Research on the Diclofenac Dissolution Process: Solubility Determination, Model Correlation, Solvent Effect, and Solvation Behavior Analysis

Solubility still plays an important role in the field of drug development, purification, absorption, and delivery. In this work, the diclofenac (DIC) solubility in 1,4-dioxane, acetone, 2-butanone, acetonitrile, ethyl acetate, cyclohexane, methanol, ethanol, 1-propanol, 1-butanol, 2-propanol, water, and ethanol/acetone + water was determined using the isothermal saturation method at 278.15–318.15 K. The solubility regularity, solvent effect, solvation behavior, and model correlation were discussed. DIC solubility increased with rising temperature and exhibited different rates of increase in various solvents (or cosolvent compositions). The analysis indicated that DIC solubility showed a strong dependence on the solvent polarity, cohesive energy density, and viscosity. The solvent effect quantified by the Kamlet and Taft linear solvation energy relationship (KAT-LSER) model suggested that the contributions were 57.80 and 42.20% from solute–solvent interactions and solvent–solvent interactions, respectively. Thus, hydrogen bond acceptor (HBA) interactions and nonspecific dipolarity and polarizability dominated DIC dissolution. Afterward, solvation behavior analysis revealed positive δ values, suggesting that local ethanol/acetone was enriched around the DIC molecules. This demonstrates that DIC was preferentially solvated locally by ethanol/acetone. Additionally, model correlation revealed that the highest observed relative average deviation and root-mean-square deviation were 3.10% and 2.91 × 10–4, respectively. Consequently, the Apelbat, λh, Jouyban–Acree, and Apelbat–Jouyban–Acree models can accurately correlate the DIC solubility data.