19F-nuclear magnetic resonance spectroscopy as a tool to investigate host-guest complexation of some antidepressant drugs with natural and modified cyclodextrins
Purpose: 19F-Nuclear magnetic resonance spectroscopy (19F-NMR) was used to study host-guest complexation of three fluorine containing antidepressant drugs, viz, fluoxetine hydrochloride, citalopram hydrobromide and fluvoxamine maleate, with various cyclodextrins (CD), including α-, β-cyclodextrin, methylated α-cyclodextrin (M-α-CD), diamino derivative of methylated α-cyclodextrin, (DAM-α-CD) and tetramino derivative of methylated α-cyclodextrin (TAM-α-CD).
Methods: Using the mole ratio method, a 1:1 stoichiometry was determined for the resulting inclusion complexes. 19F chemical shifts were used to determine the formation constant of the complexes. Experiments were performed with solutions containing 0.001 M drug and various concentrations of CDs. NMR data were plotted as 19F chemical shift versus CD/drug mole ratio, and fitted using the nonlinear least-squares curve fitting program, KINFIT, to obtain the formation constant of CD-drug complex. Molecular modeling (MM) calculations were used to predict the geometry of the complex of fluvoxamine and β-CD. Molecular modeling studies were performed in vacuum phase, employing empirical force fields and semi-empirical quantum theory using AM1 Hamiltonian.
Results: Complex formation caused separation of the fluorine peaks that can be assigned to the two enantiomers of fluoxetine hydrochloride. Molecular modeling data suggest that fluvoxamine/β-CD inclusion complexes have a 1:1 stoichiometry and that the CF3-substituted ring of fluvoxamine is embedded in the cavity of β-CD, indicating a good agreement between molecular modeling calculation and experimental data (NMR data).
Conclusion: One-dimensional 19F-NMR is a fast and convenient method for the determination of complex stoichiometry and complexation constants of natural and modified CDs and fluorinated drugs.
Keywords: Antidepressant drugs, Cyclodextrins, Complexation, Inclusion complex, Formation constant, 19F-NMR