Isothermal titration calorimetry (ITC) study of natural cyclodextrins inclusion complexes with drugs

Isothermal titration calorimetry (ITC) was used to characterize inclusion complex formation of natural cyclodextrins (alpha- and beta-cyclodextrin) with three drugs ((+)brompheniramine, (+/-)brompheniramine, cyclopentolate) in aqueous solutions. ITC measurements were carried out at 298.15 K on a Microcal OMEGA ultrasensitive titration calorimeter (MicroCal Inc.). The experimental data were analyzed on the basis of the model of a single set of identical sites (ITC tutorial guide). beta-CD forms inclusion complexes of stoichiometry 1:1 with the all investigated drugs. In turn, smaller molecule of alpha-CD forms inclusion complexes of two different stoichiometry: with bigger molecules ((+)brompheniramine and (+/-)brompheniramine) of a stoichiometry 2:1 and with smaller molecules (cyclopentolate) of a stoichiometry 1:2. Based on the experimental values of equilibrium constant (K) and enthalpy of complex formation (Delta H), the Gibbs energy of complex formation (Delta G), and the entropy of complex formation (Delta S), have been calculated, for all the investigated systems. Obtained results showed that complex formation of beta-CD (bigger molecule with wider cavity compared to beta-CD) with both (+)brompheniramine, (+/-)brompheniramine, and cyclopentolate is enthalpy driven while complexes of alpha-CD with the all investigated drugs are enthalpy-entropy stabilized. This indicated that the difference in the cavity dimensions is reflecting in different driving forces of complex formation and binding modes what resulted in different stoichiometry of the obtained inclusion complexes.