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Form selection of concomitant polymorphs: A case study informed by crystallization kinetics modeling |
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| Authors: | Weiwei Tang Yufeng Quan Junbo Gong Jingkang Wang Qiuxiang Yin Tonglei Li |
| Affiliation: | 1. School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin, People's Republic of China;2. School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin, People's Republic of China
Contribution: Data curation, Formal analysis, ?Investigation, Methodology;3. School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin, People's Republic of China Contribution: Conceptualization, Funding acquisition, Resources, Supervision;4. School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin, People's Republic of China Contribution: Data curation, Resources, Supervision;5. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA |
| Abstract: | Molecular mechanisms and process kinetics of crystallizing concomitant polymorphs remain poorly understood. Solvent-mediated phase transformation and concomitant crystallization are difficult to be distinguished in practice, as multiple forms can be detected at the same time. Herein, we developed a population balance model to simulate a concomitant crystallization process of two polymorphs of tolfenamic acid. Our kinetic modeling aims to understand concomitant crystallization and help guide form selection of such a molecular system. Crystallization kinetics of ethanolic solutions were uncovered from induction time measurements, as well as seeded and unseeded crystallization experiments. Experimental and simulation results demonstrate that the stable form I crystallizes concomitantly with the metastable form II. The faster growing form II results in an intermediate decline in the composition of form I in crystallized samples, a characteristic feature of the concomitantly crystallized system. A four-quadrant scheme of attainable polymorph outcome was simulated under various crystallization conditions. |
| Keywords: | concomitant polymorphism crystal nucleation and growth pharmaceutical crystallization polymorphic control population balance modeling |
