Taking advantage of solvate formation to modulate drug-drug ratio in clofaziminium diclofenac salts

Non-steroidal anti-inflammatory drugs, such as diclofenac, are gaining attention as repurposed compounds for the treatment of multi-drug resistant tuberculosis. In this study, salts combining diclofenac with clofazimine, are prepared by solvent crystallization and by liquid-assisted grinding. Diclofenac anion possesses an H-bond acceptor which can strongly interact with protic solvent molecules. In this context, selected solvents (protic, aprotic and solvents with increasing molecular volume) are screened in order to investigate solvent impact on crystallization of solvated or unsolvated salt of clofazimine with diclofenac in 1 : 1 ratio. Five solvated salts and one unsolvated salt were successfully crystallized. The ability of the diclofenac anion to interact with a protic molecule is also exploited in order to crystallize a cocrystal of salt with drug : drug ratio different from 1 : 1. Structures of two solvated cocrystal of salts (with acetonitrile and ethylacetate) and two polymorphs of an unsolvated cocrystal of salt combining clofazimine with diclofenac in 1 : 2 ratios are determined.