Similar modes of inclusion in complexes of β-cyclodextrin with sulfonylureahypoglycemic drugs

Abstract

In an attempt to gain insight in the mode of inclusion of sulfonylurea hypoglycemic drugs into β-cyclodextrin (βCD), the molecular structures of the inclusion complexes of three such drugs, tolbutamide (TBM), tolazamide (TLZ) and glimepiride (GLP), have been determined for the first time by X-ray crystallography. The drugs share a common moiety, a H-bond forming sulfonylurea group in the middle, flanked by a tolyl-group at one end and an additional hydrophobic group (different in the three drugs) at the other end, GLP being further elongated by a 2-pyrrolidinone moiety at the tolyl end. The structures of the inclusion complexes comprise βCD dimers aligned in channels. The hydrophobic groups enter the cavities of two adjacent βCD dimers from the primary sides, whereas the hydrophilic sulfonylurea moiety is located in-between, forming H-bonds with the hosts without disturbing the dimers. In the GLP/βCD complex, the pyrrolidinone extension threads the βCD cavity and emerges from the secondary side. These results are supported by NMR 2D ROESY spectra in aqueous solutions. The extended length of GLP imposes a change in the crystal packing placing the βCD dimers further apart. However, the overall inclusion mode of the three drugs is the same, thus a common inclusion and crystallization process is proposed for sulfonylurea drugs. The structures of the complexes explain the effects of complexation on dissolution, bioavailability and hypoglycemic activity.