Form selection of concomitant polymorphs: A case study informed by crystallization kinetics modeling

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.

Kinetic Retraction at the Onset of Concomitant Crystallization and Implication on Polymorphic Formation

“…If it were solvent-mediated phase transformation, then the mass composition of Form I would monotonically increase, and only Form II would nucleate initially (Scheme b). We further supported through population balance modeling that this characteristically kinetic phenomenon is a sufficient condition indicator of concomitant crystallization of polymorphic systems . Nonetheless, as illustrated later in the report, when Δ w is insignificant, concomitant crystallization is also possible.…”

“…We have recently studied a diarylamine compound, tolfenamic acid (TFA), and examined its solution chemistry, , crystallization kinetics, − and molecular interactions. , The polymorphic system typically crystallizes as Form I or II, or both concurrently, with Form I being the most stable at room temperature. Both polymorphic structures are composed of hydrogen-bonded, carboxyl homodimers as the supramolecular synthon .…”

“…By examining the kinetic retraction and onset fraction over simulated crystallization conditions, we derived a four-quadrant plot that defines the polymorphic outcome by the relative nucleation and crystal growth rates between the two forms (i.e., J I / J II and G II / G I , where J i and G i denote respectively the nucleation and growth rates of polymorph i ). Specifically, we numerically spanned values of log­( J I / J II ) and log­( G II / G I ) respectively from −4 to 10 and from −3 to 3 in order to cover the majority of crystallization conditions typically encountered experimentally. ,, Figure shows the so-called four-quadrant regimes of attainable polymorph crystallization (FQR-APC) plot. The ratios, J I / J II and G II / G I , epitomize the kinetic competition in nucleation and crystal growth between the two polymorphs, allowing the FQR plot to illustrate the polymorphic outcome under different crystallization conditions.…”

“…The polymorphic composition of dimorphic crystallization suggested by the FQR-APC plot (Figure ) is jointly determined by the values of both Δ w and w 0 . These values were calculated from the established population balance modeling coupled with crystallization kinetic simulation of dipolymorphs, as reported in our recent work . Nucleation of a pure form is regarded when w 0 < 0.01 (pure Form II) or w 0 > 99.99% (pure Form I), respectively mainly located in FQR-APC regions 1 and 4.…”

Molecular Mechanism of Organic Crystal Nucleation: A Perspective of Solution Chemistry and Polymorphism

“…The solvation effect of solutes imposed by solvent molecules has an important influence on solute assembly and affects polymorphic nucleation. It has been demonstrated from both experiments and mathematical modeling that desolvation of solutes in the nucleation pathway results in concurrent nucleation of TFA form I and form II and the appearance of concomitant polymorphism (Figure 8) [136,137]. The solvated monomers may initially form dimers or aggregates through weak intermolecular interactions, e.g., aromatic stacking and/or van der Waals forces, which occurs in either the pre-nucleation or nucleation stage.…”