Practical Crystallization Strategies for Medicinal Chemists

Numerous advantages are afforded by crystallizing a compound directly from a reaction mixture; however, general information, strategies, and institutional knowledge surrounding solubility theory and crystallization are often not readily available to medicinal chemists. Herein, a series of general workflows are presented that leverage the use of antisolvents to manipulate solubility and facilitate direct-drop isolations. Distinctions are made for aqueous miscible versus aqueous immiscible reaction solvents. For high-impact reactions, a workflow is described that simplifies reaction mixtures to improve chances of success. Reslurry and recrystallization workflows are discussed with an emphasis on solvent selection to purge impurities based on LCMS retention factors. Finally, two case studies are described that successfully implemented these direct-drop workflows and significantly impacted project acceleration.