(707b) Identification and Crystallization Development of Potential Conformational Polymorphs of an Active Pharmaceutical Ingredient

Solid form control is essential in the development of active pharmaceutical ingredient (API) as polymorphs may have different physical properties that could impact the drug product performance and processing. Only one polymorph (Form I) was initially reported in the early solid form screen of a development compound (Compound A). However, during the crystallization development and scale-up batches, very minor XRPD differences were observed between batches, which triggered a comprehensive solid form characterization using advanced solid state tools like ssNMR and Raman. It was found that a new polymorph (Form II) was identified in the crystallization development that had very similar XRPD pattern to Form I. Based on ssNMR and Raman data, Form I and Form II are likely conformational polymorphs though single crystal structure data have yet available for confirmation. Relative stability study between Form I and Form II showed that Form II is the most stable polymorph, which was later designated as the new development form.

Extensive efforts were made to develop a crystallization process that can produce the new Form II. A process was successfully developed in IPA/H₂O with seeding, extended H₂O addition and aging and in-process control (by SSNMR/Raman). This process was successfully applied to all the subsequent scale-up batches with good polymorph control, purification and recovery yield. Systematic process robustness studies on the crystallization and polymorph control, as well as efforts to modify the powder property for the drug product formulation, will also be discussed in the presentation.