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Host-guest chemistry of the sulfasalazine-β-cyclodextrin inclusion complex

M. N. Tahir,Yihong Cao,A. Azzouz,R. Roy

Published 2021 in Tetrahedron

ABSTRACT

ABSTRACT Sulfasalazine (SLZ) is an azo drug used for the treatment of rheumatoid arthritis and ulcerative colitis. Its limited water solubility results into low permeability and bioavailability leading to higher daily recommended doses and greater side effects. Host-guest complexation of drugs with β-cyclodextrin (β-CD) is a common strategy to improve oral bioavailability and drug delivery. Traditional studies of inclusion complexes between SLZ and β-CD have been merely limited to UV analysis. We present herein, several structural evidences describing the detailed molecular architecture and binding constant of the inclusion complex using 1H-NMR spectroscopy, isothermal titration calorimetry, ATR-IR spectroscopy, thermogravimetric analysis, and molecular modelling. Both 1H-NMR and ITC methods converged toward closed values of Ka 1175 and 1220 M-1, respectively for the SLZ-β-CD inclusion complex. The modelling experiments also helped supporting the relative orientation of the SLZ into β-CD. The analysis revealed that SLZ integrates to β-CD exclusively from the benzoic acid end group and not through the pyridine residue which is otherwise precluded because of its tilted structure that formed steric hindrance with the β-CD residues. In addition, immobilization of SLZ through its benzoic acid residue on CM5 sensor chip using surface plasmon resonance spectroscopy completely abolished the inclusion complex formation with β-CD. This comprehensive study of SLZ inclusion complexation with β-CD allows envisaging alternative strategies to improve SLZ solubility, bioavailability, and permeability for therapeutic applications.

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