Isoniazid–Saccharin Salts: Synthesis, Structural Aspects, Thermal Properties and Spectroscopic Characterization

This investigation focused on isoniazid (INH)—saccharin (SAC) salts. One hydrate and one anhydrous INH-SAC salt form were synthesized and characterized spectroscopically by Raman and infrared spectroscopy. Solvent (methanol, acetone, acetonitrile)-assisted synthesis in the presence of water, or in water, resulted in production of the monohydrated form of the salt (MH: (INH+H)+/(SAC–H)−.H2O). The anhydrous form (A: (INH+H)+/(SAC–H)−) was obtained using the same synthesis method but in the absence of water or, together with the hydrate, in the presence of traces of water. Differential scanning calorimetry studies revealed that the hydrate can be converted into the anhydrous form of the salt upon heating, with the latter melting at a Tm (onset) of 131.7 ± 0.5 °C. Melting was followed by a reaction between isoniazid and saccharin leading to saccharin ring opening and formation of a new covalent hydrazide–amide derivative, via nucleophilic acyl substitution at the saccharin carbonyl. The newly formed adduct, 2-[2-(pyridine-4-carbonyl)hydrazine-1-carbonyl] benzene-1-sulfonamide, melts at Tm (onset) = 204.4 ± 0.5 °C. The crystal structures of the hydrate and of the anhydrous form were determined by single-crystal X-ray diffraction, and the dominant intermolecular interactions in the crystalline INH-SAC salts were evaluated using Hirshfeld surface analysis. To complement the experimental results, density functional theory (DFT) calculations were performed both on relevant isolated structural units and on the two salts, employing fully periodic DFT methods.