Inclusion of the niflumic acid anion in β-cyclodextrin:: A solution NMR and X-ray structural investigation

We report parallel solution and solid state studies of the inclusion of the anionic form of the non-steroidal anti-inflammatory drug niflumic acid (2-[[3-(trifluoromethyl)phenyl]-amino]-3-pyridinecarboxylic acid) in the host beta-cyclodextrin (beta-CD). H-1 NMR data for the interaction between host and guest in aqueous solution recorded at 300 MHz indicated a strong preference for insertion of the trifluoromethylphenyl residue, rather than the pyridinecarboxylate moiety, in the host cavity. A 1:1 complex stoichiometry was determined by the continuous variation method utilising chemical shifts of both host and guest protons. Analysis of the data using a new flexible program developed for this purpose yielded an overall association constant K of 336 M-1 at 298 K. The NMR data indicate a dynamic equilibrium between complexed and uncomplexed species but do not distinguish guest entry from the primary and secondary sides of the host. Reaction between the Cs+ salt of niflumic acid and beta-CD yielded the crystalline complex (beta-CD)(2)(.)(Cs+ niflumate(-))(4)(.)22H(2)O whose single crystal X-ray structure was determined. A novel inclusion mode for this host, namely entry of guest trifluoromethylphenyl residues from both the primary and secondary sides, was revealed by the X-ray analysis.