Solvatochromism and Preferential Solvation of Isoxicam in Pure Solvents and Binary Aqueous Mixtures: Experimental and Molecular Modeling Study

The solvatochromic characteristics of isoxicam (ISOX) were investigated in pure solvents and binary aqueous–organic mixtures. The spectral shifts of this drug in pure solvents were correlated with Catalán and Kamlet–Taft parameters using linear solvation energy relationships. The multiparametric analysis indicates that solvent polarity and hydrogen bond donor capacity have the greatest influence on the wavenumber position of ISOX. The maximum absorption wavelengths calculated using TD‐DFT methods showed good agreement with the experimental values, except in water and DMF. Inclusion of explicit solvent effects through molecular dynamics simulations combined with ONIOM/TD‐DFT calculations improved the accuracy. The molecular orbitals involved in these electronic transitions are HOMO–LUMO with a π→π* character mixed with intra‐ligand charge transfer. Preferential solvation of ISOX was detected in seven aqueous–organic mixtures. In methanol, ethanol, and dimethylsulfoxide aqueous systems, the data followed a sigmoidal curve, with an initial positive deviation followed by a negative deviation. In 2‐propanol and 1,4‐dioxane aqueous mixtures, the deviations were positive; whereas in dimethylformamide and acetonitrile solutions, the deviations were negative, with synergism observed in acetonitrile–water and 1,4‐dioxane–water mixtures. A multiparametric analysis was also performed on the maximum absorption wavelength of ISOX in binary mixtures, showing that the solvatochromism vary depending on the co‐solvent used.