Stress degradation study of bortezomib: effect of co-solvent, isolation and characterization of degradation products by UHPLC-Q-TOF-MS/MS and NMR and evaluation of the toxicity of the degradation products

Udutha, Suresh; Borkar, Roshan M.; Shankar, G.; Sony, T.; Jala, Aishwarya; Krisna, E. Vamshi; Kumar, T. Kiran; Misra, Sunil; Prabhakar, S.; Srinivas, R.

doi:10.1039/d0nj05781a

Cited by 3 publications

(1 citation statement)

References 18 publications

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“…Thus, the stability of drug substances and pharmaceutical dosage forms are evaluated and tested under drastic conditions by studying the effect of different factors like heat, pH of the medium, and light to understand the behavior of drug molecules (Blessy et al 2014 ). Identification of the degradation products followed by isolation and characterization steps are helpful to predict the degradation mechanism of the drug molecule subjected to various conditions such as hydrolysis, oxidation, and photolysis (Udutha et al 2021 ). Furthermore, the toxicity of isolated degradation products can be evaluated by performing in vivo and in vitro toxicity studies (M. A. Mohd Shafiee, 2021 ; Wang et al 2002 ).…”

Section: Introductionmentioning

confidence: 99%

The anti-COVID-19 drug Favipiravir: Degradation, Method development, Validation, NMR/LC–MS characterization, and In-vitro safety evaluation

et al. 2022

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It is critical to characterize the degradation products of therapeutic drugs to determine their safety as these degradation products may possess fatal effects on the human physiological system. Favipiravir (FVP), a novel anti-Covid-19 drug, that is recently used all over the world with a great impact on humanity was our target to explore more about its toxicity, the margins of its safety, and its degradants in different degradation conditions. The goal of this study is to identify, characterize, and confirm the structures of FVP oxidative and alkaline breakdown products, as well as to assess their safety utilizing in-vitro SRB cytotoxicity assay on normal human skin fibroblasts (NHSF) cell lines. After oxidative and alkaline degradation of FVP, one degradation product was produced in each condition which was isolated from FVP using flash chromatography, characterized by 1HNMR and LC–MS/MS techniques. A reversed-phase Thermo Fischer Hypersil C18 column (4.6 × 150 mm, 5 m) was used to achieve HPLC chromatographic separation. Acetonitrile-5 mM potassium dihydrogen phosphate (pH 2.5) (50:50, v/v) was employed as the mobile phase, with a flow rate of 1 mL/min. At 332 nm, the column effluent was measured. Over the concentration range of 0.5–100 µg/mL, the calibration curve was linear. The intra-day and inter-day relative standard deviations were less than 2%, and good percentage recoveries were obtained that fulfilled the acceptance criteria of the International Conference on Harmonization (ICH) recommendations. The Plackett–Burman design was used to assess the robustness. Each degradant was isolated single using Flash chromatography and methylene chloride: methanol gradient mobile phase. The chemical structures of the degradation products have been confirmed and compared to the intact FVP using 1H-NMR, and Mass spectroscopy. A postulated mechanism of the degradation process has been depicted and the degradants fragmentation pattern has been portrayed. In addition, the in vitro SRB cytotoxicity assay to evaluate the safety profile of FVP and the degradation end products showed their high safety margin in both conditions with IC50 ˃100 µg/ml with no signs of toxicity upon examination of the treated NHSF cells under the optical microscope

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Section: Introductionmentioning

confidence: 99%

The anti-COVID-19 drug Favipiravir: Degradation, Method development, Validation, NMR/LC–MS characterization, and In-vitro safety evaluation

et al. 2022

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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 disulfide bridges containing cyclic peptide Linaclotide and its degradation products by using LC-HRMS/MS

Chaturvedi,

Titkare,

Sharma

et al. 2025

Journal of Pharmaceutical and Biomedical Analysis

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Stress degradation study of bortezomib: effect of co-solvent, isolation and characterization of degradation products by UHPLC-Q-TOF-MS/MS and NMR and evaluation of the toxicity of the degradation products

Abstract: Bortezomib (BTZ) is a first in class, potent reversible inhibitor of proteasome used in the treatment of multiple myeloma, the second most common hematological cancer. Stress degradation studies were performed...

Cited by 3 publications

References 18 publications

The anti-COVID-19 drug Favipiravir: Degradation, Method development, Validation, NMR/LC–MS characterization, and In-vitro safety evaluation

The anti-COVID-19 drug Favipiravir: Degradation, Method development, Validation, NMR/LC–MS characterization, and In-vitro safety evaluation

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

Characterization of disulfide bridges containing cyclic peptide Linaclotide and its degradation products by using LC-HRMS/MS

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Stress degradation study of bortezomib: effect of co-solvent, isolation and characterization of degradation products by UHPLC-Q-TOF-MS/MS and NMR and evaluation of the toxicity of the degradation products

Abstract: Bortezomib (BTZ) is a first in class, potent reversible inhibitor of proteasome used in the treatment of multiple myeloma, the second most common hematological cancer. Stress degradation studies were performed...

Cited by 3 publications

References 18 publications

The anti-COVID-19 drug Favipiravir: Degradation, Method development, Validation, NMR/LC–MS characterization, and In-vitro safety evaluation

The anti-COVID-19 drug Favipiravir: Degradation, Method development, Validation, NMR/LC–MS characterization, and In-vitro safety evaluation

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

Characterization of disulfide bridges containing cyclic peptide Linaclotide and its degradation products by using LC-HRMS/MS

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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