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.