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

Abstract

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. 1 H NMR spectroscopic studies showed the inclusion complexation between β-CD and LPR, based on the upfield shift changes in the β-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 β-CD as well as LPR protons and 2D ROESY spectral data to know the inclusion of LPR inside the β-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 β-CD cavity can be from narrower as well as the wider rim side and the six possible 1 : 1 LPR : β-CD inclusion complexes have been proposed. Thus, we anticipate that complexation of LPR with β-CD would increase its solubility and stability in biological system.

Enhancement of Loperamide Dissolution Rate by Liquisolid Compact Technique

“…10 Hence, it is necessary to improve the dissolution rate so as to improve the bioavailability of drug. Various techniques such as emulsion solvent diffusion technique, 12 β-Cyclodextrin inclusion complex 13 and oral disintegrating tablets 14 were reported previously. The present study was aimed to improve the dissolution rate of LPM using liquisolid compaction technique.…”

Synthesis and characterization of [N‐methyl‐3H]loperamide

“…However, this may not necessarily be the actual conformation of 1 in solution. The literature appears to contain only a single study of the proton NMR of 1 in solution. Examining the host–guest inclusion complexation of 1 with beta‐cyclodextrin, these authors also assigned the very same methyl chemical shift values (δ 2.33 and 2.95 ppm), which we observed for 4 but made no attempt to explain the dramatic differences for them.…”

Theoretical and Experimental Studies on Inclusion Complexes of Pinostrobin and β-Cyclodextrins

“…Interestingly, physical and biological properties were notably improved by a complexation with modified βCDs rather than parental βCD. In these studies the favorable orientation of the guest molecule binding within the lipophilic cavity of βCDs was characterized with various techniques e.g., differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) spectroscopy [ 18 , 19 , 20 ] and X-ray crystallography [ 21 , 22 ], as well as computational simulations [ 23 , 24 , 25 ]. For example, the solubility and anti-oxidant activity of apigenin was significantly increased with a 1:1 molar ratio between several βCD derivatives and apigenin [ 14 ].…”