Cyclodextrins as Enhancers of the Aqueous Solubility of the Anthelmintic Drug Mebendazole: Thermodynamic Considerations

Abstract

Inclusion complexes of mebendazole with α-, β-, and γ-cyclodextrins, hydroxylpropyl-β-cyclodextrin (HP-β-CD), and methyl-β-cyclodextrin (Me-β-CD) were investigated employing the Higuchi and Connors solubility method. The solubility of mebendazole increased as a function of cyclodextrin concentration showing an AL phase diagram indicating the formation of soluble complexes with 1:1 stoichiometry. The Gibbs free energies of transfer of the drug from aqueous solution to the cavity of cyclodextrin are negative and increase negatively with increasing cyclodextrin concentration. The solubility of mebendazole as well as the stability constant of its complex with Me-β-CD are found to be affected by the pH of the medium. The Me-β-CD cavity was found to have a greater affinity for the unionized mebendazole rather than the protonated one. Effects of methanol and temperature on these interactions were also investigated to gain further knowledge on the mechanism of the inclusion process. It was found that the interaction between the drug and the cyclodextrin is weakened as the medium becomes more apolar and the temperature increases. Moreover, the thermodynamic parameters for the binding were derived from the dependence of the stability constants on the temperature (van’t Hoff analysis). The formation of the inclusion complexes between the drug and β-CD or its derivatives was found to be enthalpy controlled, with |ΔH °| > T|ΔS °|. This suggests that hydrophobic and van der Waals interactions as well as solvent reorganization are the main driving forces. Furthermore, the size of the cavity of cyclodextrins plays an important role in the association process.