Degradation kinetics and characterization of major degradants of binimetinib employing liquid chromatography-high resolution mass spectrometry

Rajput, Niraj; Soni, Fatema; Sahu, Amit Kumar; Jadav, Tarang; Sharma, Satyasheel; Sengupta, Pinaki

doi:10.1016/j.jpba.2022.114753

Cited by 11 publications

(10 citation statements)

References 21 publications

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“…The forced degradation study offers a deeper insight into the inherent stability of pharmaceuticals with a better understanding of how different environmental factors affect the stability of the drug and dosage form 3–5 . Analytical techniques like reversed‐phase high‐performance liquid chromatography (RP‐HPLC), liquid chromatography‐tandem mass spectrometry (LC–MS/MS), quadrupole‐time of flight (Q‐TOF) and nuclear magnetic resonance (NMR) are widely used to identify structures of the degradation product and predict their degradation pathways 6–8 . International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q1A and Q1B provide the guidance to perform forced degradation study in various stress environments such as oxidation, hydrolysis, photolysis and thermolysis.…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5] Analytical techniques like reversed-phase high-performance liquid chromatography (RP-HPLC), liquid chromatography-tandem mass spectrometry (LC-MS/MS), quadrupole-time of flight (Q-TOF) and nuclear magnetic resonance (NMR) are widely used to identify structures of the degradation product and predict their degradation pathways. [6][7][8] International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q1A and Q1B provide the guidance to perform forced degradation study in various stress environments such as oxidation, hydrolysis, photolysis and thermolysis. For analysis of the degraded samples, it is recommended to develop a stability-indicating assay method (SIAM).…”

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confidence: 99%

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Mechanism of capmatinib degradation in stress conditions including degradation product characterization using ultra‐high‐performance liquid chromatography‐quadrupole‐time of flight mass spectrometry and stability‐indicating analytical method development

Bhangare

Rajput

Jadav

et al. 2022

Rapid Comm Mass Spectrometry

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Rationale Capmatinib (CMT) has been recently approved for the treatment of non‐small cell lung cancer by the United States Food and Drug Administration (USFDA). Till date, the degradation mechanism of CMT in different stress conditions is not known. Moreover, degradation products (DPs) of the drug are yet to be identified. Characterization study on degradation products of CMT has not been reported before. Furthermore, no previously reported literature is available on the stability‐indicating method of CMT. Methods Owing to the lack of such scientific reports, we developed a sensitive, stability‐indicating method for CMT which can resolve it from all its degradation products. The method was validated as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH Q2 [R1]) guideline. We studied and established the degradation mechanism of CMT in different stress conditions. One degradation product (DP2) was isolated and characterized using 1H NMR. Results The degradation products (DP1, DP2 and DP3) of the drug have been identified and characterized for the first time by using high‐resolution mass spectrometry and 1H NMR spectroscopy. CMT was found to become degraded under acidic, basic and photolytic stress conditions in the solution phase to yield three major DPs. The drug was found to be stable in neutral hydrolysis, oxidation and thermal stress conditions. Conclusions DP1 was formed under acidic and basic hydrolytic conditions, whereas DP2 and DP3 were formed under photolytic conditions. Characterization of all the DPs has been carried out to establish their structures and understand the molecular mechanism behind the degradation of the drug. Few studies reported quantitative analysis of CMT and its metabolites in biological fluids. However, this is the first study to identify the unknown DPs of CMT and the mechanism of its degradation. Moreover, this article reports a stability‐indicating analytical method for CMT which has not yet been reported in any literature.

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Mechanism of capmatinib degradation in stress conditions including degradation product characterization using ultra‐high‐performance liquid chromatography‐quadrupole‐time of flight mass spectrometry and stability‐indicating analytical method development

Bhangare

Rajput

Jadav

et al. 2022

Rapid Comm Mass Spectrometry

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“…Indeed, the investigation of a drug’s degradation behavior toward various stressed conditions as well as the characterization of the DP structures is an integral part of the pharmaceutical drug development process. , Moreover, it is also pivotal for the design of the manufacturing process, shelf-life determination, formulation, and packaging development. In detail, forced degradation studies aim to accelerate the formation of DPs by exposing the drug to different physicochemical stress conditions to evaluate its stability and degradation pathways. , High-performance liquid chromatography (HPLC) or ultra HPLC (UHPLC) coupled with high-resolution mass spectrometry (HRMS) and/or with UV–vis detectors represent the analytical technique commonly used to evaluate DPs allowing both their structure elucidation and quantification. ,− Several regulatory agencies (e.g., FDA, WHO, and ICH) recommend exposure of the drug to acidic, basic, dry heat, oxidation, and light (UV) stress conditions among others. , The same agencies indicate in their protocols the ranges of pH, temperature, and maximum exposure time recommended to perform these studies. However, the conditions reported are not stringent.…”

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“… 3 , 5 High-performance liquid chromatography (HPLC) or ultra HPLC (UHPLC) coupled with high-resolution mass spectrometry (HRMS) and/or with UV–vis detectors represent the analytical technique commonly used to evaluate DPs allowing both their structure elucidation and quantification. 1 , 6 − 9 Several regulatory agencies (e.g., FDA, WHO, and ICH) recommend exposure of the drug to acidic, basic, dry heat, oxidation, and light (UV) stress conditions among others. 10 , 11 The same agencies indicate in their protocols the ranges of pH, temperature, and maximum exposure time recommended to perform these studies.…”

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MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

et al. 2023

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Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC–MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated. MassChemSite has been recently described as a promising informatics solution for LC–MS/MS and UV data analysis of forced degradation experiments and for the automated structural identification of DPs. Here, we applied MassChemSite to investigate the forced degradation of three poly(ADP-ribose) polymerase inhibitors (olaparib, rucaparib, and niraparib) under basic, acidic, neutral, and oxidative stress conditions. Samples were analyzed by UHPLC with online DAD coupled to high-resolution mass spectrometry. The kinetic evolution of the reactions and the influence of solvent on the degradation process were also assessed. Our investigation confirmed the formation of three DPs of olaparib and the wide degradation of the drug under the basic condition. Intriguingly, base-catalyzed hydrolysis of olaparib was greater when the content of aprotic-dipolar solvent in the mixture decreased. For the other two compounds, whose stability has been much less studied previously, six new degradants of rucaparib were identified under oxidative degradation, while niraparib emerged as stable under all stress conditions tested.

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“…The toxicity of the metabolites was assessed using a confidence score. The software identified a metabolite as toxically active for the specified toxicity criterion whenever the confidence score exceeded 0.7(70%) [17][18][19].…”

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High resolution mass spectrometry‐driven metabolite profiling of baricitinib to report its unknown metabolites and step‐by‐step reaction mechanism of metabolism

Rachmale

Rajput

Jadav

et al. 2022

Rapid Comm Mass Spectrometry

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Rationale Metabolite profiling is an integral part of the drug development process for selecting candidates with high therapeutic efficacy and low risk. Baricitinib (BARI) was approved in 2018 by the US Food and Drug Administration to treat rheumatoid arthritis. According to the available literature, no systematic study has been reported on the metabolite profiling of BARI. The biotransformation pathway of the drug has also not been established until recently. This study aims to identify BARI metabolites generated in in vitro matrices. Methods The in vitro metabolism study was carried out using rat liver microsome, human liver microsomes, and human S9 fraction. Ultra high‐performance liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry (U‐HPLC‐Q/TOF) and ultra‐high‐performance liquid chromatography/linear ion trap‐Orbitrap mass spectrometry (U‐HPLC/LTQ‐Orbitrap‐MS/MS) were used to identify and characterize the metabolites of BARI. The in silico toxicity of BARI and its metabolite was studied using ProTox‐II toxicity predictor software. Results A total of five new metabolites have been identified amongst which two (M1 and M2) were detected on both U‐HPLC/LTQ‐Orbitrap‐MS/MS and U‐HPLC‐Q/TOF and two additional metabolites (M4 and M5) were detected on U‐HPLC/LTQ‐Orbitrap‐MS/MS. Moreover, one metabolite (M3) was only detected on LC‐QTOF. Conclusions The major metabolic changes were found to be N‐dealkylation, demethylation, hydroxylation, and hydrolysis. Metabolites M3 and M4 were found to have the potential for carcinogenicity. The novelty of the study can be justified by the unavailability of any previous research on in vitro metabolite profiling of BARI. Furthermore, this is the first time the biotransformation pathway of BARI and the toxicity potential of its metabolites have been reported.

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Degradation kinetics and characterization of major degradants of binimetinib employing liquid chromatography-high resolution mass spectrometry

Cited by 11 publications

References 21 publications

Mechanism of capmatinib degradation in stress conditions including degradation product characterization using ultra‐high‐performance liquid chromatography‐quadrupole‐time of flight mass spectrometry and stability‐indicating analytical method development

Mechanism of capmatinib degradation in stress conditions including degradation product characterization using ultra‐high‐performance liquid chromatography‐quadrupole‐time of flight mass spectrometry and stability‐indicating analytical method development

MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

High resolution mass spectrometry‐driven metabolite profiling of baricitinib to report its unknown metabolites and step‐by‐step reaction mechanism of metabolism

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