Untersuchung von Cyclodextrinkomplexen - OPUS - Universität ...

Summary
7 Summary and Perspective
In this thesis various methods were applied to gather information about complexes formed
by natural cyclodextrins and typical sulfa drugs. Sulfadiazine, sulfadimidine, sulfafurazole,
sulfaguanidine, sulfamerazine, sulfameter, sulfamethoxazole, sulfanilamide and sulfathiazole
were chosen as model substances. Owing to their molecular size these guests form
complexes preferably with β-cyclodextrin at a ratio of 1:1 in aqueous solution. The
interactions are relatively weak compared with other guest molecules.
Phase solubility analysis was used to investigate several effects on complexation in solution.
α-Cyclodextrin and γ-cyclodextrin show no or, in individual cases, extremely low interactions
with the model substances. Consistently, the inclusion in β-cyclodextrin was favoured by all
drugs with association constants of 100 - 2000 M -1 . The complexes of the model substances,
with exception of sulfathiazole, are well soluble in water. This result is uncommon for natural
cyclodextrins [54]. The thermodynamic parameters for the complexation were derived from
linear van’t Hoff plots. Generally speaking, the process can be described as enthalpy-driven,
combined with a loss of entropy. The linear correlation of these quantities indicates the
presence of the enthalpy-entropy-compensation phenomenon.
Phase solubility analysis in different buffer solutions showed that complex formation occurs
independently of the current pH value. The association constants decrease with increasing
pH values while the slope of the isotherms gets steeper. This can be attributed either to
higher rates of complex formation or shifts in complex stoichiometry. In summary, the phase
solubility studies provided deeper insight into complexation of sulfa drugs by natural
cyclodextrins. The obtained data served as a basis for the subsequent experiments.
For most sulfa drugs complexation not only results in a solubility enhancement of the guest,
but also increases the low intrinsic solubility of β-cyclodextrin itself. This effect was quantified
within the course of this work. It is of comparable extent for all guest molecules with
exception of sulfathiazole. Quantification at several pH-values showed a dependency on the
guest’s protonation state. A higher solubility enhancement was observed for the neutral form.
Making use of the described phenomenon one can achieve β-cyclodextrin concentrations
many times higher than its intrinsic solubility in solution.
The complex stoichiometry was derived both from phase solubility isotherms and from Job’s
plots employing 1 H-NMR-spectroscopy. The results indicate a predominant occurance of 1:1
complexes.
The structure of the inclusion complexes was examined in solution and in the solid state
using the means of spectroscopy. ROESY spectra of some model substances show that the
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