Structure and stability of warfarin-sodium inclusion complexes formed with permethylated monoamino-β-cyclodextrin

Gábor Tárkányi, Krisztina Németh, Réka Mizsei, Orsolya Todoubleacuteke, Júlia Visy, Miklós Simonyi, László Jicsinszky, Julianna Szemán, Lajos Szente

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11 Citations (Scopus)

Abstract

Inclusion complexes of warfarin enantiomers with permethylated monoamino-β-cyclodextrin (PMMABCD) were characterized using CE and 1H NMR spectroscopy in aqueous solution. These techniques gave complementary information on the stability and the structure of the diastereomeric host-guest inclusion complexes. The stability constants were determined from CE experiments in a wide pH range. Change in the migration order on the variation of the pH was observed. 1H NMR assignments have been established for the seven non-equivalent carbohydrate units of the host in the complex at pH 7-9. Specific H-H distance restraints were obtained from NOESY experiments and were introduced into molecular modeling to establish the geometry of the inclusion complexes. It was found that the open side chain warfarin enters the cavity from the primary side of the CD. The orientation of the coumarin ring within the cavity has the same preference for the two warfarin enantiomers owing to an ionic interaction with the amino group of the CD. Accordingly, enantioselectivity at pH 8.5 arises from the difference in the CH/π interactions between warfarin aromatics and the manifold of CH groups of the CD.

Original languageEnglish
Pages (from-to)292-298
Number of pages7
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume72
DOIs
Publication statusPublished - Jan 18 2013

Keywords

  • Cationic selector
  • Complex stability constant
  • Enantiomer migration order reversal
  • NOE distance restraints
  • Primary side inclusion

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry

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