Solvent dependent 4-aminosalicylic acid-sulfamethazine co-crystal polymorph control.

Abstract Despite polymorphism of crystalline active pharmaceutical ingredients (APIs) being a common phenomenon, reports on polymorphic co-crystals are limited. As polymorphism can vastly affect API properties, controlling polymorph generation is crucial. Control of the polymorph nucleation through the use of different solvents during solution crystallization has been used to obtain a desirable crystal polymorph. There have been two reported polymorphic forms of the 4-aminosalicylic acid-sulfamethazine co-crystals. These forms were found to have different thermodynamic stabilities. However, the control of co-crystal polymorph generation using preparation parameter manipulation has never been reported. The aim of this study was to establish the effect of different solvent parameters on the formation of different co-crystal polymorphic forms. Selection of the solvents was based on Hansen Solubility Parameters (HSPs) as solvents with different solubility parameters are likely to interact differently with APIs, ultimately affecting co-crystallization. Eight solvents with different HSPs were used to prepare co-crystals by solvent evaporation at two different temperatures. Through characterization of the co-crystals, a new polymorph has been obtained. The hydrogen bond acceptability seemed to affect the co-crystal form obtained more than the hydrogen bond donation ability. Furthermore, the use of HSPs can be utilized as an easy calculation method in screening and design of co-crystals.