Freeze-Drying of Pharmaceuticals and Biopharmaceuticals -- Contents -- Chapter 1 Historical Background -- 1.1 History of Drying as a Preservation Method -- 1.2 Advent of Industrial Freeze-Drying -- 1.3 Elements of Stability -- 1.4 Why Freeze-Dry? -- 1.5 Stability: The Downside -- Chapter 2 The Process Sequence in Summary -- 2.1 Equipment -- 2.2 Drying Process: Coupled Heat and Mass Transfer -- 2.3 How Dry Is "Dry"? -- 2.4 Why Not Freeze-Dry? -- Chapter 3 Essential Product and Process Parameters in Summary -- 3.1 General Considerations -- 3.2 Formulation Parameters -- 3.3 Process Parameters -- 3.4 Multidisciplinary Nature of Freeze-Drying -- 3.5 Conclusions -- Chapter 4 Essential Physics of Low Temperature and Freezing -- 4.1 Chill Versus Freezing: Undercooling -- 4.2 Deep Chill: Undercooled Water -- 4.3 Physical Properties of Undercooled Water -- 4.4 Ice: Its Nucleation in Undercooled Water -- 4.5 Ice: Crystallisation and Crystal Habits -- 4.6 Nucleation and Crystallisation of Ice and Solutes in Aqueous Solutions -- 4.7 Polymorphic Transitions, Hydrates and Transient Hydrates -- 4.8 Vitrification as Avoidance of Crystallisation -- 4.9 Freeze-Drying of Complex Biological Materials -- Chapter 5 Essential Chemistry and Biochemistry Associated with Low Temperature and Freezing -- 5.1 Physicochemical Properties of Water-Based Systems under Conditions of Deep Chill -- 5.2 Cold Inactivation of Proteins -- 5.3 Changing Phase Relationships during Freezing -- 5.4 Eutectic Crystallisation of pH Buffer Components -- 5.5 Effects of Freeze-Concentration on Reaction Kinetics -- 5.6 Complex Ternary and Multicomponent Phase Behaviour -- 5.7 Supersaturation and Vitrification: The Importance of the State Diagram -- 5.8 Aqueous Glasses as Solid Solutions -- Chapter 6 Physical Properties of Crystalline and Amorphous Solids.

6.1 Crystalline and Amorphous Solids: A Comparison -- 6.2 Non-Equilibrium Processes in Amorphous Solids -- 6.3 Slow Relaxation during Cooling and Heating -- 6.4 Glass Transition: A Summary -- 6.5 Amorphous States and Freezing Behaviour -- 6.6 Materials Science of the Glass Transition: Its Relevance to Freeze-Drying -- Chapter 7 Excipients: Their Role in Rational Formulation Design -- 7.1 Definitions and Classifications -- 7.2 Attributes and Requirements -- 7.3 Estimation of Tg of Complex Mixtures -- 7.4 Effects of Excipients on Product Attributes -- 7.5 Implications for Freeze-Drying -- 7.6 Devitrification of Excipients in Dried Amorphous Preparations -- 7.7 Pharmaceutical Glasses: Formulation Aspects -- 7.8 Constraints -- 7.9 Operational Degrees of Freedom -- Chapter 8 Primary Drying: The Sublimation of Ice -- 8.1 Principles of Coupled Heat and Mass Transfer -- 8.2 Model -- 8.3 Heat Transfer Mechanisms -- 8.4 Influences of Formulation and Freezing Procedure on Ice Sublimation -- 8.5 Interplay of Pressure, Temperature and Time -- 8.6 Adjustable Parameters: Formulation, Concentration and Fill Depth -- 8.7 Ideal Conditions -- 8.8 Accelerated Freeze-Drying -- 8.9 Monitoring Ice Sublimation -- 8.10 Summary -- Chapter 9 Secondary Drying: The Removal of Unfrozen Water -- 9.1 Unfrozen (Residual) Water -- 9.2 Removal of Unfrozen Water by Diffusion -- 9.3 Effects of Pressure -- 9.4 Effect of Water Content -- 9.5 Effects of Fill Depth and Cake Morphology -- 9.6 Effect of Temperature -- 9.7 Softening and Collapse -- 9.8 Operational Drying Protocols: Temperature Ramping and Stepwise Heating -- Chapter 10 Some Practical Aspects -- 10.1 Scale-Up and ICH Manufacture -- 10.2 Economics -- 10.3 Vial Closure and Packaging -- 10.4 Process Monitoring and Control -- 10.5 Stability Issues -- Chapter 11 The Dried Product -- 11.1 Physical State: Crystalline or Amorphous?.

11.2 Essential Materials Science of Crystalline and Amorphous Products -- 11.3 Essentials of Thermoanalytical Techniques -- 11.4 Fragility and Its Estimation -- 11.5 Monitoring Physical and Chemical Stability -- 11.6 Estimation of Useful Shelf Life -- 11.7 Dynamics in Supersaturated Solutions -- 11.8 Residual Water and Its Estimation -- 11.9 Residual Water: Its Influence on Stability -- 11.10 Unresolved Issues -- 11.11 Reconstitution at Point of Administration -- Chapter 12 Case Histories -- 12.1 Introduction -- 12.2 Choice of Formulation -- 12.3 Process Cycle Optimisation -- 12.4 Concurrent Product and Process Refinement -- 12.5 Inadvertent Failures: "Unexpected Problems" -- 12.6 Unfamiliarity with Freeze-Drying Parameters -- 12.7 In situ Water Release during Storage -- 12.8 Summary and Conclusions -- Chapter 13 Beyond Freeze-Drying -- 13.1 Alternative Water Removal Technologies -- 13.2 Evaporative Drying: Principles and Practice -- 13.3 Evaporative Drying: The Current State -- 13.4 Comparisons with Freeze-Drying -- Acknowledgements -- Bibliography -- Subject Index.