O. Bekers

Cyclodextrins in the Pharmaceutical Field

AbstractCyclodextrins (CyDs) are cyclic oligosaccharides, containing a minimum of six D-(+)-glycopyranose units attached by α-1, 4-linkages produced by the action of the cyclodextrin-trans-glycosidase enzyme on a medium containing starch. CyDs are somewhat cone-shaped. The outside of CyDs is hydrophilic and the inside of the cavity is hydrophobic in character. If a molecule fits entirely or at least partially into the cavity, an inclusion complex may be formed. In general, hydrophobic molecules, rather than hydrophilic ones, have a higher affinity to the CyD cavity in aqueous solutions. The CyD complexes thus formed are stabilized by various intermolecular forces, such as hydrophobic interaction, van der Waals forces, hydrogen bonding, release of high energy water molecules in complex formation and release of strain energy in the macromolecular CyD ring. Orally administered CyDs have shown to be harmless, because insignificant amounts are absorbed.Parenterally administered natural CyDs may cause severe ne...

Inclusion complexation of doxorubicin and daunorubicin with cyclodextrins

The interaction of alpha-, beta- and gamma-cyclodextrins with the anthracycline antibiotics doxorubicin and daunorubicin was investigated by LC, circular dichroism (CD) and absorption spectroscopy. All studies were performed in aqueous media at different temperatures and pH values. The anthracyclines complex only with gamma-cyclodextrin. Lineweaver-Burk and Scotts plots were used to calculate the stability constants of the anthracycline-gamma-cyclodextrin inclusion complexes.

Stabilization of mitomycins on complexation with cyclodextrins in aqueous acidic media

Abstract The effect of various cyclodextrins (α-, β-, dimethyl-β- and γ-cyclodextrin) on the acidic hydrolysis of several mitomycin antibiotics was investigated using a stability-indicating ultraviolet spectrophotometry assay. The mitomycins appear to complexate most prominently with γ-cyclodextrin. Although the degradation pattern does not change, complexation results in a decrease in degradation rate. The influences of the γ-cyclodextrin concentration as well as pH, ionic strength, buffer components and temperature on the complex stability were studied. The structure of the mitomycin C-γ-cyclodextrin inclusion complex has been proposed on the basis of nuclear magnetic resonance spectroscopic measurements.

Effect of cyclodextrin complexation on the chemical stability of doxorubicin and daunorubicin in aqueous solutions

Abstract The influences of cyclodextrins on the chemical stability of the antineoplastic drugs doxorubicin and daunorubicin in aqueous media have been studied using a stability-indicating high-performance liquid chromatographic method. Various parameters, such as cyclodextrin structure, pH, structure of the anthracycline, cyclodextrin concentration and the presence of a co-solvent, were investigated. In the acidic region, the degradation rates of both doxorubicin and daunorubicin decrease in the presence of γ-cyclodextrin, whereas α- and β-cyclodextrin show no effect in acid as well as in alkaline media. Above pH 4 the degradation of daunorubicin is accelerated by γ-cyclodextrin, while for doxorubicin this effect is only observed in strong alkaline solutions. On complexation, the order of the reactions as well as the degradation mechanisms of the anthracyclines do not change. In the presence of acetonitrile the anthracycline-γ-cyclodextrin complexes decompose because the organic co-solvent is embedded in the cavity of the cyclodextrin host.

A rapid, simple and accurate method for the bioanalysis of zidovudine

Abstract A rapid and simple method has been developed for the bioanalysis of zidovudine, a new antiviral drug, which has proven to show some effectiveness in the treatment of AIDS and AIDS-related complex. After extraction of the compound from the biological matrix with ethyl acetate, evaporation of the organic solvent and reconstitution of the residue with methanol reversed-phase HPLC on RP8 material is applied with 1% acetate buffer pH 5-methanol (82/18, v/v) as the solvent, and detection at 265 nm. Detection limits in plasma and urine were 20 and 200 ng/ml, respectively. The method has been validated with a single dose pharmacokinetic study in an AIDS patient.

Effect of cyclodextrins on the chemical stability of mitomycins in alkaline solution

The effects of cyclodextrins on the chemical stability of several mitomycin antibiotics in an alkaline medium have been investigated. A stability-indicating high-performance liquid chromatographic method was used to determine the overall degradation rate constants. The influence of various parameters such as structural variations of the cyclodextrins and mitomycins, temperature and pH was studied. It appears that complexation is most favourable with gamma-cyclodextrin. All mitomycin-gamma-cyclodextrin complexes degrade at lower rates than those of the free drugs. Moreover, it was shown that gamma-cyclodextrin influences the equilibrium between mitomycin C and its zwitterion mesomer.

Effect of cyclodextrins on anthracycline stability in acidic aqueous media

The effect of cyclodextrins on the stability of six anthracyclines in acidic medium at 50°C has been investigated using a stability-indicating high pressure liquid Chromatographic method. The influences of various parameters, such as the structure of cyclodextrins (α-cyclodextrin, β-cyclodextrin, dimethyl-β-cyclodextrin and γ-cyclodextrin) and anthracyclines, cyclodextrin concentration, the pH and the presence of a co-solvent, are investigated. Lineweaver-Burk plots were used to calculate the stability constants of the various inclusion complexes as well as the rate constants for degradation of the anthracycline guest molecules in the complexes with the host cyclodextrins. Anthracyclines complexate only with γ-cyclodextrin to a substantial extent. On complexation the stability of the guest molecule increases, however, the degradation pattern does not alter. The influence of the pH on the degradation of the included molecule is identical to that of the free drug. Addition of co-solvents, such as acetonitrile, causes decomposition of the complex.

A general approach to the interpretation of pH degradation profiles in the presence of ligands

Abstract A general equation of pH-dependent degradation profiles of polybasic weak electrolytes in the presence of a ligand is presented. The potential information which can be deduced from such profiles is discussed. The method is graphically illustrated with a hypothetical example.

Stabilization of daunorubicin and 4-demethoxydaunorubicin on complexation with octakis(2,6-di-O-methyl)-γ-cyclodextrin in acidic aqueous solution

Abstract The effects of octakis(2,6-di-O-methyl)-γ-cyclodextrin (DM-γ-CyD) on the chemical stability of the anthracycline antibiotics daunorubicin (Dr) and 4-demethoxydaunorubicin (4-demethoxyDr) in acidic aqueous media have been investigated. As determined from the analysis of inclusion complexation of anthracyclines with CyDs, DM-γ-CyD displayed the highest stabilizing ability, followed in descending order by 3-hydroxypropyl-γ-CyD > γ-CyD > hydroxyethyl-γ-CyD, whilst octakis(2,3,6-tri-O-methyl)-γ-CyD showed no effect. Nevertheless, 4-demethoxyDr formed a much more stable inclusion complex with DM-γ-CyD; surprisingly, the effect of stabilization by DM-γ-CyD is significantly smaller compared with Dr. 1H-NMR data indicate that the aglycone region of the anthracycline molecule is included within the DM-γ-CyD cavity.

Effects of cyclodextrins on N-trifluoroacetyldoxorubicin-14-valerate (AD-32) stability and solubility in aqueous media

The effects of cyclodextrins on the chemical stability of N-trifluoroacetyldoxorubicin-14-valerate (AD-32) have been investigated using a stability-indicating HPLC assay. The influences of various parameters, such as structure of the cyclodextrin, cyclodextrin concentration and pH, were studied. A phase solubility study of AD-32 with different cyclodextrins has been performed and it was found that all cyclodextrins resulted in an A-type phase-solubility diagram, whereas hydroxypropyl-β-cyclodextrin has the largest solubilizing effect.