Often as the APIs and intermediates we produce grow larger and more complex, so too do the challenges associated with crystallizing and isolating them. We present the first scale-up of the production of a large macrocyclic drug substance intermediate and the rapid process development required to address the complications which emerged during the first batch. Filtration times of several minutes on the bench translated to several days at the multi-kilogram scale. As a consequence of this slow deliquoring, removal of a high-boiling solvent from the product took weeks of drying and sufficient removal of a nonvolatile reagent was impossible. An improved seeding and crystallization strategy developed as the first batch was still drying enabled a much faster filtration during the second batch. Faster filtration then allowed for more efficient washing and faster drying. This talk will cover how improvements to the crystallization, isolation, washing, and drying of this intermediate enabled a 4-week reduction in cycle time per batch and improvement in product quality.
