Molecular modelling and H-1-NMR: Ultimate tools for the investigation of tolbutamide : beta-cyclodextrin and tolbutamide : hydroxypropyl-beta-cyclodextrin complexes

A structural study of the inclusion compound of tolbutamide (TBM) with beta -cyclodextrin (beta -CD) and hydroxypropyl-beta -cyclodextrin (HP-beta -CD ) was attempted by means of H-1-nuclear magnetic resonance (H-1-NMR) experi ments and computer molecular modelling. To establish the stoichiometry and stability constant of the beta -CD:TBM complex, the continuous variation me thod was used. The presence of true inclusion complexes between TBM and bet a -CD or HP-beta -CD in solution was clearly evidenced by the H-1-NMR techn ique. Changes in chemical shifts of H-3 and H-5 protons, located inside the CD cavity, associated with variations in the chemical shifts of TBM aromat ic protons provided clear evidence of inclusion complexation, suggesting th at the phenyl moiety of the drug molecule was included in the hydrophobic c avity of CDs. This view was further supported by the observation of intermo lecular NOEs between TBM and beta -CD and by the aid of a molecular modelli ng program, which established the most probable structure of the complex. T he molecular graphic computation confirmed that the minimum energy, positio ning TBM relative to beta -CD, occurs when the aromatic ring of TBM is incl uded within the beta -CD cavity by its wider side, leaving the aliphatic ch ain externally, which is in good agreement with the results of H-1-NMR stud ies.