A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance
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 str...
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Wiley
2009-01-01
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| Series: | International Journal of Analytical Chemistry |
| Online Access: | http://dx.doi.org/10.1155/2009/768743 |
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| author | Maria Victoria Silva Elipe Zhixin Jessica Tan Michael Ronk Tracy Bostick |
| author_facet | Maria Victoria Silva Elipe Zhixin Jessica Tan Michael Ronk Tracy Bostick |
| author_sort | Maria Victoria Silva Elipe |
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| description | 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 |
| format | Article |
| id | doaj-art-16d1035075644c3c93f30a7b89eeaadb |
| institution | Kabale University |
| issn | 1687-8760 1687-8779 |
| language | English |
| publishDate | 2009-01-01 |
| publisher | Wiley |
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| series | International Journal of Analytical Chemistry |
| spelling | doaj-art-16d1035075644c3c93f30a7b89eeaadb2025-02-03T06:13:22ZengWileyInternational Journal of Analytical Chemistry1687-87601687-87792009-01-01200910.1155/2009/768743768743A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug SubstanceMaria Victoria Silva Elipe0Zhixin Jessica Tan1Michael Ronk2Tracy Bostick3Department of Analytical Research and Development, Amgen Inc., Thousand Oaks, CA 91320, USADepartment of Analytical Research and Development, Amgen Inc., Thousand Oaks, CA 91320, USADepartment of Analytical Research and Development, Amgen Inc., Thousand Oaks, CA 91320, USAGenentech Inc., One DNA Way, Mail Stop 432A, South San Francisco, CA 94080, USAIn 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 impuritieshttp://dx.doi.org/10.1155/2009/768743 |
| spellingShingle | Maria Victoria Silva Elipe Zhixin Jessica Tan Michael Ronk Tracy Bostick A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance International Journal of Analytical Chemistry |
| title | A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance |
| title_full | A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance |
| title_fullStr | A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance |
| title_full_unstemmed | A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance |
| title_short | A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance |
| title_sort | multidisciplinary investigation to determine the structure and source of dimeric impurities in amg 517 drug substance |
| url | http://dx.doi.org/10.1155/2009/768743 |
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