Interaction of hydrochlorothiazide with beta-cyclodextrin

ABSTRACT

Interaction of hydrochlorothiazide with beta-cyclodextrin was investigated by spectrophotometry, vapor pressure osmometry and differential scanning calorimetry. The results revealed a very strong evidence for molecular interaction between hydrochlorothiazide and cyclodextrin. The continuous variation method was utilized to elucidate the stoichiometry of molecular interaction via spectrophotometric as well as vapor pressure measurements. Both types of data are in full agreement and revealed the formation of 11 complex. The stability constant of the complex was determined at different temperatures by the vapor pressure osmometric method. The complex was found to undergo partial dissociation with increasing temperature above 25C and more or less complete dissociation at 60C. The apparent solubility of the drug in presence of beta-cyclodextrin was found to increase to a marked extent. The amount of drug solubilized in the form of complex was determined and the results revealed that the solubilizing effect of beta-cyclodextrin is entirely due to complex-formation. The dissolution profiles of the drug, physical mixture of the drug and beta-cyclodextrin as well as the prepared complex showed an enhancement of drug dissolution from the prepared complex or the physical mixture compared to the drug per se. The effect of beta-cyclodextrin on the bioavailability of hydrochlorothiazide was determined by quantifying the diuretic effect of the drug in healthy human volunteers. The data revealed that, coadministration of the drug with beta-cyclodextrin either in the form of physical mixture or complex leads to an increase in the diuretic response intensity and there is a good correlation between the in vivo performance of the drug and its dissolution rate determined according to the USP rotating basket method: