Enhanced separation of d-mannitol polymorphs I and II via nucleation control in swift cooling crystallization

The nucleation behaviour of d-mannitol polymorph which is influenced by supersaturation was scrutinized by swift cooling crystallization process in pure aqueous solution. During swift cooling, concentration of d-mannitol in the solution creates different level of relative supersaturation leads to substantial differences in induction time, nucleation and morphology of the resultant polymorphs. This technique is employed to generate wide range of relative supersaturation (0.159 < σ < 3.860) corresponds to the rapid decrease in the temperature from 55 °C to shifting temperature of 54–1 °C. Specifically, lower level of relative supersaturation promotes the stable form I polymorph, while the nucleation of form I and form II polymorph is flavoured in intermediate level. Conversely, higher level of relative supersaturation induces the formation of only metastable form II polymorph. In-situ optical microscopy was employed to analysis the morphology of the nucleated polymorphs. Further characterization was done to validate the internal structure and thermal stability of the grown polymorphs through powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analyses. Rietveld refinement was employed to confirm the structures of both polymorphs, supporting a reliable interpretation of the PXRD results. This work shows a key advantage in understanding the crystallization behaviour which can be employed for the nucleation of d-mannitol polymorphs without any external additives within the solution.