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<p>This study investigated the solubility enhancement of minoxidil (a poorly water-soluble drug that belongs to BCS Class II) using 1-propanol + water mixtures through experimental measurement, thermodynamic evaluation, and mathematical modeling. Minoxidil, a peripheral vasodilator used in resistant hypertension and androgenic alopecia, suffers from low aqueous solubility, limiting its oral bioavailability and posing formulation challenges. Minoxidil solubility was experimentally determined using the shake-flask method in different mass fractions of 1-propanol and water across 298.2–318.2&#xa0;K, with UV analysis at 231&#xa0;nm. Dissolution rate studies confirmed equilibrium after 48&#xa0;h. It should be noted that all measurements were conducted in triplicate with <i>RSD</i>% below 5%. The maximum solubility was consistently observed at a 0.7 mass fraction of 1-propanol. This mass fraction represented the most thermodynamically favorable condition. Thermodynamic analysis indicated an endothermic and spontaneous solubility process, with enthalpy making a greater contribution than entropy (ζ<sub><i>TS</i></sub> &lt; ζ<sub><i>H</i></sub>). Positive slopes in Δ<i>H°</i>–Δ<i>G°</i> plots further emphasized enthalpy-driven solubility enhancement. Mathematical modeling was applied using various equations, including the van’t Hoff, Buchowski–Ksiazczak, modified Wilson, Jouyban–Acree, and Jouyban–Acree–van’t Hoff models. All models, except the Yalkowsky equation (average error 50.3%), successfully predicted minoxidil solubility in mixed solvents with good accuracy, with van’t Hoff and Buchowski models demonstrating superior predictive performance. Overall, the combination of experimental solubility measurement, thermodynamic interpretation, and modeling approaches provides valuable insights into solubilization behavior, supporting formulation development strategies for minoxidil and other poorly soluble drugs. These findings highlight cosolvency as an effective approach and mathematical models as reliable tools for predicting rapid solubility.</p>

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Increasing the solubility of minoxidil using a mixture of 1-propanol and water by the shake flask method: experimental measurements, thermodynamic analyses, and mathematical modeling

  • 期刊论文

  • 发表日期：

    2025年12月26日

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  • Esmaeil Mohammadian,
  • Amir Mohammad Ahmadi,
  • Mahmoud Omidi,
  • Fleming Martinez,
  • Seyyed Mohammad Hassan Hashemi

摘要

This study investigated the solubility enhancement of minoxidil (a poorly water-soluble drug that belongs to BCS Class II) using 1-propanol + water mixtures through experimental measurement, thermodynamic evaluation, and mathematical modeling. Minoxidil, a peripheral vasodilator used in resistant hypertension and androgenic alopecia, suffers from low aqueous solubility, limiting its oral bioavailability and posing formulation challenges. Minoxidil solubility was experimentally determined using the shake-flask method in different mass fractions of 1-propanol and water across 298.2–318.2 K, with UV analysis at 231 nm. Dissolution rate studies confirmed equilibrium after 48 h. It should be noted that all measurements were conducted in triplicate with RSD% below 5%. The maximum solubility was consistently observed at a 0.7 mass fraction of 1-propanol. This mass fraction represented the most thermodynamically favorable condition. Thermodynamic analysis indicated an endothermic and spontaneous solubility process, with enthalpy making a greater contribution than entropy (ζTS < ζH). Positive slopes in ΔH°–ΔG° plots further emphasized enthalpy-driven solubility enhancement. Mathematical modeling was applied using various equations, including the van’t Hoff, Buchowski–Ksiazczak, modified Wilson, Jouyban–Acree, and Jouyban–Acree–van’t Hoff models. All models, except the Yalkowsky equation (average error 50.3%), successfully predicted minoxidil solubility in mixed solvents with good accuracy, with van’t Hoff and Buchowski models demonstrating superior predictive performance. Overall, the combination of experimental solubility measurement, thermodynamic interpretation, and modeling approaches provides valuable insights into solubilization behavior, supporting formulation development strategies for minoxidil and other poorly soluble drugs. These findings highlight cosolvency as an effective approach and mathematical models as reliable tools for predicting rapid solubility.