UPLC, HR-MS, and in-silico tools for simultaneous separation, characterization, and in-silico toxicity prediction of degradation products of atorvastatin and olmesartan

[摘要] The aim of this work was to simultaneously separate, identify, and characterize all the degradation products (DPs) of atorvastatin (AT) and olmesartan (OM) formed under different stress conditions as per International Conference on Harmonization (ICH) Q1A(R2) guideline. AT showed labile behavior in acidic, basic, neutral, and oxidative stress and led to the formation of two DPs, while OM degraded under acidic, basic, and neutral and resulted in the formation of four DPs. All the stressed samples of AT and OM were resolved on a C-18 column in single run on a gradient liquid chromatographic (LC) mode. A complete mass fragmentation pathway of both the drugs was established with the help of tandem mass spectrometry (MS/MS) studies. The fragmentation was further supported by MSn studies, and for AT, it was carried out up to MS6, while for OM, it was up to MS5. Then, the stressed samples were analyzed by LC–MS/MS to get the fragmentation patterns of DPs. LC–MS/MS data helped to propose chemical structure of all the DPs. Based on this entire information, degradation pathway of both the drugs was established. The developed method has shown excellent linearity over the range of 10 to 150 μg/mL of OM and AT. The correlation coefficient (r2) for OM and AT is 0.999 and 0.998, respectively. The main recovery value of OM and AT ranged from 99.97% to 100.54%, while the limit of detection (LOD) for OM and AT was 0.018 and 0.021 μg/mL, and limit of quantitation (LOQ) was found to be 0.051 and 0.063 μg/mL. Finally, the in-silico carcinogenicity, mutagenicity, and hepatotoxicity predictions of AT, OM, and all the DPs were performed by using toxicity prediction softwares, viz., TOPKAT, LAZAR, and Discovery Studio ADMET, respectively.

[学科分类] 化学（综合）

[关键词] Atorvastatin;olmesartan;LC–MS;characterization;in-silico toxicity