Development of the Crystallization Process for Rivaroxaban–Oxalic Acid Cocrystal Preparation Using a Combination of Phase Diagrams and In Situ Measurements

Abstract

This study presents the development of the crystallization process for the rivaroxaban–oxalic acid cocrystal. The solvent screening was conducted by means of the crystallization of the cocrystal from a saturated solution of acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, and ethyl formate. Two selected solvents, namely, ethyl formate and acetone, were subjected to ternary phase diagram construction in order to ascertain the system equilibrium and identify the boundaries for pure cocrystal crystallization. The crystallization process was subsequently examined through the utilization of an in situ Raman spectroscopy probe. It was observed that the rate of transformation decreased at higher temperatures, which is most probably due to lower saturation in terms of the cocrystal. The reaction mechanism was observed by an in situ imaging probe, showing that new crystals were growing directly from the solution instead of growing from the surface of existing crystals. These findings were employed in the development of a crystallization process for both solvents, resulting in enhanced time and cost efficiency. A notable difference in particle size was observed between solvents, with acetone producing larger crystals. Consequently, ethyl formate was selected as the optimal solvent for further scale-up of the process, given its favorable impact on dissolution enhancement.