(381ba) Crystallization Solvent Design Methodology for Pharmaceutical Processes Based on Crystal Morphology Quantitative Control

Solution crystallization is an important and efficient purification/separation unit operation in active pharmaceutical ingredient (API) production processes. The requirements of crystal products include not only purity and yield, but also crystal morphology. To obtain optimal crystal products, it is crucial to reveal the influence of solvents and mechanisms for the control of crystal growth. Nowadays, crystallization solvent selection methods are mostly experimental trial and error. Therefore, it is urgent to develop a systematic crystallization solvent design method from the interdisciplinary studies of supramolecular chemistry, condensed matter physics, and product design principles. In this paper, the organic small molecules gliflozin drugs are studied as an example for the crystallization solvent design. First, based on molecular dynamics, the crystal morphology in different solvents is predicted, and the quantitative relationship between crystal morphology and solvent descriptor is further established, which is the solvent evaluation index system to quantitatively regulate crystal morphology. Then, the Computer-Aided Molecular Design model, which integrates the established mechanism model, is developed for the design of crystallization solvent. Mathematical optimization model is established for the design of crystallization solvent to consider the requirements of crystal morphology, yield, green and safety simultaneously. Finally, experiments are implemented for verification. The results of the study are able to be expanded to various APIs for the efficient and clean production of pharmaceutical processes, and contribute to the pharmaceutical products upgraded and crystal engineering.