Co-crystal and salt forms of an imidazopyridazine antimalarial drug lead.

Co-crystallization and salt formation were employed to produce new multi-component forms of a novel antimalarial imidazopyridazine drug lead (MMV652103) that displayed improved physicochemical properties. The drug lead had earlier shown good in vitro potency against multidrug resistant (K1) and sensitive (NF54) strains of the human malaria parasite Plasmodium falciparum, and high in vivo efficacy in both Plasmodium berghei and Plasmodium falciparum mouse models. A major drawback of MMV652103 is its limited aqueous solubility. Various new supramolecular products, including several multi-component solid forms, are reported here, namely three co-crystal forms with the dicarboxylic acid coformers adipic acid, glutaric acid and fumaric acid, and a salt form with malonic acid. These were characterized by thermal methods and their structures elucidated by single crystal X-ray diffraction. A customised solubility experiment was performed in fasted state simulated intestinal fluid for comparison of the solubility behavior of each new form of the drug lead with that of the untreated starting material. All of the multi-component forms showed an improvement in the maximum concentrations (Cmax ) attained by the drug lead and the rate at which it dissolved. The recorded Cmax values exceeded the concentration of the untreated compound by factors in the range 4.6 - 5.6.