Quantitative NMR spectroscopy on fluorine-containing drugs - a comparative study on pharmaceutical raw materials and different dosage forms

Abstract: Nuclear Magnetic Resonance (NMR) is a technique with several advantages, such as high rapidity and easy operation as no sample specific standard or sample derivatization is required. Proton NMR is the most common NMR experiment, since hydrogen is “NMR active” and present in most organic compounds. Because of this, there is a high risk of overlapping signals in 1H-NMR spectra in samples containing multiple components, e.g. pharmaceutical preparations. Since Fluorine (19F) is “NMR active”, but not as common in organic molecules as hydrogen, peak overlapping is unlikely. A quantitative 19F-NMR method was therefore developed in this study.   Certain parameters (number of scans, relaxation delay, excitation frequency, pre-scan delay, spectral width & pulse angle) were examined during the method development, based on samples containing fludrocortisone acetate and 4,4´-difluorobenzophenone. For evaluation of the developed method, experiments were set up with different active pharmaceutical ingredients as well as pharmaceutical products. Good linearity and precision was obtained, and conclusions from the research experiments are that the developed method gives reliable purities compared to the reference method 1H-qNMR, and can therefore be used to achieve estimated assays on pharmaceutical raw materials. The method is also applicable on analysing registered pharmaceutical products as well as determining whether the strength of a suspected illegal drug is within the therapeutic range or not. Finally, the range of the method was determined to approximately 1-20 mg/mL, if examined on a 300 MHz NMR instrument.