Multimodal inclusion complexes of ampicillin with β-cyclodextrins in aqueous solution

The inclusion complexation of ampicillin (ABPC) with beta-cyclodextrin (betaCD) and 2-hydroxypropyl-beta-cyclodextrin (HPCD) in aqueous solution has been investigated by microcalorimetry, NMR spectrometry and molecular dynamics simulation (MDS). The heat of reaction of the complexation decreased as the pH value increased. ABPC and beta-cyclodextrins formed one or two types of inclusion complexes by hydrophobic interactions and the complexation significantly depended on the species of ABPC based on the pH values of the solutions. Two different types of inclusion complexes with a 1: 1 stoichiometry were realized for the cation species of ABPC in the strong acid solution. In the first type of inclusion with higher association constants of (6.0-10) x 10(3) M-1, the penam ring of ABPC was inserted in the cyclodextrin cavity, whereas in the second type with lower association constants of 1.0 x 10(3) M-1 the phenyl ring seemed to penetrate into the cavity. The beta-lactam ring of ABPC was included in both types to be protected from the acid-catalyzed hydrolysis. The zwitterion and anion species of ABPC formed only one type of inclusion complex with beta-cyclodextrins, where the phenyl ring and the penam ring were included, respectively. These association constants and enthalpic changes were smaller than those for the first type inclusion complex of the cation species. These results indicate that the inclusion complexes of ABPC with beta-cyclodextrins would be useful to the drug delivery system. (C) 2003 Elsevier B.V. All rights reserved.