Inclusion complexation of propofol with 2-hydroxypropyl-β-cyclodextrin.: Physicochemical, nuclear magnetic resonance spectroscopic studies, and anesthetic properties in rat

An aqueous formulations of propofol 1 can be prepared by solubilizing it in the presence of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). This is potentially useful for parenteral administration of the drug. The aqueous solubility of 1 linearly increased as a function of HP-beta-CD concentration and showed features of an A(L) type diagram. Thermodynamic parameters were obtained by using the temperature dependence of the stability constant at temperatures of between 25 and 37 degrees C. The results indicate that complex formation is enthalpically, rather than entropically, driven and that it may involve van der Waals (dispersive) forces, rather than hydrophobic interactions. The structure of the inclusion complex propofol/HP-beta-CD was investigated in D2O, using H-1 and C-13 NMR spectroscopy. These studies revealed that the whole aromatic ring, as well as part of the isopropyl groups of the guest molecule, is located inside the HP-beta-CD cavity, while the hydroxy group is located at the rim of the wider cavity end. The geometrical features of the inclusion complex 1-HP-beta-CD are confirmed by 1D NOE difference spectra and molecular modeling experiments. The anesthetic activity in rat was investigated, and it was found that there are significant differences in induction time and sleeping time between 1 solubilized in the presence of HP-beta-CD and the formulation currently used (Diprivan), which is a 1% w/v oil/water emulsion.