Solubility of Tetracycline in Aqueous Media Using 1,4-Dioxane as Cosolvent: Correlation, Dissolution Thermodynamics and Preferential Solvation

Tetracycline is a first-line antibiotic used to treat various infections. Given its widespread use in human and veterinary medicine, it is a potentially hazardous emerging contaminant. This study aimed to perform a thermodynamic and preferential solvation analysis of tetracycline in 1,4-dioxane and water cosolvent mixtures. Equilibrium solubility was determined via UV/vis spectrophotometry using the shaking-flask method at temperatures ranging from T/K = 278.15 to T/K = 313.15. Apparent thermodynamic functions were calculated using van’t Hoff and Gibbs equations. Preferential solvation was evaluated using inverse Kirkwood-Buff integrals (IKBI). The results show that solubility increases with temperature and 1,4-dioxane concentration increases. The process is endothermic throughout the system; however, the enthalpy-entropy compensation analysis demonstrates an entropy-driven mechanism for drug transfer from more polar to less polar solvent systems. IKBI analysis confirmed preferential solvation by 1,4-dioxane in all cosolvent mixtures, peaking at a mole fraction of 0.55. 1,4-Dioxane increases solubility by mitigating the large solvent-excluded volume effect characteristic of pure water. This relieves the entropic penalty associated with cavity creation for the bulky drug molecule, while simultaneously promoting favorable specific interactions where tetracycline acts as a Lewis acid toward 1,4-dioxane oxygen atoms.