Crystallization Process Development Using Quality-By-Design Methodology for Producing a Needle-Shaped Active Pharmaceutical Ingredient with Improved Processability

A novel active pharmaceutical ingredient (API) exhibiting needlelike morphology displayed variable and poor solid-state bulk properties, including low flowability, strong adhesion, and high electrostatic charge, which negatively impacted formulation manufacturing. Applying a quality-by-design methodology, an improved API with enhanced flowability and reduced adhesion and electrostatic charge was obtained through batch-seeded cooling crystallization. A robust crystallization process was developed using statistical design of experiments, chemical engineering calculation-driven crystallization experiments, and process analytical technology. This process, combined with delumping via comilling, was demonstrated at the pilot scale. The solid-state properties of the API were comprehensively characterized, and it was successfully integrated into the drug product workflow. The crystallization process was optimized within approximately 9 months.