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cules. According to the European Medicines Agency (EMA),
cyclodextrins are used as excipients in several marketed drugs
mainly to increase the aqueous solubility, bioavailability and stability of the active substance [1]. Another advantage of these supramolecules is their low toxicity allowing their administration in high
doses. For example, HP-β-CD is not toxic when administered daily
at doses lower than 16 g [3]. The above characteristics make cyclodextrins promising drug carriers and this is evident by the increasing number of cyclodextrin-drug formulations presented in
literature and applied in the pharmaceutical industry [4–6].
Their application in drug encapsulation can sight toward different routes of administration including oral, parenteral, ocular,
dermal and nasal [1]. However, not every class of cyclodextrin is
suitable for the incorporation and delivery of a drug as their physicochemical properties, contingent on their structural characteristics, can affect the biopharmaceutical behavior and efficacy of
the drug. In terms of delivery for example, cyclodextrins with low
aqueous solubility like β-CD and methylated β-CDs are not being
utilized for parenteral drug administration due to their high toxicity [7]. In terms of inclusion, factors like the size [8], type of
derivatization, and degree of substitution (DS) of the cyclodextrin
are of great importance in the complex formation with a guest
molecule [7]. The inclusion of a small molecule into the cyclodextrin core not only depends on the cyclodextrin type but also on the
guest’s physicochemical properties and other conditions such as
the solvent [9], pH [10–12] and temperature [7]. Thus, it is crucial to explore each potential host-guest system individually in
order to define the driving forces of interaction.
Various analytical and spectroscopic techniques have been
recruited to characterize cyclodextrin complexes like surface plasmon resonance [13], nuclear magnetic resonance spectroscopy
[14, 15], UV–Vis and fluorescence spectroscopy [16, 17], mass
spectrometry [18], capillary electrophoresis [19], liquid chromatography [20], cyclic voltammetry [21], and calorimetry [22, 23].
This chapter is focused on the ITC, a widely used technique to
chart such interactions, since it can estimate with high precision
both the binding affinity and the thermodynamic parameters of the
cyclodextrin complexes.
ITC is based on the determination of the heat changes that
occur during a binding process [24]. Briefly, the calorimeter consists of two parts. The first is an adiabatic jacket bearing a sample
cell, where one of the two interactants is placed and usually—but
not necessarily—is the molecule with the highest molecular weight
and a reference cell which is loaded with buffer or water. The second part is an automated syringe containing the other interactant
(ligand). The instrument aims to keep the temperature difference
between the two cells stable and close to zero (ΔΤ ≈ 0) and this is
succeeded by constantly providing power to the system. This
Maria V. Chatziathanasiadou et al.
cules. According to the European Medicines Agency (EMA),
cyclodextrins are used as excipients in several marketed drugs
mainly to increase the aqueous solubility, bioavailability and stability of the active substance [1]. Another advantage of these supramolecules is their low toxicity allowing their administration in high
doses. For example, HP-β-CD is not toxic when administered daily
at doses lower than 16 g [3]. The above characteristics make cyclodextrins promising drug carriers and this is evident by the increasing number of cyclodextrin-drug formulations presented in
literature and applied in the pharmaceutical industry [4–6].
Their application in drug encapsulation can sight toward different routes of administration including oral, parenteral, ocular,
dermal and nasal [1]. However, not every class of cyclodextrin is
suitable for the incorporation and delivery of a drug as their physicochemical properties, contingent on their structural characteristics, can affect the biopharmaceutical behavior and efficacy of
the drug. In terms of delivery for example, cyclodextrins with low
aqueous solubility like β-CD and methylated β-CDs are not being
utilized for parenteral drug administration due to their high toxicity [7]. In terms of inclusion, factors like the size [8], type of
derivatization, and degree of substitution (DS) of the cyclodextrin
are of great importance in the complex formation with a guest
molecule [7]. The inclusion of a small molecule into the cyclodextrin core not only depends on the cyclodextrin type but also on the
guest’s physicochemical properties and other conditions such as
the solvent [9], pH [10–12] and temperature [7]. Thus, it is crucial to explore each potential host-guest system individually in
order to define the driving forces of interaction.
Various analytical and spectroscopic techniques have been
recruited to characterize cyclodextrin complexes like surface plasmon resonance [13], nuclear magnetic resonance spectroscopy
[14, 15], UV–Vis and fluorescence spectroscopy [16, 17], mass
spectrometry [18], capillary electrophoresis [19], liquid chromatography [20], cyclic voltammetry [21], and calorimetry [22, 23].
This chapter is focused on the ITC, a widely used technique to
chart such interactions, since it can estimate with high precision
both the binding affinity and the thermodynamic parameters of the
cyclodextrin complexes.
ITC is based on the determination of the heat changes that
occur during a binding process [24]. Briefly, the calorimeter consists of two parts. The first is an adiabatic jacket bearing a sample
cell, where one of the two interactants is placed and usually—but
not necessarily—is the molecule with the highest molecular weight
and a reference cell which is loaded with buffer or water. The second part is an automated syringe containing the other interactant
(ligand). The instrument aims to keep the temperature difference
between the two cells stable and close to zero (ΔΤ ≈ 0) and this is
succeeded by constantly providing power to the system. This
Maria V. Chatziathanasiadou et al.