On the utility of nonuniformly sampled two‐dimensional NMR spectra in the pharmaceutical industry

Abstract

In this work, we discuss representative examples of the application of nonuniform sampling (NUS) in small-molecule structure determination in a pharmaceutical research and development and quality control setting. We demonstrate the advantages of NUS over traditional sampling in various industrial applications of nuclear magnetic resonance (NMR). We propose an optimal trade-off between the quality and the time efficiency of 'routine' measurements, as demonstrated via a test sample of vinpocetine analyzed on a 'work horse' NMR spectrometer. In addition, we present case studies where the application of NUS contributed significantly to the successful completion of some challenging structure determination task at hand. To that end, in some cases, we combined NUS with a method of decoupling in the indirect dimension that gives 'constant time' nuclear Overhauser effect spectroscopy (NOESY) and 'constant time' heteronuclear multiple bond correlation (HMBC) spectra. NUS proved to be superior over traditional sampling even for the analysis of trace impurities, where the need to cope with a thousand-fold or even larger dynamic range and low signal-to-noise ratio for the impurity signals is quite a challenge.

An approach to fast 2D nuclear magnetic resonance at low concentration based on p‐H2‐induced polarization and nonuniform sampling

“…Conversely, by acquiring only a fraction of the points on the Nyquist grid, it is possible to significantly reduce the measurement time. This is important also for 2D NMR of small molecules as demonstrated by the NUS applications in the context of pharmaceutical research [ 21 ] and metabolomics. [ 22 ]…”

An Optimized Two-Dimensional Quantitative Nuclear Magnetic Resonance Strategy for the Rapid Quantitation of Diester-Type C19-Diterpenoid Alkaloids from Aconitum carmichaelii

“…Although relaxation optimization by adding Cr(acac) 3 could reduce the experimental time by 80%, it still reached 2.5 h (Table 2), which was unacceptable for 2D HSQC qNMR due to the limitation of machine hours and high price of NMR experiments. NUS is a multidimensional NMR data acquisition method that can decrease the acquisition time without loss of spectral integrity and is widely used in the pharmaceutical industry 46 and for metabolic analysis. 47 Compared to traditional sampling mode, NUS collects proportional data points in a random manner and then reconstructs the 2D NMR data using CS, multidimensional decomposition (MDD), maximum entropy (MaxEnt), multidimensional Fourier transform (MFT), or sparse multidimensional iterative lineshapeenhanced (SMILE) reconstruction.…”

Applications of alternative sampling methods

“…Further, the applications of alternative sampling in the solid-state, where NMR experiments are still usually performed in a classical manner, are described by Porat et al [3] and Paluch et al [4] The former describes the acceleration of high-dimensional (4D) acquisition, while the latter the application of the Hadamard approach. Also, medical applications are described, including Hoyt et al [5] and Szigetvári et al [6] discussing the applications of NUS in the pharmaceutical industry, while Jeeves et al [7] and Joseph et al [8] show how NUS can be useful in metabolomics.…”