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Hydrolytic Degradation Study of Dabigatran Etexilate Mesylate: Isolation and Structural Elucidation of New Degradants

Hydrolytic Degradation Study of Dabigatran Etexilate Mesylate: Isolation and Structural... AbstractDabigatran etexilate mesylate is a prodrug salt prescribed to prevent stroke with atrial fibrillation. It was subjected to stability testing by hydrolysis in both acid and basic media at room temperature. The degradation resulted in two degradants in each medium and one of which was found to be common in both the media. The degradants have been isolated by mass based preparative HPLC and SFC. All of them were unambiguously characterized by HRMS and extensive NMR (including 2D) spectroscopic techniques. Of the three impurities isolated (referred as DP-1, 2 and 3), DP-2 and DP-3 are being reported for the first time. DP-1 was identified earlier but was not characterized by NMR. DP-3 was obtained in both acid and base mediated hydrolysis. Based on 1D-NMR, 2D-NMR and HRMS spectral data, the structures of degradation products were confirmed as (Z)-3-(2-((4-(N’-(hexyloxycarbonyl) carbamimidoyl) phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoicacid for DP-1 (Known); 2-((4-carbamimidoylphenyl amino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid for DP-2 (New); (Z)-2-((4-(N’-(hexyloxycarbonyl) carbamimidoyl) phenylamino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid for DP-3 (New). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Analytical Chemistry Letters Taylor & Francis

Hydrolytic Degradation Study of Dabigatran Etexilate Mesylate: Isolation and Structural Elucidation of New Degradants

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Hydrolytic Degradation Study of Dabigatran Etexilate Mesylate: Isolation and Structural Elucidation of New Degradants

Abstract

AbstractDabigatran etexilate mesylate is a prodrug salt prescribed to prevent stroke with atrial fibrillation. It was subjected to stability testing by hydrolysis in both acid and basic media at room temperature. The degradation resulted in two degradants in each medium and one of which was found to be common in both the media. The degradants have been isolated by mass based preparative HPLC and SFC. All of them were unambiguously characterized by HRMS and extensive NMR (including 2D)...
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Publisher
Taylor & Francis
Copyright
© 2018 Har Krishan Bhalla & Sons
ISSN
2230-7532
eISSN
2229-7928
DOI
10.1080/22297928.2018.1449664
Publisher site
See Article on Publisher Site

Abstract

AbstractDabigatran etexilate mesylate is a prodrug salt prescribed to prevent stroke with atrial fibrillation. It was subjected to stability testing by hydrolysis in both acid and basic media at room temperature. The degradation resulted in two degradants in each medium and one of which was found to be common in both the media. The degradants have been isolated by mass based preparative HPLC and SFC. All of them were unambiguously characterized by HRMS and extensive NMR (including 2D) spectroscopic techniques. Of the three impurities isolated (referred as DP-1, 2 and 3), DP-2 and DP-3 are being reported for the first time. DP-1 was identified earlier but was not characterized by NMR. DP-3 was obtained in both acid and base mediated hydrolysis. Based on 1D-NMR, 2D-NMR and HRMS spectral data, the structures of degradation products were confirmed as (Z)-3-(2-((4-(N’-(hexyloxycarbonyl) carbamimidoyl) phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoicacid for DP-1 (Known); 2-((4-carbamimidoylphenyl amino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid for DP-2 (New); (Z)-2-((4-(N’-(hexyloxycarbonyl) carbamimidoyl) phenylamino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid for DP-3 (New).

Journal

Analytical Chemistry Letters – Taylor & Francis

Published: May 4, 2018

Keywords: Dabigatran; stability study; hydrolytic degradation; NMR spectroscopy; super critical fluid chromatography

References

  • Dabigatran Etexilate: A Review in Nonvalvular Atrial Fibrillation
  • Dabigatran Etexilate for the Prevention of Venous Thromboembolism in Patients Undergoing Elective Hip or Knee Surgery: A NICE Single Technology Appraisal
  • The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans
  • Pharmaceutical stress testing: predicting drug degradation
  • Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape
  • Stability testing of new drug substances and products
  • Development and validation of a liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of dabigatran etexilate, intermediate metabolite and dabigatran in 50 μL rat plasma and its application to pharmacokinetic study
  • Identification of Carboxyl- esterase-Dependent Dabigatran Etexilate Hydrolysis
  • Development and validation of LC-MSMS assay for the determination of the prodrug dabigatran etexilate and its active metabolites in human plasma
  • Identification, Synthesis, and Strategy for the Reduction of Potential Impurities Observed in Dabigatran Etexilate Mesylate Processes
  • Development and Validation of a Stability-Indicating Liquid Chromatography Method for the Determination of Dabigatran Etexilate in Capsules
  • Method Validation for Stability Indicating Method of Related Substance in Active Pharmaceutical Ingredients Dabigatran Etexilate Mesylate by Reverse Phase Chromatography
  • A validated stability-indicating reversed phase high performance liquid chromatographic method for the determination of Dabigatran Etexilate mesylate. Inventi Impact - Pharm Analysis & Quality Assurance
  • Development and validation of stability-indicating RP-HPLC method for estimation of dabigatran etexilate
  • Identification of dabigatran etexilate major degradation pathways by liquid chromatography coupled to multi stage high-resolution mass spectrometry
  • Main Degradation Products of Dabigatran Etexilate Evaluated by LC-UV and LC-ESI-MS, Degradation Kinetics and in vitro Cytotoxicity Studies
  • Liquid Chromatographic Method Development for Forced Degradation Products of Dabigatran Etexilate: Characterisation and In Silico Toxicity Evaluation
  • Gradient RP-HPLC method for the determination of potential impurities in dabigatran etexilate in bulk drug and capsule formulations