Co-crystallization offered a promising strategy to improve the physicochemical and pharmacological properties of active pharmaceutical ingredients (APIs). Metformin, a first-line antidiabetic, suffers from gastrointestinal issues and limited bioavailability, while hesperetin, a flavonoid with antioxidant potential, exhibits poor water solubility. Designing metformin and hesperetin co-crystals could provide synergistic benefits in molecular stability and overall pharmacological performance. Here, we investigated the potential for metformin-hesperetin co-crystal formation using a combined computational approach. Molecular docking with AutoDock Vina identified stable poses driven by hydrogen bonding between the amine and hydroxyl groups of the two molecules. Subsequent DFT calculations, employing ORCA with the B3LYP/def2-SVP basis set, optimized three independent complexes, confirming key O...H (~2.1 Å) and H...N (~1.8 Å) hydrogen bonds with near-linear geometries (>140°). Analysis of electron density (ρ = 0.0179-0.0770 a.u.) and Laplacian values (∇²ρ = 0.053-0.101 a.u.) at bond critical points indicated strong closed-shell interactions, and an average binding energy of ΔE ≈ -63 kcal/mol suggests thermodynamic stability. These results provide strong theoretical support for the formation of a stable metformin-hesperetin co-crystal, laying a computational groundwork for future experimental validation and rational drug design.
