INTERACTIONS OF AMPHIPHILIC DRUGS WITH ALPHA-CYCLODEXTRIN, BETA-CYCLODEXTRIN, AND GAMMA-CYCLODEXTRIN

The association of several amphiphilic drugs with alpha-, beta-, and g amma-cyclodextrins has been measured by use of drug-sensitive electrod es. Drugs investigated are hydrochlorides of chlorpromazine, dibucaine , tetracaine, and procaine, and valethamate bromide. Each drug forms t he drug:cyclodextrin = 1 : 1 complex with alpha- and beta-cyclodextrin , and both the 1 : 1 and 2 : 1 complex with gamma-cyclodextrin, except valethamate which only forms the 1 : 1 complex. The strength of the 1 : 1 complex formations is in the order of beta-CyD > alpha-CyD > gamm a-CyD. The association constant of the 2 : 1 complex in drug-gamma-CyD is larger than that of 1 : 1 complex. The free energy change of the c omplex formation has a positive correlation with that of the micelle f ormation of drugs. The deviation from this relation is explained in te rms of fittability of the bulky hydrophobic group of drugs into the cy clodextrin's cavity. The free energy change for the complex formation between chlorpromazine or valethamate and beta-CyD is governed by the enthalpy term and not by the entropy term which controls the surfactan t-beta-CyD interactions.