Unexpected seed dissolution during the final crystallization step of a synthetic drug substance revealed lack of robustness in the final crystallization of an active ingredient. Concurrently, the API’s needle-like morphology and low bulk density created challenges in handling during formulation. These issues prompted an investigation into the crystallization parameters. Experimental work was conducted showing the crystallization space operated in a kinetic regime, where variations in incoming water content influenced solubility. Additionally, Ostwald ripening led to variations in needle growth and drug substance with varying physical properties. Understanding the impact of process parameters on these attributes was important in achieving robustness and process control. Control was achieved by setting a water specification during cleaning operations and altering the crystallization temperature, solvent composition, and aging time. The revised process was implemented at scale, resulting in successful seeding and consistent crystallization performance, producing drug substance with consistent physical properties. This presentation will summarize the journey from problem identification through process redesign, illustrating how targeted process insights and control improvements led to a robust process for both drug substance and drug product.
