Harnessing Supramolecular Self-Assembly of Ethionamide and Sorbic Acid through Cocrystallization: A Promising Alternative for Tuberculosis Treatment

Tuberculosis (TB) treatment, particularly against drug-resistant strains, is significantly hindered by the poor aqueous solubility and pronounced adverse effects of second-line drugs such as ethionamide (ETH). This study presents the successful development of a novel pharmaceutical cocrystal of ETH with sorbic acid (SA), which is designed to overcome these critical limitations. The ETH-SA cocrystal, synthesized via slow solvent evaporation and characterized by single-crystal X-ray diffraction, crystallizes in the monoclinic system within the P21/n-space group. Structural analysis reveals a primary O–H···N hydrogen bond (distance = 1.848 Å, angle = 174.20°) between the carboxylic acid group of SA and the pyridinic nitrogen of ETH, forming a stable 1:1 supramolecular heterosynthon, further stabilized by C–H···O contacts and π–π stacking interactions. Hirshfeld surface and void analyses quantified the intermolecular contacts, revealing efficient molecular packing with a low void volume (10.6%). Thermal analyses demonstrated thermal stability up to 384 K, with a melting point at 393 K, significantly higher than that of previously reported ETH solid dispersions, attributed to the hydrogen bonding lattice in the supramolecular structure. Periodic density functional theory (DFT) calculations provided insights into the electronic structure, revealing an energy band gap of 2.06 eV. The experimental Raman spectrum showed excellent agreement with the theoretical predictions. Dissolution studies demonstrated a substantial 2.75-fold enhancement in the aqueous solubility of the ETH-SA cocrystal compared to pure ETH, representing a significant improvement over earlier related ETH formulations. In silico absorption, distribution, metabolism, and excretion data confirmed that the cocrystal retains favorable pharmacokinetic and drug-likeness profiles while maintaining the therapeutic activity of ETH. These results establish the ETH-SA cocrystal as a promising pharmaceutical strategy with optimized physicochemical properties for enhanced therapeutic efficacy and improved patient compliance in TB treatment.