Identification and characterization of new degradation products of belinostat using UHPLC-Q-TOF-MS/MS and <i>in silico</i> toxicity prediction

Mehta, Lovekesh; Naved, Tanveer; Grover, Parul; Bhardwaj, Monika; Mukherjee, Debaraj; Vennapu, Dushyanth R.

doi:10.1080/10826076.2021.1906271

Cited by 9 publications

(3 citation statements)

References 21 publications

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“…[16][17][18][19][20][21][22][23][24][25][26] Separation, identification and characterization of degradation products of few anticancer drugs using the UPLC-MSMS technique have been reported. [27][28][29][30] HPLC is now an outdated technology in terms of sensitivity and cost-effectiveness. Till date, no study is reported on the degradation and stability of drugs under varied conditions such as hydrolytic, oxidative, thermal and photolytic.…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of Novel and Highly Sensitive Stability-Indicating Reverse Phase UPLC Method for Quantification of Dabrafenib and its ten Degradation Products

Bhardwaj¹,

Mehta²,

Naved³

et al. 2022

IJPER

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Objectives: Dabrafenib is used as an active pharmaceutical ingredient acts as an inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth. In the current study, we focused on developing a robust, highly sensitive and stabilityindicating RP-UPLC method for estimation of DBR and its degradation products for the very first time. A stress study has been performed to demonstrate the stability-indicating capability of the method. Materials and Methods: Chromatographic separation was achieved using advanced UPLC technology with high resolution on Acquity BEH C-18 (100 mm × 2.1 mm, 1.8 μm) column using a mobile phase composed of orthophosphoric acid and methanol with very less consumption of solvents results in an eco-friendly method. Analysis was performed at 225 nm detector wavelength with 5 μL of injection volume and 0.3 mL min -1 of flow rate. Results: Forced degradation study was performed under hydrolytic (acid, alkali and neutral), oxidative, photolytic and thermal degradation as per ICH Q1 (R2) guidelines. The optimized method was observed to be linear in the concentration range of 12.5 to 125ng mL -1 with R 2 value of 1.0000. Conclusion: This is the first very sensitive stability-indicating UPLC method capable of separating dabrafenib and its ten degradation products at the nanogram (ng) level. The method was validated as stated by ICH guidelines.

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Section: Introductionmentioning

confidence: 99%

Development and Validation of Novel and Highly Sensitive Stability-Indicating Reverse Phase UPLC Method for Quantification of Dabrafenib and its ten Degradation Products

Bhardwaj¹,

Mehta²,

Naved³

et al. 2022

IJPER

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“…[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] Separation, identification and characterization of DPs of few anticancer drugs using the UPLC-MSMS technique have been reported. [25][26][27][28][29][30][31][32][33][34] Based on the recommendations of ICH guidelines Q3A (R2) and Q3B (R2), identification and characterization of all the DPs or process-related impurities of dabrafenib have been carried out. [35][36] But to date, no study is reported on the degradation and stability of drugs under varied conditions such as hydrolytic, oxidative, thermal and photolytic.…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of a Stability-indicating Method for Neostigmine Bromide: Separation, Identification and Characterization of Degradation Product using LC-MS and ESI-Q-TOF-MS/MS

Makkar¹,

Singh²,

Bhardwaj³

et al. 2022

Ind. J. Pharm. Edu. Res

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Objectives: Forced degradation study of the drug product and drug substance is very much important in drug development and drug discovery to establish the intrinsic stability and understand its behaviors towards different stress conditions. In the present work, stress testing of neostigmine bromide (NBr) was carried out as per ICH guidelines to identify and characterize the degradation product (DP) formed. Materials and Methods: According to ICH guidelines, drug substance was subjected to various degradation conditions. Waters BEH (Ethylene Bridge Hybrid) C-18 column (1.7 m, 100 mm 2.1 mm) having the composition of mobile phase Eluent A: 0.01M KH 2 PO 4 in water pH-2.5 with orthophosphoric acid and Eluent B: Acetonitrile utilizing 220 nm wavelengths provided the best separation of DP and drug component. Throughout the analysis, the injection volume (5 µL) and flow rate (0.3 mLmin -1 ) were kept constant. Results: The limits of detection (LOD) and quantitation (LOQ) were set at 25 ngmL -1 and 50 ngmL -1 , respectively. The method showed excellent linearity over a concentration range of 25-250 ngmL -1 with a regression coefficient (R 2 ) value of 0.9999. The results showed that significant degradation was observed in base and oxidative degradation conditions whereas found in neutral, acidic, photolytic and thermal degradation conditions. Conclusion: The DP was identified and characterized using a sophisticated HRMS/MS/TOF approach for accurate mass measurement using the ESI positive mode of ionization. In the present study, the establishment of the degradation pathway of drug substance and fragmentation pathway of DP-I were explained which was never reported in any literature.

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“…The samples generated after in vitro incubation and in vivo exposure are then injected for metabolite profiling and identification by Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS). There are several LC-MS/MS and High Performance Liquid Chromatography (HPLC) methods available in literature showing the capacity to analyze the degradation products of different anticancer drugs [16][17][18] .…”

mentioning

confidence: 99%

Identification and Characterization of In Vitro Metabolites of Ibrutinib by Rat Liver Microsomes Using Ultra-Performance Liquid Chromatography Coupled with Tandem Mass Spectrometry

Grover¹,

Bhardwaj²,

Naved³

et al. 2022

IJPS

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Grover et al.: In Vitro Metabolite Profiling of Ibrutinib Using Liquid Chromatography-Tandem Mass SpectrometryDrug metabolism is very important in determining the safety and efficacy of the drug. We worked towards this direction and designed a new strategy to study the in vitro metabolites of Food and Drug Administration approved anticancer drug, ibrutinib which is known to inhibit the Bruton's tyrosine kinase. The metabolites were formed by incubating the drug, ibrutinib with rat liver microsomes, at 37° for 24 h. The newly formed metabolites were identified and characterized with the help of ultra-high performance liquid chromatography which is interlinked with tandem quadrupole time-of-flight mass spectrometry. We then elucidated the structures of our new metabolites based on liquid chromatography with tandem mass spectrometry data which included accurate masses, the fragmentation of ions and chromatographic retention times. This study described the detailed in vitro metabolite profiling of ibrutinib which will be further helpful to predict the in vivo metabolism of ibrutinib in the human body. Enzyme kinetic parameters (K m and V max ) for both the metabolites were also established using different substrate concentrations. This newly developed biotransformation method will further help in determining the elimination mechanism of ibrutinib which in turn will assist in predicting the effectiveness and toxicity of the drug.

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Identification and characterization of new degradation products of belinostat using UHPLC-Q-TOF-MS/MS and in silico toxicity prediction

Cited by 9 publications

References 21 publications

Development and Validation of Novel and Highly Sensitive Stability-Indicating Reverse Phase UPLC Method for Quantification of Dabrafenib and its ten Degradation Products

Development and Validation of Novel and Highly Sensitive Stability-Indicating Reverse Phase UPLC Method for Quantification of Dabrafenib and its ten Degradation Products

Development and Validation of a Stability-indicating Method for Neostigmine Bromide: Separation, Identification and Characterization of Degradation Product using LC-MS and ESI-Q-TOF-MS/MS

Identification and Characterization of In Vitro Metabolites of Ibrutinib by Rat Liver Microsomes Using Ultra-Performance Liquid Chromatography Coupled with Tandem Mass Spectrometry

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