(207c) Leveraging Development Knowledge Post-Validation to Control Form and Improve Operational Consistency for a Pharmaceutical Intermediate with Multiple Polymorphs

The importance of controlling crystal polymorph is well-known for active pharmaceutical ingredients (APIs) as the polymorph can influence solubility, crystal morphology, residual solvent content, bioavailability, and formulation. For process intermediates, the need to control the polymorph is determined by the impact of the form on downstream processing and the risk to intermediate and API quality.

This talk provides a case study in crystallization development for a pharmaceutical intermediate with four distinct polymorphs, each with distinct crystal morphologies. These different polymorphs were observed in laboratory and pilot scale batches during development, but had no impact on the intermediate or API quality. This observation, along with the desire to provide the widest possible operating ranges for manufacturing, led to polymorph control being de-emphasized during development.

The manufacturing process consistently demonstrated production of high quality intermediate with observed variations in the polymorph. However, at the manufacturing scale, the variations in polymorph led to variable cycle times for the isolation and drying operations. Further studies were performed post-validation to confirm the impact of crystallization solvent composition on the resulting polymorph.  Adjustments to the target operating conditions within the filed acceptable parameter ranges resulted in crystallization of the preferred polymorph to provide operational consistency in the post-crystallization unit operations.