Discovery of a novel acetone hemisolvate of metacetamol via swift cooling crystallization

Abstract

In this work, we report the discovery of a new solvated form of metacetamol—an acetone hemisolvate—obtained through a swift cooling crystallization process. The method generated relative supersaturation levels ranging from σ = 0.03 to 2.55, enabling systematic examination of nucleation behavior. At lower supersaturation values (σ = 0.33–1.01), only the stable form I crystals nucleated, whereas higher supersaturation levels (σ = 1.09–2.55) exclusively yielded the acetone hemisolvate. Induction time decreased markedly with increasing supersaturation, confirming the strong kinetic influence of supersaturation on nucleation. The resulting crystals were characterized by in situ optical microscopy, Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Single Crystal X-ray Diffraction (SCXRD) and Thermo Gravimetric-Differential Thermal Analysis (TG-DTA). Hot Stage Microscopy (HSM) further revealed the thermal desolvation behavior of the hemisolvate, corroborating DSC results and confirming transformation into stable form I upon solvent loss. These findings establish the acetone hemisolvate as a novel pseudopolymorphic form of metacetamol and provide insight into its nucleation, morphology, and stability profile.