Abstract
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 & apos;t Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy Delta H-sol degrees, entropy Delta S-sol degrees, and Gibbs free energy Delta(sol)G degrees). 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 x 10(-1)) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 x 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 Delta H-sol degrees and Delta(sol)G degrees. Interestingly, Delta(sol)G degrees 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 Delta(sol)G degrees and Delta S-sol degrees 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.