Inclusion Complexation of Cyclodextrin

Inclusion complexes refer to compounds in which one molecule is encapsulated within another. Cyclodextrin (CD) can establish interactions with various types of molecules (guests) in solid phase or aqueous solution to form stable host-guest inclusion complexes. The inclusion complexation phenomenon is caused by multiple interactions between the three components of the system CD-guests-solvent, leading to an overall thermodynamically more stable state ^[1,2].

Mechanism of Inclusion Complexation

In general, a guest molecule does not immediately enter the cavity of a CD molecule, but first exists in aqueous solution in an ideal free state. It then enters the CD cavity, and displaces the high-energy water retained in the cavity. Under the action of van der Waals forces and hydrogen bonds, the inclusion complex formed is in a stable equilibrium state. The inclusion complexation process using citral as a guest molecule is shown in Fig. 1.

This inclusion process essentially involves guest molecules replacing high-energy water molecules in the cavity, resulting in a stabilizing reduction in the whole system's energy. This substitution occurs for two reasons: (a) water molecules are in an unfavorable energy state, which allows water molecules to be easily replaced by more suitable molecules with less polarity; (2) Organic guests dissolved in water prefer a hydrophobic environment, making them more conducive to entering hydrophobic cavities.

Fig. 1 Inclusion complexation mechanism of CDs, taking citral as a guest molecule ^[1].

Factors Affecting Inclusion Complexation

Inclusion complexation is reflected in the stability of the inclusion complex, which means that the more stable the inclusion complex, the stronger the inclusion complexation between the host and the guest. Factors affecting inclusion complexation include the size/shape match between the CD cavity and the guest molecule, intermolecular interactions, the polarity of guests, and the presence of other molecules ^[1].

• Size/shape match

To encapsulate a guest molecule in a CD cavity, the size or shape of the guest molecule must match that of the cavity. A CD molecule with a specific cavity size/shape can selectively recognize a guest molecule with the desired shape/size among a variety of guest molecules. When the sizes and shapes of the two match, the inclusion complexation between them is stronger, and the resulting inclusion complex is more stable.

• Intermolecular interactions

The driving force of inclusion complexation is the intermolecular interaction between CDs and host molecules, including hydrophobic interactions, van der Waals forces, hydrogen bonding, and electrostatic interactions. These interactions serve as the primary driver forces that can be in the form of a single type or a synergistic interaction. And the type of interactions between the host and guest molecules affect inclusion complexation.

• Polarity of guests

In the ternary CD-guest-solvent system, water is a polar solvent and the CD cavity is nonpolar. The introduction of hydrophilic groups to a guest molecule can enhance the guest molecule's interaction with water, correspondingly reducing the interaction strength with CD. In contrast, if the guest molecule is less polar than water or has non-polar groups, it is more likely to interact with the nonpolar CD cavity to form a stable inclusion complex. In short, inclusion complexation decreases with the increasing hydrophilicity of guest molecules.

• Presence of other molecules

In addition to the three factors mentioned above, the presence of other molecules different from guests also affects inclusion complexation. The addition of water-soluble polymers, acids or bases, anionic organic salts, and other compounds may improve inclusion efficiency. However, these molecules may also be encapsulated in CD cavities, leading to competition with guest molecules. It was found that when the encapsulation of guest molecules and CD reached relative equilibrium, the addition of other competitive molecules could cause the original guest molecules to be replaced and released non-spontaneously.

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