Cyclodextrins(CDs) are cyclic oligosaccharides of α-D glucose, each connected by a glycosidic bond. This molecule has been of great interest to researchers due to its ability to encapsulate a wide range of molecules in its hydrophobic cavity. Nonetheless, the presence of hydroxyl groups in the upper (O2-O3) and lower (O6) rims, makes the molecule water-soluble. β CD is one of the most widely used drug carriers owing to its low cost, ease of availability, and appropriate cavity size. However, β-CD has a very low aqueous solubility of 18.5 gL−1. The major factor contributing towards the low solubility of β CD is the intramolecular O2-O3 hydrogen bond present in the secondary hydroxyl rim. Substitution with functional groups leads to the disruption of the intramolecular hydrogen bond leading to an enhancement in the solubility of the β CD molecule. The 2- hydroxypropyl(HP) group is one of the most popular and widely used substituents in CD. In our work, we intend to explore the role of the degree (DS), position, and pattern of substitution on the structure and energetics of the molecule. Substitution in the hydroxyl rims with the bulky 2-HP group leads to many structural deviations in the CD molecules. The glucose units in native CDs dominantly exist in 4C1 conformation in solution. However, structural parameters such as dihedral angles, exhibit that the glucose ring could be puckered upon substitution in the CD structures. In HP CD molecules with DS = 4 to 14, it is observed that the tendency of puckering of glucose units is higher when substituted at O2. Units monosubstituted at O6 positions have a fairly rigid structure compared to those with mono-substitutions at O2 or di-substitutions at O2 and O6. The puckering intensity is also dependent on the uniformity of substitution. Evenly substituted structures are less puckered than uneven ones. Circularity of CD is also affected by ring puckering of glucose units. Overcrowding of the CD with substituents could also play a role in this case. Higher water interactions of CD lead to higher solubility. However, such systems are highly deformed which could ultimately lead to a collapse of the CD cavity. For a stable and effective host-guest complex, a balance of the two factors should be taken into account. The solute-solvent interaction can also throw light upon the aggregation propensity of HP CD. Substitution also plays an important role on the hydrogen bond and interaction energy of the CDs.

Structural deformations and cavity closure of hydroxypropyl-β CD : An effect of substitution

ACS Spring 2022

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