Liquid–liquid phase separation and crystallization of aspirin polymorphs from a water–acetonitrile mixed solvent medium through a swift cooling process

Abstract

This study highlights the occurrence of liquid–liquid phase separation (LLPS) or oiling-out during the crystallization of polymorphic forms of aspirin, which was successfully revealed for the first time through a swift cooling crystallization process from a water–acetonitrile mixed solvent medium. Saturated aspirin solutions with nine different mixing compositions of water–acetonitrile solvents, from pure water to pure acetonitrile, were prepared at 310 K and swiftly cooled down to 274 K. Prior to the experiment, variations in the solubility and pH with different solvent mixture compositions were studied and after the swift cooling of the solutions, variations in the induction time for the occurrence of both LLPS and polymorphic nucleation were evaluated with respect to the various levels of supersaturation generated within the solution. Furthermore, the preferred conditions for the occurrence of LLPS and the polymorphic nucleation were precisely mapped by constructing a phase diagram with the different crystallization parameters involved, which clearly revealed that the nucleation of only form-I of the polymorph occurred in the acetonitrile-rich compositions (≥0.58A) without LLPS and form-II occurred in the water-rich compositions (≥0.92W), mostly in the presence of micro-level LLPS in the solution. Whereas, in the intermediate compositions, LLPS occurred at micro and macro levels between the mixed compositions 0.92W : 0.08A and 0.42W : 0.58A, which completely prevented the nucleation of the aspirin polymorphs. The thermal stability and unit cell structures of the grown polymorphs were confirmed through differential scanning calorimetry, and powder and single-crystal X-ray diffraction analyses.