Development of a reactive slurry salt crystallization to improve solid properties and process performance and scalability

Crystallization of a potent oncology drug candidate under development at GlaxoSmithKline proved to be challenging in terms of obtaining acceptable yield, consistent and desirable Active Pharmaceutical Ingredient (API) powder properties, with satisfactory process robustness and scalability. In order to address these issues, the salt formation crystallization was redesigned with a novel reactive slurry crystallization. The process developed allowed significant improvement in yield (from ≈70% to ≈95%), consistent API powder attributes within the desired range, and improved manufacturability. The new approach was designed based on the solubility behavior of both the base and the salt, whilst utilizing a seed bed of the base to mitigate spikes in supersaturation with respect to the salt. The process was scaled-up successfully in the pilot plant to manufacture material for clinical supply.