Síntese, caracterização e estudos computacionais do fármaco etionamida e suas dispersões sólidas com ácido mandélico e ácido ftálico

Abstract

This work presents the structural, spectroscopic, thermal, and computational investigation of different solid systems involving Ethionamide (ETH), a second-line drug widely used in the treatment of multidrug-resistant tuberculosis (MDR-TB), whose low solubility limits its bioavailability. Three distinct approaches were studied: the pure crystalline form of ETH, the coamorphous ETH–Mandelic Acid (MAD) system, and the pharmaceutical salt ETH–Phthalic Acid (PHT), with the aim of understanding and optimizing their physicochemical and biopharmaceutical properties. The compounds were obtained using the slow solvent evaporation method in different media (methanol and ethanol) and characterized by X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) spectroscopy, Raman spectroscopy, thermal analyses, density functional theory (DFT) calculations, and Hirshfeld surface analyses. The crystalline form of ETH exhibited a monoclinic system (space group C1c1) stabilized mainly by H⋯H and H⋯S/S⋯H contacts, with dispersion energy accounting for approximately 60% of the total stabilization. Thermal analysis indicated stability up to 162 °C, and DFT calculations revealed a high electronic gap(HOMO–LUMO) (7.84–8.09 eV), supporting its low reactivity. The study of the coamorphous ETH–MAD system, prepared in 1:2 and 1:3 ratios, demonstrated the formation of an amorphous phase stabilized by hydrogen bonds between the NH2 groups of ETH and the C=O groups of MAD. The solid dispersions exhibited glass transition temperatures of 59 °C (1:2 ratio) and 61 °C (1:3 ratio), indicating good stability in the amorphous phase. In addition, the amorphous ETH–MAD (1:3) system remained stable in the amorphous state for up to 150 days. Dissolution tests showed a 3.58-fold increase in the solubility of ETH in the coamorphous system compared to the crystalline form, as well as controlled drug release when encapsulated in sodium alginate beads. The pharmaceutical salt ETH–PHT was obtained as a triclinic crystalline system (space group P1̅), stabilized by a strong N–H+···O− hydrogen bond (d = 1.742 Å). Thermal analyses revealed stability up to approximately 339 K, with endothermic events characteristic of melting and decomposition. Electronic analysis showed a direct band gap of 1.58 eV, indicating higher conductivity and enhanced pharmacological potential. Furthermore, periodic DFT calculations demonstrated the thermodynamic stability of the salt, with entropy increasing to 2192 kJ/mol·K and enthalpy to 957 kJ/mol at 1000 K, while the Gibbs free energy decreased, suggesting spontaneous phase reorganization. Dissolution studies under physiological pH (6.8; 37 °C) showed solubility 2.44 times greater than pure ETH (1.01 mg/mL versus 0.41 mg/mL). The results demonstrate that solid-state modifications of Ethionamide, through the formation of coamorphous systems and pharmaceutical salts, significantly enhance solubility, thermal stability, and controlled-release properties. Such advances reinforce the potential of these approaches as effective strategies for the development of optimized formulations aimed at treating multidrug-resistant tuberculosis.