Theoretical insights into the formation, structure, and energetics of some cyclodextrin complexes

To investigate the physicochemical aspects relevant for the formation of various cyclodextrin inclusion complexes and to search for corresponding general structure-complex-stability relationships, stability data of 1 : 1 complexes for 179, 310, and 51 guest molecules with unsubstituted alpha-, beta-, and gamma-cyclodextrin were collected. Statistical analysis using structure-based parameters such as molecular size, hydrophobicity, rotatable bonds, electronic properties, and the presence or absence of more than 150 various functional or structural moieties were performed. The complexation thermodynamics could be well described within the framework of our recently introduced molecular size-based model for nonassociative liquids. With increasing guest size, 1 : 1 complex stability, as measured by ln K or DeltaG(0), increases linearly up to a size limit characteristic for each CD, and the corresponding slopes and intercepts are in agreement with those predicted by the model. For larger structures, values level off and are scattered around an average value depending on shape, goodness of fit, and possibly lipophilicity and some specific effects (e.g. such as those caused by presence of phenol functionality). The complexation between beta-cyclodextrin and certain large steroidal guest molecules, especially a brain-targeted estradiol chemical delivery systems (E-2-CDS) that is under clinical development, was investigated in details based on fully relaxed semiempirical AM1 quantum chemical calculations. A deformation index (DI) of the CD ring computed using these fully optimized host-guest geometries could be used to characterize the conformational change of the guest.