Selective crystallization of D-mannitol polymorphs in water-isopropyl alcohol through swift cooling process

Abstract

In this study, we examine the polymorphic control and separation of D-mannitol in 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) produces obvious changes in the crystallization outcome of D-mannitol polymorphs. At low supersaturation level only the stable form I nucleated. Under high supersaturation conditions metastable form II was observed, while at extremely high supersaturation level, the metastable form III was obtained. Notably, form III convert into form I through a solution-mediated transformation confirming its transient stability and tendency to change toward the thermodynamically stable form. The morphological analysis was observed through in-situ optical microscopy. The structural and thermal characteristics were confirmed by powder X-ray diffraction (PXRD), the crystalline phases were further verified by Le Bail profile fitting and differential scanning calorimetry (DSC). This approach effectively describes the supersaturation region governing D-mannitol polymorphs formation, enabling selective crystallization of the desired metastable form with enhanced control.