Inclusion complexes of hydrochlorothiazide and β-cyclodextrin: Physicochemical characteristics, in vitro and in vivo studies

Abstract

Hydrochlorothiazide is a thiazide diuretic widely used in clinics to treat arterial hypertension. It is a class IV drug according to the Biopharmaceutical Classification System, that is, it presents low solubility and low permeability and, consequently, low absorption in the gastrointestinal tract. As a strategy to improve stability and biopharmaceutical properties of hydrochlorothiazide, the use of cyclodextrins to produce inclusion complexes, applying different methods, was investigated. In the phase solubility studies, β-cyclodextrin was identified as the cyclodextrin which provided the most promising results in terms of the solubilization of the drug. The thermal analysis verified the interaction between hydrochlorothiazide and β-cyclodextrin, indicating the formation of inclusion complexes, and the thermal stability varied according to the preparation technique. The physicochemical characterization showed that in the inclusion complexes obtained by co-evaporation, kneading followed by freeze-drying and kneading followed by spray-drying the hydrochlorothiazide complexation mostly occurred with different degrees of amorphization and the drug solubility was improved. These three inclusion complexes presented better in vitro characteristics and the inclusion complex obtained by kneading followed by freeze-drying increased the in vivo diuretic activity of the drug accompanied by significant effects on natriuresis, kaliuresis and chloriuresis. The inclusion complex formation was effective in improving the biopharmaceutical properties of hydrochlorothiazide and protecting the drug from hydrolysis. This paper describes an important alternative approach to the development of liquid pharmaceutical formulations to pediatric administration, a real need of the current pharmaceutical market.