Screening for polymorphs of cocrystals: a case study

Abstract

A comprehensive crystal form screen was performed on the phenazine:mesaconic acid system using a variety of techniques including solution based approaches, dry and liquid assisted grinding, thermal methods and sublimation. A novel approach to preparing pharmaceutical cocrystals involving crystallisation at a solvent–solvent interface was also employed, and produced a new thermodynamically stable polymorph of the anhydrous cocrystal. In total, three anhydrous polymorphs, a monohydrate and a DMSO solvate were obtained from the screen, and the crystal structures of Form II (the thermodynamically stable polymorph) and the hydrate were determined. Traditional solution based approaches to polymorphism screening were found to have limitations when applied to this cocrystal system due to differences in the solubilities of phenazine and mesaconic acid in many solvents. Furthermore, several cocrystal preparation methods were required in order to isolate all of the crystal forms that were identified during the study, confirming the need for a multi-technique approach when screening for polymorphs of cocrystals.