Application of LC-NMR to the identification of bulk drug impurities in GART inhibitor AG2034

Abstract

Liquid chromatography (LC)–NMR spectroscopy was used to obtain detailed information regarding the structure of a bulk drug impurity present in glycinamide ribonucleotide transformylase (GART) inhibitor AG2034. The LC–NMR experiments (1D 1H and 2D TOCSY) were performed in the stop‐flow mode on crude retained impurity‐enriched samples of the synthetic precursor to AG2034. Comparative analysis of the data for the parent compound with those for the impurity indicated that the impurity was nearly a dimer of the parent, and allowed all major substructures to be delineated. The structural information derived from both LC–NMR and LC–MS data provided insights into purification methods, which ultimately led to the full characterization of the impurity by high‐resolution NMR spectroscopy. Copyright © 1999 John Wiley & Sons, Ltd.

Determination of organic impurities in pharmaceutical preparations

“…It requires the use of several independent approaches. The problem can be partially solved by HPLC using the diode-array UV detector [58,[70][71][72][73][74][75], mass spectrometer (MS) [51,71,[76][77][78][79], and nuclear magnetic resonance (NMR) spectrometer [50,60,72,[80][81][82][83][84][85].…”

“…NMR spectrometry is finding increasing application for the identification of unknown organic impurities in pharmaceutical preparations [50,60,72,[80][81][82][83][84][85]. This method is highly informative and allows conclusions to be drawn on the structure of the components in a mixture of related compounds because the form of the NMR spectrum changes on even an insignificant change in the geometry of the molecule and bond orders.…”

“…Commonly, NMR is used to obtain and confirm data on the structure of molecular fragments formed in MS. In some cases, only the combination of NMR and MS gives the full information on the structure of the studied component [50,72,82,84,90]. NMR spectrometry also allows the quantitative determination of impurities; however, its low sensitivity and poor reproducibility are substantial limitations of the method.…”

Hyphenated HPLC-NMR and its applications in drug discovery

“…On-line LC-NMR has been employed to identify bulk drug impurities in a glycinamide ribonucleotide transformylase inhibitor compound (Potts et al, 1999). In this study, both one-and two-dimensional 500 MHz NMR spectra were acquired to fully characterize the structure of a drug impurity (60 mg injected) in the stop-flow mode.…”

The application of LC–NMR and LC–MS for the separation and rapid structure elucidation of an unknown impurity in 5-aminosalicylic acid

“…Recently, improvements in cryotechnology, capillary columns and micro-coil probes [7], as well as coupling of the solid-phase extraction [8] have drastically increased the sensitivity of LC-NMR experiments, which in turn made it possible to analyze compounds in the low nanogram quantities. In the last decade LC-NMR and LC-NMR-MS have been widely used to analyze natural products and drug metabolites [6][7][8][9][10][11][12], however, drug impurities and their degradation products have less frequently been reported in the literature [13,14].…”