New NMR Tools for Impurity Analysis

Common characterization methods for pharmaceutical drugs include HPLC, mass spectrometry, 1H NMR, and 13C NMR. NMR is rich in structural information, but for impurity analysis, it is not generally the tool of choice. While 1H NMR is quite sensitive, due to its narrow chemical shift range (0 - 10 ppm) and the high abundance of hydrogen atoms in most drugs, its resolution is often poor, with much signal overlap. Impurity signals, especially for chemically cognate species, are therefore frequently obscured in 1H NMR.About a quarter of current drugs contain fluorine. 19F NMR shares the relatively high sensitivity of 1H NMR, but has a far wider chemical shift range, of ± 300 ppm. Since typical drugs contain only one or two fluorine atoms, 19F NMR therefore offers extremely high resolution for pharmaceutical applications. However, the very wide spectra seen in fluorine NMR present a significant technical problem. Modern NMR spectrometers are designed to give quantitative excitation of 1H spectra, and to a lesser extent 13C spectra, but the limited power of the radiofrequency amplifiers used means that it is not possible to excite a full 19F spectrum uniformly with conventional methods. This means that it is common in quantitative NMR (qNMR) to acquire fluorine spectra in sections, with a separate reference compound for each chemical shift range.In this presentation, new methods for exciting the full range of 19F signals are explored. A new type of pulse sequence, CHORUS, is presented that increases the quantitative bandwidth of NMR measurements, yielding accurate integrals even for nuclei such as 19F that have very wide chemical shift ranges. Using CHORUS it is possible to obtain excellent results for quantitative 19F NMR, with accuracies better than 0.1% over the entire chemical shift range, in a single experiment. The new family of pulse sequences can also be used to extend the range of many other NMR experiments, for example diffusion-ordered spectroscopy (DOSY), which disperses the signals of different species in an intact mixture according to their diffusion coefficients.