Cyclodextrin/imatinib complexation: Binding mode and charge dependent stabilities

Szabolcs Béni, Zoltán Szakács, Orsolya Csernák, Lajos Barcza, Béla Noszál

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Host-guest interactions in various protonation forms of the anticancer drug imatinib with beta-cyclodextrin (CD) and randomly methylated beta-CD (RAMEB) have been investigated using techniques of proton magnetic resonance spectroscopy (1H NMR), phase solubility, pH-potentiometry and electrospray ionization mass spectrometry (ESI-MS). Phase-solubility analysis showed AL-type diagram with beta-CD, which suggested the formation of 1:1 inclusion complexes. The 1:1 stoichiometry was confirmed by potentiometry in aqueous solution and by ESI-MS in the gas phase. Charge-specific stability constants of the neutral, mono-, di-, and tricationic forms of imatinib were determined for both the beta-CD and RAMEB. Stability of the beta-CD complexes shows an unexpected minimum at the monoprotonated form, while a stepwise decrease with increasing guest charge was observed for RAMEB. The 1:1 complex stoichiometry and stability constants of selected imatinib protonation species were verified by 1H NMR titrations. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out to identify the interacting host-guest moieties. The observed ROESY cross-peaks indicated spatial proximities between several aromatic hydrogens of imatinib and β-CD protons, revealing that the inclusion occurs by accommodation of the benzamide ring of imatinib.

Original languageEnglish
Pages (from-to)167-174
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume30
Issue number2
DOIs
Publication statusPublished - Feb 1 2007

    Fingerprint

Keywords

  • Gleevec
  • H NMR-titration
  • Inclusion complex
  • Potentiometry
  • ROESY
  • Stability constant

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this