Experimental Solubility of Ketoconazole, Validation Models, and In vivo Prediction in Human Based on GastroPlus

The study aimed to identify a suitable cosolvent + water mixture for subcutaneous (sub-Q) delivery of ketoconazole (KETO). The solubility was assessed for several dimethyl acetamide (DMA) + water mixtures at T = 293.2 to 318.2 K and pressure P = 0.1 MPa. The experimental solubility (x_e) was validated using the Van 't Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy Δ_solH°, entropy Δ_solS°, and Gibbs free energy Δ_solG°). The in vitro drug release study was performed at physiological pH, and the data served as the input to GastroPlus, which predicted the in vivo performance of KETO dissolved in a DMA + water cosolvent mixture for sub-Q delivery in human. The maximum solubility (mole fraction) of KETO (9.81 × 10^-1) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 × 10^-5) was for pure water at 293.2 K. An apparent thermodynamic analysis based on x_e gave positive values for the functional parameters. KETO dissolution requires energy, as evidenced by the high positive values of Δ_solH° and Δ_solG°. Interestingly, Δ_solG° progressively decreased with increasing concentration of DMA in the DMA + water mixture, suggesting that the DMA-based molecular interaction improved the solubilization. Positive values of Δ_solG° and Δ_solS° for each DMA + water cosolvent mixture corroborated the endothermic and entropy-driven dissolution. GastroPlus predicted better absorption of KETO through sub-Q delivery than oral delivery. Hence, the DMA + water mixture may be a promising system for sub-Q delivery of KETO to control topical and systemic fungal infections.