Untersuchung von Cyclodextrinkomplexen - OPUS - Universität ...

126 Summary
chemically related molecules occupy considerably different positions and orientations inside
the cyclodextrin’s cavity. The benzene ring carrying the aromatic amino group is always at
least partially included. Inclusion depth varies with substitution of the guest. Although there
are differing influences and conditions in the solid state, FTIR spectra of solid complex
formulations support the more detailed NMR-results in most cases.
In addition, theoretical structures for the inclusion complexes were created by molecular
mechanics. Cyclodextrin flexibility and a possible ‘induced-fit’ were simulated by generating
multiple conformations of β-cyclodextrin. Docking experiments were carried out in order to
characterize the inclusion mode of the sulfonamides. Under the experimental conditions we
observed those orientations to be predominant where the aromatic amino group and the
oxygen atoms of the sulfonamide are able to establish H-bonds to the host’s hydroxyl
groups. The resulting disturbance of the intermolecular and intramolecular H-bonds of
β-cyclodextrin is one possible explanation for the synergistic solubility effects between host
and guest.
The preparation of different solid complex formulations by freeze drying provided samples of
increasing content of inclusion complexes. FTIR spectra and thermal analysis were not
applicable to quantify the success of inclusion ultimately. However, the experiments suggest
that the choice of preparation method does have a considerable contribution to the results of
these methods. Therefore, a simple comparison of probable inclusion complexes with
physical mixtures, as carried out in many publications, may not be the appropriate method
for the detection of complexation.
Overall, studying a larger group of model substances of similar chemical properties and
molecular structure showed the variations of the inclusion process even in such a
homogenous group of guests. The results of this thesis make it obvious that predictions
concerning complex formation with cyclodextrins are not possible by considering
investigations of related model substances. Instead, complex formation should always be
regarded as an individual case. For example, the limited solubility of β-cyclodextrin/
sulfathiazole cannot simply be deduced from the guest’s molecular structure. Thus, a
cyclodextrin’s guest determines substantially the properties of the formed complex. In
addition, complex structures from practical and theoretical studies suggest a variable
position of molecules inside the cavity. From there, a complete deactivation of the guest’s
reactive potential is improbable. For instance, some sulfonamides expose large parts of the
molecule to the medium even if complexed by cyclodextrin. Reactions with other species
outside the cavity are possible. For these reasons, standardization of dosage form
development using natural cyclodextrins where the active ingredient is freely
interchangeable may not be feasible.