(141c) Designing a Reactive Crystallization Process for An Agglomerating API
Agglomeration is a common issue in crystallizations which may provide inconsistencies upon scale-up if not controlled or understood. For the API described in this case study, the drug product requirement was a d90< 90 ?Ým. Due to industrial hygiene concerns with this highly potent API, dry milling was not an attractive option to reach the desired particle size. The API is formed in a reactive crystallization through multiple salt forms, to the final API-salt. Traditional batchwise reactive crystallizations were not successful as there were difficulties with both precipitation of intermediate salts and finding a consistent seed point for particle size control. The crystallization process was therefore evaluated as a seeded co-addition crystallization, which consistently afforded the correct API salt, but provided highly agglomerated materials. Several variations of the seeded co-addition crystallization were evaluated to minimize agglomeration, including seeded co-additions with different modified seed, seeded co-additions via mixing elbows, and seeded co-additions in which a large in-situ seed bed was generated with an initially unmodified seed bed. The resulting process minimized industrial hygiene concerns as no dry milling is required, fit into a manufacturing environment using existing equipment, and afforded a high quality API salt which has been successfully formulated into the drug product.