E-Book, Englisch, 978 Seiten
Qiu / Chen / Zhang Developing Solid Oral Dosage Forms
1. Auflage 2009
ISBN: 978-0-08-093272-9
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark
Pharmaceutical Theory and Practice
E-Book, Englisch, 978 Seiten
ISBN: 978-0-08-093272-9
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark
This book is intended for pharmaceutical professionals engaged in research and development of oral dosage forms. It covers essential principles of physical pharmacy, biopharmaceutics and industrial pharmacy as well as various aspects of state-of-the-art techniques and approaches in pharmaceutical sciences and technologies along with examples and/or case studies in product development. The objective of this book is to offer updated (or current) knowledge and skills required for rational oral product design and development. The specific goals are to provide readers with:
Basics of modern theories of physical pharmacy, biopharmaceutics and industrial pharmacy and their applications throughout the entire process of research and development of oral dosage forms
Tools and approaches of preformulation investigation, formulation/process design, characterization and scale-up in pharmaceutical sciences and technologies
New developments, challenges, trends, opportunities, intellectual property issues and regulations in solid product development
The first book (ever) that provides comprehensive and in-depth coverage of what's required for developing high quality pharmaceutical products to meet international standards
It covers a broad scope of topics that encompass the entire spectrum of solid dosage form development for the global market, including the most updated science and technologies, practice, applications, regulation, intellectual property protection and new development trends with case studies in every chapter
A strong team of more than 50 well-established authors/co-authors of diverse background, knowledge, skills and experience from industry, academia and regulatory agencies
Autoren/Hrsg.
Weitere Infos & Material
1;Front Cover;1
2;Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice;4
3;Copyright Page;5
4;Contents;6
5;List of Contributors;30
6;Foreword;32
7;PART I: THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS;34
7.1;Chapter 1. Solubility of Pharmaceutical Solids;36
7.1.1;1.1 Introduction;36
7.1.1.1;1.1.1 Implication of Solubility in Dosage Form Development;36
7.1.1.2;1.1.2 Basic Concepts of Solubility and Dissolution;37
7.1.2;1.2 Thermodynamics of Solutions;38
7.1.2.1;1.2.1 Volume of Mixing;38
7.1.2.2;1.2.2 Enthalpy of Mixing;38
7.1.2.3;1.2.3 Entropy of Mixing;39
7.1.2.4;1.2.4 Free Energy of Mixing;39
7.1.3;1.3 Theoretical Estimation of Solubility;39
7.1.3.1;1.3.1 Ideal Solutions;39
7.1.3.2;1.3.2 Effect of Crystallinity;40
7.1.3.3;1.3.3 Non-ideal Solutions;41
7.1.3.4;1.3.4 Regular Solution Theory;41
7.1.3.5;1.3.5 Aqueous Solution Theory;42
7.1.3.6;1.3.6 The General Solubility Equation (GSE);43
7.1.4;1.4 Solubilization of Drug Candidates;44
7.1.4.1;1.4.1 Solubility Enhancement by pH Control and Salt Formation;44
7.1.4.2;1.4.2 Solubilization Using Complexation;46
7.1.4.3;1.4.3 Solubilization by Cosolvents;48
7.1.4.4;1.4.4 Solubilization by Surfactants (Micellar Solubilization);49
7.1.4.5;1.4.5 Solubilization by Combination of Approaches;49
7.1.5;1.5 Experimental Determination of Solubility;52
7.1.5.1;1.5.1 Stability of Solute and Solvent;53
7.1.5.2;1.5.2 Shakers and Containers;53
7.1.5.3;1.5.3 Presence of Excess Undissolved Solute;53
7.1.5.4;1.5.4 Determination of Equilibrium;54
7.1.5.5;1.5.5 Phase-separation;54
7.1.5.6;1.5.6 Determination of Solute Content in the Dissolved Phase;54
7.1.5.7;1.5.7 Experimental Conditions;55
7.2;Chapter 2. Crystalline and Amorphous Solids;58
7.2.1;2.1 Introduction;58
7.2.2;2.2 Definitions and Categorization of Solids;58
7.2.3;2.3 Thermodynamics and Phase Diagrams;60
7.2.3.1;2.3.1 Polymorphs;60
7.2.3.2;2.3.2 Solvates/Hydrates;65
7.2.3.3;2.3.3 Cocrystals;67
7.2.3.4;2.3.4 Amorphous Solids;68
7.2.4;2.4 Pharmaceutical Relevance and Implications;69
7.2.4.1;2.4.1 Solubility;70
7.2.4.2;2.4.2 Dissolution Rate and Bioavailability;71
7.2.4.3;2.4.3 Hygroscopicity;71
7.2.4.4;2.4.4 Reactivity and Chemical Stability;72
7.2.4.5;2.4.5 Mechanical Properties;73
7.2.5;2.5 Transformations Among Solids;73
7.2.5.1;2.5.1 Induced by Heat;73
7.2.5.2;2.5.2 Induced by Vapor;75
7.2.5.3;2.5.3 Induced by Solvents;76
7.2.5.4;2.5.4 Induced by Mechanical Stresses;77
7.2.6;2.6 Methods of Generating the Solids;77
7.2.6.1;2.6.1 Through Gas;77
7.2.6.2;2.6.2 Through Liquid;78
7.2.6.3;2.6.3 Through Solid;79
7.2.7;2.7 Amorphous Drugs and Solid Dispersions;79
7.2.7.1;2.7.1 Characteristics of Amorphous Phases;79
7.2.7.2;2.7.2 Characteristics of Amorphous Solid Dispersions;81
7.2.7.3;2.7.3 Crystallization of Amorphous Drug and Dispersions;84
7.2.8;2.8 Special Topics;87
7.2.8.1;2.8.1 Polymorph Screening and Stable Form Screening;87
7.2.8.2;2.8.2 High Throughput Crystallization;88
7.2.8.3;2.8.3 Miniaturization in Crystallization;88
7.3;Chapter 3. Analytical Techniques in Solid-state Characterization;94
7.3.1;3.1 Introduction;94
7.3.2;3.2 Review of Analytical Techniques and Methods;95
7.3.3;3.3 Microscopic Methods;95
7.3.3.1;3.3.1 Optical Microscopy;95
7.3.3.2;3.3.2 Electron Microscopy;96
7.3.4;3.4 Thermal Analysis;96
7.3.4.1;3.4.1 Differential Scanning Calorimetry;97
7.3.4.2;3.4.2 Thermogravimetric Analysis;98
7.3.4.3;3.4.3 Microcalorimetry;98
7.3.5;3.5 Diffraction Methods;98
7.3.5.1;3.5.1 Single-crystal X-ray Diffraction;98
7.3.5.2;3.5.2 Powder X-ray Diffraction;99
7.3.6;3.6 Vibrational Spectroscopy;100
7.3.6.1;3.6.1 Infrared Spectroscopy;100
7.3.6.2;3.6.2 Raman Spectroscopy;101
7.3.6.3;3.6.3 Near-infrared;101
7.3.7;3.7 Solid-State Nuclear Magnetic Resonance Spectroscopy;101
7.3.8;3.8 Sorption Techniques;103
7.3.9;3.9 Other Techniques;104
7.3.10;3.10 Characterization of Solids Using Complementary Analytical Techniques;104
7.3.11;3.11 Conclusion;106
7.4;Chapter 4. Salt Screening and Selection: New Challenges and Considerations in the Modern Pharmaceutical Research and Development Paradigm;108
7.4.1;4.1 Introduction;108
7.4.2;4.2 Theoretical Considerations;109
7.4.2.1;4.2.1 pH-Solubility Profiles and the Role of pK[sub(a)];109
7.4.2.2;4.2.2 Prediction of Salt Solubility and In Situ Salt Screening;110
7.4.2.3;4.2.3 Solubility and Dissolution Rate of Salts;110
7.4.2.4;4.2.4 Dissolution of Salts in GI Fluids;111
7.4.2.5;4.2.5 Impact of Salt Form on Other Solubilization Techniques;113
7.4.2.6;4.2.6 Effect of Salts on Chemical Stability;114
7.4.2.7;4.2.7 Potential Disadvantages of Salts;114
7.4.3;4.3 Practical Considerations;114
7.4.3.1;4.3.1 Drug Substance Considerations;114
7.4.3.2;4.3.2 Dosage Form Considerations;114
7.4.3.3;4.3.3 Toxicity Considerations;115
7.4.3.4;4.3.4 Salt and Form Screening and Selection Strategies;115
7.4.3.5;4.3.5 The Role of Automation and High Throughput Designs in Salt Screening;117
7.4.4;4.4 Conclusions;118
7.5;Chapter 5. Drug Stability and Degradation Studies;120
7.5.1;5.1 Introduction;120
7.5.2;5.2 Chemical Stability;120
7.5.2.1;5.2.1 Solution Kinetics;121
7.5.2.2;5.2.2 Rate Equations;121
7.5.2.3;5.2.3 Elemental Reactions and Reaction Mechanism;121
7.5.2.4;5.2.4 Typical Simple Order Kinetics;122
7.5.2.5;5.2.5 Complex Reactions;124
7.5.2.6;5.2.6 Arrhenius Equation, Collision Theory, and Transition State Theory;125
7.5.2.7;5.2.7 Catalysts and Catalysis;127
7.5.2.8;5.2.8 pH-rate Profiles;128
7.5.2.9;5.2.9 Solid-state Reaction Kinetics;131
7.5.2.10;5.2.10 Solid-state Kinetic Models;132
7.5.2.11;5.2.11 Physical Parameters Affecting Solid-state Kinetics;134
7.5.2.12;5.2.12 The Role of Moisture;135
7.5.2.13;5.2.13 Topochemical Reactions;136
7.5.3;5.3 Common Pathways of Drug Degradation;136
7.5.3.1;5.3.1 Hydrolysis;136
7.5.3.2;5.3.2 Oxidative Degradation;138
7.5.3.3;5.3.3 Photochemical Degradation;140
7.5.3.4;5.3.4 Other Degradation Pathways;142
7.5.4;5.4 Experimental Approaches to Studying the Chemical Degradation of Drugs;142
7.5.4.1;5.4.1 Solution Thermal Degradation Studies;142
7.5.4.2;5.4.2 Solid-state Thermal Degradation Studies;145
7.5.4.3;5.4.3 Oxidative Degradation Studies;146
7.5.4.4;5.4.4 Photodegradation Studies;147
7.5.5;5.5 Physical Stability and Phase Transformations;148
7.5.5.1;5.5.1 Types of Phase Transformations;148
7.5.5.2;5.5.2 Mechanisms of Phase Transformations;148
7.5.6;5.6 Phase Transformations during Pharmaceutical Processing;150
7.5.6.1;5.6.1 Processes for Preparing Solid Dosage Forms and Associated Potential Phase Transformations;150
7.5.6.2;5.6.2 Anticipating and Preventing Phase Transformations in Process Development;154
7.6;Chapter 6. Excipient Compatibility;158
7.6.1;6.1 Introduction;158
7.6.2;6.2 Chemistry of Drug–Excipient Interactions;159
7.6.2.1;6.2.1 Influence of Water and Microenvironmental pH;159
7.6.2.2;6.2.2 Reactions with Excipients and their Impurities;160
7.6.2.3;6.2.3 Stabilizing Excipients;165
7.6.3;6.3 Current Practices;166
7.6.3.1;6.3.1 Experimental Design;167
7.6.3.2;6.3.2 Sample Preparation and Storage;168
7.6.3.3;6.3.3 Sample Analysis and Data Interpretation;171
7.6.4;6.4 Conclusions;176
7.7;Chapter 7. Theory of Diffusion and Pharmaceutical Applications;180
7.7.1;7.1 Introduction;180
7.7.1.1;7.1.1 Basic Equations of Diffusion;180
7.7.1.2;7.1.2 Solutions for Diffusion Equations;181
7.7.2;7.2 The Diffusion Coefficient and Its Determination;186
7.7.2.1;7.2.1 Steady State Flux Method;187
7.7.2.2;7.2.2 Lag Time Method;188
7.7.2.3;7.2.3 Sorption and Desorption Methods;188
7.7.3;7.3 Pharmaceutical Applications;189
7.7.3.1;7.3.1 Controlled Release;189
7.7.3.2;7.3.2 Particle Dissolution;191
7.7.3.3;7.3.3 Packaging Study;192
7.7.4;7.4 Appendix;193
7.7.4.1;7.4.1 The Error Function and Its Application;193
7.7.4.2;7.4.2 Derivation of Solution by Separation of Variables;193
7.8;Chapter 8. Particle, Powder, and Compact Characterization;196
7.8.1;8.1 Introduction;196
7.8.2;8.2 Particle Size Characterization;196
7.8.2.1;8.2.1 Light Microscopy;197
7.8.2.2;8.2.2 Scanning Electron Microscopy;198
7.8.2.3;8.2.3 Sieving;199
7.8.2.4;8.2.4 Light Diffraction;199
7.8.2.5;8.2.5 Importance/Impact of Particle Size Characterization;200
7.8.3;8.3 Powder Characterization;200
7.8.3.1;8.3.1 Density;200
7.8.3.2;8.3.2 Flow;202
7.8.4;8.4 Compact (Mechanical Property) Characterization;206
7.8.4.1;8.4.1 Important Mechanical Properties;207
7.8.4.2;8.4.2 Overview of Methods;208
7.8.4.3;8.4.3 Quasi-static Testing;209
7.8.4.4;8.4.4 Dynamic Testing;212
7.8.5;8.5 Conclusions;216
7.9;Chapter 9. Polymer Properties and Characterization;220
7.9.1;9.1 Introduction;220
7.9.1.1;9.1.1 Definition, Structure, and Nomenclature;221
7.9.1.2;9.1.2 Types of Homopolymers and Copolymers;223
7.9.2;9.2 Commonly Used Cellulose Derivatives in Solid Oral Products;224
7.9.3;9.3 Basic Concepts and Characterization of Polymeric Materials;228
7.9.3.1;9.3.1 Polymer Composition;230
7.9.3.2;9.3.2 Molecular Weight;231
7.9.3.3;9.3.3 Polymers in Solution;238
7.9.3.4;9.3.4 Structure–Property Relationships;240
7.9.4;9.4 Conclusion;249
7.10;Chapter 10. Applied Statistics in Product Development;252
7.10.1;10.1 Introduction;252
7.10.1.1;10.1.1 Statistics: A Tool for Decision Making and Risk Assessment;252
7.10.1.2;10.1.2 Sources of Uncertainty;253
7.10.1.3;10.1.3 Natural (Random) Variation;253
7.10.1.4;10.1.4 Systematic Error (Bias) and Blunders;254
7.10.2;10.2 Exploring Data: Types of Data;254
7.10.2.1;10.2.1 Nominal (Categorical) Data;254
7.10.2.2;10.2.2 Ordinal Data;255
7.10.2.3;10.2.3 Numerical Data;256
7.10.2.4;10.2.4 Continuously Variable Data and Digitization Pitfalls;256
7.10.3;10.3 Exploring Data: Graphical Techniques;257
7.10.3.1;10.3.1 Graphing Nominal Data;257
7.10.3.2;10.3.2 Bar Charts;257
7.10.3.3;10.3.3 Pie Charts;257
7.10.3.4;10.3.4 Graphing Univariate Numerical Data;257
7.10.3.5;10.3.5 Histograms;258
7.10.3.6;10.3.6 Quantile Plots;259
7.10.3.7;10.3.7 Box Plots;259
7.10.3.8;10.3.8 Graphing Bivariate Data;259
7.10.3.9;10.3.9 One Variable Nominal: Bar Graphs, Dot Plots, and Line Plots;260
7.10.3.10;10.3.10 One Variable Nominal: Box Plots;260
7.10.3.11;10.3.11 Both Variables Numeric and Random: Quantile–Quantile Plots;260
7.10.3.12;10.3.12 Both Variables Numeric: Scatterplots;261
7.10.3.13;10.3.13 Multivariate Data;261
7.10.3.14;10.3.14 Scatterplot Matrices;262
7.10.4;10.4 Data Distributions;262
7.10.4.1;10.4.1 Binomial Distribution;262
7.10.4.2;10.4.2 Poisson Distribution;263
7.10.4.3;10.4.3 Normal (Gaussian) Distribution;263
7.10.4.4;10.4.4 Other Useful Distributions;263
7.10.5;10.5 Location: Central Tendencies;263
7.10.5.1;10.5.1 Data for Central Value and Dispersion Examples;264
7.10.5.2;10.5.2 Arithmetic Mean;264
7.10.5.3;10.5.3 Median;264
7.10.6;10.6 Dispersion;265
7.10.6.1;10.6.1 Range;265
7.10.6.2;10.6.2 Interquartile Range and Median Absolute Deviation from the Median;265
7.10.6.3;10.6.3 Variance and Standard Deviation;265
7.10.6.4;10.6.4 Coefficient of Variation;267
7.10.6.5;10.6.5 Multivariate Covariance and Correlation;267
7.10.6.6;10.6.6 Correlation and Causality;267
7.10.6.7;10.6.7 Error Propagation;267
7.10.7;10.7 Probability;268
7.10.7.1;10.7.1 Chebyshev's Inequality;269
7.10.7.2;10.7.2 The Normal Probability Assumption;270
7.10.8;10.8 Interval Estimation;271
7.10.8.1;10.8.1 Confidence Intervals;271
7.10.8.2;10.8.2 Prediction Intervals;274
7.10.8.3;10.8.3 Tolerance Intervals;274
7.10.8.4;10.8.4 Rounding;275
7.10.9;10.9 Process Modeling and Experimental Design;276
7.10.9.1;10.9.1 Models, Parameters, and Hypotheses;277
7.10.9.2;10.9.2 Confidence Interval Estimation and Hypothesis Testing;277
7.10.9.3;10.9.3 Are Two Processes Different or the Same?;278
7.10.9.4;10.9.4 More Complex Models;278
7.10.9.5;10.9.5 Regression Models and the Analysis of Variance;279
7.10.9.6;10.9.6 One-way ANOVA with One Nominal Factor;279
7.10.9.7;10.9.7 Two-way ANOVA with Two Nominal Factors;279
7.10.9.8;10.9.8 Regression Analysis with One Continuous Factor;280
7.10.9.9;10.9.9 Regression Analysis with Multiple Continuous Factors;280
7.10.9.10;10.9.10 Regression with Nominal and Continuous Variables (ANCOVA);280
7.10.9.11;10.9.11 Nonlinear Models;280
7.10.9.12;10.9.12 Data Snooping (Data Mining);280
7.10.9.13;10.9.13 Outliers;281
7.10.10;10.10 The Measurement Process;282
7.10.10.1;10.10.1 Models and Assay Design in Analytical Chemistry;282
7.10.10.2;10.10.2 Direct Assays (Titrations);282
7.10.10.3;10.10.3 Slope–Ratio Assays;282
7.10.10.4;10.10.4 Parallel Line and Ligand-binding Assays;283
7.10.10.5;10.10.5 Calibration Lines and Curves;283
7.10.10.6;10.10.6 Accuracy, Precision, Bias, and Blunders;284
7.10.10.7;10.10.7 Detecting and Eliminating Bias;284
7.10.10.8;10.10.8 Precision;285
7.10.10.9;10.10.9 Short-term Repeatability;285
7.10.10.10;10.10.10 Long-term Reproducibility;286
7.10.10.11;10.10.11 Measurement Reliability Analysis Based on ANOVA with Random Factors;286
7.10.10.12;10.10.12 Measurement Reliability Analysis Based on Prior Information and In-Process Standards;287
7.10.10.13;10.10.13 Reporting Measurement Reliability;287
7.10.10.14;10.10.14 Multivariate Methods;287
7.10.11;10.11 The Production Process;288
7.10.11.1;10.11.1 Controlled and Uncontrolled Factors;288
7.10.11.2;10.11.2 Response Surface Modeling: The Design Space;288
7.10.11.3;10.11.3 Classical Factorial Designs;289
7.10.11.4;10.11.4 Confounding Variables: Fractional Factorials;289
7.10.11.5;10.11.5 Screening Designs;289
7.10.11.6;10.11.6 Taguchi Designs;289
7.10.11.7;10.11.7 Model Assumptions;289
7.10.11.8;10.11.8 Choosing an Experimental Design;290
7.10.11.9;10.11.9 Data Analysis and Model Simplification;290
7.10.11.10;10.11.10 Evolutionary Operation;291
7.10.11.11;10.11.11 Process Stability and Capability;291
7.10.11.12;10.11.12 Statistical Process Control Revisited;291
7.10.11.13;10.11.13 In-process Monitoring and Control Using Process Analytical Technology;292
7.10.11.14;10.11.14 Process "Wellness";292
7.10.12;10.12 Software;292
7.10.13;10.13 Summary;292
8;PART II: BIOPHARMACEUTICAL AND PHARMACOKINETIC EVALUATIONS OF DRUG MOLECULES AND DOSAGE FORMS;296
8.1;Chapter 11. Oral Absorption Basics: Pathways, Physico-chemical and Biological Factors Affecting Absorption;298
8.1.1;11.1 Barriers to Oral Drug Delivery;298
8.1.1.1;11.1.1 Intestinal Barrier;299
8.1.1.2;11.1.2 Hepatic Barrier;299
8.1.2;11.2 Pathways of Drug Absorption;299
8.1.2.1;11.2.1 Paracellular Diffusion;300
8.1.2.2;11.2.2 Passive Diffusion;300
8.1.2.3;11.2.3 Carrier-mediated Transport;301
8.1.2.4;11.2.4 Active Transport;302
8.1.2.5;11.2.5 Facilitated Transport;306
8.1.3;11.3 Pathways of Drug Metabolism;307
8.1.3.1;11.3.1 Phase I Metabolism;308
8.1.3.2;11.3.2 Phase II Enzymes;309
8.1.4;11.4 Pathways of Drug Elimination;310
8.1.4.1;11.4.1 P-glycoprotein (P-gp);310
8.1.4.2;11.4.2 Multidrug-resistance Associated Proteins (MRPs);311
8.1.4.3;11.4.3 Organic Anion Transporters;312
8.1.5;11.5 Coupling of Enzymes and Efflux Transporters;312
8.1.5.1;11.5.1 Double Jeopardy Theorem;312
8.1.5.2;11.5.2 Revolving Door Theorem;313
8.1.6;11.6 Physico-Chemical Factors Affecting Drug Absorption;314
8.1.6.1;11.6.1 Lipophilicity;315
8.1.6.2;11.6.2 Size;315
8.1.6.3;11.6.3 Charge;315
8.1.6.4;11.6.4 Solubility;315
8.1.6.5;11.6.5 Dissolution;315
8.1.7;11.7 Biological Factors Affecting Drug Absorption;315
8.1.7.1;11.7.1 Transit Time;316
8.1.7.2;11.7.2 pH;316
8.1.7.3;11.7.3 Food;317
8.1.7.4;11.7.4 Luminal Enzymes;317
8.1.8;11.8 Summary;317
8.2;Chapter 12. Oral Drug Absorption, Evaluation, and Prediction;322
8.2.1;12.1 Introduction;322
8.2.2;12.2 Biopharmaceutics Classification System (BCS);322
8.2.2.1;12.2.1 FDA Guidance on Biowaivers;323
8.2.2.2;12.2.2 Scientific Basis for BCS;325
8.2.3;12.3 Intestinal Permeability Evaluation: Cultured Cells;326
8.2.3.1;12.3.1 Caco-2 Cells;327
8.2.3.2;12.3.2 Madin–Darby Canine Kidney Cells (MDCK);328
8.2.3.3;12.3.3 Other Cells;329
8.2.3.4;12.3.4 Limitations of Cultured Cell Models;329
8.2.4;12.4 Intestinal Permeability Evaluation: Ex-In Vivo;330
8.2.4.1;12.4.1 The Everted Gut Sac Technique;330
8.2.4.2;12.4.2 Ussing Chamber;331
8.2.4.3;12.4.3 In Situ Method;332
8.2.4.4;12.4.4 Intestinal Perfusion in Man;333
8.2.5;12.5 In Silico Methods;334
8.2.5.1;12.5.1 CAT Model;335
8.2.5.2;12.5.2 Quantitative Structure Bioavailability Relationships (QSBR);335
8.2.5.3;12.5.3 Quantitative Structure Permeability Relationships (QSPR);336
8.2.6;12.6 Future Trends;337
8.2.7;12.7 Conclusion;338
8.3;Chapter 13. Fundamentals of Dissolution;342
8.3.1;13.1 Introduction;342
8.3.2;13.2 Mechanism and Theories of Solid Dissolution;342
8.3.2.1;13.2.1 Thermodynamic Considerations;342
8.3.2.2;13.2.2 Dissolution by Pure Diffusion;343
8.3.2.3;13.2.3 Diffusion Layer Model;343
8.3.2.4;13.2.4 Convective Diffusion Model;344
8.3.3;13.3 Planar Surface Dissolution;345
8.3.3.1;13.3.1 Intrinsic Dissolution Rate;345
8.3.3.2;13.3.2 Convective Diffusion Model for Flow Past a Planar Surface;345
8.3.4;13.4 Particulate Dissolution;346
8.3.4.1;13.4.1 Diffusion Layer-based Dissolution Models;346
8.3.4.2;13.4.2 Convective Diffusion-based Particulate Dissolution Model;348
8.3.4.3;13.4.3 Dissolution Under Non-sink Conditions;348
8.3.4.4;13.4.4 Effects of Particle Shape;349
8.3.4.5;13.4.5 Polydispersity Effects;349
8.4;Chapter 14. Dissolution Testing of Solid Products;352
8.4.1;14.1 Introduction;352
8.4.2;14.2 Components of Dissolution Test Method Development;353
8.4.2.1;14.2.1 Dissolution Apparatuses;353
8.4.2.2;14.2.2 Analytical Assay;355
8.4.2.3;14.2.3 Medium Selection;356
8.4.3;14.3 Dissolution Tests for Immediate-Release Products;360
8.4.3.1;14.3.1 Dissolution Tests for Tablets or Solid-Filled Capsule Products;360
8.4.3.2;14.3.2 Dissolution Tests for Liquid-filled Capsule Products;362
8.4.3.3;14.3.3 Method Development for Quality Control of Immediate-release Products;363
8.4.4;14.4 Drug Release Test Methods for Modified-Release Products;363
8.4.4.1;14.4.1 Drug Release Test Methods for Enteric Coated Products;364
8.4.4.2;14.4.2 Drug Release Test Methods for Extended-release Products;364
8.4.5;14.5 Statistical Comparison of Dissolution Profiles;365
8.4.6;14.6 Specifications;366
8.4.6.1;14.6.1 Method Validation;366
8.4.6.2;14.6.2 Acceptance Criteria;367
8.4.7;14.7 In Vitro–In Vivo Correlation (IVIVC);368
8.4.7.1;14.7.1 Developing an IVIVC;368
8.4.7.2;14.7.2 Setting Specifications Using an IVIVC;369
8.4.8;14.8 Summary and Future State;370
8.5;Chapter 15. Bioavailability and Bioequivalence;374
8.5.1;15.1 General Background;374
8.5.2;15.2 Definitions and Key Concepts;375
8.5.2.1;15.2.1 Bioavailability;375
8.5.2.2;15.2.2 Bioequivalence;376
8.5.2.3;15.2.3 Pharmaceutical Equivalence and Therapeutic Equivalence;376
8.5.3;15.3 Statistical Concepts in Bioequivalence Studies;377
8.5.3.1;15.3.1 Selection and Transformation of Pharmacokinetic Measures;377
8.5.3.2;15.3.2 Variability in Pharmacokinetic Measures of Bioavailability;378
8.5.3.3;15.3.3 Statistical Criteria for Evaluating Bioequivalence;378
8.5.3.4;15.3.4 Bioequivalence Study Designs and Other Statistical Considerations;384
8.5.4;15.4 Other General Components of Bioequivalence Studies;385
8.5.4.1;15.4.1 Study Populations;385
8.5.4.2;15.4.2 Biofluid Matrices;385
8.5.4.3;15.4.3 Bioanalytical Methods;385
8.5.4.4;15.4.4 Drug Moieties;386
8.5.5;15.5 International Regulatory Perspectives;386
8.5.5.1;15.5.1 US Food and Drug Administration;386
8.5.5.2;15.5.2 European Agency for the Evaluation of Medicinal Products;389
8.5.5.3;15.5.3 Health Canada;390
8.5.5.4;15.5.4 Japanese Ministry of Health, Labour and Welfare;392
8.5.6;15.6 Waivers Based on the Biopharmaceutical Classification System;393
8.5.7;15.7 Summary;394
8.6;Chapter 16. In Vivo Evaluation of Oral Dosage Form Performance;398
8.6.1;16.1 Introduction;398
8.6.2;16.2 General Purpose of In Vivo Performance Evaluations;398
8.6.3;16.3 Animal Pharmacokinetic Evaluations;399
8.6.3.1;16.3.1 Animal Species Selection;399
8.6.3.2;16.3.2 Animal Data Extrapolation;400
8.6.4;16.4 Human Pharmacokinetic Evaluations;401
8.6.4.1;16.4.1 Bioavailability and Bioequivalence;401
8.6.4.2;16.4.2 Effects of Food and Other Substances on Oral Drug Absorption;403
8.6.4.3;16.4.3 Effects of Gastric pH on Oral Drug Absorption;406
8.6.4.4;16.4.4 Regional Absorption Site Assessments and Imaging Studies;406
8.6.5;16.5 In Vivo Pharmacokinetic Metrics;408
8.6.6;16.6 In Vivo Absorption Pattern Diagnostics;408
8.6.7;16.7 Generic Alternative: Opportunity or Threat?;409
8.6.8;16.8 Summary;410
8.7;Chapter 17. In Vitro–In Vivo Correlations: Fundamentals, Development Considerations, and Applications;412
8.7.1;17.1 Introduction;412
8.7.1.1;17.1.1 In Vitro–In Vivo Correlation (IVIVC);412
8.7.1.2;17.1.2 IVIVC and Product Development;413
8.7.2;17.2 Development and Assessment of an IVIVC;413
8.7.2.1;17.2.1 Study Design and General Considerations;413
8.7.2.2;17.2.2 IVIVC Modeling;414
8.7.2.3;17.2.3 Evaluation of a Correlation;420
8.7.3;17.3 Considerations in IVIVC Development;421
8.7.3.1;17.3.1 In Vivo Absorption Versus In Vitro Test Considerations;421
8.7.3.2;17.3.2 Drug and Formulation Considerations;422
8.7.4;17.4 IVIVC Development Strategies and Approach;426
8.7.4.1;17.4.1 Strategy and General Approach;426
8.7.4.2;17.4.2 Design of a Predictive In Vitro Test;427
8.7.5;17.5 Applications and Limitations;430
8.7.5.1;17.5.1 Setting Dissolution Specifications;430
8.7.5.2;17.5.2 Supporting Waiver of In Vivo Bioavailability Studies;431
8.7.5.3;17.5.3 Limitations and Additional Considerations;431
8.7.6;17.6 Case Studies;432
8.7.6.1;17.6.1 Effect of Solubility on IVIVC;432
8.7.6.2;17.6.2 Developing a Predictive In Vitro Test;433
8.7.6.3;17.6.3 Illustration of Setting an Optimal Dissolution Specification;434
8.7.7;17.7 Summary;436
9;PART III: DESIGN, DEVELOPMENT, AND SCALE-UP OF FORMULATION AND PROCESS;440
9.1;Chapter 18. Integration of Physical, Chemical, Mechanical, and Biopharmaceutical Properties in Solid Oral Dosage Form Development;442
9.1.1;18.1 Introduction;442
9.1.2;18.2 Physical and Chemical Properties;442
9.1.2.1;18.2.1 Aqueous Solubility;443
9.1.2.2;18.2.2 Dissolution Rate;444
9.1.2.3;18.2.3 Partition Coefficient;444
9.1.2.4;18.2.4 Permeability;445
9.1.2.5;18.2.5 Ionization Constant;445
9.1.2.6;18.2.6 Polymorphism;446
9.1.2.7;18.2.7 Crystallinity;447
9.1.2.8;18.2.8 Particle Size, Particle Morphology, and Surface Area;447
9.1.2.9;18.2.9 Derived Properties: Density and Porosity;448
9.1.2.10;18.2.10 Melting Point;449
9.1.2.11;18.2.11 Hygroscopicity;449
9.1.2.12;18.2.12 Chemical Stability;449
9.1.3;18.3 Mechanical Properties;450
9.1.3.1;18.3.1 Compression and Compaction;450
9.1.3.2;18.3.2 Mechanical Property Characterization;451
9.1.3.3;18.3.3 Practical Implications of Mechanical Property Characterization;453
9.1.4;18.4 Biopharmaceutical Properties;454
9.1.4.1;18.4.1 The Biopharmaceutical Classification System (BCS);454
9.1.4.2;18.4.2 BCS Class I: High Solubility and High Permeability;455
9.1.4.3;18.4.3 BCS Class II: Low Solubility and High Permeability;456
9.1.4.4;18.4.4 BCS Class III: High Solubility and Low Permeability;463
9.1.4.5;18.4.5 BCS Class IV: Low Solubility and Low Permeability;466
9.1.4.6;18.4.6 Further Clarifications of the BCS;466
9.1.4.7;18.4.7 Biopharmaceutical Drug Disposition Classification System (BDDCS);468
9.1.5;18.5 Concluding Remarks;469
9.2;Chapter 19. Improving the Oral Absorption of Poorly Soluble Drugs Using SEDDS and S-SEDDS Formulations;476
9.2.1;19.1 Introduction;476
9.2.2;19.2 Overview of Sedds and S-sedds Formulations;476
9.2.2.1;19.2.1 Growth in the Number of SEDDS/S-SEDDS Publications;477
9.2.2.2;19.2.2 Marketed SEDDS Formulations;478
9.2.3;19.3 Review of Scientific Literature Dealing with Both the Development of SEDDS/S-SEDDS Formulations, and Oral Bioavailability;479
9.2.3.1;19.3.1 Year 2008: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles;479
9.2.3.2;19.3.2 Year 2007: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles;479
9.2.3.3;19.3.3 Year 2005–2003: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles;485
9.2.3.4;19.3.4 Year 2003–2000: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles;485
9.2.3.5;19.3.5 Year 1999–1992: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles;486
9.2.4;19.4 Case Studies on the Development of SEDDS and S-SEDDS Formulations;486
9.2.4.1;19.4.1 Case Study on the Development of a SEDDS Formulation of Drug X;487
9.2.4.2;19.4.2 Development of Supersaturatable S-SEDDS Formulations;491
9.2.5;19.5 Proposed Pathways for Enhanced Oral Absorption of Poorly Soluble Drugs with SEDDS and S-SEDDS Approach;495
9.2.5.1;19.5.1 Drug Absorption Pathway;495
9.2.5.2;19.5.2 The Enterocyte Absorption of Highly Lipophilic Compounds;496
9.2.5.3;19.5.3 Significance of the Glycocalyx in Absorption of Drugs from SEDDS/S-SEDDS Formulations;496
9.2.6;19.6 Conclusions;498
9.3;Chapter 20. Rational Design of Oral Modified-release Drug Delivery Systems;502
9.3.1;20.1 Introduction;502
9.3.2;20.2 Oral Modified Release Technologies and Drug Delivery Systems;504
9.3.2.1;20.2.1 Common Oral Extended-release Systems;504
9.3.2.2;20.2.2 Other Common Oral Modified-release Systems;514
9.3.2.3;20.2.3 Materials Used for Modifying Drug Release;517
9.3.3;20.3 Rational Design of Modified-Release Systems;518
9.3.3.1;20.3.1 Identification of the Clinical Need and Definition of the In Vivo Target Product Profile;519
9.3.3.2;20.3.2 Feasibility Study;520
9.3.3.3;20.3.3 Selecting the Modified-release System and Testing System Design;523
9.3.3.4;20.3.4 Case Studies: Impact of Drug Property and Formulation Design;525
9.3.4;20.4 Summary;529
9.4;Chapter 21. Development of Modified-Release Solid Oral Dosage Forms;534
9.4.1;21.1 Introduction;534
9.4.2;21.2 Development of Modified-Release Solid Oral Products;535
9.4.2.1;21.2.1 Rational Development Approach;535
9.4.2.2;21.2.2 Preformulation Studies;537
9.4.2.3;21.2.3 Dosage Form Development;538
9.4.2.4;21.2.4 Product and Process Understanding;539
9.4.3;21.3 Technology Transfer;541
9.4.4;21.4 Case Studies;541
9.4.4.1;21.4.1 Extended-Release Dosage Forms of Verapamil;541
9.4.4.2;21.4.2 Extended-Release Dosage Forms of Nifedipine;544
9.4.4.3;21.4.3 Pulsatile Release Dosage Form of Methylphenidate;546
9.4.5;21.5 Intellectual Property Considerations;548
9.4.6;21.6 Summary;549
9.5;Chapter 22. Analytical Development and Validation for Solid Oral Dosage Forms;552
9.5.1;22.1 Introduction;552
9.5.2;22.2 Analytical Method Development and Validation Strategy;552
9.5.3;22.3 Category of Analytical Method and Method Development;553
9.5.3.1;22.3.1 Identification;554
9.5.3.2;22.3.2 Potency Assay;554
9.5.3.3;22.3.3 Impurities;554
9.5.3.4;22.3.4 Dissolution;555
9.5.3.5;22.3.5 Blend Homogeneity and Dosage Uniformity;555
9.5.3.6;22.3.6 Cleaning Test Method Development;555
9.5.3.7;22.3.7 Other Analytical Techniques;556
9.5.4;22.4 Analytical Method Validation;556
9.5.4.1;22.4.1 Verification of Compendial Methods;557
9.5.4.2;22.4.2 Characterization of Reference Standard;557
9.5.4.3;22.4.3 Stability Indicating Method;557
9.5.4.4;22.4.4 High Performance Liquid Chromatography Co-elution Peak Evaluation;557
9.5.4.5;22.4.5 Forced Degradation Studies;558
9.5.4.6;22.4.6 Method Validation Parameters;558
9.5.5;22.5 Method Transfers (MT) and Inter-Laboratory Qualification (ILQ);565
9.5.5.1;22.5.1 Definition;565
9.5.5.2;22.5.2 Potency;566
9.5.5.3;22.5.3 Related Substance Assay;566
9.5.5.4;22.5.4 Residual Solvent Assay;566
9.5.5.5;22.5.5 Dissolution or Release Assay;566
9.5.6;22.6 Case Studies;567
9.5.7;22.7 Conclusions;569
9.6;Chapter 23. Statistical Design and Analysis of Long-term Stability Studies for Drug Products;572
9.6.1;23.1 Introduction;572
9.6.2;23.2 Stability Study Objectives;572
9.6.3;23.3 Regulatory Guidance;573
9.6.4;23.4 Test Methods and Data Management;573
9.6.5;23.5 Modeling Instability;574
9.6.5.1;23.5.1 Stability Study Variables;574
9.6.5.2;23.5.2 A Statistical Model for Instability;576
9.6.6;23.6 Long-term Stability Study Design;577
9.6.6.1;23.6.1 Full and Reduced Designs;577
9.6.6.2;23.6.2 Bracketing;577
9.6.6.3;23.6.3 Matrixing;577
9.6.6.4;23.6.4 Stability Design Generation;578
9.6.6.5;23.6.5 Comparing Stability Designs;581
9.6.7;23.7 Determination of Shelf Life;584
9.6.7.1;23.7.1 Definition of Shelf Life;584
9.6.7.2;23.7.2 Model Pruning;584
9.6.7.3;23.7.3 Simple Fixed Batch Case;586
9.6.7.4;23.7.4 Simple Random Batch Case;586
9.6.7.5;23.7.5 Shelf Life Estimation in More Complex Studies;587
9.6.8;23.8 Release Limit Estimation;587
9.6.9;23.9 Probability of Future Out-of-specification Stability Test Results;588
9.6.9.1;23.9.1 Random Batch Model for Prediction;589
9.6.9.2;23.9.2 Prior Distributions for Model Parameters;589
9.6.9.3;23.9.3 Predicted Quantities of Interest;590
9.6.9.4;23.9.4 Implementation in WinBUGS;590
9.6.9.5;23.9.5 Results;591
9.6.9.6;23.9.6 Bayesian Prediction Using SAS Proc MIXED;594
9.7;Chapter 24. Packaging Selection for Solid Oral Dosage Forms;596
9.7.1;24.1 Introduction;596
9.7.1.1;24.1.1 Definitions;596
9.7.1.2;24.1.2 General Considerations;597
9.7.2;24.2 Material Considerations;597
9.7.2.1;24.2.1 Containers;597
9.7.2.2;24.2.2 Determination of Container Moisture Vapor Transmission Rate;599
9.7.2.3;24.2.3 Gas Absorbers;601
9.7.2.4;24.2.4 Drug Products;604
9.7.3;24.3 Linking Packaging Property with Drug Property;605
9.7.3.1;24.3.1 The Use of Moisture Vapor Transmission Rate per Unit Product for Container Comparison;605
9.7.3.2;24.3.2 Modeling of Moisture Uptake by Packaged Products;605
9.7.4;24.4 Post-approval Packaging Changes;607
9.8;Chapter 25. Clinical Supplies Manufacture: Strategy, Good Manufacturing Process Considerations, and Cleaning Validation;610
9.8.1;25.1 Introduction;610
9.8.2;25.2 Strategy of Clinical Supplies Manufacture;611
9.8.2.1;25.2.1 Clinical Plan;612
9.8.2.2;25.2.2 Clinical Supplies Liaison;613
9.8.2.3;25.2.3 Lean Manufacturing;613
9.8.2.4;25.2.4 Cross-functional Training;615
9.8.2.5;25.2.5 Outsourcing of Manufacturing and Packaging;615
9.8.2.6;25.2.6 New Technology;616
9.8.3;25.3 Good Manufacturing Practice (GMP) Considerations in Manufacturing Clinical Supplies;617
9.8.3.1;25.3.1 Current Good Manufacturing Practice (cGMP) Considerations;617
9.8.3.2;25.3.2 A Risk-based Approach;620
9.8.4;25.4 Cleaning Validation and Verification;621
9.8.4.1;25.4.1 Cleaning Validation Versus Cleaning Verification;622
9.8.4.2;25.4.2 Swab Test Acceptance Criteria;622
9.8.4.3;25.4.3 Swab Selection;623
9.8.4.4;25.4.4 Analytical Methodologies;623
9.8.4.5;25.4.5 Analytical Method Validation;624
9.8.4.6;25.4.6 Case Study;627
9.8.5;25.5 Summary;629
9.9;Chapter 26. Specification Setting and Manufacturing Process Control for Solid Oral Drug Products;632
9.9.1;26.1 Introduction;632
9.9.2;26.2 Specifications for the Drug Substance;633
9.9.3;26.3 Specifications for Clinical Trial Materials;637
9.9.3.1;26.3.1 Early Development Stage (Phases 1 and 2);637
9.9.3.2;26.3.2 Late Development Stage (Phase 3);638
9.9.4;26.4 Specifications for Commercial Drug Products;638
9.9.4.1;26.4.1 Product In-house Release Specifications and Regulatory Specifications;641
9.9.4.2;26.4.2 Product Stability and Expiration Date;642
9.9.5;26.5 Process Control for Solid Oral Drug Products;643
9.9.5.1;26.5.1 In-process Material Tests and Quality Attributes;643
9.9.5.2;26.5.2 Powder Blending Uniformity;643
9.9.5.3;26.5.3 Statistical Methodology for Process Control;644
9.9.5.4;26.5.4 Process Analytical Technology (PAT) and In-process Controls;645
9.9.6;26.6 Analytical Procedures;646
9.9.7;26.7 Conclusions;646
9.10;Chapter 27. Scale-up of Pharmaceutical Manufacturing Operations of Solid Dosage Forms;648
9.10.1;27.1 Introduction to Scale-up;648
9.10.1.1;27.1.1 What is Scale-up?;648
9.10.1.2;27.1.2 The Importance of Scale-up in Pharmaceutical Manufacturing;648
9.10.1.3;27.1.3 How is Scale-up Performed?;649
9.10.2;27.2 Models and Modeling in Scale-up;649
9.10.2.1;27.2.1 Introduction to Models;649
9.10.3;27.3 Dimensional Analysis: Scale-up with Semi-empirical Modeling;652
9.10.3.1;27.3.1 Introduction to Dimensional Analysis;652
9.10.3.2;27.3.2 Effective Application of Dimensional Analysis;657
9.10.3.3;27.3.3 Similitude;661
9.10.4;27.4 Mechanistic Models for Scale-up;662
9.10.4.1;27.4.1 Mechanistic Modeling versus Dimensional Analysis;662
9.10.4.2;27.4.2 Developing a Mechanistic Model;663
9.10.4.3;27.4.3 Definition;663
9.10.4.4;27.4.4 Identification;664
9.10.4.5;27.4.5 Limitation;664
9.10.4.6;27.4.6 Formulation;664
9.10.4.7;27.4.7 Solution;664
9.10.4.8;27.4.8 Validation;664
9.10.4.9;27.4.9 Iteration;665
9.10.4.10;27.4.10 Application;665
9.10.5;27.5 Practical Strategies for Pharmaceutical Scale-up;665
9.10.5.1;27.5.1 Strategies for Practical Application;665
9.10.5.2;27.5.2 Quality by Design Using Scaling Principles;666
9.10.6;27.6 Conclusion;669
9.11;Chapter 28. Process Development, Optimization, and Scale-up: Powder Handling and Segregation Concerns;670
9.11.1;28.1 Introduction;670
9.11.1.1;28.1.1 Introduction to Flowability;671
9.11.1.2;28.1.2 Introduction to Blending;671
9.11.1.3;28.1.3 Introduction to Segregation;672
9.11.2;28.2 Common Powder Handling Equipment;673
9.11.2.1;28.2.1 Processing Steps Prior to Final Blending;673
9.11.2.2;28.2.2 Final Blending;674
9.11.2.3;28.2.3 Intermediate Bulk Containers;675
9.11.3;28.3 Typical Flow and Segregation Concerns;677
9.11.3.1;28.3.1 Common Flow Problems;677
9.11.3.2;28.3.2 Flow Patterns;679
9.11.3.3;28.3.3 Common Segregation Mechanisms;679
9.11.4;28.4 Measurement of Flow Properties;682
9.11.4.1;28.4.1 Cohesive Strength Tests: Preventing Arching and Ratholing;683
9.11.4.2;28.4.2 Bulk Density;688
9.11.4.3;28.4.3 Permeability;688
9.11.4.4;28.4.4 Segregation Tests;689
9.11.5;28.5 Basic Equipment Design Techniques;691
9.11.5.1;28.5.1 Reliable Funnel Flow Design (Preventing a Rathole);691
9.11.5.2;28.5.2 Reliable Mass Flow Designs for the Bin, Chute, and Press Hopper;692
9.11.5.3;28.5.3 Minimizing Adverse Two-phase Flow Effects;694
9.11.5.4;28.5.4 Minimizing Segregation in the Blender-to-Press Transfer Steps;695
9.12;Chapter 29. Process Development and Scale-up of Wet Granulation by the High Shear Process;700
9.12.1;29.1 Introduction;700
9.12.2;29.2 Principles of Wet Granulation and Process Consideration;700
9.12.3;29.3 Purpose of Wet Granulation;700
9.12.4;29.4 Common Wet Granulation Equipment Used for Manufacture;701
9.12.5;29.5 Equipment Selection Considerations;702
9.12.6;29.6 Introduction to the Wet Granulation Process;703
9.12.6.1;29.6.1 Granule Growth Stages;703
9.12.6.2;29.6.2 Granule Size Change Mechanism during Granulation Process;703
9.12.6.3;29.6.3 Process Considerations for Particle Size Growth;703
9.12.7;29.7 Overall Consideration for Process Parameters;704
9.12.7.1;29.7.1 Pre-blend Stage;704
9.12.7.2;29.7.2 Infusion Stage I;704
9.12.7.3;29.7.3 Infusion Stage II;705
9.12.7.4;29.7.4 Wet Mass Stage;705
9.12.7.5;29.7.5 Popular End Point Observations;706
9.12.7.6;29.7.6 Example: Typical Considerations for a High Shear Granulation Process;707
9.12.8;29.8 Complexity of Wet Granulation;707
9.12.9;29.9 Common Issues;708
9.12.10;29.10 Considerations of Process Design;708
9.12.10.1;29.10.1 Identify Impact from Active Pharmaceutical Ingredient (API) and Other Raw Materials;708
9.12.10.2;29.10.2 Proper Selection of Which Type of Equipment to be Used;709
9.12.10.3;29.10.3 Understand the Impact of Process Parameters;709
9.12.10.4;29.10.4 Select a Design that Reduces the Sensitivity of End Point Determination;709
9.12.10.5;29.10.5 Utilize the Contribution from Each Stage and Maintain a Balanced Design;710
9.12.10.6;29.10.6 Consideration of the Design of the Equipment;710
9.12.11;29.11 Impacts of the Process Parameters for the High Shear Process;710
9.12.11.1;29.11.1 Function of Parameters;710
9.12.11.2;29.11.2 Amount of Granulation Agent;711
9.12.11.3;29.11.3 Extent of Wet Mass Time;711
9.12.11.4;29.11.4 Peripheral Speed/Tip Speed;712
9.12.11.5;29.11.5 Temperature of Granulation Agent;712
9.12.11.6;29.11.6 Case Study: Spray Rate/Gun to Bed Distance Position of Nozzle(s);713
9.12.11.7;29.11.7 Method of Infusion;713
9.12.11.8;29.11.8 Design of Granulation Equipment;714
9.12.11.9;29.11.9 Different Drying Methods;715
9.12.11.10;29.11.10 Difference in Chopper Application;715
9.12.11.11;29.11.11 Impact by Residue Heat and by Residual Materials in Multi-batch Consecutive Process;716
9.12.12;29.12 End Point Determination;717
9.12.12.1;29.12.1 Consideration of End Point;717
9.12.12.2;29.12.2 Common Methods for End Point Determination in Production;717
9.12.12.3;29.12.3 Manufacturing Considerations;717
9.12.13;29.13 Application of Process Analytical Technology (PAT);718
9.12.14;29.14 Design of Experiment (DOE);718
9.12.15;29.15 Statistical Aids for Process Control;718
9.12.16;29.16 Scale-up and Process Measurement of Granulation;719
9.12.16.1;29.16.1 End Point Determination;720
9.12.16.2;29.16.2 End Point Scale-up;721
9.12.16.3;29.16.3 Practical Considerations;723
9.12.17;29.17 Best Practices;723
9.12.17.1;29.17.1 Consideration of Robust Process;723
9.12.17.2;29.17.2 Emerging Concept of Process Design and Control;724
9.12.18;29.18 Principles and Scale-up of Foam Granulation;724
9.12.18.1;29.18.1 Introduction;724
9.12.18.2;29.18.2 Experimental;725
9.12.18.3;29.18.3 Results and Discussion;728
9.12.18.4;29.18.4 Conclusion of Foam Granulation Study;730
9.12.19;29.19 Bottom Lines;730
9.13;Chapter 30. Process Development, Optimization, and Scale-up: Fluid-bed Granulation;734
9.13.1;30.1 Overview of the Fluid-bed Granulation Process;734
9.13.2;30.2 Equipment Design;734
9.13.2.1;30.2.1 Batch-wise Models;734
9.13.2.2;30.2.2 Semi-continuous Design;736
9.13.2.3;30.2.3 Continuous Models;737
9.13.3;30.3 Fluid-bed Hydrodynamics;737
9.13.3.1;30.3.1 Product Temperature and Moisture Content Profiles through Fluid-bed Processing;737
9.13.3.2;30.3.2 Moisture Mass Balance during the Fluid-bed Process;737
9.13.4;30.4 Mechanisms of Agglomeration;739
9.13.4.1;30.4.1 Phases in Granule Growth;739
9.13.4.2;30.4.2 Bonding Mechanisms;739
9.13.5;30.5 Formulation and Process Variables and their Control;740
9.13.5.1;30.5.1 Formulation Variables;740
9.13.5.2;30.5.2 Key Process Variables;740
9.13.5.3;30.5.3 Granule Growth under Drier Conditions (Low Moisture Content of Wet Granules during the Granulation Process);741
9.13.5.4;30.5.4 Granule Growth under Wetter Conditions (High Moisture Content of Wet Granules);742
9.13.6;30.6 Scale-up Considerations;742
9.13.6.1;30.6.1 Batch Size and Equipment Selection;743
9.13.6.2;30.6.2 Spray Rate Scale-up;743
9.13.6.3;30.6.3 Rotary Disk Speed Scale-up;744
9.13.6.4;30.6.4 Rational Scale-up;745
9.13.6.5;30.6.5 Scale-up via Semi-continuous (Batch-continuous) Processing;746
9.13.6.6;30.6.6 Scale-up via Continuous Processing;746
9.13.7;30.7 Summary;746
9.14;Chapter 31. Development, Scale-up, and Optimization of Process Parameters: Roller Compaction;748
9.14.1;31.1 History;748
9.14.2;31.2 General Operational Principles;748
9.14.3;31.3 Reasons to use Roller Compaction;748
9.14.4;31.4 Advantages and Disadvantages of Roller Compaction;749
9.14.4.1;31.4.1 Advantages;749
9.14.4.2;31.4.2 Disadvantages;749
9.14.5;31.5 Feed System;749
9.14.6;31.6 Roll Designs;749
9.14.7;31.7 Compaction Theory;749
9.14.8;31.8 Deaeration;750
9.14.9;31.9 Control Mechanisms;750
9.14.10;31.10 Scale-up;751
9.14.10.1;31.10.1 Scale-up Throughput Calculations;751
9.14.10.2;31.10.2 Scale-up for Achieving Consistent Sheet Density;752
9.14.11;31.11 Case Studies;752
9.14.11.1;31.11.1 Scale-up Case Study;752
9.14.11.2;31.11.2 Bulk Densities of Various Materials Before and After Roller Compaction;754
9.14.11.3;31.11.3 Effect of Compaction Pressure on Bulk Density;754
9.14.11.4;31.11.4 Compaction of Aspirin;754
9.14.11.5;31.11.5 Troubleshooting;755
9.14.12;31.12 Application of Process Analytical Technology to Roller Compaction;756
9.14.12.1;31.12.1 Case Study;756
9.14.13;31.13 Roller Compactor Suppliers;757
9.15;Chapter 32. Development, Optimization, and Scale-up of Process Parameters: Tablet Compression;758
9.15.1;32.1 Introduction;758
9.15.2;32.2 Operational Principles of Compression by Rotary Press;758
9.15.3;32.3 Best Practice;759
9.15.4;32.4 Tool Design;759
9.15.4.1;32.4.1 Terminology;760
9.15.4.2;32.4.2 Common Tooling Standards;762
9.15.4.3;32.4.3 EU, TSM, B, and D Type Punches;762
9.15.4.4;32.4.4 Recent Innovations;764
9.15.4.5;32.4.5 Cup Depth, Overall Length, and Working Length;764
9.15.4.6;32.4.6 Tooling Options;765
9.15.4.7;32.4.7 Tool Configuration for Small and Micro Tablets;768
9.15.4.8;32.4.8 Tapered Dies;768
9.15.5;32.5 Tablet Designs;769
9.15.5.1;32.5.1 Tablet Shapes;770
9.15.5.2;32.5.2 Tablet Face Configurations;771
9.15.5.3;32.5.3 Undesirable Shapes;771
9.15.5.4;32.5.4 Tablet Identification;772
9.15.5.5;32.5.5 Bisects;773
9.15.5.6;32.5.6 Steel Types;774
9.15.5.7;32.5.7 Inserted Dies;774
9.15.5.8;32.5.8 Multi-tip Tooling;775
9.15.5.9;32.5.9 Punch Tip Pressure Guide;776
9.15.6;32.6 Care of Punches and Dies;776
9.15.7;32.7 Tooling Inspection;777
9.15.8;32.8 Tooling Reworking;777
9.15.9;32.9 Press Wear;777
9.15.10;32.10 Purchasing Tablet Compression Tooling;778
9.15.11;32.11 Consideration of Tooling;778
9.15.12;32.12 Scale-up of Compression;781
9.15.12.1;32.12.1 Compaction and Compression;781
9.15.12.2;32.12.2 Tableting Failure;782
9.15.12.3;32.12.3 Main Factors of Tableting;783
9.15.12.4;32.12.4 Compaction Event;784
9.15.12.5;32.12.5 Tableting Time Definitions;784
9.15.12.6;32.12.6 Dwell Time and Contact Time;785
9.15.12.7;32.12.7 Tableting Geometry;786
9.15.12.8;32.12.8 Tableting Scale-up;788
9.16;Chapter 33. Development, Optimization, and Scale-up of Process Parameters: Pan Coating;794
9.16.1;33.1 Introduction;794
9.16.1.1;33.1.1 Theory of Film-coating;794
9.16.1.2;33.1.2 Evolution of Pharmaceutical Coating Technologies;794
9.16.1.3;33.1.3 Coating Equipment: Introduction;795
9.16.2;33.2 Film-coating Formulations;795
9.16.2.1;33.2.1 Overview of Types of Film-coating Formulations;795
9.16.2.2;33.2.2 Overview of Types of Materials Used in Film-coating Formulations;797
9.16.2.3;33.2.3 Film-coating Formulations Used for Immediate-release Applications;803
9.16.2.4;33.2.4 Film-coatings Used for Modified-release Applications;804
9.16.3;33.3 Design and Development of the Film-Coating Processes;808
9.16.3.1;33.3.1 General Introduction to Coating Processes and Equipment;808
9.16.3.2;33.3.2 Pan Units;810
9.16.3.3;33.3.3 Comparison of Continuous-coating Equipment;812
9.16.4;33.4 Process Air Equipment;812
9.16.5;33.5 Spray Systems;814
9.16.5.1;33.5.1 Comparison of Different Spray Guns;814
9.16.5.2;33.5.2 Pneumatic Spray Gun;814
9.16.5.3;33.5.3 Hydraulic Spray Gun;814
9.16.5.4;33.5.4 Solution Delivery Pump;815
9.16.5.5;33.5.5 Delivery Control;815
9.16.6;33.6 System Controls;816
9.16.7;33.7 General Characteristics of the Pharmaceutical Coating Process;816
9.16.7.1;33.7.1 Typical Process Steps;816
9.16.7.2;33.7.2 Coating Pan Set-up;817
9.16.7.3;33.7.3 Loading/Charging;817
9.16.7.4;33.7.4 Preheat/Dedusting;817
9.16.7.5;33.7.5 Seal/Barrier Coat;818
9.16.7.6;33.7.6 Film-coating Application;818
9.16.7.7;33.7.7 Gloss Coat;818
9.16.7.8;33.7.8 Wax Addition;818
9.16.7.9;33.7.9 Product Discharge;818
9.16.8;33.8 Understanding Process Thermodynamics;819
9.16.8.1;33.8.1 Adequate Evaporative Rate;819
9.16.9;33.9 Process Air;819
9.16.9.1;33.9.1 Volume;819
9.16.10;33.10 Humidity;819
9.16.11;33.11 Temperature;820
9.16.11.1;33.11.1 Coating Solution Characteristics;820
9.16.11.2;33.11.2 Product Temperature Limits;820
9.16.11.3;33.11.3 Pan Speed;820
9.16.11.4;33.11.4 Understanding Spray Dynamics;821
9.16.11.5;33.11.5 Coating Analysis;822
9.16.12;33.12 Controlling Coating Processes: Critical Factors;823
9.16.12.1;33.12.1 Uniformity of the Spray Application;823
9.16.12.2;33.12.2 Uniformity of Product Movement;824
9.16.12.3;33.12.3 Adequate Evaporative Capacity;825
9.16.12.4;33.12.4 Scale-up;826
9.16.12.5;33.12.5 Spray Rate to Pan Speed Ratio;827
9.16.12.6;33.12.6 Air Flow to Spray Ratio;827
9.16.13;33.13 Troubleshooting;827
9.16.13.1;33.13.1 Introduction to Troubleshooting;827
9.16.13.2;33.13.2 Up-front Approaches to Avoid Troubleshooting Issues;828
9.16.14;33.14 Consideration of Product Substrate;828
9.16.14.1;33.14.1 Hardness/Friability;829
9.16.14.2;33.14.2 Weight Variation;829
9.16.14.3;33.14.3 Stability;829
9.16.14.4;33.14.4 Compatibility;829
9.16.14.5;33.14.5 Shape;829
9.16.14.6;33.14.6 Logo Design;829
9.16.14.7;33.14.7 Core Porosity;829
9.16.14.8;33.14.8 Disintegration;830
9.16.15;33.15 Coating Solution;830
9.16.15.1;33.15.1 Film Mechanical Strength;830
9.16.15.2;33.15.2 Plasticizer Level;830
9.16.15.3;33.15.3 Pigment Level;830
9.16.15.4;33.15.4 Film Solution Solids;830
9.16.15.5;33.15.5 Solution Viscosity;830
9.16.15.6;33.15.6 Stability;830
9.16.15.7;33.15.7 Compatibility;830
9.16.15.8;33.15.8 Processing Issues as They Relate to Troubleshooting;831
9.16.15.9;33.15.9 Troubleshooting: Summary;832
9.16.16;33.16 Application of Systematic and Statistical Tools for Troubleshooting and Process Optimization;832
9.17;Chapter 34. Development, Optimization, and Scale-up of Process Parameters: Wurster Coating;840
9.17.1;34.1 Introduction;840
9.17.2;34.2 Basic Design;840
9.17.3;34.3 HS Wurster Considerations;843
9.17.4;34.4 Coating and Process Characteristics;844
9.17.5;34.5 Processing Examples;844
9.17.6;34.6 Process Variables;846
9.17.6.1;34.6.1 Batch Size;846
9.17.6.2;34.6.2 Fluidization Pattern;846
9.17.6.3;34.6.3 Atomizing Air Pressure and Volume;847
9.17.6.4;34.6.4 Nozzle Port Size;848
9.17.6.5;34.6.5 Evaporation Rate;848
9.17.6.6;34.6.6 Product Temperature;849
9.17.7;34.7 Case Studies for Layering and Fine Particle Coating;849
9.17.8;34.8 Scale-up of Wurster Processing;853
9.17.8.1;34.8.1 Batch Size;855
9.17.8.2;34.8.2 Spray Rate;855
9.17.8.3;34.8.3 Droplet Size and Nozzle Considerations;855
9.17.8.4;34.8.4 Process Air Volume;856
9.17.8.5;34.8.5 Process Air and Product Temperatures;858
9.17.8.6;34.8.6 Mass Effects;858
9.17.9;34.9 Summary;858
9.18;Chapter 35. Process Analytical Technology in Solid Dosage Development and Manufacturing;860
9.18.1;35.1 Introduction;860
9.18.2;35.2 Regulatory Developments;861
9.18.2.1;35.2.1 The FDA: Process Analytical Technology (PAT) guidance;861
9.18.2.2;35.2.2 United States Pharmacopeia (USP);861
9.18.2.3;35.2.3 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH);861
9.18.2.4;35.2.4 American Society for Testing and Materials (ASTM) Standards;862
9.18.3;35.3 Process Analytical Technology (PAT) Tools;862
9.18.3.1;35.3.1 Analytical Techniques;862
9.18.3.2;35.3.2 Chemometrics and Multivariate Analysis;867
9.18.4;35.4 Process Analytical Technology (PAT) Applications;867
9.18.4.1;35.4.1 Raw Material Identification;868
9.18.4.2;35.4.2 Blending;868
9.18.4.3;35.4.3 Granulation;869
9.18.4.4;35.4.4 Near-infrared Monitoring of Fluid-bed Drying;871
9.18.4.5;35.4.5 Encapsulation;871
9.18.4.6;35.4.6 Compression;872
9.18.4.7;35.4.7 Coating;872
9.18.5;35.5 Conclusion;872
10;PART IV: SELECTED TOPICS IN PRODUCT DEVELOPMENT;876
10.1;Chapter 36. The Product Development Process;878
10.1.1;36.1 Introduction;878
10.1.1.1;36.1.1 Organizational Considerations;879
10.1.1.2;36.1.2 The Target Product Profile: A Strategic Development Process Tool;880
10.1.2;36.2 Summary of the Drug Development Process;880
10.1.3;36.3 Preclinical Research;882
10.1.3.1;36.3.1 Discovery Research;882
10.1.3.2;36.3.2 Preclinical Development;883
10.1.4;36.4 Clinical Research;888
10.1.4.1;36.4.1 Phase 1;889
10.1.4.2;36.4.2 Phase 2;890
10.1.4.3;36.4.3 Phase 3;891
10.1.4.4;36.4.4 Pre-New Drug Application (NDA) Meeting and the New Drug Application;892
10.1.5;36.5 Concluding Remarks;892
10.2;Chapter 37. Product Registration and Drug Approval Process in the United States;894
10.2.1;37.1 Background for Product Registration in the United States;894
10.2.2;37.2 The New Drug Application (NDA) and Review Process;894
10.2.2.1;37.2.1 Food and Drug Administration (FDA) Interactions;894
10.2.2.2;37.2.2 New Drug Applications (NDA);895
10.2.2.3;37.2.3 Common Technical Document (CTD);900
10.2.2.4;37.2.4 User Fees;900
10.2.2.5;37.2.5 New Drug Application (NDA) Review Process;901
10.2.3;37.3 Generic Drug Product Registration and Review Process;903
10.2.3.1;37.3.1 Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Office of Generic Drugs;903
10.2.3.2;37.3.2 Abbreviated New Drug Application (ANDA);903
10.2.3.3;37.3.3 Abbreviated New Drug Application (ANDA) Review Process;905
10.2.4;37.4 Post-approval Activities for New Drug Applications and Abbreviated New Drug Applications;908
10.2.4.1;37.4.1 Reports;908
10.2.4.2;37.4.2 Changes to an Approved Application (21CFR314.70);909
10.2.5;37.5 Other Considerations for New Drug Applications and Abbreviated New Drug Applications;910
10.2.5.1;37.5.1 Supplemental Applications (21CFR314.71);910
10.2.5.2;37.5.2 Establishment Registration and Drug Listing Requirements for Foreign Establishments (21CFR 207.40);911
10.2.6;37.6 Pre-Approval Inspection (PAI);911
10.2.6.1;37.6.1 Background and Purpose;911
10.2.6.2;37.6.2 On-site Inspection;912
10.2.6.3;37.6.3 Preparation;914
10.2.6.4;37.6.4 Outcome of the Pre-approval Inspection;915
10.2.6.5;37.6.5 Summary;916
10.3;Chapter 38. Modern Pharmaceutical Quality Regulations: Question-based Review;918
10.3.1;38.1 Introduction;918
10.3.2;38.2 Issues with QbT and the Old Pharmaceutical Quality Assessment System;919
10.3.3;38.3 Quality by Design;920
10.3.4;38.4 Question-based Review for Generic Drugs;922
10.3.5;38.5 QbR Questions Embody QbD;923
10.3.5.1;38.5.1 Questions Related to Desired Product Performance;923
10.3.5.2;38.5.2 Questions Related to Product Design;924
10.3.5.3;38.5.3 Questions Related to Process Design;926
10.3.5.4;38.5.4 Questions Related to Process Understanding and Control;927
10.3.6;38.6 Conclusions;931
10.3.7;38.A1 Appendix: QbR Questions;931
10.4;Chapter 39. Intellectual Property Law Primer;936
10.4.1;39.1 Introduction;936
10.4.2;39.2 Patent Prosecution;936
10.4.2.1;39.2.1 Types of United States Patent Applications;936
10.4.2.2;39.2.2 Standards for Patentability;937
10.4.2.3;39.2.3 The United States Utility Patent Application;938
10.4.2.4;39.2.4 Representative Pharmaceutical Related Patent Subject Matter and Claims;939
10.4.3;39.3 Patent Enforcement/Litigation;941
10.4.3.1;39.3.1 Example: Patentability Versus Freedom to Operate;941
10.4.3.2;39.3.2 Patent Infringement Litigation;942
10.4.3.3;39.3.3 Remedies for Patent Infringement;943
10.4.3.4;39.3.4 Defenses to Patent Infringement;943
10.5;Chapter 40. Product Lifecycle Management (LCM);944
10.5.1;40.1 Introduction;944
10.5.2;40.2 Basic Patent Laws Governing the Life of Pharmaceutical Products;945
10.5.3;40.3 Lifecycle Management Through Salts, Crystal Forms and Formulations;945
10.5.4;40.4 Extension of Product Lifecycle by Shortening Product Development Time;946
10.5.5;40.5 Lifecycle Management through New Drug Delivery Systems;946
10.5.5.1;40.5.1 Modified-Release;947
10.5.5.2;40.5.2 Formulations with Enhanced Bioavailability;948
10.5.5.3;40.5.3 Examples of Successful New Drug Delivery Systems;949
10.5.6;40.6 Lifecycle Management Through Fixed Combination Products;949
10.5.6.1;40.6.1 Benefit of Fixed Combination Products;950
10.5.6.2;40.6.2 Clinical Challenges;951
10.5.6.3;40.6.3 Technical Challenges;952
10.5.6.4;40.6.4 Business Challenges;952
10.5.7;40.7 Conclusions;953
11;Index;956
11.1;A;956
11.2;B;957
11.3;C;958
11.4;D;960
11.5;E;962
11.6;F;962
11.7;G;964
11.8;H;964
11.9;I;964
11.10;J;965
11.11;K;965
11.12;L;965
11.13;M;966
11.14;N;967
11.15;O;968
11.16;P;968
11.17;Q;971
11.18;R;972
11.19;S;972
11.20;T;974
11.21;U;975
11.22;V;975
11.23;W;976
11.24;X;976
11.25;Y;976
11.26;Z;976
