Essential Physics of Low Temperature and Freezing - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 40

Figure 15 Effects of temperature and frozen storage on ice crystal dimensions in details.
After Calvelo. 45 Reproduced from Franks 17 with permission from Cambridge
University Press
solution, quench cooled and kept at 1961C. 32 The average ice crystal
diameter is 100 nm. In the particular study shown, after allowing the
temperature to rise to 201C and repeated quenching, a process that took
o 1 min, the mean ice crystal diameter had already risen to 410 mm.
In freeze-drying technology, maturation of the frozen matrix has certain
advantages, e.g. a reduction of the required drying time, but these must be
weighed against distinct disadvantages, such as a decreased rate of
reconstitution of the dried cake at the point of use. Note also the curious
spherical appearance of the freeze-concentrated polymer solution phase.
Such supramolecular spherical assemblies have also been observed with
other polymers, e.g. polyvinyl alcohol and polyethylene glycol (PEG) in
frozen solutions. It is not obvious how an ostensibly homogeneous
solution is converted into such uniform hydrated spheres of submicron
dimensions during freeze concentration, but the possibility of a demixing
process (lower critical solution temperature, LCST) in such systems
cannot be ruled out.
4.7 Polymorphic Transitions, Hydrates and Transient
Hydrates
The basic outlines of the solid/liquid phase diagram of water have
gradually been developed, beginning with the advent of X-ray crystallo-
graphy in the 1930s and with a further boost from more recent advances