The structural differences in the interaction between natural γ-cyclodextrin and bile salts common in rat, dog and man was were investigated by 1H-ROESY and 13C NMR and molecular modeling and the thermodynamic parameters of the reaction by isothermal titration calorimetry. The γ-cyclodextrin was selected based upon its frequent use in drug formulation as excipients to facilitate the solubilisation of drug substances with low aqueous solubility upon oral administration. The NMR studies and the molecular modeling demonstrated an interaction with inclusion of the C-ring of the steroid body of the bile salt and partly inclusion of the B and D ring. A large variation was observed in the stability constants among the investigated bile salt. The variations in the enthalpic and entropic contributions to the overall Gibbs free energy and consequently the stability constants revealed structural differences between the bile salts, where bile salts with a hydroxyl group on C12 has a weaker interaction than the bile salts without the hydroxyl group. Based upon the theoretical calculations of the available surface area the differences observed in the entropic contribution seems to be mainly driven by dehydration effects.
Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2013, Vol 75, Issue 1-2, p. 223-233
Isothermal titration calorimetry; Bile salts; Complexation; Cyclodextrin; Gamma-cyclodextrin; Molecular modelling