**2. Inclusion complexes**

Franz Schardinger, studying microorganisms which play a role in the deterioration of foods and by action of cyclodextrinase-Bacillus macerans amylase on the starch, obtained two distinct crystalline substances with similar properties to the already known partial degradation products of starch, the dextrins, so he named them α-, and β-dextrin. The separation of the cycloalkyls may be carried out by selective precipitation by means of organic compounds or by high temperature chromatography on a cellulose column. French et al. demonstrated that CDs are cyclic oligosaccharides composed of several D-(+) glucopyranose units in the form of a saddle [4]. In the second half of the 1930s, Freudenberg and his co-workers elucidated the cyclic structure of α-, and β-dextrin [5]. They consist of (α-1,4)-linked glucose units. A Greek letter preceding the abbreviation CD—for cyclodextrin—indicates the number of glucose units (α for 6, β for 7, and γ for 8) entering the composition of the cycloamylose. CDs constituted of less than 6 glucopyranose units cannot be formed due to steric hindrances [6]. Approximately, 1500 CD derivatives have been

CDs have a truncated cone appearance [7–12], and a doughnut, toroidal- or cylinder-like shape, due to the spatial arrangement characteristic of the various functional groups of the glucose units. As a consequence of this conformation, all the secondary hydroxyl groups (corresponding to the C2 and C3 carbon atoms of the glucose units) are at one of the edges of the cavity, whereas the primary hydroxyls are in the other end of the cavity. Rotation of these –OH groups reduces the effective size of the cavity, making it have a more open conical trun-

This spatial arrangement gives an apolar character to the interior of the cavity, whereas the presence of the –OH groups at the edges of the cone trunk makes them very water soluble. For instance, hydrophobic hosts will be housed inside the cavity because of the hydrophobic van der Waals type interactions, whereas simultaneously polar interactions

cated aspect [13] toward the side of the secondary hydroxyls (**Figures 1** and **2**).

reported [7] in the literature.

4 Cyclodextrin - A Versatile Ingredient

**Figure 1.** Molecular structure of (a) α, (b) β, and (c) γ-CDs.

An inherent interest surrounds these compounds due to their physical and chemicals properties [26–38]. The common feature of CDs is their ability to form inclusion complexes with a variety of molecules and ions, both in the solid state (crystalline substances) and in solution. As results of the structure of CDs, they can establish apolar-apolar interactions encapsulating other apolar molecules which may undergo structural changes [33–38], acting as molecular capsules [27–32]. However, the idea that one molecule could envelop another one to form a new compound (adduct, inclusion complex) was not accepted until X-ray diffraction showed the formation of an inclusion complex between α-CD and iodine [37]. They constitute a significant example of relatively simple organic compounds showing complex formation with other organic molecules. They are excellent models of enzymes that lead to their use as catalysts [21, 24, 39], both in enzymatic and non-enzymatic reactions. Additionally, they are natural products and readily available to most researchers.

are weakly complexed. Additionally, although a 1:1 stoichiometry between the substrate and the CD molecule is typical [46, 54–56], with certain systems (**Figure 3**), 1:2 and 2:1 complex formations are possible. Experimentally determined formation constant can be the function (**Figure 4**) of the formation constants of the isomeric complexes [46]. In addition, substitution of one or more hydroxyls results in most cases in better water-soluble derivatives. For example, CDs can be polymerized [32, 36, 40, 42, 44, 45, 57] by suitable bio- or polyfunctional agents to oligomers, long-chain polymers or crosslinked or immobilized networks in various supports. Low molecular weight oligomeric CDs are readily soluble in water. Polymers (molecular mass over 10,000) are swollen gels which can be prepared in bead forms. The rigid structure of CDs "host" translates into well-defined and differentiated inclusion complex

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depending on the nature of the "guest" molecule.

**Figure 3.** Complexes of α-CDs and 1,4-disubstituted benzene [13].

**Figure 4.** Isomeric complexes from substrate and free ligand [55].

It is accepted [18, 38, 40–43] that the binding forces involved in complex formation are, in general:


The role of the hydrogen bond is not universal since stable complexes are formed with hosts such as benzene, which do not form hydrogen bonds.

#### **2.1. Factors affecting stability**

Regardless of which type of stabilizing force is involved, the most important factors in determining the stability of the inclusion complex are [36, 40–45]:


Geometric, rather than chemical factors, are critical in determining the type of "guest" molecules that can penetrate into the cavity. If the guest is too small, it passes easily through the cavity and the bond will be weak or will not occur. The formation of complexes with molecules significantly larger than the cavity is also possible, but only some limited groups or side chains penetrate into the CD cavity.

The stability of an inclusion complex also depends on the polarity of the "guest" molecule. Only substrates that are less polar than water may form inclusion complexes with the CDs. The stability of a complex is proportional to the hydrophobic character of the "guest" molecule. Highly hydrophilic molecules form complex CDs very weakly or do not complex at all.

On the other hand, stability depends heavily on the nature of the medium used for complexation. In principle, the inclusion complexes may be formed either in solution [46–49] (generally carried out in the presence of water) or in the crystalline [40, 50–52] state. Although the formation of inclusion complexes also takes place [53] in an organic solvent, the guest molecules are weakly complexed. Additionally, although a 1:1 stoichiometry between the substrate and the CD molecule is typical [46, 54–56], with certain systems (**Figure 3**), 1:2 and 2:1 complex formations are possible. Experimentally determined formation constant can be the function (**Figure 4**) of the formation constants of the isomeric complexes [46]. In addition, substitution of one or more hydroxyls results in most cases in better water-soluble derivatives. For example, CDs can be polymerized [32, 36, 40, 42, 44, 45, 57] by suitable bio- or polyfunctional agents to oligomers, long-chain polymers or crosslinked or immobilized networks in various supports. Low molecular weight oligomeric CDs are readily soluble in water. Polymers (molecular mass over 10,000) are swollen gels which can be prepared in bead forms. The rigid structure of CDs "host" translates into well-defined and differentiated inclusion complex depending on the nature of the "guest" molecule.

**Figure 3.** Complexes of α-CDs and 1,4-disubstituted benzene [13].

new compound (adduct, inclusion complex) was not accepted until X-ray diffraction showed the formation of an inclusion complex between α-CD and iodine [37]. They constitute a significant example of relatively simple organic compounds showing complex formation with other organic molecules. They are excellent models of enzymes that lead to their use as catalysts [21, 24, 39], both in enzymatic and non-enzymatic reactions. Additionally, they are natu-

It is accepted [18, 38, 40–43] that the binding forces involved in complex formation are, in

**i.** van der Waals type interactions (or hydrophobic interactions) between the hydrophobic

**ii.** Hydrogen bond between the polar functional groups of the guest molecules and the hy-

**iii.** Release of high energy water molecules from the cavity in the complex formation process.

The role of the hydrogen bond is not universal since stable complexes are formed with hosts

Regardless of which type of stabilizing force is involved, the most important factors in deter-

Geometric, rather than chemical factors, are critical in determining the type of "guest" molecules that can penetrate into the cavity. If the guest is too small, it passes easily through the cavity and the bond will be weak or will not occur. The formation of complexes with molecules significantly larger than the cavity is also possible, but only some limited groups or

The stability of an inclusion complex also depends on the polarity of the "guest" molecule. Only substrates that are less polar than water may form inclusion complexes with the CDs. The stability of a complex is proportional to the hydrophobic character of the "guest" molecule. Highly hydrophilic molecules form complex CDs very weakly or do not complex at all. On the other hand, stability depends heavily on the nature of the medium used for complexation. In principle, the inclusion complexes may be formed either in solution [46–49] (generally carried out in the presence of water) or in the crystalline [40, 50–52] state. Although the formation of inclusion complexes also takes place [53] in an organic solvent, the guest molecules

ral products and readily available to most researchers.

unit of the guest molecules and the CD cavity.

such as benzene, which do not form hydrogen bonds.

mining the stability of the inclusion complex are [36, 40–45]:

**iv.** Release of strain energy into the ring structure system of the CD.

droxyl groups of the CD.

6 Cyclodextrin - A Versatile Ingredient

**2.1. Factors affecting stability**

the geometric capability

the medium temperature

polarity of the guest molecules

side chains penetrate into the CD cavity.

general:

**Figure 4.** Isomeric complexes from substrate and free ligand [55].

Finally, the stability of the inclusion complex, in general, decreases when temperature increases [46]. Enthalpy and entropy changes can be obtained from the temperature dependence of the equilibrium constant. An important issue, often overlooked in the CD field, is that the magnitudes of the standard free energy and entropy changes are dependent on the standard state chosen by the experimentalist.

CDs increase the selectivity of chromatographic separations [72–74], because the separation process is more selective than that between the eluent and the stationary phase alone. In HPLC, the application of the CDs has achieved a spectacular success. Their incorporation into the mobile phase allows improving the separations, since they are soluble in water and provide reversible and selective complexation. In addition, they are stable and show no absorption in the UV-visible region of the electromagnetic spectrum. These characteristics mean that CDs are generally used in reverse phase separation processes, achieving the separation of isomers, diastereoisomers, and enantiomers [75–78]. The high resolution obtained is due to the differences in the stability constants of the complexes in the mobile phase and the different adsorption of these complexes in the stationary phase. CDs may also be incorporated as support for the stationary phases. Capillary electrophoresis has also found use in

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**4. A primer on pharmaceutical, food and cosmetic cyclodextrin** 

CDs have mainly been used as complexing agents to improve the aqueous solubility of molecules. This allows the use of CDs to reduce or prevent gastrointestinal or ocular irritation by lowering the local concentration of the free drug below the irritancy threshold. Also, unpleasant odor or taste of drugs can be hidden by complexation of the functional groups that produce them with CDs, occulting them from the sensory receptors [83–85], furthermore, reducing their hydrophobicity using CDs. Finally, CDs can increase percutaneous or rectal absorption of drugs and their derivatives can increase the guest molecule bioavailability [84]. Recently, CDs and their derivatives have been used in dispersed vehicle systems such as emulsions, microcapsules, microspheres, nanospheres, nanocapsules, liposomes, and beads [86]. Additionally, the host-guest property allows CDs to be used as building blocks in supramolecular chemistry [7]. Suvarna et al. [87] explain an insight in the use of CDs to increase the bioavailability to resolve the problem of solubility and stability of phytochemicals. The authors describe that some chemicals as quercetin, curcumin, arteminsinin, resveratrol or naringenin increased their bioavailability due to the inclusion complexes with CDs. Authors concluded that CDs need to be more explored to cover some molecules that have potential

The encapsulation with CDs is gaining interest in different industries; this is reflected in the large number of publication and products related with it, such as drug delivery systems [7, 35]. This capacity of encapsulating compounds is used for a wide variety of things, among them is to protect the compounds, or to transport them to a target. This ability is due to the toroidal shape of CDs which makes possible to encapsulate hydrophobic molecules fully or

chiral analytical separations [79–82].

biological activity but have not been approached.

**studies**

**4.1. Bioavailability**

**4.2. Encapsulation**
