Mechanistic insight into the selective crystallization of the metastable polymorph of tolbutamide in ethanol–water solution

Abstract

The rapid-cooling crystallization of tolbutamide (TB) was carried out from ethanol and ethanol–water solutions at different initial supersaturations (3.5 and 2.7). PXRD and FTIR were used to characterize the polymorphs. It was found that the metastable Form IV with advanced solubility and bioavailability was obtained from ethanol–water solutions at the higher supersaturation, while stable Form III directly crystallized from ethanol at both supersaturations and from ethanol–water solution at the lower supersaturation. Hirshfeld surface analysis and the associated 2D fingerprint plots of the five TB polymorphs clearly quantify the interactions within the crystal structures. The mechanism of selective crystallization of the metastable polymorph of tolbutamide in ethanol–water solution was disclosed by molecular dynamics simulation. It was indicated that stronger interactions between TB and solvents weaken the TB–TB intermolecular NH⋯O hydrogen bonds and thus promote TB molecules to form dimers by π⋯π stacking. This work provides a feasible approach, combining experimental and molecular dynamics simulation methods, to better understanding the effect of solvent and supersaturation on polymorph outcomes by studying the competitive relationship between solute–solute and solute–solvent interactions, which is fundamental to the rational design of experimental work for controlling organic crystal polymorphs by simply varying solvents and supersaturations.