Journal
AICHE JOURNAL
Volume 67, Issue 4, Pages -Publisher
WILEY
DOI: 10.1002/aic.17129
Keywords
concomitant polymorphism; crystal nucleation and growth; pharmaceutical crystallization; polymorphic control; population balance modeling
Categories
Funding
- National Natural Science Foundation of China [NNSFC21676179, NNSFC21808159]
- State Key Laboratory of Chemical Engineering [SKL-ChE-18B04]
- Natural Science Foundation of Tianjin [19JCQNJC04800]
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The study developed a population balance model to simulate a concomitant crystallization process of tolfenamic acid polymorphs, revealing the shared crystallization feature of stable form I and metastable form II, with an intermediate decline in the composition of form I in crystallized samples. Additionally, a four-quadrant scheme was used to simulate possible polymorph outcomes under various crystallization conditions.
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.
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