Supramolecular synthesis and thermochemical investigations of pharmaceutical inorganic isoniazid salts

Abstract

In multiple-drug therapy, isoniazid (INH) is considered one of the most important antibiotics for the treatment of tuberculosis. Beyond its pharmacological importance, INH is also a versatile compound that can be combined with several other molecules to produce salts and co-crystals. In this study, novel salts of INH, obtained from the reaction with pharmaceutically accepted inorganic acids (HBr, HNO3 and H2SO4), were investigated. The reaction of INH with H2SO4, gives rise to two forms: an INH sulfate and an INH sulfate hemihydrate salt. The four salts feature a supramolecular assembly quite different from the one described for INH hydrochloride. INH hydrobromide and INH nitrate adopt a head-to-tail assembly, where the cations (INH+) are directly connected to each other. However, this is not the case for the sulfate forms, where the cations appear surrounded by the anions, being connected to them through their pyridinium and hydrazide groups. Interestingly, an unexpected homodimer is observed in the INH sulfate salt. Hirshfeld surface analysis was used to highlight and quantify the contributions of the main interactions. The relative thermal stability of these salts was studied by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and hot-stage microscopy (HSM). Although the melting points of both sulfate forms are practically the same, the four INH salts have distinct thermal profiles.