Ternary phase diagram and investigation of slurry conversion of 1:1 sulfamethazine-acetylsalicylic acid cocrystal

Abstract

Successful production of 1:1 sulfamethazine-acetylsalicylic acid (SMZ-ASA) cocrystal was achieved through slow solvent evaporation, liquid-assisted grinding, and slurry conversion method. SCXRD, PXRD, DSC, FTIR, and Raman spectroscopy were employed to characterize the cocrystal. Ternary phase diagrams (TPD) for SMZ and ASA in acetonitrile (ACN) and deionized water (DIW) has been constructed at 25 ℃. Using TPD of the incongruent system, slurry compositions for stable production of cocrystal was determined in both the solvents. The cocrystal conversion process in slurry was monitored using in-situ Raman spectroscopy. Intermittent sampling was also carried out to determine the purity of the solid phase from the slurry using offline PXRD. In-situ Raman and offline PXRD measurements confirmed fast conversion of the pure coformer crystals to the cocrystal in ACN, within a span of 5 minutes. However, the conversion in DIW was much slower and the in-situ Raman measurements significantly underpredicted the transformation time in comparison to offline PXRD analysis. The study highlights the utilization of TPD for developing the cocrystallization process and the need for multiple characterization techniques for monitoring cocrystallization.