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International Journal of Analytical Chemistry
Volume 2009 (2009), Article ID 768743, 12 pages
Research Article

A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance

1Department of Analytical Research and Development, Amgen Inc., Thousand Oaks, CA 91320, USA
2Genentech Inc., One DNA Way, Mail Stop 432A, South San Francisco, CA 94080, USA
3Chemical Process Research and Development Department, Amgen Inc., Thousand Oaks, CA 91320, USA

Received 27 August 2008; Accepted 10 October 2008

Academic Editor: Peter L. Rinaldi

Copyright © 2009 Maria Victoria Silva Elipe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


In the initial scale-up batches of the experimental drug substance AMG 517, a pair of unexpected impurities was observed by HPLC. Analysis of data from initial LC-MS experiments indicated the presence of two dimer-like molecules. One impurity had an additional sulfur atom incorporated into its structure relative to the other impurity. Isolation of the impurities was performed, and further structural elucidation experiments were conducted with high-resolution LC-MS and 2D NMR. The dimeric structures were confirmed, with one of the impurities having an unexpected C-S-C linkage. Based on the synthetic route of AMG 517, it was unlikely that these impurities were generated during the last two steps of the process. Stress studies on the enriched impurities were carried out to further confirm the existence of the C-S-C linkage in the benzothiazole portion of AMG 517. Further investigation revealed that these two dimeric impurities originated from existing impurities in the AMG 517 starting material, N-acetyl benzothiazole. The characterization of these two dimeric impurities allowed for better quality control of new batches of the N-acetyl benzothiazole starting material. As a result, subsequent batches of AMG 517 contained no reportable levels of these two impurities