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<p>This study investigated the solubility of ketoconazole in binary mixtures of ethyl acetate and ethanol within the temperature range of 298.2–323.2&#xa0;K using the shake-flask method and spectrophotometry at 246&#xa0;nm. Solubility was determined at six temperatures and across solvent mass fractions (0.0–1.0). The highest solubility, 0.941 (± 0.009)&#xa0;mol·L<sup>−1</sup>, occurred at 323.2&#xa0;K with an ethyl acetate mass fraction of 0.6, while the lowest, 0.147 (± 0.003)&#xa0;mol·L<sup>−1</sup>, was observed in pure ethanol at 298.2&#xa0;K. Results confirmed that both temperature rise and ethyl acetate enrichment enhanced solubility. For instance, at a 0.6 mass fraction of ethyl acetate, solubility increased from 0.633 (± 0.011)&#xa0;mol·L<sup>−1</sup> at 298.2&#xa0;K to 0.941 (± 0.009)&#xa0;mol·L<sup>−1</sup> at 323.2&#xa0;K, demonstrating the synergistic influence of temperature and solvent composition. Thermodynamic analysis revealed positive enthalpy values (12.60 (± 0.30)–27.55 (± 1.08)&#xa0;kJ·mol<sup>−1</sup>), indicating an endothermic dissolution. Gibbs free energy values (Δ<i>G°</i>) were positive across all conditions, suggesting non-spontaneity, while entropy ranged from 0.039 (± 0.001) to 0.077 (± 0.003)&#xa0;kJ·mol<sup>−1</sup>·K<sup>−1</sup>, reflecting increased disorder. Ethyl acetate-rich environments showed comparatively more favorable dissolution behavior. Mathematical modeling demonstrated that the Buchowski–Ksiazczak (<i>λh</i>) and van’t Hoff models provided the highest accuracy with <i>MRDs%</i> of 1.3% and 1.5%, respectively. The CNIBS/R–K model (7.2%) and Jouyban–Acree models (7.8%) showed acceptable performance, whereas the modified Wilson and Yalkowsky equation model was least accurate (20.8% and 32.54%, respectively). Overall, ethyl acetate significantly enhanced ketoconazole solubility, and reliable predictive models were identified. These findings highlight cosolvency as an effective approach for improving poorly soluble drugs, supporting pharmaceutical formulation design and drug delivery optimization.</p>

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Ketoconazole Solubility in Ethyl Acetate + Ethanol Mixtures at T = (298.2 to 323.2) K: Experimental Measurement, Thermodynamic Analysis, and Mathematical Modeling

  • 期刊论文

  • 发表日期：

    2026年6月1日

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  • Forough Dorostkar,
  • Sonia Abbasloo,
  • Seyyed Mohammad Hassan Hashemi,
  • Fleming Martinez,
  • Sepideh Ketabi,
  • Esmaeil Mohammadian

摘要

This study investigated the solubility of ketoconazole in binary mixtures of ethyl acetate and ethanol within the temperature range of 298.2–323.2 K using the shake-flask method and spectrophotometry at 246 nm. Solubility was determined at six temperatures and across solvent mass fractions (0.0–1.0). The highest solubility, 0.941 (± 0.009) mol·L−1, occurred at 323.2 K with an ethyl acetate mass fraction of 0.6, while the lowest, 0.147 (± 0.003) mol·L−1, was observed in pure ethanol at 298.2 K. Results confirmed that both temperature rise and ethyl acetate enrichment enhanced solubility. For instance, at a 0.6 mass fraction of ethyl acetate, solubility increased from 0.633 (± 0.011) mol·L−1 at 298.2 K to 0.941 (± 0.009) mol·L−1 at 323.2 K, demonstrating the synergistic influence of temperature and solvent composition. Thermodynamic analysis revealed positive enthalpy values (12.60 (± 0.30)–27.55 (± 1.08) kJ·mol−1), indicating an endothermic dissolution. Gibbs free energy values (ΔG°) were positive across all conditions, suggesting non-spontaneity, while entropy ranged from 0.039 (± 0.001) to 0.077 (± 0.003) kJ·mol−1·K−1, reflecting increased disorder. Ethyl acetate-rich environments showed comparatively more favorable dissolution behavior. Mathematical modeling demonstrated that the Buchowski–Ksiazczak (λh) and van’t Hoff models provided the highest accuracy with MRDs% of 1.3% and 1.5%, respectively. The CNIBS/R–K model (7.2%) and Jouyban–Acree models (7.8%) showed acceptable performance, whereas the modified Wilson and Yalkowsky equation model was least accurate (20.8% and 32.54%, respectively). Overall, ethyl acetate significantly enhanced ketoconazole solubility, and reliable predictive models were identified. These findings highlight cosolvency as an effective approach for improving poorly soluble drugs, supporting pharmaceutical formulation design and drug delivery optimization.