Stress degradation study on entrectinib and characterization of its degradation products using HRMS and NMR
| Autor: | Vivek Dhiman, Ankit Balhara, Saranjit Singh, Laximan Velip, Gananadhamu Samanthula, Vijaya Madhyanapu Golla, Bhoopendra Singh Kushwah |
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| Rok vydání: | 2022 |
| Předmět: |
Drug
Indazoles media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Entrectinib High-performance liquid chromatography Analytical Chemistry chemistry.chemical_compound Hydrolysis Drug Stability Tandem Mass Spectrometry Drug Discovery Acetonitrile Chromatography High Pressure Liquid Spectroscopy media_common Chromatography Hydrogen Peroxide chemistry Benzamides Degradation (geology) Oxidation-Reduction Ammonium acetate Two-dimensional nuclear magnetic resonance spectroscopy |
| Zdroj: | Journal of Pharmaceutical and Biomedical Analysis. 208:114459 |
| ISSN: | 0731-7085 |
| Popis: | Entrectinib is a potent inhibitor of receptor tyrosine kinases and anaplastic lymphoma kinase. It is designated as an orphan drug. There exists no report of comprehensive degradation profiling of the drug in the literature. Therefore, the present study focused on establishment of its stress degradation chemistry under hydrolytic (acidic, alkaline, neutral), oxidative (H2O2), photolytic and thermal conditions. For the purpose, the stressed solutions were subjected to HPLC studies on a C8 column by employing a gradient elution method, in which acetonitrile and 10 mM ammonium acetate were used as the mobile phase components. The results showed that entrectinib was labile to alkaline, H2O2, and photoneutral conditions in the solution state. The drug proved to be stable under acidic, solid-state photolytic, and thermal conditions. A total of sixteen degradation products were formed, which were characterized with the help of high resolution mass spectrometry, and in one case additional help was taken of 1D and 2D NMR data. The knowledge of the structures of the degradation products helped in establishment of degradation pathway of the drug and the involved mechanisms. Also, the toxicity profile of the drug and its degradation products was predicted using ADMET PredictorTM software, which indicated mutagenic potential of atleast five degradation products. |
| Databáze: | OpenAIRE |
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