دورية أكاديمية
Discerning the stability behaviour of mavacamten availing liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy: In silico toxicity and mutagenicity prediction of degradation products.
| العنوان: | Discerning the stability behaviour of mavacamten availing liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy: In silico toxicity and mutagenicity prediction of degradation products. |
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| المؤلفون: | Golla VM; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, India., Kalyan M; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, India., Gholap U; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, India., Padhy HP; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, India., Ramachandran RK; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, India., Samanthula G; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, India. |
| المصدر: | Journal of mass spectrometry : JMS [J Mass Spectrom] 2024 Mar; Vol. 59 (3), pp. e5007. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley Country of Publication: England NLM ID: 9504818 Publication Model: Print Cited Medium: Internet ISSN: 1096-9888 (Electronic) Linking ISSN: 10765174 NLM ISO Abbreviation: J Mass Spectrom Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Chichester, UK : Wiley, c1995- |
| مواضيع طبية MeSH: | Mutagens*/toxicity , Liquid Chromatography-Mass Spectrometry* , Benzylamines* , Phenethylamines*, Uracil/*analogs & derivatives, Magnetic Resonance Spectroscopy |
| مستخلص: | The present study aimed to separate, identify, and characterise the degradation products formed when mavacamten is exposed to stress degradation as well as the stability of the drug in various environments and also to understand its degradation chemistry. Prediction of in silico toxicity and mutagenicity was aimed at the observed degradation products. Stress degradation along with stability studies and degradation kinetics were performed on mavacamten, and separation of degradation products was carried out by high-performance liquid chromatography. Tandem mass spectrometry studies were executed to characterise the structures of degradation products using product ion fragments. Orthogonally, nuclear magnetic resonance experiments were conducted to elucidate the structures having ambiguity in characterising them. Deductive Estimation of Risk from Existing Knowledge and Structure Activity Relationship Analysis using Hypotheses software were used to establish in silico toxicity and mutagenic profiles of mavacamten and its degradation products. Two degradation products of mavacamten found in acidic hydrolytic stress conditions were separated, identified, characterised, and proposed as 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione and 1-phenylethanamine. Mavacamten was found to be stable under different pH and gastrointestinal conditions. The degradation kinetics of mavacamten under 1 N acidic condition followed zero-order kinetics, and it was degraded completely within 6 h. In silico toxicity and mutagenicity studies revealed that 1-phenylethanamine can be a skin sensitiser. A high-performance liquid chromatography method was developed for the separation of degradation products of mavacamten and characterised by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance. During the manufacturing and storage of drug product, precautions need to be taken when dealing with acidic solutions as the drug is prone to hydrolysis in acidic conditions. The formation of 1-phenylethanamine under these conditions is to be monitored as it is a skin sensitiser. (© 2024 John Wiley & Sons Ltd.) |
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| فهرسة مساهمة: | Keywords: degradation chemistry; in silico studies; mass spectrometry; mavacamten; nuclear magnetic resonance |
| المشرفين على المادة: | 0 (Mutagens) HZ9DM6B2MT (1-phenethylamine) 0 (MYK-461) 0 (Benzylamines) 0 (Phenethylamines) 56HH86ZVCT (Uracil) |
| تواريخ الأحداث: | Date Created: 20240306 Date Completed: 20240307 Latest Revision: 20240307 |
| رمز التحديث: | 20240307 |
| DOI: | 10.1002/jms.5007 |
| PMID: | 38445805 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1096-9888 |
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| DOI: | 10.1002/jms.5007 |