Selective crystallization of d-mannitol polymorphs in a water–isopropyl alcohol mixture through a swift cooling process

Abstract

In this study, we examine the polymorphic control and separation of D-mannitol in a 1 : 1 (v/v) ratio of water–isopropyl alcohol solvent mixture using a swift-cooling crystallization process. This method created supersaturation (0.01 < σ < 13.18), producing obvious changes in the crystallization outcome of D-mannitol polymorphs. At low supersaturation levels, only the stable form I nucleated. Under high supersaturation conditions, metastable form II was observed, while at extremely high supersaturation levels, the metastable form III was obtained. Notably, form III converted into form I through a solution-mediated transformation, confirming its transient stability and its tendency to transform into the thermodynamically stable form. Morphological analysis was conducted through in situ optical microscopy. The structural and thermal characteristics were confirmed by powder X-ray diffraction. The crystalline phases were further verified by Le Bail profile fitting and differential scanning calorimetry. This approach effectively describes the supersaturation region governing D-mannitol polymorph formation, enabling selective crystallization of the desired metastable form with enhanced control.