Form selection of concomitant polymorphs: A case study informed by crystallization kinetics modeling
Weiwei Tang, Yufeng Quan, Junbo Gong, Jingkang Wang, Qiuxiang Yin, Tonglei Li
Abstract
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.