Thermodynamic, Computational Solubility Parameters in Organic Solvents and In Silico GastroPlus Based Prediction of Ketoconazole

Publication: ACS Omega


The study aimed to select a suitable solvent capable to solubilize ketoconazole (KETO) and serve as a permeation enhancer across the skin. Experimental solubility and Hansen solubility parameters were obtained in ethanol, dimethyl sulfoxide (DMSO), ethylene glycol, oleic acid, span 80, limonene, eugenol, transcutol (THP), labrasol, and propylene glycol. Thermodynamic functional parameters and computational models (vanʼt Hoff and Apelblat) validated the determined solubility in various solvents at T = 298.2 K to 318.2 K and P = 0.1 MPa. The HSPiP software estimated the solubility parameters in the solvents. The maximum mole fractional solubility values of KETO were found to be in an order as oleic acid (8.5 × 10–3) > limonene (7.3 × 10–3) > span 80 (6.9 × 10–2) > THP (4.9 × 10–2) > eugenol (4.5 × 10–3) at T = 318.2 K. The results of the apparent thermodynamic analysis confirmed that the dissolution rate was endothermic and entropy driven. The GastroPlus program predicted significantly high permeation of KETO (79.1%) in human skin from the KETO-THP construct as compared to drug solution (38%) and excellent immediate release from THP-solubilized construct (90% < 1 h). Hence, THP could be a better option for topical, transdermal, and oral formulation.

By Sultan Alshehri, Afzal Hussain, Mohd Neyaz Ahsan, Raisuddin Ali, and Mohd Usman Mohd Siddique