Optimization of Venetoclax Napsylate Crystallization

ABSTRACT

Venetoclax napsylate is a promising new salt that exhibits enhanced dissolution properties, which are crucial to improving the bioavailability of this poorly soluble drug. However, it exhibits significant polymorphism. In fact, five forms of venetoclax napsylate were identified during the screening process, and the most promising one, Form E, was selected for further development due to its superior intrinsic dissolution rate. This study presents a comprehensive optimization approach to the crystallization process for venetoclax napsylate, which is crucial to ensure high purity and reproducible yield in pharmaceutical manufacturing. It investigates key parameters influencing crystallization, including solvent selection, supersaturation control, and crystallization temperature profiles, using in situ monitoring tools as well as product analysis. Experimental results demonstrate that fine‐tuning these parameters and the introduction of seeding enable phase‐selective crystallization and enhance product quality while maintaining process robustness and significantly reducing crystallization time from 20 to 2.5 h. The findings enable the efficient production of venetoclax napsylate with enhanced control over the particle size distribution. The refined process yields high‐purity venetoclax napsylate, suitable for pharmaceutical development, which may potentially enable dose reduction in clinical applications.