Molecular modeling study of β- and γ-cyclodextrin complexes with miconazole

Different authors have demonstrated the inclusion of miconazole in cyclodextrins (CD). Miconazole can be included in the CD cavity both in the neutral and in the ionized form. The present study tries to understand which fragment of the miconazole molecule is involved in the inclusion. Austin Model 1 approximate molecular orbital calculations have been performed on several complexes between beta -cyclodextrin (beta CD) or gamma -cyclodextrin (gamma CD) and miconazole in the ionized and the non-ionized forms of the two R and S enantiomers in three different orientations. We observed that beta CD is a good vehicle to transport miconazole which can be very easily released. The complexation energy between miconazole and beta CD is not very high but the entropic factor has a great incidence on the stability of the formed complex. The inclusion of the dichlorobenzene-CH2-O- and of the imidazole part of the S isomer gives rise to the most probable complex in acidic conditions (ionized miconazole). Nevertheless, the inclusion should be considered as a dynamic process in which different parts of the molecule could be alternatively included in beta CD. The present work demonstrates the high capability of deformation of beta CD which could easily accommodate several types of ligand. By opposite, the cycle extension in gamma CD leads to a more rigid vehicle with regards to miconazole. (C) 2001 Elsevier Science B.V. All rights reserved.