2 TYPES OF INCLUSION REALIZED IN THE COMPLEXATION BETWEEN PHENOBARBITAL AND 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN IN AQUEOUS-SOLUTION

The inclusion complexation of phenobarbital (PHB) with 2-hydroxypropyl -B-cyclodextrin (HPCyD) in aqueous solution has been investigated by m icrocalorimetry, C-13-NMR spectroscopy and molecular dynamics simulati ons. Two different types of PHB-HPCyD inclusion complexes at 1 : 1 sto ichiometry were realized by un-ionized PHB. In the first type of inclu sion with higher affinity with HPCyD, the phenyl ring of PHB was inclu ded within the HPCyD cavity, whereas in the second type, the barbituri c acid ring seemed to penetrate into the cavity. The ethyl side-chain remained outside of the cavity in both types. Complexation was indepen dent of the concentrations of both PHB and HPCyD. The first type of in clusion was characterized by an entropy-driven reaction associated wit h constant values of Delta G(1) (-2.69+/-1.0 kJ mol(-1)), Delta H-1 (- 3.73+/-0.86 kJ mol(-1)), and Delta S-1 (77.5+/-1.5 J mol(-1) K-1) at v arious pH, and the hydrophobic interaction dominated the stabilization of the complex. The second type was characterized by large negative v alues of Delta H-2 (-19.2+/-0.7 kJ mol(-1)) and small Delta S-2 (8.6+/ -2.5 J mol(-1) K-1) at pH below 7.0, reflecting van der Waals' and/or electrostatic interactions, and all the thermodynamic parameters marke dly decreased at pH>8.0. C-13-NMR chemical shifts of barbituric acid r ing and of a phenyl ring substituted at C5 on barbituric acid ring wer e significantly moved upheld upon penetrating into HPCyD cavity. (C) 1 998 Elsevier Science B.V.