A new coamorphous ethionamide with enhanced solubility: Preparation, characterization, in silico pharmacokinetics,...

This study reports the synthesis and the experimental-theoretical characterization of a new coamorphous system consisting of ethionamide (ETH) and mandelic acid (MND) as a coformer. The solid dispersion was synthesized using the slow solvent evaporation method in an ethanolic medium. The structural, vibrational, and thermal properties of the system were characterized. Density functional theory (DFT) calculations were performed to analyze the interactions between ETH and MND in the heterodimer. These results contributed to the suitable assignment of infrared (IR) vibrational modes, to determine the chemical reactivity descriptors and the electronic indices of each component of the molecule. Additionally, Hirshfeld surfaces analysis and calculations of absorption, distribution, metabolism, and excretion (ADME) parameters were performed to examine intermolecular interactions and predict the in silico pharmacokinetic profile of the ETH-MND compound and its forming molecules. Powder X-ray diffraction data confirmed the formation of a coamorphous binary system in the 1:2 and 1:3 ETH and MND ratios. Furthermore, the ETH-MND (1:3) solid dispersion remained amorphous for up to 150 days when stored at 38 °C and 75 % relative humidity. DFT calculations, conducted both in vacuum and in ethanol, indicated that the formation of the coamorphous system is driven by hydrogen bonding between the NH₂ groups of ETH and the C=O group of MND. Thermodynamic analysis showed that intermolecular interactions are favored in the gas phase, with Gibbs free energy of -3.20 kcal/mol. The IR spectra showed a correlation between experimental and calculated data. Thermal analyses revealed glass transition temperatures of 59 °C (1:2 ratio) and 61 °C (1:3 ratio), indicating thermal stability of the coamorphous materials. Additionally, dissolution tests showed a 3.58-fold increase in the solubility of ETH compared to its crystalline form. The encapsulation of ETH-MND coamorphous systems in sodium alginate spheres via polyelectrolyte complexation was also investigated, demonstrating significant controlled drug release over 480 min.