Liquid Chromatographic Method Development for Forced Degradation Products of Dabigatran Etexilate: Characterisation and In Silico Toxicity Evaluation

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• 作者：Debasish Swain ; Prinesh N. Patel ; Gangam Nagaraj ; Kona S. Srinivas…
• 关键词：Dabigatran etexilate ; UHPLC ; LC ; Q ; TOF/ESI/MS/MS ; Forced degradation ; In ; silico toxicity
• 刊名：Chromatographia
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：79
• 期：3-4
• 页码：169-178
• 全文大小：1,151 KB
• 参考文献：1.Van Ryn J, Stangier J, Haertter S, Liesenfeld K-H, Wienen W, Feuring M, Clemens A (2010) Thromb Haemost 103:1116CrossRef
  2.Holmes M, Carroll C, Papaioannou D (2012) Pharmacoeconomics 30:137–146CrossRef
  3.Larsen TB, Rasmussen LH, Skjøth F, Due KM, Callréus T, Rosenzweig M, Lip GY (2013) J Am Coll Cardiol 61:2264–2273CrossRef
  4.Hankey GJ, Eikelboom JW (2011) Circulation 123:1436–1450CrossRef
  5.Prajapati A, Kumar S, Sen AK, Zanwar A, Seth A (2014) Pharma Sci Monit 5:31–35
  6.Bernardi RM, Fröehlich PE, Bergold AM (2013) J AOAC Int 96:37–41CrossRef
  7.Damle MC, Bagwe RA (2014) J Adv Sci Res 5:39–44
  8.Reddy MBS, Rao NVB (2014) South Pac J Pharm Bio Sci 2:80–92
  9.Hu Z-Y, Parker RB, Herring VL, Laizure SC (2013) Anal Bioanal Chem 405:1695–1704CrossRef
  10.Delavenne X, Moracchini J, Laporte S, Mismetti P, Basset T (2012) J Pharm Biomed Anal 58:152–156CrossRef
  11.Bernardi RM, D’Avila FB, Todeschini V, Andrade JM, Fröehlicha PE, Bergolda AM (2015) J Braz Chem Soc 26:660–666
  12.ICH guideline (2003) Q1A (R2) stability testing of new drug substances and products. In: International Conference on Harmonisation, IFPMA, Geneva
  13.ICH guideline (1996) Q1B photostability testing of new drug substances and products. In: International Conference on Harmonisation, IFPMA, Geneva
  14.Singh S, Handa T, Narayanam M, Sahu A, Junwal M, Shah RP (2012) J Pharm Biomed Anal 69:148–173CrossRef
  15.Bakshi M, Singh S (2002) J Pharm Biomed Anal 28:1011–1040CrossRef
  16.Snyder RD, Pearl GS, Mandakas G, Choy WN, Goodsaid F, Rosenblum I (2004) Environ Mol Mutagen 43:143–158CrossRef
  17.Dearden JC (2003) J Comput Aided Mol Des 17:119–127CrossRef
  
• 作者单位：Debasish Swain (1)
  Prinesh N. Patel (1)
  Gangam Nagaraj (1) (2)
  Kona S. Srinivas (2)
  Mahesh Sharma (3)
  Prabha Garg (3)
  Gananadhamu Samanthula (1)
  
  1. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
  2. Daiichi Sankyo Life Science Research Centre (RCI), Gurgaon, Haryana, India
  3. National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, India
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Analytical Chemistry
  Organic Chemistry
  Pharmacy
  Biochemistry
  Plant Sciences
  Measurement Science and Instrumentation
  
• 出版者：Vieweg Verlag
• ISSN：1612-1112

文摘

A simple and accurate UHPLC method was developed for Dabigatran etexilate (DAB) using Acquity CSH C18 (100 mm × 2.1 mm × 1.7 µm) column with mobile phase containing ammonium acetate (pH 5.0) and methanol in gradient program. This method was used to study the forced degradation products of DAB. The drug was found to degrade in all hydrolytic and oxidative conditions resulting in formation of four major degradation products (DP1 to DP4). DAB and its degradation products were well separated using the proposed method. The degradation products were characterized using LC-Q-TOF/ESI/MS/MS and accurate mass measurements for obtaining the structural information. The degradation pathway leading to the formation of the degradation products was also proposed. In silico tools like TOPKAT and DEREK software were used to evaluate the toxicity associated with DAB and its degradation products. The developed method was validated as per ICH Q2 (R1) guidelines. The method showed linear response over a concentration range of 45–105 µg mL−1 with correlation coefficient of 0.9998. The accuracy of the method was observed within the acceptable limits of 98–102 %. The precision of the method was good as indicated by %RSD values less than 1.0. The proposed method was found to be robust when deliberate changes were made in pH of buffer, column temperature and flow rate of the mobile phase. The developed method finds its application as a stability indicating assay method for the determination of DAB. Keywords Dabigatran etexilate UHPLC LC-Q-TOF/ESI/MS/MS Forced degradation In-silico toxicity