(495d) Continuous Crystallization of the Desired Solid Forms Via Integrated Transformation Process of the Undesired Solvate Form

Crystallization is mostly involved in the intermediate and final steps of active pharmaceutical ingredients (APIs) manufacturing to deliver crystalline solids with high purity, yield, and controlled critical quality attributes (e.g., solid form). For the development of such crystallization processes, the selection of an appropriate solvent/solvent mixture (ideally Class III) is one of the key parameters for a viable concept. For some APIs, it is challenging to identify a solvent/solvent mixture with suitable characteristics to achieve both (i) solubility ≥20 mg/mL and (ii) the desired solid form (e.g., polymorph, solvate). For the latter characteristic, additional step(s) after the crystallization might be necessary to transform the undesired solid form, generated from a suboptimal solvent/solvent mixture chosen for solubility reasons, into the desired commercial form. Most reported studies on such challenges focus on a single crystallization step for the desired form typically in batch mode and without the integration of the overall downstream API purification and separation processes. This study presents an integrated process scheme for continuous crystallization coupled with solid form correction steps to deliver nitrofurantoin, an antibiotic, in the commercial solid forms. Specifically, an undesired hemisolvate produced by a continuous antisolvent crystallization using dimethyl sulfoxide and water is transformed by either (i) solvent-mediated phase transformation (e.g., slurry crystallization) or (ii) drying. Process analytical technologies is utilized for in-situ monitoring and full characterization of the integrated approach.