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.