Cocrystallization by Freeze-Drying: Preparation of Novel Multicomponent Crystal Forms

We demonstrate the utility of freeze-drying
as a general method
for cocrystal synthesis as well as for the preparation of new solid
forms of drug–coformer cocrystal systems. Using this approach,
several previously reported cocrystal phases containing pharmaceutical
compounds were reproduced. In addition, a novel solid solution of
caffeine and theophylline and a potential new crystal form of the
theophylline:oxalic acid cocrystal were prepared. It is shown that
cocrystal formation proceeds via an amorphous phase that is generated
as solvent sublimes during the freeze-drying process. The application
of freeze-drying to cocrystallization is advantageous as it avoids
problems caused by differences in the solubilities of coformers and
is a technique that is widely used to prepare products on an industrial
scale, such as in the manufacture of pharmaceutical dosage forms.