How good are the crystallisation methods for co-crystals? A comparative study of piroxicam

Co-crystallisation of two components into one crystal form can enhance the solid-state properties of drug compounds. A plethora of crystallisation methods has been applied to co-crystallisation and the reported study compares the three most common ones (crystallisation from the melt, from solution and solvent-drop grinding) with respect to their applicability and necessity for a co-crystal screening. Piroxicam, a non-steroidal anti-inflammatory drug, was chosen as a model system and submitted to an extensive co-crystal screening using twenty different acids as co-crystal formers, six crystallisation techniques and five solvents. A total of 46 co-crystal forms were obtained, 38 of which are novel. Solvent-drop grinding showed the highest absolute number of experiments resulting in co-crystals, while crystallisation from the melt yielded the highest number of co-crystal formation when crystalline material was obtained. Evaporation resulted in a high number of crystalline products but many of those were binary and ternary mixtures of crystal forms. Cooling and precipitation techniques gave only poor results. Acetone and THF showed the highest number of crystalline products while chloroform gave the highest relative yield of co-crystals. Ethanol and acetonitrile showed extensive hydrate formation. No influence of the co-crystal former on the co-crystal formation could be detected.