Phase solubility and structure of the inclusion complexes of prednisolone and 6α-methyl prednisolone with various cyclodextrins

The purpose of this work was to study the inclusion binding interaction of two structurally related steroids, prednisolone and 6α-methyl prednisolone with a wide variety of cyclodextrins (CDs), both native (α-, β- and γ-CD) as well as modified (hydroxypropyl-, sulfobutyl ether-, glucosyl-, and maltosyl-β-CD and sulfobutyl ether-γ-CD), and to relate the binding constants to structural differences in the steroids. Phase-solubility diagrams of the steroids with various CDs were obtained. The stability constants (K1:1) revealed that β-CD formed the strongest complex with prednisolone, followed by γ-CD. With 6α-methyl prednisolone, the stability constants of both β- and α-CD were considerably lower compared with prednisolone. In contrast, γ-CD formed a stronger complex with 6α-methyl prednisolone compared with prednisolone. Derivatives of β-CD gave slightly altered stability constants compared with native β-CD. The structures of the complexes between the two guest molecules and native β-CD were studied by nuclear magnetic resonance spectroscopy. This clearly showed that the introduction of the methyl group led to a different binding geometry of 6α-methyl prednisolone compared with prednisolone. Additionally, the nuclear magnetic resonance results indicate the presence of an additional, weaker binding site, which is less populated in prednisolone. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:507–515, 2005