ESTE RESUMEN SERA PUBLICADO EN LA REVISTA APPS COMO PROCEEDING.
Introduction
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 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.
Materials and Methods
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).
Results
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 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 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 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.
.Conclusions
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.