A preformulation co-crystal screening case study: Polymorphic co-crystals of an imidazopyridazine antimalarial drug lead with the coformer succinic acid

Abstract

A crystal engineering approach combined with experimental screening methods was employed as a preformulation step for producing expectedly useful forms of a novel antimalarial drug lead (MMV652103). In previous experiments, this drug lead had shown promise both in vitro and in vivo against the human malaria parasite Plasmodium falciparum. Various new forms of MMV652103 were produced earlier, including co-crystals, a salt, polymorphs and a hydrated form and these were reported elsewhere. Three distinct new forms are reported here, of which two are conformational and synthon (2:1) co-crystal polymorphs produced with the coformer succinic acid, while the third is a co-crystal with a different stoichiometric ratio (1:1) of the same components. The crystal structures of the co-crystal polymorphs were elucidated by single-crystal X-ray diffraction. The different forms were also characterised by powder X-ray diffraction, Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, hot stage microscopy, differential thermal analysis, differential scanning calorimetry, thermogravimetric analysis and in some cases variable-temperature powder X-ray diffraction. It was determined that the polymorphs are monotropically related. Methods were developed to prepare each of these forms reproducibly and rapidly identify each form.