187
Thomas Mavromoustakos et al. (eds.), Supramolecules in Drug Discovery and Drug Delivery: Methods and Protocols,
Methods in Molecular Biology, vol. 2207, https://doi.org/10.1007/978-1-0716-0920-0_15,
© Springer Science+Business Media, LLC, part of Springer Nature 2021
Chapter 15
Unveiling the Thermodynamic Aspects of DrugCyclodextrin Interactions Through Isothermal Titration
Calorimetry
Maria V. Chatziathanasiadou, Thomas Mavromoustakos,
and Andreas G. Tzakos
Abstract
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.
Key words Isothermal titration calorimetry, 2-hydroxypropyl-β-cyclodextrin, Losartan, Inclusion
complex, Enthalpy, Entropy
1 Introduction
Cyclodextrins are cyclic oligosaccharides widely used in the pharmaceutical industry for the inclusion of drugs suffered by reduced
stability and solubility to name some [1] and in the food industry
as additives [2]. Their cone-shaped structure composed of glucopyranose units forms a distinctive supramolecule with a hydrophilic
outer surface and a lipophilic inner cavity able to host small mole-
Thomas Mavromoustakos et al. (eds.), Supramolecules in Drug Discovery and Drug Delivery: Methods and Protocols,
Methods in Molecular Biology, vol. 2207, https://doi.org/10.1007/978-1-0716-0920-0_15,
© Springer Science+Business Media, LLC, part of Springer Nature 2021
Chapter 15
Unveiling the Thermodynamic Aspects of DrugCyclodextrin Interactions Through Isothermal Titration
Calorimetry
Maria V. Chatziathanasiadou, Thomas Mavromoustakos,
and Andreas G. Tzakos
Abstract
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.
Key words Isothermal titration calorimetry, 2-hydroxypropyl-β-cyclodextrin, Losartan, Inclusion
complex, Enthalpy, Entropy
1 Introduction
Cyclodextrins are cyclic oligosaccharides widely used in the pharmaceutical industry for the inclusion of drugs suffered by reduced
stability and solubility to name some [1] and in the food industry
as additives [2]. Their cone-shaped structure composed of glucopyranose units forms a distinctive supramolecule with a hydrophilic
outer surface and a lipophilic inner cavity able to host small mole-