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This study reports the synthesis and comprehensive characterization of a novel ethionamide (ETH) and phthalic acid (PHT) pharmaceutical salt (ETH-PHT), designed to enhance the ETH dissolution profile for improved tuberculosis treatment. This new solid dispersion was prepared via slow evaporation in methanol and thoroughly characterized using single-crystal X-ray diffraction (XRD), Hirshfeld surface analysis, density functional theory (DFT) calculations, thermal measurements, and infrared (IR) and Raman spectroscopy. Structural analysis confirmed the formation of a salt stabilized by a strong N–H+···O– hydrogen bonding (d = 1.742 Å). XRD data revealed a triclinic crystal system with the P1̅(Ci)-space group, with two ETH and two PHT molecules per unit cell (Z = 2). Hirshfeld surface analysis identified dominant intermolecular interactions, with H···H (71.5%) and H···O/O···H (19.5%) contacts determining crystal packing. Crystal void analysis showed an 11.11% void volume (88.19 Å3), indicating potential for physicochemical property modulation. DFT-periodic calculations revealed the salt’s thermodynamic stability, with entropy increasing to 2192 kJ/mol·K and enthalpy to 957 kJ/mol at 1000 K, while Gibbs free energy decreased, suggesting spontaneous phase reorganization. Electronic structure analysis via DFT revealed a direct band gap of 1.58 eV, with p-orbital hybridization dominating near the Fermi level. Thermoanalytical measurements indicated that the salt remains stable up to approximately 339 K, exhibiting endothermic events characteristic of the melting (9.73 kJ/mol) and decomposition (290.83 kJ/mol) processes. Furthermore, the experimental IR and Raman spectra showed full agreement with the theoretical predictions, enabling accurate assignment of the observed fundamental vibrational modes. Dissolution studies under simulated physiological conditions (pH 6.8, 37 °C) revealed that this new salt achieves 2.44-fold higher solubility (1.01 mg/mL) compared to pure ETH (0.41 mg/mL). This significant improvement can be attributed to modified lattice energy and enhanced hydrophilicity. These results establish the ethionamide-phthalate salt as a promising strategy to enhance the solubility of ETH, offering potential clinical advantages for tuberculosis treatment.
Bezerra et al. (Fri,) studied this question.