Application of molecular modeling to the study of cyproterone acetate stability in the presence of cyclodextrin derivatives

• Published in: Journal of drug delivery science and technology Vol. 14; no. 5; pp. 357 - 362
• Main Authors: Henry de Hassonville, S., Dive, G., Evrard, B., Barillaro, V., Bertholet, P., Delattre, L., Piel, G.
• Format: Journal Article Web Resource
• Language: English
• Published: Elsevier B.V 2004; Editions Sante
• Subjects: Cyclodextrins; Cyproterone acetate; gamma-cyclodextrin; Human health sciences; methylated-beta-cyclodextrin; Methylated-β-cyclodextrin; Molecular modeling; Pharmacie, pharmacologie & toxicologie; Pharmacy, pharmacology & toxicology; Sciences de la santé humaine; Stability; γ-cyclodextrin; γ-cyclodextrin; Cyclodextrins; Stability; Cyproterone acetate; Molecular modeling; Methylated-β-cyclodextrin
• ISSN: 1773-2247
• DOI: 10.1016/S1773-2247(04)50064-3

The ability of cyclodextrins (CDs) to increase the solubility of cyproterone acetate (CPA) was previously shown by phase-solubility and NMR studies [1]. In the present work, the influence of various CDs on the stability of CPA was studied in pH6 and pH8 aqueous solutions at 25°C. Different CDs were tested: hydroxypropyl-β-cyclodextrin (HPβCD), randomly methylated β-cyclodextrin (RAMEB), hydroxypropyl-γ-cyclodextrin (HPγCD) and γ-cyclodextrin (γCD). At pH6, the presence of these CDs reduces the degradation of CPA. Nevertheless, at pH8, the γ-CD derivatives are ineffective against the degradation of CPA, whereas the β-CD derivatives (HPβCD and RAMEB) allow decreasing CPA hydrolysis. Molecular modeling was performed to theoretically calculate some of the most energetically favorable conformations for γ-CD and RAMEB complexes with CPA. The position of the ester group in the CD cavity seems to be the most important factor influencing the hydrolysis of CPA. Other factors, such as the size of the cavity, the substitution of the CD hydroxyls and the stability constant also have a strong incidence on CPA stability.