Examination of 19F-NMR as a tool for investigation of drug-cyclodextrin complexes

Fluorine nuclear magnetic-resonance spectroscopy (19F-NMR) was used to measure complexation of three fluorine-containing drugs--dexamthasone, fluoxetine hydrochloride, and diflunisal sodium--with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). Poor aqueous solubility inhibited investigation of dexamethasone complexes with this method. Complexation caused separation of the fluorine peaks that could be assigned to the two enantiomers of fluoxetine hydrochloride. The trifluoromethyl group of the drug was not included, or only partially included, in the cyclodextrin cavity and the shift changes resulting from complexation were small (0.04 and -0.05 ppm). The NMR method, therefore, could not be used to determine complex stoichiometry and complex stability constants, as chemical-shift changes were influenced by changes in the composition of the solvent medium. The difluorophenyl group of diflunisal sodium was fully included in the cyclodextrin cavity and the chemical-shift changes were large, 2.0 and 1.4 ppm, for C2' and C4' fluorine atoms, respectively. Using the continuous variation method, a 1:1 stoichiometry was determined for the complex. The chemical shift changes could also be used to determine the stability constant (Kc) for complex formation. The value obtained for the fluorine that enters deeper into the cavity was 2000 M(-1). The data shows that, given that the drug has sufficient solubility, one-dimensional 19F-NMR can be a fast and convenient method to investigate drug-cyclodextrin complexes. However, when the results are interpreted it must be taken into account that the solvent medium can affect the chemical shifts of the fluorine peaks.