Experimental and computational analyses for elucidation of structural, electronic, thermal, and vibrational properties of ethionamide crystal

Ethionamide (ETH) is a second-line drug widely used to treat multidrug-resistant tuberculosis (MDR-TB), but its low aqueous solubility compromises bioavailability and limits its therapeutic efficacy. To understand the ways to improve these properties, we combined experimental and computational approaches to elucidate the structural, electronic, thermal, and vibrational properties of ETH crystals. Powder X-ray diffraction analysis revealed a monoclinic crystal system (C1c1-space group), stabilized by intermolecular interactions, primarily H⋯H (49.3%) and H⋯S/S⋯H (22.1%) contacts. Energy framework analysis revealed the anisotropic nature of intermolecular interactions, with dispersion forces accounting for approximately 60% of the total stabilization energy, while Coulombic interactions showed significant directionality along the crystallographic a-axis and within the bc-plane. The total energy framework indicated that the strongest stabilization propagates along the b-axis, suggesting the formation of highly stable molecular chains, which directly influence crystal morphology and dissolution behavior. Thermal analysis confirmed ETH stability up to 162.2 °C, with melting and decomposition events characterized by endothermic peaks. Density functional theory (DFT) calculations confirmed ETH high electronic gap (7.84–8.09 eV), indicating low reactivity, while solvation studies highlighted its greater stability in polar solvents like water and methanol. Theoretical nuclear magnetic resonance studies (1H and13C) showed minimal solvent influence on chemical shifts, reinforcing the structural stability of ETH across environments. Vibrational spectroscopy, supported by DFT, identified key modes associated with the pyridine ring, NH2, and C=S groups. Hirshfeld surface analysis further revealed the dominance of hydrogen bonds and van der Waals interactions, with minimal void space (5.3%) in the crystal lattice. Electrostatic potential maps identified electron-rich regions around nitrogen atoms as potential sites for hydrogen bonding and protonation, which are relevant for pharmacological interactions. These findings offer critical insights for optimizing ETH’s solid-state properties to enhance its solubility and bioavailability, paving the way for improved formulations against MDR-TB.