(670e) An Approach to Significantly Increase Crystal Size of a Drug Substance

In preclinical stages of drug development, processes are typically quickly designed to enable fast deliveries to support various preclinical studies. These processes are usually Fit-for-Purpose processes with a main emphasis on purity and yield and no efforts spent to controlling particle size and morphology. This strategy often results in non-desired particle properties that need to be addressed if the drug is selected for clinical phases. In particular, agglomerates are often not desired as they increase the risk of solvent entrapment. This study presents such a case where a first-generation crystallization process produced agglomerates formed by very small primary crystals. This particle morphology resulted in high residual organic solvents, which needed to be decreased to acceptable levels before the drug substance can be delivered for clinical trials. This presentation shows efforts undertaken to increase crystal size and avoid agglomerate formation, which faced multiples challenges such as slow crystal growth and poor solubility. The various approaches explored led to the design of a process involving an intermediate salt, which delivered considerably larger crystals with a significant reduction of the levels of residual solvents. In addition, the increase in particle size also resulted in substantial improvement of powder flow and density, highly desired properties for drug product manufacturability.