Mechanism of Solvent Effect in Polymorphic Crystallization of BPT

Abstract

The effect of solvent on the crystallization behavior of the polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (BPT) was investigated under rapid cooling. From methanol (MeOH) and ethanol (EtOH) solutions, only the solvated crystals of the D forms of methanol (D(MeOH)) and ethanol (D(EtOH)) crystallized. Both D forms are stable and have similar crystal structures. However, the solubility of the D(EtOH) form is 1.5 times higher than that of the D(MeOH) form. With the release of alcohol molecules, both D forms transformed to the C form with an increase in temperature for the DSC measurement. After that, the C form transformed to the A form via a melt-mediated mechanism. The release temperature of alcohol was higher for D(EtOH) than for D(MeOH). When the crystallization was performed in 1-propanol (1-PrOH) and 2-propanol (2-PrOH), the metastable A form preferentially crystallized. On the other hand, in acetonitrile (MeCN) solutions the stable C form was selectively obtained. These crystallization behaviors in each solvent did not depend on supersaturation in solutions. The FTIR spectra of BPT in EtOH and 1-PrOH suggested that BPT molecules in solution take a conformation similar to that in each crystal. These results suggest that the solvent effect is controlled by the thermodynamic equilibrium properties such as the conformation of the solute and the solute–solvent interactions rather than the crystallization kinetics of the polymorphs. Furthermore, the solution-mediated transformation rate from the A form to the C form is higher in MeCN than those in 1-PrOH and 2-PrOH. In the mixed solvents of 1-PrOH and MeCN with water, the same polymorphs crystallized as those obtained in pure solvents in the water volume fraction up to the range of 0.1. However, the hydrated crystals (BH form) predominantly crystallized with further addition of water. Solubility measurements suggested that such behavior is related to the solvated structure surrounding the BPT molecule.

Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure

“…In general, it is found that the closer the conformational population in solution is to the conformer(s) in the nucleating crystal structure, the faster the nucleation becomes . Different solvents can cause solute molecules to assume vastly different conformations, with the result that different solvents can nucleate different conformational polymorphs …”

“…[15] Different solvents can cause solute molecules to assumev astly different conformations, with the result that dif-ferent solvents can nucleate different conformational polymorphs. [16] After statistically measuring the induction time in several organic solvents, [17] our group has recently shown that the rate of nucleationo fs alicylica cid, as mall inflexible organic molecule, is relatedt ot he strength with which the solvent binds the molecule in solution. [6] As trong positive correlation is shown between the interfacial energy calculated from induction times and several experimental and modelled variables describing solvent-solute bonding at SA'sc arboxyl group:t he carbonyl peak shift in the Raman spectrumf or the salicylic acid monomer,t he DFT-derived (1:1) binding energyt ot he carbonyl group, the calorimetrically-derived enthalpyo fs olvent-solutei nteraction, and the DFT-derived solvation energy.…”

On the Influence of Solvent Properties on the Structural Characteristics of Molecular Crystal Polymorphs

“…Apart from the aforementioned effects, there are numerous examples of solvent influence on solute conformation , in cases where the solute molecule is flexible. For instance, there are many examples of molecules for which more polar conformations are stabilized in polar solvents. − As shown in ref , conformations of the solute molecule in ethanol and n -propanol resemble those found in crystals that precipitate out of the respective solvents. At the same time, some conformations are unable “to crystallize” for some reason and, even though the solvent can change the distribution of solute conformers, it does not guarantee the crystallization of polymorphs with a molecular conformation close to that present in solution.…”

Solvation and Aggregation of Meta-aminobenzoic Acid in Water: Density Functional Theory and Molecular Dynamics Study

“…2,4 The nature of the solvent can significantly influence the thermodynamics and kinetics of crystal growth, [5][6][7] and control the formation of one specific polymorph over another. [8][9][10] In the case of metaaminobenzoic acid, Form II preferentially crystallizes from dimethyl sulfoxide (DMSO), 4 where metaaminobenzoic acid only exist in the nonionic form in this solvent. Hughes and co-workers 11 monitored the crystallization of meta-aminobenzoic acid from organosulfur solutions using a combined liquid-and solid-state in-situ NMR apparatus and proposed the existence of nonionic mABA aggregates linked by H bonds, but the authors could not however uniquely determine the identity of these species.…”