Interactions of amphiphilic drugs with?-,?-, and?-cyclodextrins

The association of several amphiphilic drugs with α-, β-, and γ-cyclodextrins has been measured by use of drug-sensitive electrodes. Drugs investigated are hydrochlorides of chlorpromazine, dibucaine, tetracaine, and procaine, and valethamate bromide. Each drug forms the drug:cyclodextrin=1∶1 complex with α- and β-cyclodextrin, and both the 1∶1 and 2∶1 complex with γ-cyclodextrin, except valethamate which only forms the 1∶1 complex. The strength of the 1∶1 complex formations is in the order of βCyD>α-CyD>γ-CyD. The association constant of the 2∶1 complex in drug-γ-CyD is larger than that of 1∶1 complex. The free energy change of the conplex formation has a positive correlation with that of the micelle formation of drugs. The deviation from this relation is explained in terms of fittability of the bulky hydrophobic group of drugs into the cyclodextrin's cavity. The free energy change for the complex formation between chlopromazine or valethamate and β-CyD is governed by the enthalpy term and not by the entropy term which controls the surfactant-β-CyD interactions.