Driving forces for the inclusion of the drug tolmetin by beta-cyclodextrinin aqueous medium. Conductometric and molecular modeling studies

The encapsulation of tolmetin, a nonsteroidal antiinflammatory and antirrhe umatic drug, by beta-cyclodextrin (P-CD) has been analyzed from thermodynam ic and structural points of view, by means of conductometric and molecular mechanics studies. Conductivity measurements of aqueous solutions of tolmet inate (TOL-) were performed as a function of beta-CD concentration, at diff erent temperatures ranging from 15 to 40 degrees C. The stoichiometry of th e complex ( 1: 1), its association constant (similar to 2000 M-1),and the i onic molar conductivities at infinite dilution of the free (lambda(DRUG)(0) ) and complexed (lambda(CD:DRUG)(0)) drug were obtained from these conducti vity data. A slightly negative change in enthalpy and a positive change in entropy, obtained from the dependence of K values with the temperature, rev eal that both the enthalpy and the entropy favor the inclusion process. Mol ecular mechanics (MM) calculations, also employed to study the complexation in vacuo and in the presence of water, show that the drug prefers to penet rate into the beta-CD cavity by the wider entrance, with toluol group end f irst. From both MM calculations and experimental results, the hydrophobic e ffect and electrostatic interactions, possibly arising from the presence of intermolecular hydrogen bonds, seem to have a relevant role in the formati on of the beta-CD:TOL- complex in aqueous media.