Cyclodextrin/imatinib complexation: Binding mode and charge dependent stabilities

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.