Implications for Freeze-Drying

Depending on the physical behaviour and stability of the bioactive component, both amorphous and eutectic systems can be successfully freeze-dried but require different approaches. The most difficult cases are those that exhibit partial crystallisation, which may lead to uncontrollable intrabatch variability. Irrespective of the physical state of the system, maximum temperatures for ice sublimation (7/. or T can be identified. Above these temperatures, ice will melt at an appreciable rate, thus diluting the solution phase. The product may then exhibit mechanical collapse, and most probably it will also become subject to chemical changes (usually deterioration). 

In a eutectic system, the whole composition or just the excipient may be subject to crystallisation, but this process takes time to reach completion. It may be much longer than the time taken to freeze the product to the desired temperature (Tg). After primary drying (ice sublimation), only solid solutes remain. The mixture may then be carefully warmed to its final storage temperature. The residual solid will not necessarily be anhydrous and may, for example, contain water of crystallisation. In addition, as the temperature is raised, the crystalline product may undergo solid-solid transitions, i.e. over a period of time, a different polymorph may become the preferred crystal habit. In a completely crystalline preparation, the maximum safe storage temperature will be governed by the component with the lowest melting point. 

The physical state and the appearance of the dried cake are set during the freezing process, i.e. the kinetics of ice nucleation and crystal growth. Both can be controlled to some extent by variations in formulation and 

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Oesterle, J., Franks, F., Auffret, T. The influence of tertiary butyl alcohol and volatile salts on the sublimation of ice from frozen sucrose solution Implications for freeze drying. Pharmaceutical Developments and Technology, 3 (2), p. 175-183, 1998. Copyright 1998 by Marcel Dekker, Inc., New York, N. Y., USA... 

Shalaev EY, Johnson-Elton TD, Chang L, Pikal MJ (2002) Thermophysical properties of pharmaceutically compatible buffers at sub-zero temperatures implications for freeze-drying. Pharm Res 19 195-201... 

Sheehy PM, Ramstad T. 2005. Determination of the molecular complexation constant between alprostadil and alpha-cyclodextrin by conductometry implications for a freeze-dried formulation. Journal of Pharmaceutical and Biomedical Analysis 39(5) 877-885. 

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