(341a) Streamlining Crystallization Process for a Low Solubility and Highly Solvating API System to Achieve Robust Scale-up Performance

A robust performing crystallization is of utmost importance in the final step of drug substance synthesis, to meet the critical quality attributes (CQAs) for an active pharmaceutical ingredient (API). A case-study is presented involving an API step of a rapidly advancing portfolio molecule, wherein the API had very poor solubility in most solvents that prevented designing a realistically scalable conventional crystallization process. Moreover, the API molecule readily solvated with most solvents and had a complex polymorph landscape. To supply the clinical material needs, early campaigns implemented a first-generation process involving a distillative crystallization to isolate the API, followed by form conversion by drying. As the clinical program advanced, requiring scale-up to manufacture the API at several hundred kilograms, the drying operation performed robustly and always achieved the desired form (neat Form A). However, distillative crystallization processes can be challenging to scale up and this process was evaluated to have a considerable risk of failing the API specifications via generation of new impurities due to thermal stresses and degradation of on-wall solids. There was a critical need to explore an alternate controlled crystallization option. A second-generation process was quickly developed, allowing streamlining of the reaction followed by an antisolvent crystallization and eliminating the need to do distillations. The isolated solid from this process was a new polymorph, THF solvate A, which was classified as a flammable solid under UN Class 4 division 1. Based on the results of polymorph screening and a phase diagram, a slurry conversion unit operation was added to convert the THF solvate A to the desired neat Form A. Thus, a combination of understanding of form landscape in process space, safety assessment, and scale-up data guided the development of a commercial ready process, balancing a fast-moving clinical supply deliverable.