Comparison of the Complexation between Methylprednisolone and Different Cyclodextrins in Solution by 1H-NMR and Molecular Modeling Studies

ABSTRACTComplexation in solution between methylprednisolone and three different cyclodextrins [2-hydroxypropyl-β-cyclodextrin (HP-β-CD), γ-cyclodextrin (γ-CD), and 2-hydroxypropyl-g-cyclodextrin (HP-γ-CD)] was studied using phase solubility analysis, one and two-dimensional 1H-NMR and molecular modeling. Estimates of the complex formation constant (K1:1) show that the tendency of methylprednisolone to complex with CDs follows the order: γ-CD > HP-γ-CD > HP-β-CD. The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (H-3′, H-5′, and H-6′) coupled with minimal variation of shifts from protons located on the outer sphere of γ-CD (H-1′, H-2′, and H-4′) provided clear evidence of inclusion complexation. The molecular modeling study, indicated inclusion complexation between methylprednisolone and γ-CD and HP-γ-CD by entrance of the A and B rings of methylprednisolone into the CD cavity from its bigger rim. For the methylprednisolone: HP-β-CD complex, the molecular modeling study could not be carried out; hence, two possibilities of complex formation are proposed: (1) methylprednisolone enters HP-β-CD from the wider rim by its D and C ring, (2) the A and B ring of methylprednisolone enters deeper in to the CD cavity so that a part of the A ring of steroidal structure is outside of the cavity. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3863–3873, 2010