Characterization of stress degradation products of nintedanib by UPLC, UHPLC-Q-TOF/MS/MS and NMR: Evidence of a degradation product with a structure alert for mutagenicity

Dhiman, Vivek; Balhara, Ankit; Singh, Saranjit; Tiwari, Sanjay; Samanthula, Gananadhamu; Talluri, M.V.N. Kumar

doi:10.1016/j.jpba.2021.114037

Cited by 14 publications

(11 citation statements)

References 25 publications

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“…Hydrogen peroxide oxidation involves the transfer of electrophilic peroxide oxygen on nitrogen to form N-oxide. 16,17 Prediction of in silico toxicity of the osimertinib mesylate and its DPs…”

Section: Proposed Degradation Pathway Of Dp1-dp8mentioning

confidence: 99%

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Insight into in silico prediction and chemical degradation study of osimertinib mesylate by LC-HRMS and NMR: Investigation of a typical case of alkaline pH-mediated oxidative degradation product

Dhiman

Chavan

Ramarapu

et al. 2023

Eur J Mass Spectrom (Chichester)

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Osimertinib mesylate is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor used to treat nonsmall-cell lung cancer. The objective was to understand in silico prediction and chemical-based stress testing of the osimertinib mesylate. A total of eight degradation products (DPs) were formed under chemical stress testing. An in silico tool viz., Zeneth predicted a higher percentage of DPs. The separation of all the DPs was achieved using reversed phase high-performance liquid chromatography, employing X-Bridge C18 column with ammonium acetate (pH adjusted to 7.50 with ammonia) and acetonitrile as mobile phase. The overall results showed it underwent significant degradation in acidic, alkaline, and oxidative conditions. In rest of the conditions, osimertinib mesylate was found to be stable or slight degradation was observed in photolytic condition. The structure of DPs was elucidated with a comparison of data generated from high-resolution mass spectrometry (HRMS) of osimertinib mesylate and its degradation products. To confirm the unambiguous regioisomers, one-dimensional (1D) and two-dimentional (2D) nuclear magnetic resonance studies were performed. Furthermore, the N-oxide position was assigned for the first time using the Meisenheimer rearrangement reaction in atmospheric pressure chemical ionization mode. Interestingly, an unusual reaction of DP2 formation was observed at alkaline conditions. In silico tools such as DEREK and Sarah predicted osimertinib mesylate and most of the DPs found to be structural alert for mutagenicity.

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Section: Proposed Degradation Pathway Of Dp1-dp8mentioning

confidence: 99%

“…Hydrogen peroxide oxidation involves the transfer of electrophilic peroxide oxygen on nitrogen to form N-oxide. 16,17…”

Section: Proposed Degradation Pathway Of Dp1–dp8mentioning

confidence: 99%

Insight into in silico prediction and chemical degradation study of osimertinib mesylate by LC-HRMS and NMR: Investigation of a typical case of alkaline pH-mediated oxidative degradation product

Dhiman

Chavan

Ramarapu

et al. 2023

Eur J Mass Spectrom (Chichester)

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“…The proposed degradation pathway of tinoridine hydrochloride under various stress conditions is outlined in Figure 8. The degradation of the drug to DP 1 is a typical ester hydrolysis under the basic condition 13,14 . DP 2 was formed in the presence of co‐solvent (acetonitrile) through a two‐step reaction: (i) Ritter reaction, followed by (ii) a new bond formation between amine and electron‐deficient carbon of nitrile 13–16 .…”

Section: Degradation Pathway Of Dp 1 To Dpmentioning

confidence: 99%

“…The degradation of the drug to DP 1 is a typical ester hydrolysis under the basic condition 13,14 . DP 2 was formed in the presence of co‐solvent (acetonitrile) through a two‐step reaction: (i) Ritter reaction, followed by (ii) a new bond formation between amine and electron‐deficient carbon of nitrile 13–16 . DP 3 was formed by aromatic hydroxylation in the acidic condition, which was observed in the case of nadifloxacin 17 .…”

Section: Degradation Pathway Of Dp 1 To Dpmentioning

confidence: 99%

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Comprehensive degradation profiling and influence of different oxidizing reagents on tinoridine hydrochloride: Structural characterization of its degradation products using HPLC and HRMS

Dhiman

Patil

Velip

et al. 2021

Rapid Comm Mass Spectrometry

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Rationale Stress testing on tinoridine hydrochloride was carried out using a multidimensional approach. This included different conditions: hydrolytic (acidic, alkaline, and neutral conditions), different oxidative reagents, thermal, photolytic conditions, HPLC method development, and structural elucidation using high‐resolution mass spectrometry (HRMS). It provides the basis for quality control of tinoridine hydrochloride and its derivatives during storage conditions. Methods The tinoridine hydrochloride was subjected to a variety of stress conditions. A gradient reversed‐phase HPLC method was developed on a X‐Bridge C18 column (250 × 4.6 mm, 5 μm) to separate all the degradation products (DPs). HRMS studies have been performed to elucidate the structure of DPs. Results HPLC‐PDA study revealed that significant degradation products were formed in hydrolytic, AIBN (radical initiator at 40°C), thermal, and solid‐state photolight stress conditions, but the drug was stable under oxidative conditions (H2O2, Fenton's reagent at room temperature and ferric chloride at 40°C). The structure of degradation products was elucidated, and mechanism of their formation was explained. Conclusion Stress study was successfully carried out as per ICH Q1A (R2) guideline on tinoridine hydrochloride. A total of six new degradation products were characterized, DP 2 and DP 6 formed by the effect of co‐solvent. This study provides the scientifically sound basis for quality monitoring and storage conditions of tinoridine hydrochloride.

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Identification and characterization of two new oxidation degradation impurities in cinnarizine through LC‐HRMS/MS and ¹H NMR, along with in silico toxicity predictions of its degradation products

Jain,

Khan

2024

Biomedical Chromatography

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Cinnarizine (CIN) drug substance is a US FDA and EMA approved antihistaminic drug, There is no report available on CIN for the identification of degradation products and their degradation pathway. Herein, we report a stability‐indicating assay method for CIN, the formation and characterization of its major degradation products using LC‐HRMS/MS and 1H‐NMR techniques. CIN was subjected to oxidation, acid, base, thermal and photolytic degradation conditions. Two unknown degradation products (DP‐1 and DP‐2) of CIN were formed under oxidative conditions. We successfully separated these degradants using gradient elution on an Inertsil ODS 3 V column (150 × 4.6 mm, 5 μm) using mobile phase A consisting of 0.1% formic acid and the mobile phase B consisting of 0.1% formic acid/acetonitrile (20/80, v/v). CIN was labile to oxidative conditions and stable to acidic, alkaline hydrolytic, photolytic and thermal conditions. The degradation pathways were derived from the nature of the product formed under oxidative degradation conditions and available reports for confirmation of the mechanism. Since the stability‐indicating assay method can be utilized for stability studies and routine quality control of CIN in both the pharmaceutical industry and research laboratories. This method has been validated in compliance with the guidelines set forth by the ICH.

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Characterization of stress degradation products of nintedanib by UPLC, UHPLC-Q-TOF/MS/MS and NMR: Evidence of a degradation product with a structure alert for mutagenicity

Cited by 14 publications

References 25 publications

Insight into in silico prediction and chemical degradation study of osimertinib mesylate by LC-HRMS and NMR: Investigation of a typical case of alkaline pH-mediated oxidative degradation product

Insight into in silico prediction and chemical degradation study of osimertinib mesylate by LC-HRMS and NMR: Investigation of a typical case of alkaline pH-mediated oxidative degradation product

Comprehensive degradation profiling and influence of different oxidizing reagents on tinoridine hydrochloride: Structural characterization of its degradation products using HPLC and HRMS

Identification and characterization of two new oxidation degradation impurities in cinnarizine through LC‐HRMS/MS and ¹H NMR, along with in silico toxicity predictions of its degradation products

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Characterization of stress degradation products of nintedanib by UPLC, UHPLC-Q-TOF/MS/MS and NMR: Evidence of a degradation product with a structure alert for mutagenicity

Cited by 14 publications

References 25 publications

Insight into in silico prediction and chemical degradation study of osimertinib mesylate by LC-HRMS and NMR: Investigation of a typical case of alkaline pH-mediated oxidative degradation product

Insight into in silico prediction and chemical degradation study of osimertinib mesylate by LC-HRMS and NMR: Investigation of a typical case of alkaline pH-mediated oxidative degradation product

Comprehensive degradation profiling and influence of different oxidizing reagents on tinoridine hydrochloride: Structural characterization of its degradation products using HPLC and HRMS

Identification and characterization of two new oxidation degradation impurities in cinnarizine through LC‐HRMS/MS and 1H NMR, along with in silico toxicity predictions of its degradation products

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Identification and characterization of two new oxidation degradation impurities in cinnarizine through LC‐HRMS/MS and ¹H NMR, along with in silico toxicity predictions of its degradation products