Thermodynamic evaluation of ibuprofen solubility in aqueous and non-aqueous cosolvent systems
Abstract
The purpose of this research was to investigate the mechanism of solubilization of a model drug, ibuprofen, in cosolvent-water mixtures by applying enthalpy-entropy compensation analysis. The solubility of ibuprofen in pure solvents decreased in the following order: DMSO > methanol > ethanol > isopropanol > n-propanol > PEG-200 > PG > water. The addition of ibuprofen to n-propanol-water mixtures, isopropanol-water mixtures and DMSO-water mixtures resulted in phase-separation. The increase in ibuprofen solubility in the binary cosolvent-water mixtures decreased in the following order: isopropanol-water mixtures > n-propanol-water mixtures > ethanol-water mixtures > methanol-water mixtures > PEG-water mixtures > PG-water mixtures. The solubility of ibuprofen in PG-ethanol mixtures decreased linearly as the amount of PG in the solvent mixture increased. The enthalpy of solution of ibuprofen in the solvent mixtures varied nonlinearly with solvent composition. In aqueous systems, the enthalpy of solution increased to a maximum and then decreased as the cosolvent mole fraction increased. The entropy of solution of ibuprofen showed similar trend as that of heat of solution. The maximum in enthalpy and entropy of solution appeared at the same cosolvent mole fraction. The free energy evaluated at the harmonic mean of experimental temperature decreased as the cosolvent mole fraction increased. At low cosolvent mole fraction, up to the maximum in enthalpy and entropy versus composition curves, the solubility of ibuprofen was entropy driven while beyond the peaks, the solubility of ibuprofen was enthalpy driven. For PG-ethanol system, a linear increase in both enthalpy and entropy of solution as a function of PG mole fraction was found. The mechanism of decrease in ibuprofen solubility was due to unfavorable increase in enthalpy of solution. Enthalpy-entropy compensation analysis, showed that a nonlinear compensation existed between enthalpy and entropy due to variation in solvent composition and not to propagation of experimental errors. The change in the slope of ΔH versus ΔGhm curves for aqueous systems indicated that two different mechanisms contribute to the solubility of ibuprofen depending on the nature of the solvent system. However, for PG-ethanol mixtures, no peak was observed in the ΔH versus ΔGhm plot suggesting that one mechanism is responsible for the decrease in ibuprofen solubility as the amount of PG was increased.
Degree
Ph.D.
Advisors
Kildsig, Purdue University.
Subject Area
Pharmaceuticals
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