Complexation of steroid hormones with cyclodextrin derivatives: substituent effects of the guest molecule on solubility and stability in aqueous solution.
The inclusion complexation of homologous derivatives of steroid hormones with cyclodextrins and 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) was investigated with regard to underlying structure-interaction relationship. The interaction was studied by phase solubility analysis and stabilization effects of complex formation with 2-HP-beta-CD. The solubilizing and stabilizing abilities of 2-HP-beta-CD were generally more effective for testosterone derivatives than for estradiol esters. Within a homologous series of steroid hormones, the steepest linear solubility isotherms were found for 17-methyl and 3-methyl derivatives. The solubilization of steroid esters by 2-HP-beta-CD depended on the structure and length of the ester side chain. The interaction of 2-HP-beta-CD with the steroids was hindered by long-chain fatty acid ester groups. With increasing length of the side chain, a decline of the isotherms occurred and the phase solubility behavior changed from linear to exponential. Contrary to expectations, benzoylation of steroids considerably decreased the guest-host interaction. The observed rates of degradation of the steroid esters were significantly reduced by 2-HP-beta-CD, depending on the chain length, and correlated well with the order found in phase solubility analysis. The degradation showed no deviations from pseudo-first-order kinetics, and the degradation mechanism was not changed because of complexation. The results suggest that interaction of 2-HP-beta-CD with steroid esters involves the ester functions of the prodrugs and is more suitable for unsubstituted guest molecules.
Albers
E
E
Department of Pharmaceutical Development, Byk Gulden Research Centre, Konstanz, Germany.
Müller
B W
BW
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000728:Androgens / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry*; D004355:Drug Stability; D004952:Esters / Q000737:chemistry; D004958:Estradiol / Q000031:analogs & derivatives / Q000737:chemistry; D006728:Hormones / Q000737:chemistry*; D007700:Kinetics; D009994:Osmolar Concentration; D011355:Prodrugs / Q000737:chemistry; D012995:Solubility; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship; D047392:beta-Cyclodextrins
D000728:Androgens; D003505:Cyclodextrins; D004952:Esters; D006728:Hormones; D011355:Prodrugs; D013256:Steroids; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D004958:Estradiol