Enhancing the Solubility of Metronidazole Using Deep Eutectic Solvents: A Computational Insight Into a Green Formulation Strategy

This study investigates the potential of choline chloride–propylene glycol (CHL-PG) deep eutectic solvents (DES) to enhance the solubility of metronidazole (MNZ), a widely used but poorly water-soluble antimicrobial drug via computational modeling approach. Density functional theory (DFT) with the ωB97X-D functional and 6-31G(D) [3-21G(*)] dual basis set in Spartan software was used, various interactions and configurations of CHL and PG were modeled to identify the most stable DES formation pathways. HOMO–LUMO energy gaps were evaluated to determine component stability, while solubility strength was obtained using binding energy calculations of MNZ in the DES and water. Finding from our study indicates that the CHL–PG system feasibly formed a stable DES through a dual hydrogen-bonding pathway involving H₂CO–HOCH₂ and NCl–HOCH, which exhibited a formation energy of − 1.50 to − 1.51 eV, making it the most favorable route among all pathways evaluated. MNZ demonstrated significantly higher solubility in the formed DES, with a solubility strength of − 0.93 eV, compared to − 0.50 eV in water, indicating solubility enhancement potential. The narrow HOMO–LUMO gap in the DES further supports its molecular reactivity and suitability for pharmaceutical applications. These findings highlight the feasibility of CHL-PG as a green and effective solubilizing medium for MNZ providing insight to guide the design of DES-based drug formulations as alternative to conventional solvent in pharmaceutical development.