Cyclodextrin in Drug Stability and Complexation: A Summary of Recent Findings

Cyclodextrins (CDs) are widely used pharmaceutical excipients that enhance drug solubility, permeability, and stability through inclusion complex formation. These cyclic oligosaccharides originate from enzymatic starch degradation and their structure contains α-1,4-linked D-glucopyranose units. The natural forms of CDs (Native Cyclodextrins) -αCD, βCD, and γCD-consist of 6 glucose units for αCD, 7 glucose units for βCD, and 8 glucose units for γCD, while larger CDs have also been discovered.

Fig.1 Molecular structure and schematic representation of the truncated cone shape of cyclodextrins[1].

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Cyclodextrin modification and complex formation

Cyclodextrins achieve improved solubility and complexation efficiency through hydroxyl group substitutions at glucose unit positions 2, 3, and 6. The most frequently used cyclodextrin derivatives consist of hydroxypropyl-β-cyclodextrin (HP-β-CD), methyl-β-cyclodextrin (M-β-CD), carboxymethyl-β-cyclodextrin (CM-β-CD), and sulfobutyl ether-β-cyclodextrin (SBE-β-CD). The ^4C_1 chair conformation of glucopyranose gives CDs their truncated cone shape, which contains a hydrophilic outer surface and a hydrophobic inner cavity, enabling guest molecule inclusion.

Fig.2 Schematic representation of substituted cyclodextrins[1].

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Effect of Cyclodextrin Inclusion Complexes on Drug Stability

Drug molecules easily form inclusion complexes with CD derivatives. The capability to form inclusion complexes has resulted in many pharmaceutical applications. Many drugs experience improved solubility, dissolution rate, permeability, absorption, bioavailability, physical state, volatility, partition coefficient, biological activity, and stability through complexation with cyclodextrins. Drug formulations with cyclodextrins are currently being sold in the market.

Fig.3 Some pharmaceutical products that have been approved and marketed contain CDs to minimize drug degradation[1].

Cyclodextrins increase stability, but they also have been shown to promote degradation of other drugs. Drug-CD complex stability varies based on the particular CD and drug combination. In the presence of low complexation efficiencies (CE), ternary complexes incorporating cofactors (e.g., amino acids, polymers, or organic bases) can enhance drug stability by modulating thermodynamic interactions. However, improper selection of ternary components may reduce complex efficiency. Scientists now extensively employ molecular modeling techniques to identify ideal excipients for drug CD formulations.

Table 1 List of drugs complexed with different cyclodextrins and their effect on drug stability^[1].

Case Study: Beta-Lactam Antibiotics and Cyclodextrins

Cyclodextrin derivatives significantly affect beta-lactam antibiotics that are susceptible to hydrolysis and degradation, such as penicillin. Research demonstrates that HP-β-CD and randomly methylated-β-cyclodextrin (RM-β-CD) regulate penicillin stability when exposed to acidic and alkaline environments. HP-β-CD protects the β-lactam ring from hydrolysis to stabilize penicillin at low pH but speeds up degradation at neutral to alkaline pH because it binds ionized penicillin less effectively. RM-β-CD demonstrates greater lipophilicity and reduced hydroxylation, which improves stability in acidic environments while showing reduced catalytic properties in alkaline conditions.

The process of hydroxymethylation in CD decreases its ability to catalyze reactions by restricting hydrogen bond formation with the β-lactam ring. For example, random methylation of γCD significantly improves penicillin stability by reducing catalytic hydrolysis. Highly methylated β-CD derivatives, such as hepta(2,3,6-tri-O-methyl)-βCD, enhance drug protection by eliminating CD-induced hydrolysis. In contrast, substitution with quaternary ammonium, sulfobutyl ether, or hydroxypropyl increased the hydrolytic degradation of β-lactam antibiotics.

Fig.4 Complexation of cyclodextrins with antibiotics and antimicrobial agents[2].

The results demonstrate that cyclodextrins serve dual functions in drug formulation while stressing the importance of appropriate CD selection based on medicinal chemistry needs and stability requirements. Drug delivery systems based on cyclodextrins could benefit from enhanced precision through upcoming research that combines molecular modeling with thermodynamic analysis.

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