Determination of inclusion geometry of cyclodextrin host-guest complexes: Applicability of 1D selective NMR methods

The main objective of the present study is to highlight the most favourable set of 1D selective experiments based on NMR relaxation and NOE to elucidate inclusion geometry of cyclodextrin based host-guest complexes. Prediction of the mode of insertion of a model drug diflunisal (DFL) inside β-Cyclodextrin (β-CD) and 2-hydroxylpropyl-β-Cyclodextrin (HP- β-CD) has been attempted by employing one dimensional (1D) selective NMR experiments. The respective spectral complexity observed in case of β-CD and HP-β-CD inclusion complexes dictates the choice of selective measurements. A combination of non-selective (R₁^ns), selective (R₁^se) and bi-selective (R₁^bs) spin-lattice relaxation rate measurements has exhibited potential in quantifying molecular rotational correlation time (τ_c) and prediction of mode of insertion for DFL:β-CD complex while in case of DFL:HP-β-CD complex selective ROE experiment is the valid alternative to extract the inter nuclear distance data. In both the cases the fluorinated ring of DFL remains outside the CD cavity. Further, the observation of higher shift of chemical shift positions, enhanced peak intensities, slightly shorter spin-lattice relaxation times and slower molecular motion in case of HP-β-CD complex compared to the β-CD complex clearly suggested a better encapsulation of the drug by the former. In conclusion, 1D selective ROESY will be a superior method for intermediate sized CD inclusion complexes while multi-selective relaxation experiments are apt for non-intermediate sized inclusion complexes with better peak resolution.