Analytical and Bioanalytical Chemistry

, Volume 405, Issue 10, pp 3215–3231 | Cite as

LC-MS/TOF, LC-MSn, on-line H/D exchange and LC-NMR studies on rosuvastatin degradation and in silico determination of toxicity of its degradation products: a comprehensive approach during drug development

  • Ravi P. Shah
  • Archana Sahu
  • Saranjit SinghEmail author
Original Paper


The present study dealt with the forced degradation behaviour of rosuvastatin under ICH prescribed stress conditions. The drug was found to be labile under acid hydrolytic and photolytic conditions, while it was stable to base/neutral hydrolytic, oxidative and thermal stress. In total, 11 degradation products were formed, which were separated on a C-18 column using a stability-indicating method. LC-MS analyses indicated that five degradation products had the same molecular mass as that of the drug, while the remaining six had 18 Da less than the drug. Structure elucidation of all the degradation products was executed using sophisticated and modern structural characterization tools, viz. LC-MS/TOF, LC-MSn, on-line H/D exchange and LC-NMR. The degradation pathway and mechanisms of degradation of the drug were delineated. Additionally, in silico toxicity was predicted for all the degradation products using TOPKAT and DEREK software and compared with the drug. This study demonstrates a comprehensive approach of degradation studies during the drug development phase.


Degradation pathway of rosuvastatin


Rosuvastatin Stress studies Degradation product LC-MS/TOF MSn studies LC-NMR 

Supplementary material

216_2013_6760_MOESM1_ESM.pdf (3.5 mb)
ESM 1 (PDF 3.45 MB)


  1. 1.
    ICH (2003) Stability testing of new drug substances and products Q1A(R2). International Conference on Harmonisation, IFPMA, GenevaGoogle Scholar
  2. 2.
    WHO (2009) Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. Technical Report Series No. 953. World Health Organization, GenevaGoogle Scholar
  3. 3.
    Singh S, Handa T, Narayanam M, Sahu A, Junwal M, Shah RP (2012) J Pharm Biomed Anal 69:148–173CrossRefGoogle Scholar
  4. 4.
    ICH (2009) Pharmaceutical development Q8(R2). International Conference on Harmonisation, IFPMA, GenevaGoogle Scholar
  5. 5.
    Gao T, Liu Y, Ji Y, Wu X, Xu J (2012) J Pharm Biomed Anal 66:381–386CrossRefGoogle Scholar
  6. 6.
    Holčapek M, Jirásko R, Lísa M (2012) J Chromatogr A 1259:3–15CrossRefGoogle Scholar
  7. 7.
    Mehta S, Shah RP, Priyadarshi R, Singh S (2010) J Pharm Biomed Anal 52(3):345–354CrossRefGoogle Scholar
  8. 8.
    Modhave DT, Handa T, Shah RP, Singh S (2011) J Pharm Biomed Anal 56:538–545CrossRefGoogle Scholar
  9. 9.
    Shah RP, Sahu A, Singh S (2011) Eur J Chem 2:152–157CrossRefGoogle Scholar
  10. 10.
    Sturm S, Seger C (2012) J Chromatogr A 1259:50–61CrossRefGoogle Scholar
  11. 11.
    Thomas S, Joshi SC, Vir D, Agarwal A, Rao RD, Sridhar I, Xavier CM, Mathela CS (2012) J Pharm Biomed Anal 63:112–119CrossRefGoogle Scholar
  12. 12.
    Jackson EK (2001) In: Brunton LL (ed) Goodman & Gilman's the pharmacological basis of therapeutics, 10th edn. McGraw-Hill, New YorkGoogle Scholar
  13. 13.
    Gao J, Peart TE, Syoboda L, Backus S (2007) J Chromatogr B 856:35–40CrossRefGoogle Scholar
  14. 14.
    Hussain S, Patel H, Tan A (2009) Bioanalysis 1:529–535CrossRefGoogle Scholar
  15. 15.
    Kallem RR, Karthik A, Chakradhar L, Mullangi R, Srinivas NR (2007) Arzneim Forsch 57:705–711Google Scholar
  16. 16.
    Tian L, Jiang J, Huang Y (2007) Chin Pharm J 42:1174–1177Google Scholar
  17. 17.
    Xu DH, Ruan ZR, Zhou Q, Yuan H, Jiang B (2006) Rapid Commun Mass Spectrom 20:2369–2375CrossRefGoogle Scholar
  18. 18.
    Zhang H, Liang C, Cheng XH, Chen YJ, Li YY, Xiong YQ (2006) Chin J New Drugs Clin Remedies 25:909–914Google Scholar
  19. 19.
    Krishnaiah C, Murthy MV, Prasad BJD, Satyanarayana B, Kumar RKM (2009) Anal Chem: Indian J 8:277–283Google Scholar
  20. 20.
    Mehta TN, Patel AK, Kulkarni GM, Suubbaiah G (2005) J AOAC Int 88:1142–1147Google Scholar
  21. 21.
    Raj HA, Rajput SJ, Dave JB, Patel CN (2009) Int J ChemTech Res 1:677–689Google Scholar
  22. 22.
    Gajjar AKK, Shah VDD (2010) Eurasian J Anal Chem 5:280–298Google Scholar
  23. 23.
    Gomes FP, García PL, Alves JMP, Singh AK, Kedor-Hackmann ERM, Santoro MIRM (2009) Anal Lett 42:1784–1804CrossRefGoogle Scholar
  24. 24.
    Astarita A, DellaGreca M, Lesce MR, Montanaro S, Previtera L, Temussi F (2007) J Photochem Photobiol A 187:263–268CrossRefGoogle Scholar
  25. 25.
    Finkelstein N (2007) US Patent 7,244,844Google Scholar
  26. 26.
    Reddy GVR, Reddy BV, Haque SW, Gautam HD, Kumar P, Kumar AP, Park JH (2011) Quim Nova 34:250–255CrossRefGoogle Scholar
  27. 27.
    Trivedi HK, Patel MC (2012) Sci Pharm 80:393–406CrossRefGoogle Scholar
  28. 28.
    ICH (1996) Photostability testing of new drug substances and products Q1B. International Conference on Harmonization, IFPMA, GenevaGoogle Scholar
  29. 29.
    Bakshi M, Singh S (2002) J Pharm Biomed Anal 28:1011–1040CrossRefGoogle Scholar
  30. 30.
    Singh S, Bakshi M (2000) Pharm Technol Online 24:1–14Google Scholar
  31. 31.
    Introduction to the preparation and properties of hydrogen peroxide. Laboratory of Inorganic Synthesis and Catalysis, Switzerland. Accessed 22 Dec 2012
  32. 32.
    Shah RP, Kumar V, Singh S (2008) Rapid Commun Mass Spectrom 22:613–622CrossRefGoogle Scholar
  33. 33.
    Shah RP, Kumar V, Singh S (2008) J Pharm Pharmacol 60:A9–A10Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Pharmaceutical AnalysisNational Institute of Pharmaceutical Education and Research (NIPER)S.A.S. NagarIndia
  2. 2.Biocon Bristol-Myers Squibb R&D Centre (BBRC)BangaloreIndia

Personalised recommendations