutical Classification System 393
15.7 Summary 394
Chapter 16. In Vivo Evaluation of Oral Dosage Form Performance 398
16.1 Introduction 398
16.2 General Purpose of In Vivo Performance Evaluations 398
16.3 Animal Pharmacokinetic Evaluations 399
16.3.1 Animal Species Selection 399
16.3.2 Animal Data Extrapolation 400
16.4 Human Pharmacokinetic Evaluations 401
16.4.1 Bioavailability and Bioequivalence 401
16.4.2 Effects of Food and Other Substances on Oral Drug Absorption 403
16.4.3 Effects of Gastric pH on Oral Drug Absorption 406
16.4.4 Regional Absorption Site Assessments and Imaging Studies 406
16.5 In Vivo Pharmacokinetic Metrics 408
16.6 In Vivo Absorption Pattern Diagnostics 408
16.7 Generic Alternative: Opportunity or Threat? 409
16.8 Summary 410
Chapter 17. In Vitro–In Vivo Correlations: Fundamentals, Development Considerations, and Applications 412
17.1 Introduction 412
17.1.1 In Vitro–In Vivo Correlation (IVIVC) 412
17.1.2 IVIVC and Product Development 413
17.2 Development and Assessment of an IVIVC 413
17.2.1 Study Design and General Considerations 413
17.2.2 IVIVC Modeling 414
17.2.3 Evaluation of a Correlation 420
17.3 Considerations in IVIVC Development 421
17.3.1 In Vivo Absorption Versus In Vitro Test Considerations 421
17.3.2 Drug and Formulation Considerations 422
17.4 IVIVC Development Strategies and Approach 426
17.4.1 Strategy and General Approach 426
17.4.2 Design of a Predictive In Vitro Test 427
17.5 Applications and Limitations 430
17.5.1 Setting Dissolution Specifications 430
17.5.2 Supporting Waiver of In Vivo Bioavailability Studies 431
17.5.3 Limitations and Additional Considerations 431
17.6 Case Studies 432
17.6.1 Effect of Solubility on IVIVC 432
17.6.2 Developing a Predictive In Vitro Test 433
17.6.3 Illustration of Setting an Optimal Dissolution Specification 434
17.7 Summary 436
PART III: DESIGN, DEVELOPMENT, AND SCALE-UP OF FORMULATION AND PROCESS 440
Chapter 18. Integration of Physical, Chemical, Mechanical, and Biopharmaceutical Properties in Solid Oral Dosage Form Development 442
18.1 Introduction 442
18.2 Physical and Chemical Properties 442
18.2.1 Aqueous Solubility 443
18.2.2 Dissolution Rate 444
18.2.3 Partition Coefficient 444
18.2.4 Permeability 445
18.2.5 Ionization Constant 445
18.2.6 Polymorphism 446
18.2.7 Crystallinity 447
18.2.8 Particle Size, Particle Morphology, and Surface Area 447
18.2.9 Derived Properties: Density and Porosity 448
18.2.10 Melting Point 449
18.2.11 Hygroscopicity 449
18.2.12 Chemical Stability 449
18.3 Mechanical Properties 450
18.3.1 Compression and Compaction 450
18.3.2 Mechanical Property Characterization 451
18.3.3 Practical Implications of Mechanical Property Characterization 453
18.4 Biopharmaceutical Properties 454
18.4.1 The Biopharmaceutical Classification System (BCS) 454
18.4.2 BCS Class I: High Solubility and High Permeability 455
18.4.3 BCS Class II: Low Solubility and High Permeability 456
18.4.4 BCS Class III: High Solubility and Low Permeability 463
18.4.5 BCS Class IV: Low Solubility and Low Permeability 466
18.4.6 Further Clarifications of the BCS 466
18.4.7 Biopharmaceutical Drug Disposition Classification System (BDDCS) 468
18.5 Concluding Remarks 469
Chapter 19. Improving the Oral Absorption of Poorly Soluble Drugs Using SEDDS and S-SEDDS Formulations 476
19.1 Introduction 476
19.2 Overview of Sedds and S-sedds Formulations 476
19.2.1 Growth in the Number of SEDDS/S-SEDDS Publications 477
19.2.2 Marketed SEDDS Formulations 478
19.3 Review of Scientific Literature Dealing with Both the Development of SEDDS/S-SEDDS Formulations, and Oral Bioavailability 479
19.3.1 Year 2008: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles 479
19.3.2 Year 2007: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles 479
19.3.3 Year 2005–2003: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles 485
19.3.4 Year 2003–2000: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles 485
19.3.5 Year 1999–1992: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles 486
19.4 Case Studies on the Development of SEDDS and S-SEDDS Formulations 486
19.4.1 Case Study on the Development of a SEDDS Formulation of Drug X 487
19.4.2 Development of Supersaturatable S-SEDDS Formulations 491
19.5 Proposed Pathways for Enhanced Oral Absorption of Poorly Soluble Drugs with SEDDS and S-SEDDS Approach 495
19.5.1 Drug Absorption Pathway 495
19.5.2 The Enterocyte Absorption of Highly Lipophilic Compounds 496
19.5.3 Significance of the Glycocalyx in Absorption of Drugs from SEDDS/S-SEDDS Formulations 496
19.6 Conclusions 498
Chapter 20. Rational Design of Oral Modified-release Drug Delivery Systems 502
20.1 Introduction 502
20.2 Oral Modified Release Technologies and Drug Delivery Systems 504
20.2.1 Common Oral Extended-release Systems 504
20.2.2 Other Common Oral Modified-release Systems 514
20.2.3 Materials Used for Modifying Drug Release 517
20.3 Rational Design of Modified-Release Systems 518
20.3.1 Identification of the Clinical Need and Definition of the In Vivo Target Product Profile 519
20.3.2 Feasibility Study 520
20.3.3 Selecting the Modified-release System and Testing System Design 523
20.3.4 Case Studies: Impact of Drug Property and Formulation Design 525
20.4 Summary 529
Chapter 21. Development of Modified-Release Solid Oral Dosage Forms 534
21.1 Introduction 534
21.2 Development of Modified-Release Solid Oral Products 535
21.2.1 Rational Development Approach 535
21.2.2 Preformulation Studies 537
21.2.3 Dosage Form Development 538
21.2.4 Product and Process Understanding 539
21.3 Technology Transfer 541
21.4 Case Studies 541
21.4.1 Extended-Release Dosage Forms of Verapamil 541
21.4.2 Extended-Release Dosage Forms of Nifedipine 544
21.4.3 Pulsatile Release Dosage Form of Methylphenidate 546
21.5 Intellectual Property Considerations 548
21.6 Summary 549
Chapter 22. Analytical Development and Validation for Solid Oral Dosage Forms 552
22.1 Introduction 552
22.2 Analytical Method Development and Validation Strategy 552
22.3 Category of Analytical Method and Method Development 553
22.3.1 Identification 554
22.3.2 Potency Assay 554
22.3.3 Impurities 554
22.3.4 Dissolution 555
22.3.5 Blend Homogeneity and Dosage Uniformity 555
22.3.6 Cleaning Test Method Development 555
22.3.7 Other Analytical Techniques 556
22.4 Analytical Method Validation 556
22.4.1 Verification of Compendial Methods 557
22.4.2 Characterization of Reference Standard 557
22.4.3 Stability Indicating Method 557
22.4.4 High Performance Liquid Chromatography Co-elution Peak Evaluation 557
22.4.5 Forced Degradation Studies 558
22.4.6 Method Validation Parameters 558
22.5 Method Transfers (MT) and Inter-Laboratory Qualification (ILQ) 565
22.5.1 Definition 565
22.5.2 Potency 566
22.5.3 Related Substance Assay 566
22.5.4 Residual Solvent Assay 566
22.5.5 Dissolution or Release Assay 566
22.6 Case Studies 567
22.7 Conclusions 569
Chapter 23. Statistical Design and Analysis of Long-term Stability Studies for Drug Products 572
23.1 Introduction 572
23.2 Stability Study Objectives 572
23.3 Regulatory Guidance 573
23.4 Test Methods and Data Management 573
23.5 Modeling Instability 574
23.5.1 Stability Study Variables 574
23.5.2 A Statistical Model for Instability 576
23.6 Long-term Stability Study Design 577
23.6.1 Full and Reduced Designs 577
23.6.2 Bracketing 577
23.6.3 Matrixing 577
23.6.4 Stability Design Generation 578
23.6.5 Comparing Stability Designs 581
23.7 Determination of Shelf Life 584
23.7.1 Definition of Shelf Life 584
23.7.2 Model Pruning 584
23.7.3 Simple Fixed Batch Case 586
23.7.4 Simple Random Batch Case 586
23.7.5 Shelf Life Estimation in More Complex Studies 587
23.8 Release Limit Estimation 587
23.9 Probability of Future Out-of-specification Stability Test Results 588
23.9.1 Random Batch Model for Prediction 589
23.9.2 Prior Distributions for Model Parameters 589
23.9.3 Predicted Quantities of Interest 590
23.9.4 Implementation in WinBUGS 590
23.9.5 Results 591
23.9.6 Bayesian Prediction Using SAS Proc MIXED 594
Chapter 24. Packaging Selection for Solid Oral Dosage Forms 596
24.1 Introduction 596
24.1.1 Definitions 596
24.1.2 General Considerations 597
24.2 Material Considerations 597
24.2.1 Containers 597
24.2.2 Determination of Container Moisture Vapor Transmission Rate 599
24.2.3 Gas Absorbers 601
24.2.4 Drug Products 604
24.3 Linking Packaging Property with Drug Property 605
24.3.1 The Use of Moisture Vapor Transmission Rate per Unit Product for Container Comparison 605
24.3.2 Modeling of Moisture Uptake by Packaged Products 605
24.4 Post-approval Packaging Changes 607
Chapter 25. Clinical Supplies Manufacture: Strategy, Good Manufacturing Process Considerations, and Cleaning Validation 610
25.1 Introduction 610
25.2 Strategy of Clinical Supplies Manufacture 611
25.2.1 Clinical Plan 612
25.2.2 Clinical Supplies Liaison 613
25.2.3 Lean Manufacturing 613
25.2.4 Cross-functional Training 615
25.2.5 Outsourcing of Manufacturing and Packaging 615
25.2.6 New Technology 616
25.3 Good Manufacturing Practice (GMP) Considerations in Manufacturing Clinical Supplies 617
25.3.1 Current Good Manufacturing Practice (cGMP) Considerations 617
25.3.2 A Risk-based Approach 620
25.4 Cleaning Validation and Verification 621
25.4.1 Cleaning Validation Versus Cleaning Verification 622
25.4.2 Swab Test Acceptance Criteria 622
25.4.3 Swab Selection 623
25.4.4 Analytical Methodologies 623
25.4.5 Analytical Method Validation 624
25.4.6 Case Study 627
25.5 Summary 629
Chapter 26. Specification Setting and Manufacturing Process Control for Solid Oral Drug Products 632
26.1 Introduction 632
26.2 Specifications for the Drug Substance 633
26.3 Specifications for Clinical Trial Materials 637
26.3.1 Early Development Stage (Phases 1 and 2) 637
26.3.2 Late Development Stage (Phase 3) 638
26.4 Specifications for Commercial Drug Products 638
26.4.1 Product In-house Release Specifications and Regulatory Specifications 641
26.4.2 Product Stability and Expiration Date 642
26.5 Process Control for Solid Oral Drug Products 643
26.5.1 In-process Material Tests and Quality Attributes 643
26.5.2 Powder Blending Uniformity 643
26.5.3 Statistical Methodology for Process Control 644
26.5.4 Process Analytical Technology (PAT) and In-process Controls 645
26.6 Analytical Procedures 646
26.7 Conclusions 646
Chapter 27. Scale-up of Pharmaceutical Manufacturing Operations of Solid Dosage Forms 648
27.1 Introduction to Scale-up 648
27.1.1 What is Scale-up? 648
27.1.2 The Importance of Scale-up in Pharmaceutical Manufacturing 648
27.1.3 How is Scale-up Performed? 649
27.2 Models and Modeling in Scale-up 649
27.2.1 Introduction to Models 649
27.3 Dimensional Analysis: Scale-up with Semi-empirical Modeling 652
27.3.1 Introduction to Dimensional Analysis 652
27.3.2 Effective Application of Dimensional Analysis 657
27.3.3 Similitude 661
27.4 Mechanistic Models for Scale-up 662
27.4.1 Mechanistic Modeling versus Dimensional Analysis 662
27.4.2 Developing a Mechanistic Model 663
27.4.3 Definition 663
27.4.4 Identification 664
27.4.5 Limitation 664
27.4.6 Formulation 664
27.4.7 Solution 664
27.4.8 Validation 664
27.4.9 Iteration 665
27.4.10 Application 665
27.5 Practical Strategies for Pharmaceutical Scale-up 665
27.5.1 Strategies for Practical Application 665
27.5.2 Quality by Design Using Scaling Principles 666
27.6 Conclusion 669
Chapter 28. Process Development, Optimization, and Scale-up: Powder Handling and Segregation Concerns 670
28.1 Introduction 670
28.1.1 Introduction to Flowability 671
28.1.2 Introduction to Blending 671
28.1.3 Introduction to Segregation 672
28.2 Common Powder Handling Equipment 673
28.2.1 Processing Steps Prior to Final Blending 673
28.2.2 Final Blending 674
28.2.3 Intermediate Bulk Containers 675
28.3 Typical Flow and Segregation Concerns 677
28.3.1 Common Flow Problems 677
28.3.2 Flow Patterns 679
28.3.3 Common Segregation Mechanisms 679
28.4 Measurement of Flow Properties 682
28.4.1 Cohesive Strength Tests: Preventing Arching and Ratholing 683
28.4.2 Bulk Density 688
28.4.3 Permeability 688
28.4.4 Segregation Tests 689
28.5 Basic Equipment Design Techniques 691
28.5.1 Reliable Funnel Flow Design (Preventing a Rathole) 691
28.5.2 Reliable Mass Flow Designs for the Bin, Chute, and Press Hopper 692
28.5.3 Minimizing Adverse Two-phase Flow Effects 694
28.5.4 Minimizing Segregation in the Blender-to-Press Transfer Steps 695
Chapter 29. Process Development and Scale-up of Wet Granulation by the High Shear Process 700
29.1 Introduction 700
29.2 Principles of Wet Granulation and Process Consideration 700
29.3 Purpose of Wet Granulation 700
29.4 Common Wet Granulation Equipment Used for Manufacture 701
29.5 Equipment Selection Considerations 702
29.6 Introduction to the Wet Granulation Process 703
29.6.1 Granule Growth Stages 703
29.6.2 Granule Size Change Mechanism during Granulation Process 703
29.6.3 Process Considerations for Particle Size Growth 703
29.7 Overall Consideration for Process Parameters 704
29.7.1 Pre-blend Stage 704
29.7.2 Infusion Stage I 704
29.7.3 Infusion Stage II 705
29.7.4 Wet Mass Stage 705
29.7.5 Popular End Point Observations 706
29.7.6 Example: Typical Considerations for a High Shear Granulation Process 707
29.8 Complexity of Wet Granulation 707
29.9 Common Issues 708
29.10 Considerations of Process Design 708
29.10.1 Identify Impact from Active Pharmaceutical Ingredient (API) and Other Raw Materials 708
29.10.2 Proper Selection of Which Type of Equipment to be Used 709
29.10.3 Understand the Impact of Process Parameters 709
29.10.4 Select a Design that Reduces the Sensitivity of End Point Determination 709
29.10.5 Utilize the Contribution from Each Stage and Maintain a Balanced Design 710
29.10.6 Consideration of the Design of the Equipment 710
29.11 Impacts of the Process Parameters for the High Shear Process 710
29.11.1 Function of Parameters 710
29.11.2 Amount of Granulation Agent 711
29.11.3 Extent of Wet Mass Time 711
29.11.4 Peripheral Speed/Tip Speed 712
29.11.5 Temperature of Granulation Agent 712
29.11.6 Case Study: Spray Rate/Gun to Bed Distance Position of Nozzle(s) 713
29.11.7 Method of Infusion 713
29.11.8 Design of Granulation Equipment 714
29.11.9 Different Drying Methods 715
29.11.10 Difference in Chopper Application 715
29.11.11 Impact by Residue Heat and by Residual Materials in Multi-batch Consecutive Process 716
29.12 End Point Determination 717
29.12.1 Consideration of End Point 717
29.12.2 Common Methods for End Point Determination in Production 717
29.12.3 Manufacturing Considerations 717
29.13 Application of Process Analytical Technology (PAT) 718
29.14 Design of Experiment (DOE) 718
29.15 Statistical Aids for Process Control 718
29.16 Scale-up and Process Measurement of Granulation 719
29.16.1 End Point Determination 720
29.16.2 End Point Scale-up 721
29.16.3 Practical Considerations 723
29.17 Best Practices 723
29.17.1 Consideration of Robust Process 723
29.17.2 Emerging Concept of Process Design and Control 724
29.18 Principles and Scale-up of Foam Granulation 724
29.18.1 Introduction 724
29.18.2 Experimental 725
29.18.3 Results and Discussion 728
29.18.4 Conclusion of Foam Granulation Study 730
29.19 Bottom Lines 730
Chapter 30. Process Development, Optimization, and Scale-up: Fluid-bed Granulation 734
30.1 Overview of the Fluid-bed Granulation Process 734
30.2 Equipment Design 734
30.2.1 Batch-wise Models 734
30.2.2 Semi-continuous Design 736
30.2.3 Continuous Models 737
30.3 Fluid-bed Hydrodynamics 737
30.3.1 Product Temperature and Moisture Content Profiles through Fluid-bed Processing 737
30.3.2 Moisture Mass Balance during the Fluid-bed Process 737
30.4 Mechanisms of Agglomeration 739
30.4.1 Phases in Granule Growth 739
30.4.2 Bonding Mechanisms 739
30.5 Formulation and Process Variables and their Control 740
30.5.1 Formulation Variables 740
30.5.2 Key Process Variables 740
30.5.3 Granule Growth under Drier Conditions (Low Moisture Content of Wet Granules during the Granulation Process) 741
30.5.4 Granule Growth under Wetter Conditions (High Moisture Content of Wet Granules) 742
30.6 Scale-up Considerations 742
30.6.1 Batch Size and Equipment Selection 743
30.6.2 Spray Rate Scale-up 743
30.6.3 Rotary Disk Speed Scale-up 744
30.6.4 Rational Scale-up 745
30.6.5 Scale-up via Semi-continuous (Batch-continuous) Processing 746
30.6.6 Scale-up via Continuous Processing 746
30.7 Summary 746
Chapter 31. Development, Scale-up, and Optimization of Process Parameters: Roller Compaction 748
31.1 History 748
31.2 General Operational Principles 748
31.3 Reasons to use Roller Compaction 748
31.4 Advantages and Disadvantages of Roller Compaction 749
31.4.1 Advantages 749
31.4.2 Disadvantages 749
31.5 Feed System 749
31.6 Roll Designs 749
31.7 Compaction Theory 749
31.8 Deaeration 750
31.9 Control Mechanisms 750
31.10 Scale-up 751
31.10.1 Scale-up Throughput Calculations 751
31.10.2 Scale-up for Achieving Consistent Sheet Density 752
31.11 Case Studies 752
31.11.1 Scale-up Case Study 752
31.11.2 Bulk Densities of Various Materials Before and After Roller Compaction 754
31.11.3 Effect of Compaction Pressure on Bulk Density 754
31.11.4 Compaction of Aspirin 754
31.11.5 Troubleshooting 755
31.12 Application of Process Analytical Technology to Roller Compaction 756
31.12.1 Case Study 756
31.13 Roller Compactor Suppliers 757
Chapter 32. Development, Optimization, and Scale-up of Process Parameters: Tablet Compression 758
32.1 Introduction 758
32.2 Operational Principles of Compression by Rotary Press 758
32.3 Best Practice 759
32.4 Tool Design 759
32.4.1 Terminology 760
32.4.2 Common Tooling Standards 762
32.4.3 EU, TSM, B, and D Type Punches 762
32.4.4 Recent Innovations 764
32.4.5 Cup Depth, Overall Length, and Working Length 764
32.4.6 Tooling Options 765
32.4.7 Tool Configuration for Small and Micro Tablets 768
32.4.8 Tapered Dies 768
32.5 Tablet Designs 769
32.5.1 Tablet Shapes 770
32.5.2 Tablet Face Configurations 771
32.5.3 Undesirable Shapes 771
32.5.4 Tablet Identification 772
32.5.5 Bisects 773
32.5.6 Steel Types 774
32.5.7 Inserted Dies 774
32.5.8 Multi-tip Tooling 775
32.5.9 Punch Tip Pressure Guide 776
32.6 Care of Punches and Dies 776
32.7 Tooling Inspection 777
32.8 Tooling Reworking 777
32.9 Press Wear 777
32.10 Purchasing Tablet Compression Tooling 778
32.11 Consideration of Tooling 778
32.12 Scale-up of Compression 781
32.12.1 Compaction and Compression 781
32.12.2 Tableting Failure 782
32.12.3 Main Factors of Tableting 783
32.12.4 Compaction Event 784
32.12.5 Tableting Time Definitions 784
32.12.6 Dwell Time and Contact Time 785
32.12.7 Tableting Geometry 786
32.12.8 Tableting Scale-up 788
Chapter 33. Development, Optimization, and Scale-up of Process Parameters: Pan Coating 794
33.1 Introduction 794
33.1.1 Theory of Film-coating 794
33.1.2 Evolution of Pharmaceutical Coating Technologies 794
33.1.3 Coating Equipment: Introduction 795
33.2 Film-coating Formulations 795
33.2.1 Overview of Types of Film-coating Formulations 795
33.2.2 Overview of Types of Materials Used in Film-coating Formulations 797
33.2.3 Film-coating Formulations Used for Immediate-release Applications 803
33.2.4 Film-coatings Used for Modified-release Applications 804
33.3 Design and Development of the Film-Coating Processes 808
33.3.1 General Introduction to Coating Processes and Equipment 808
33.3.2 Pan Units 810
33.3.3 Comparison of Continuous-coating Equipment 812
33.4 Process Air Equipment 812
33.5 Spray Systems 814
33.5.1 Comparison of Different Spray Guns 814
33.5.2 Pneumatic Spray Gun 814
33.5.3 Hydraulic Spray Gun 814
33.5.4 Solution Delivery Pump 815
33.5.5 Delivery Control 815
33.6 System Controls 816
33.7 General Characteristics of the Pharmaceutical Coating Process 816
33.7.1 Typical Process Steps 816
33.7.2 Coating Pan Set-up 817
33.7.3 Loading/Charging 817
33.7.4 Preheat/Dedusting 817
33.7.5 Seal/Barrier Coat 818
33.7.6 Film-coating Application 818
33.7.7 Gloss Coat 818
33.7.8 Wax Addition 818
33.7.9 Product Discharge 818
33.8 Understanding Process Thermodynamics 819
33.8.1 Adequate Evaporative Rate 819
33.9 Process Air 819
33.9.1 Volume 819
33.10 Humidity 819
33.11 Temperature 820
33.11.1 Coating Solution Characteristics 820
33.11.2 Product Temperature Limits 820
33.11.3 Pan Speed 820
33.11.4 Understanding Spray Dynamics 821
33.11.5 Coating Analysis 822
33.12 Controlling Coating Processes: Critical Factors 823
33.12.1 Uniformity of the Spray Application 823
33.12.2 Uniformity of Product Movement 824
33.12.3 Adequate Evaporative Capacity 825
33.12.4 Scale-up 826
33.12.5 Spray Rate to Pan Speed Ratio 827
33.12.6 Air Flow to Spray Ratio 827
33.13 Troubleshooting 827
33.13.1 Introduction to Troubleshooting 827
33.13.2 Up-front Approaches to Avoid Troubleshooting Issues 828
33.14 Consideration of Product Substrate 828
33.14.1 Hardness/Friability 829
33.14.2 Weight Variation 829
33.14.3 Stability 829
33.14.4 Compatibility 829
33.14.5 Shape 829
33.14.6 Logo Design 829
33.14.7 Core Porosity 829
33.14.8 Disintegration 830
33.15 Coating Solution 830
33.15.1 Film Mechanical Strength 830
33.15.2 Plasticizer Level 830
33.15.3 Pigment Level 830
33.15.4 Film Solution Solids 830
33.15.5 Solution Viscosity 830
33.15.6 Stability 830
33.15.7 Compatibility 830
33.15.8 Processing Issues as They Relate to Troubleshooting 831
33.15.9 Troubleshooting: Summary 832
33.16 Application of Systematic and Statistical Tools for Troubleshooting and Process Optimization 832
Chapter 34. Development, Optimization, and Scale-up of Process Parameters: Wurster Coating 840
34.1 Introduction 840
34.2 Basic Design 840
34.3 HS Wurster Considerations 843
34.4 Coating and Process Characteristics 844
34.5 Processing Examples 844
34.6 Process Variables 846
34.6.1 Batch Size 846
34.6.2 Fluidization Pattern 846
34.6.3 Atomizing Air Pressure and Volume 847
34.6.4 Nozzle Port Size 848
34.6.5 Evaporation Rate 848
34.6.6 Product Temperature 849
34.7 Case Studies for Layering and Fine Particle Coating 849
34.8 Scale-up of Wurster Processing 853
34.8.1 Batch Size 855
34.8.2 Spray Rate 855
34.8.3 Droplet Size and Nozzle Considerations 855
34.8.4 Process Air Volume 856
34.8.5 Process Air and Product Temperatures 858
34.8.6 Mass Effects 858
34.9 Summary 858
Chapter 35. Process Analytical Technology in Solid Dosage Development and Manufacturing 860
35.1 Introduction 860
35.2 Regulatory Developments 861
35.2.1 The FDA: Process Analytical Technology (PAT) guidance 861
35.2.2 United States Pharmacopeia (USP) 861
35.2.3 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 861
35.2.4 American Society for Testing and Materials (ASTM) Standards 862
35.3 Process Analytical Technology (PAT) Tools 862
35.3.1 Analytical Techniques 862
35.3.2 Chemometrics and Multivariate Analysis 867
35.4 Process Analytical Technology (PAT) Applications 867
35.4.1 Raw Material Identification 868
35.4.2 Blending 868
35.4.3 Granulation 869
35.4.4 Near-infrared Monitoring of Fluid-bed Drying 871
35.4.5 Encapsulation 871
35.4.6 Compression 872
35.4.7 Coating 872
35.5 Conclusion 872
PART IV: SELECTED TOPICS IN PRODUCT DEVELOPMENT 876
Chapter 36. The Product Development Process 878
36.1 Introduction 878
36.1.1 Organizational Considerations 879
36.1.2 The Target Product Profile: A Strategic Development Process Tool 880
36.2 Summary of the Drug Development Process 880
36.3 Preclinical Research 882
36.3.1 Discovery Research 882
36.3.2 Preclinical Development 883
36.4 Clinical Research 888
36.4.1 Phase 1 889
36.4.2 Phase 2 890
36.4.3 Phase 3 891
36.4.4 Pre-New Drug Application (NDA) Meeting and the New Drug Application 892
36.5 Concluding Remarks 892
Chapter 37. Product Registration and Drug Approval Process in the United States 894
37.1 Background for Product Registration in the United States 894
37.2 The New Drug Application (NDA) and Review Process 894
37.2.1 Food and Drug Administration (FDA) Interactions 894
37.2.2 New Drug Applications (NDA) 895
37.2.3 Common Technical Document (CTD) 900
37.2.4 User Fees 900
37.2.5 New Drug Application (NDA) Review Process 901
37.3 Generic Drug Product Registration and Review Process 903
37.3.1 Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Office of Generic Drugs 903
37.3.2 Abbreviated New Drug Application (ANDA) 903
37.3.3 Abbreviated New Drug Application (ANDA) Review Process 905
37.4 Post-approval Activities for New Drug Applications and Abbreviated New Drug Applications 908
37.4.1 Reports 908
37.4.2 Changes to an Approved Application (21CFR314.70) 909
37.5 Other Considerations for New Drug Applications and Abbreviated New Drug Applications 910
37.5.1 Supplemental Applications (21CFR314.71) 910
37.5.2 Establishment Registration and Drug Listing Requirements for Foreign Establishments (21CFR 207.40) 911
37.6 Pre-Approval Inspection (PAI) 911
37.6.1 Background and Purpose 911
37.6.2 On-site Inspection 912
37.6.3 Preparation 914
37.6.4 Outcome of the Pre-approval Inspection 915
37.6.5 Summary 916
Chapter 38. Modern Pharmaceutical Quality Regulations: Question-based Review 918
38.1 Introduction 918
38.2 Issues with QbT and the Old Pharmaceutical Quality Assessment System 919
38.3 Quality by Design 920
38.4 Question-based Review for Generic Drugs 922
38.5 QbR Questions Embody QbD 923
38.5.1 Questions Related to Desired Product Performance 923
38.5.2 Questions Related to Product Design 924
38.5.3 Questions Related to Process Design 926
38.5.4 Questions Related to Process Understanding and Control 927
38.6 Conclusions 931
38.A1 Appendix: QbR Questions 931
Chapter 39. Intellectual Property Law Primer 936
39.1 Introduction 936
39.2 Patent Prosecution 936
39.2.1 Types of United States Patent Applications 936
39.2.2 Standards for Patentability 937
39.2.3 The United States Utility Patent Application 938
39.2.4 Representative Pharmaceutical Related Patent Subject Matter and Claims 939
39.3 Patent Enforcement/Litigation 941
39.3.1 Example: Patentability Versus Freedom to Operate 941
39.3.2 Patent Infringement Litigation 942
39.3.3 Remedies for Patent Infringement 943
39.3.4 Defenses to Patent Infringement 943
Chapter 40. Product Lifecycle Management (LCM) 944
40.1 Introduction 944
40.2 Basic Patent Laws Governing the Life of Pharmaceutical Products 945
40.3 Lifecycle Management Through Salts, Crystal Forms and Formulations 945
40.4 Extension of Product Lifecycle by Shortening Product Development Time 946
40.5 Lifecycle Management through New Drug Delivery Systems 946
40.5.1 Modified-Release 947
40.5.2 Formulations with Enhanced Bioavailability 948
40.5.3 Examples of Successful New Drug Delivery Systems 949
40.6 Lifecycle Management Through Fixed Combination Products 949
40.6.1 Benefit of Fixed Combination Products 950
40.6.2 Clinical Challenges 951
40.6.3 Technical Challenges 952
40.6.4 Business Challenges 952
40.7 Conclusions 953
Index 956
A 956
B 957
C 958
D 960
E 962
F 962
G 964
H 964
I 964
J 965
K 965
L 965
M 966
N 967
O 968
P 968
Q 971
R 972
S 972
T 974
U 975
V 975
W 976
X 976
Y 976
Z 976