Ketoconazole Solubility in Polyethylene Glycol 600 + Water Mixtures at T = (298.2 to 323.2) K: Experimental Measurement, Thermodynamic Analysis, and Mathematical Modeling

Abstract

Ketoconazole is an antifungal agent effective against Candida spp., Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and dermatophytes. The low solubility of a drug in water has a very important impact on reduced absorption in the gastrointestinal tract, low bioavailability, the need for higher doses, delayed onset of action, limitations in administration routes, and its therapeutic potential. This study examined the solubility of ketoconazole in binary mixtures of polyethylene glycol 600 (PEG 600) and water over 298.2–323.2 K using the shake-flask method. Saturated concentrations were determined by UV spectrophotometry at 246 nm. Experimental solubility data were analyzed using several mathematical models, including Jouyban–Acree, van’t Hoff, CNIBS/R–K, Mixture Response Surface (MRS), and λh (Buchowski–Ksiazczak) equations, with mean relative deviation percentage (MRD%) as the accuracy metric. Results revealed a strong positive influence of both temperature and PEG 600 proportion on solubility. The maximum solubility was 5.06 (± 0.02) × 10⁻¹ mol·L⁻¹ in pure PEG 600 at 323.2 K, while the minimum was 4.25 (± 0.01) × 10⁻⁷ mol∙L⁻¹ in pure water at 298.2 K. At a PEG 600 mass fraction of 0.7, solubility increased from 6.14 (± 0.07) × 10⁻² mol∙L⁻¹ at 298.2 K to 1.14 (± 0.02) × 10⁻¹ mol∙L⁻¹ at 323.2 K. Thermodynamic parameters indicated dissolution as an endothermic process (ΔH° = 8.06–70.50 kJ∙mol⁻¹) with positive Gibbs free energy (ΔG° = 2.14–35.63 kJ∙mol⁻¹), signifying limited spontaneity in water-rich mixtures, but improved favorability with increasing PEG 600 content. Modeling analysis showed CNIBS/R–K as the most accurate (MRD% = 5.7), followed by van’t Hoff (3.0%), while MRS performed poorly (35.3%). Overall, these results provide valuable insight for optimizing ketoconazole formulations, emphasizing solvent composition and temperature as key determinants of dissolution behavior.

Graphical Abstract