Identification of impurities in acarbose by using an integrated liquid chromatography‐nuclear magnetic resonance and liquid chromatography‐mass spectrometry approach

Abstract

The usefulness of applying an integrated LC-NMR and LC-MS approach to acarbose bulk drug impurity profiling is demonstrated. LC-MS and LC-NMR methodologies were employed for the online separation and structural elucidation of a final drug product. Combining data provided by the stop-flow LC-NMR and LC-MS experiments made it possible to identify the main components present in the acarbose sample. Spectral analysis revealed that A and B were known impurities while C was an unknown compound. LC-MS and LC-NMR analyses revealed that C was a pentasaccharide differing from the acarbose in number and nature of sugar subunits in the molecule. It was subsequently isolated and its structure was confirmed by the offline 1- and 2-D NMR experiments, and atom assignment was made.

NMR Spectroscopy for Studying Interactions of Bioactive Molecules

“…Kreutz et al [104] applied 19 F NMR spectroscopy to identify site-specific ligand-RNA binding. The approach relied on site-specific labelling of RNA with 2'-deoxy-2'fluoro(2'-F) nucleosides, thereby replacing the 2'-hydroxy group with a fluorine atom.…”

“…In modern drug discovery, NMR provides much more than macromolecular 3D structure determination since it has found widespread use in hit and lead generation, metabonomics and complex mixture analysis. Excellent discussions of the principles and applications of NMR techniques in metabonomics and mixture analysis can be found in a number of books and articles [14][15][16][17][18][19][20][21].…”

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

“…In our previous papers, we showed that an integrated approach, which combined LC-MS and LC-NMR, provided an efficient methodology for characterization of impurities and degradation products in final drug substances [15,16]. In this study, we further demonstrate the usefulness of LC-MS and LC-NMR for the rapid identification and structural elucidation of an unknown impurity in 5-aminosalycilic acid.…”

The Role of Analytical Chemistry in the Safety of Drug Therapy

“…Two of the rather rare applications of on-line (HP)LC-MS and -NMR are the identification of a pentasaccharide impurity in the tetrasaccharide drug [219] and the identification of 4-(4 0 -phenysulfonic acid) derivative as an impurity in 5-aminosalicylic acid [220]. For the solution of more complex problems, identification of minor impurities with difficult structures, enrichment of the impurity by on-line HPLC-SPE-NMR can be useful [221] as demonstrated by the elucidation of the structure of a pseudodimeric impurity in 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonylurea [222] (see Fig.…”