Solution structure of loperamide and β-cyclodextrin inclusion complexes using NMR spectroscopy

Loperamide (LPR) is a synthetic, poorly water soluble, peripherally acting opiate agonist drug used for the treatment of diarrhea. Major challenges in formulating this drug for clinical applications include solubility enhancement and improved stability in biological systems. Cyclodextrins (CDs) are chiral, truncated cone shaped; cyclic oligosaccharides that can encapsulate a variety of poorly water soluble drug molecules into inclusion complexes, thereby increasing their stability and solubility. H-1 NMR spectroscopic studies showed the inclusion complexation between beta-CD and LPR, based on the upfield shift changes in the beta-CD cavity protons (H-3' and H-5') and downfield shift changes in the guest (LPR) protons. 2D COSY spectral data was used for assignment of beta-CD as well as LPR protons and 2D ROESY spectral data to know the inclusion of LPR inside the beta-CD cavity. The 1 : 1 stoichiometry and overall association constant (K-a) were determined by using Scott's plot method to be 68-805 M-1. 2D ROESY spectral data suggest that the inclusion of aromatic rings of LPR in beta-CD cavity can be from narrower as well as the wider rim side and the six possible 1 : 1 LPR : beta-CD inclusion complexes have been proposed. Thus, we anticipate that complexation of LPR with beta-CD would increase its solubility and stability in biological system.