Hydrochlorothiazide (HCT), a benzothiazide diuretic, is an ionizable acid (pKas of 8.75 and 9.88),

sparingly soluble in water and a chemically stable substance. Considering the poor water solubility of

sparingly soluble in water and a chemically stable substance. Considering the poor water solubility of

HCT, this compound has been complexed with s-cyclodextrin (s-CD). CDs are cyclic oligosaccharides

with hydrophilic outer surface and a somewhat lipophilic central cavity. In aqueous solutions CDs are

able to solubilize hydrophobic drugs by taking up some lipophilic moiety of the drug molecule into the

central cavity, i.e. through formation of hydrophilic inclusion complexes (1). CDs are known to form

nanosized aggregates in aqueous solutions and thus have the potential to develop into sophisticated drug

delivery systems. The largest aggregates are observed for s-CD, which can be up to several micrometers

in diameter. The anomalously low solubility of s-CD is explained by the intensity of aggregate formation,

which becomes notable at s-CD concentrations above 3mM and it interaction with the surrounding water

structure (2). In the present work, the complexation mechanism between s-CD and HCT has been

investigated by phase-solubility diagrams under various experimental conditions, with the aim to obtain a

wide range of information about the molecular interactions that drive the complexation process.

sparingly soluble in water and a chemically stable substance. Considering the poor water solubility of

HCT, this compound has been complexed with s-cyclodextrin (s-CD). CDs are cyclic oligosaccharides

with hydrophilic outer surface and a somewhat lipophilic central cavity. In aqueous solutions CDs are

able to solubilize hydrophobic drugs by taking up some lipophilic moiety of the drug molecule into the

central cavity, i.e. through formation of hydrophilic inclusion complexes (1). CDs are known to form

nanosized aggregates in aqueous solutions and thus have the potential to develop into sophisticated drug

delivery systems. The largest aggregates are observed for s-CD, which can be up to several micrometers

in diameter. The anomalously low solubility of s-CD is explained by the intensity of aggregate formation,

which becomes notable at s-CD concentrations above 3mM and it interaction with the surrounding water

structure (2). In the present work, the complexation mechanism between s-CD and HCT has been

investigated by phase-solubility diagrams under various experimental conditions, with the aim to obtain a

wide range of information about the molecular interactions that drive the complexation process.

Phase-solubility studies of HCT in aqueous solutions of s-CD were carried out according to the Higuchi?

Connors procedure (3). The phase solubility profiles of complexes were prepared in water and in

phosphate buffers at pH values of 5.5, 6.8 and 7.4, using two temperature values (25 and 37oC).

Phase solubility profiles of HCT in the presence of s-CD showed deviations in the slope at different

sections of the solubility isotherms. Based on the shape of the generated phase?solubility relationships,

several types of behaviors could be identified. AN-type phase-solubility profiles of HCT with s-CD were

found at the two temperature values (25 and 37oC) in phosphate buffers at pH values of 6.8 and 7.4 and in

found at the two temperature values (25 and 37oC) in phosphate buffers at pH values of 6.8 and 7.4 and in

water at 25oC. These results might be ascribed to that the HCT:s-CD complex aggregates by ionic

interaction. Meanwhile, AP-type phase-solubility profiles were found in water at 37oC and in phosphate

buffer at pH 5.5 at 25oC. This might be attributed to hydrogen bond which are affected by the temperature

buffer at pH 5.5 at 25oC. This might be attributed to hydrogen bond which are affected by the temperature

increase, so aggregates dissociate upon heating increasing the relative concentration of complex

monomers. An increase of the HCT solubility with the temperature was also observed.

found at the two temperature values (25 and 37oC) in phosphate buffers at pH values of 6.8 and 7.4 and in

water at 25oC. These results might be ascribed to that the HCT:s-CD complex aggregates by ionic

interaction. Meanwhile, AP-type phase-solubility profiles were found in water at 37oC and in phosphate

buffer at pH 5.5 at 25oC. This might be attributed to hydrogen bond which are affected by the temperature

buffer at pH 5.5 at 25oC. This might be attributed to hydrogen bond which are affected by the temperature

increase, so aggregates dissociate upon heating increasing the relative concentration of complex

monomers. An increase of the HCT solubility with the temperature was also observed.

buffer at pH 5.5 at 25oC. This might be attributed to hydrogen bond which are affected by the temperature

increase, so aggregates dissociate upon heating increasing the relative concentration of complex

monomers. An increase of the HCT solubility with the temperature was also observed.

Results of this study provide some insight into the aggregation equilibrium of the HCT:s-CD complex so

the aggregate transformations greatly influence macroproperties of the solutions.