**2.1 Mechanism of inclusion complexation**

When water molecules are removed from the lipophillic cavity of cyclodextrins (which is in an energetically unfavorable environment due to the nature of the polar-polar interaction), the number of formed hydrogen bonds increases, and the repulsive interaction between guest and aqueous environment decreases, whereas the hydrophobic interaction increases as the guest molecule or lipophilic group with size, shape, and polarity compatible with the CD structure exerts itself in central cavity. As a result, a complex (**Figure 3**) is formed in an aqueous solution [19, 20].

When a complex is formed, covalent bonds are neither formed nor broken, and the drug molecules of complex as well as those of solution are in equilibrium. The capacity of guest to interact well with the host molecules to create a stable complex determines the binding strength of thus formed complex. Other factors involved in affecting this host-guest complexation mechanism are:

**Figure 3.** *Schematic illustration of the drug-CD inclusion complexation [2].* *Cyclodextrins: An Overview of Fundamentals, Types, and Applications DOI: http://dx.doi.org/10.5772/intechopen.108078*


## **2.2 Types of complexes**

It is crucial to measure the stability or dissociation constant of complexes, since they are an indicator of how a compound's physicochemical characteristics change after inclusion. The phase solubility method proposed by Connors and Higuchi [22] is most extensively used analytical procedure in this regard as shown in **Figure 4**, which is known as phase solubility profile.

Connors and Higuchi categorized complexes by examining the influence of solubilizer or ligand concentration on drug or substrate solubility. If by increasing the solubilizer or ligand concentration, there is a rise in substrate solubility, then the solubility profile is said to be A-type. Three additional profiles, that is, AP, AL, and AN make up A-type profile. The AL profile shows that solubility increases linearly with

**Figure 4.** *A and B-type phase solubility profile and their subtypes [23].*

ligand concentration or solubilizer concentration. AP type shows an isotherm with significant deviation but in a positive way implying proportionality but only at higher quantities. On the other hand, AN profile also exhibits deviation but is a negative way implying no proportionality even at higher amounts. All three trends together show that complexes formed are water-soluble. Type B profile on the other hand indicates that the complex has restricted solubility. They are typically seen with parent CDs especially with the *β*-CD. They are also of two types, that is, BS and BT [24].

Although inclusion complexes are expected to make up the majority of CD complexes but non-inclusion complexes (complex aggregate) that can dissolve drug through micelle formation can also form [2].
