(88a) Development of a Direct Crystallization Process for a Highly Polymorphic API Compound

Development of a crystallization process that controls the solid form for a highly polymorphic active pharmaceutical ingredient (API) molecule can be a significant challenge. A case study is presented for an API compound under development that has several polymorphs. This compound has the additional challenges of being poorly soluble in most standard crystallization solvents as well as a propensity for forming solvates. As previous clinical batches of this API were produced using an enabled polymorph control process that utilized successive solvation and desolvation steps, a significant research effort was undertaken to identify a more efficient and robust process for controlling the solid form. Utilizing results from solid form studies undertaken to identify the low energy polymorph, a solvent/anti-solvent system was identified that allowed for direct crystallization of the desired polymorph avoiding the formation of solvates. Subsequent studies evaluated the crystallization process for robustness and optimal yield and purity to ensure effective production of the API with all of the desired attributes. Parameters investigated include solvent volume, antisolvent volume, crystallization temperature, mixing conditions, seed amount, and cooling rate. A subset of these studies utilized Raman spectroscopy to provided real time solid form analysis to confirm control of the solid form throughout the crystallization process. Results from laboratory-scale assessment and subsequent kilo-lab scale confirmatory runs will be discussed. These results serve as the framework of a Quality by Design (QbD) approach to developing a regulatory process for the API crystallization step.