Control of Crystal Modification and Crystal Shape by Control of Solid–Solid Transitions during Crystallization and Drying: Two Industrial Case Studies

Crystallization and drying are the final steps in the manufacture of most drug substances that determine their final features and may also impact the manufacture of the formulated drug product. It is important to understand and control the mechanisms involved in the crystallization and drying processes to avoid handling and formulation problems, and this is illustrated with two examples of large-scale processes. In the first, a solid–solid phase transition between two very similar crystalline forms was shown to lead to dramatic particle size reduction and consequent processing issues; the unwanted phase transition was avoided by careful choice of crystallization conditions. In the second, control of the drying conditions allowed a rapid solid–solid phase transition of a mixed solvate into a stable anhydrous form.