Enhancement of aqueous solubility of itraconazole by complexation with cyclodextrins using supercritical carbon dioxide

Abstract

The formation of inclusion complexes between itraconazole, a highly hydrophobic drug, and α-, β-, γ-, and hydroxylpropyl-β-cyclodextrin (HP-β-CD) were assessed using phase-solubility techniques. The solubility of itraconazole 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 in magnitude with increasing cyclodextrin concentration. The solubility of itraconazole, as well as the stability constant of its complex with HP-β-CD, are found to be affected by the pH of the medium. The HP-β-CD cavity was found to have a greater affinity for the unionized itraconazole than the protonated one. It was found that the interaction between the drug and the cyclodextrin is weakened as the medium becomes more apolar by the addition of methanol. Also, the size of the cavity of the cyclodextrins plays an important role in the association process. Furthermore, the thermodynamic parameters of the complexation process were calculated, by monitoring the isothermic solubility diagrams of itraconazole–HP-β-CD and itraconazole–β-CD at various temperatures, to gain information on the driving forces for the formation of inclusion complexes. Drug formulations of itraconazole were prepared by complexation of the drug into different cyclodextrins using supercritical carbon dioxide in a static mode. The effects of cyclodextrins on the prepared inclusion complexes were studied and characterized by differential scanning calorimetry.Key words: cyclodextrin, itraconazole, inclusion complex, solubility, stability constant.