Structural variety of clofaziminium salts: effect of the counter-ion on clofaziminium conformation and crystal packing

Abstract

Clofazimine is a water-insoluble antimycobacterial agent gaining attention as a treatment for multi-drug resistant and extensively drug-resistant tuberculosis. Novel salts of clofazimine are reported with fumaric, succinic, 2,4-dihydroxybenzoic and terephthalic acids and with saccharin. The salt structures were obtained by single-crystal X-ray diffraction. The salts with 2,4-dihydroxybenzoic acid and with saccharin are solvated (methanol and acetonitrile, respectively). The reaction of clofazimine with terephthalic acid led to two salt cocrystals, one solvated and one non-solvated. These new clofaziminium salts are compared with the currently known ones in terms of crystal packing and clofazimine/ium conformation. Clofaziminium hydrogen succinate presents isostructurality with clofaziminium hydrogen malonate, an already described salt. In the structure of clofaziminium terephthalate terephthalic acid salt cocrystal, solvent evaporation leads to packing and hydrogen-bonding modifications. In all the new structures, the clofaziminium conformation is quite well conserved and steric hindrance is observed around the protonated site. Conformational optimization of clofaziminium reveals that this steric-hindrance energy penalty is compensated for by hydrogen-bond interactions with the salt counter-ions.