Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studies
In the current scenario, the safety aspect related to impurities and their permissible level in the formulation has gained worldwide importance. The ICH (International Conference on Harmonization) guidelines and the official books have addressed this issue critically as it has tremendous regulatory...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Journal of Chromatography Open |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772391722000287 |
| _version_ | 1811201801532211200 |
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| author | Rahul S Chodankar Anand A. Mahajan |
| author_facet | Rahul S Chodankar Anand A. Mahajan |
| author_sort | Rahul S Chodankar |
| collection | DOAJ |
| description | In the current scenario, the safety aspect related to impurities and their permissible level in the formulation has gained worldwide importance. The ICH (International Conference on Harmonization) guidelines and the official books have addressed this issue critically as it has tremendous regulatory implications. The present research work addresses the above-mentioned issue for the drug riociguat and toxicity profiling of its degradation impurities. As per ICH Q1A (R2) guideline, the drug was subjected to various stress conditions wherein the drug generated three unknown degradants from the four that were detected. The degradants were separated and characterized using LC and LC-QTOF/MS studies. Better separation was achieved on Agilent's Zorbax XDB column (150 mm × 4.6 mm, 5 µm) using 10 mM ammonium formate (pH adjusted to 3.7 with formic acid) and acetonitrile in the ratio of 72:28 (v/v). The flow rate was 1.0 mL/min and detection was carried out by using UV detector at 322 nm. The chemical structures of all four degradants and drug were subjected for toxicity prediction using in-silico ADMET tools and their relative affinities towards the receptor was compared with riociguat by using molecular docking. The degradants were identified as 3-(diaziridin-3-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridine (DP1), methyl (4,6-diamino-2-(3H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)(methyl)carbamate(DP2), 2-(1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine(DP3) and 6-amino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (DP4). |
| first_indexed | 2024-04-12T02:26:39Z |
| format | Article |
| id | doaj.art-8e1f406ac24147f9a480fffd108f9e9a |
| institution | Directory Open Access Journal |
| issn | 2772-3917 |
| language | English |
| last_indexed | 2024-04-12T02:26:39Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Chromatography Open |
| spelling | doaj.art-8e1f406ac24147f9a480fffd108f9e9a2022-12-22T03:51:56ZengElsevierJournal of Chromatography Open2772-39172022-11-012100058Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studiesRahul S Chodankar0Anand A. Mahajan1Department of Pharmaceutical Chemistry, Goa College of Pharmacy, 18th June road, Panaji, Goa 403001, India; Corresponding author.Department of Pharmaceutical Analysis, Goa College of Pharmacy, 18th June road, Panaji, Goa 403001, IndiaIn the current scenario, the safety aspect related to impurities and their permissible level in the formulation has gained worldwide importance. The ICH (International Conference on Harmonization) guidelines and the official books have addressed this issue critically as it has tremendous regulatory implications. The present research work addresses the above-mentioned issue for the drug riociguat and toxicity profiling of its degradation impurities. As per ICH Q1A (R2) guideline, the drug was subjected to various stress conditions wherein the drug generated three unknown degradants from the four that were detected. The degradants were separated and characterized using LC and LC-QTOF/MS studies. Better separation was achieved on Agilent's Zorbax XDB column (150 mm × 4.6 mm, 5 µm) using 10 mM ammonium formate (pH adjusted to 3.7 with formic acid) and acetonitrile in the ratio of 72:28 (v/v). The flow rate was 1.0 mL/min and detection was carried out by using UV detector at 322 nm. The chemical structures of all four degradants and drug were subjected for toxicity prediction using in-silico ADMET tools and their relative affinities towards the receptor was compared with riociguat by using molecular docking. The degradants were identified as 3-(diaziridin-3-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridine (DP1), methyl (4,6-diamino-2-(3H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)(methyl)carbamate(DP2), 2-(1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine(DP3) and 6-amino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (DP4).http://www.sciencedirect.com/science/article/pii/S2772391722000287RiociguatStress studiesHPLCIn-silico toxicityLC-QTOF |
| spellingShingle | Rahul S Chodankar Anand A. Mahajan Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studies Journal of Chromatography Open Riociguat Stress studies HPLC In-silico toxicity LC-QTOF |
| title | Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studies |
| title_full | Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studies |
| title_fullStr | Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studies |
| title_full_unstemmed | Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studies |
| title_short | Identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in-silico studies |
| title_sort | identification and toxicity profiling of degradation impurities of riociguat using tandem mass spectrometry and in silico studies |
| topic | Riociguat Stress studies HPLC In-silico toxicity LC-QTOF |
| url | http://www.sciencedirect.com/science/article/pii/S2772391722000287 |
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