Freeze-drying of Pharmaceuticals and Biopharmaceuticals (eBook)

1: Historical Background; 1.1: Drying as a preservation method; 1.2: The advent of industrial freeze-drying; 1.3: Elements of stability; 1.4: Why Freeze-Dry?; 1.5: Stability - the downside; 2: The Process Sequence in Summary; 2.1: Equipment; 2.2: The drying process - coupled heat and mass transfer; 2.3: How dry is "Dry"?; 2.4: Why not freeze-dry?; 3: Essential Product and Process Parameters; 3.1: General considerations; 3.2: Formulation parameters; 3.3: Process parameters; 3.4: The multidisciplinary nature of freeze-drying; 3.5: Conclusions; 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 - nucleation in undercooled water; 4.5: Ice - its 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: Freezing in complex biological substrates; 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: importance of the state diagram; 5.8: Aqueous glasses as solid solutions; 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: The Glass Transition - a summary; 6.5: Amorphous states and freezing behaviour; 6.6: Materials science of the glass transition - its relevance to freeze-drying; 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; 8: Primary Drying - the Sublimation of Ice; 8.1: Principles of coupled heat and mass transfer; 8.2: The model; 8.3: Heat transfer mechanisms; 8.4: Influences of formulation and freezing procedure on ice sublimation; 8.5: The 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; 9: Secondary Drying; 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; 10: Some Practical Aspects - Economics and Engineering; 10.1: Scale up and ICH manufacture; 10.2: Economics; 10.3: Vial closure; packaging; 10.4: Process monitoring and control; 10.5: Stability issues; 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 use; 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; 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; 14: Acknowledgements; 15: Bibliography