Unveiling the Thermodynamic Aspects of Drug-Cyclodextrin Interactions Through Isothermal Titration Calorimetry

Due to their low toxicity and high aqueous solubility, cyclodextrins have emerged as a distinctive class of supramolecules with wide application in the pharmaceutical and food industry. Their ability to improve the water solubility, stability and pharmacokinetic profile of small molecules has established them as a rich toolkit for drug formulation. In order to improve the physicochemical characteristics and the pharmacokinetic profile of a drug through cyclodextrin inclusion, the proper cyclodextrin type has to be selected among the existing great variety consisting of both natural and synthetic variants. The selection of the most proper cyclodextrin variant comes after drug-cyclodextrin screening studies targeting the characterization of the complex formation and evaluation of the affinity and interaction forces participating in the complexation. Numerous analytical, spectroscopic, separation and electrochemical techniques have been applied to elucidate the interaction profile in a cyclodextrin-drug complex. Herein, we describe the application of Isothermal Titration Calorimetry (ITC) on cyclodextrin-drug complexes that enables the charting of the binding affinity and the thermodynamic profile of the inclusion complexes. We focus on the experimental design and present technical tips of the ITC application. To better illustrate the technique's rationale, the interaction between 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and the antihypertensive drug losartan is investigated.