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