High-Resolution MS and MSn Investigation of UV Oxidation Products of Phenazone-type Pharmaceuticals and Metabolites

  • Maxime Favier
  • Ann Van Schepdael
  • Deirdre Cabooter
Part of the following topical collections:
  1. 50th Anniversary Commemorative Issue


The occurrence of phenazone-type analgesics, such as aminopyrine, metamizole, phenazone and propyphenazone, has been reported in the effluent of wastewater treatment plants in µg/L concentrations. The presence of the main metabolites of aminopyrine and metamizole—acetamido antipyrine and formyl aminoantipyrine—has even been detected in sub µg/L concentrations in surface water and water bodies used to produce drinking water. This points at their high persistence and the need for adequate removal strategies. The degradation of phenazone, propyphenazone, acetamido antipyrine and formyl aminoantipyrine by UV radiation was investigated under laboratory conditions. An elucidation approach based on high-resolution mass spectrometry resulted in the identification of 11 degradation products. A mechanism of ring opening via the oxidation of the N–N bond of the pyrazolone ring was observed as well as the more typical oxidation of carbon–carbon double bonds. Aside from the degradation products, the capacity of formyl aminoantipyrine to produce trimers and dimers was demonstrated. The dimers were shown to be persistent despite continuous UV radiation. The toxicity of the degradation products was assessed by quantitative structure–activity relationships. It was shown that when the carbon–carbon double bond is partially oxidized to an epoxy the toxicity towards fish and daphnid is increased with respect to the parent compound.


Phenazone-type pharmaceuticals Photolysis Pyrazolone QSAR Transformation products 



The authors would like to thank the Marie Curie initiative project Aquabase for funding under contract number MEST-CT-2004-505169. Supervision from Prof. Dr. H. Fr. Schröder and support on the Orbitrap from W. Gebhardt from the Environmental Analytical Laboratory of the Institute of Environmental Engineering of RWTH Aachen University are also greatly appreciated.

Compliance with ethical standards

Conflict of interest

The authors declare no financial/commercial conflict of interest.

Supplementary material

10337_2018_3668_MOESM1_ESM.docx (96 kb)
Supplementary material 1 (DOCX 96 KB)


  1. 1.
    Godoy AA, Kummrow F, Paulo Augusto Z, Pamplin PAZ (2015) Chemosphere 138:281–291CrossRefGoogle Scholar
  2. 2.
    Verlicchi P, Zambello E (2015) Sci Total Environ 538:750–767CrossRefGoogle Scholar
  3. 3.
    Bu Q, Wang B, Huang J, Deng S, Yu G (2013) J Hazard Mater 262:189–211CrossRefGoogle Scholar
  4. 4.
    Caracciolo AB, Topp E, Grenni P (2015) J Pharmaceut Biomed Anal 106:25–36CrossRefGoogle Scholar
  5. 5.
    Canonica S, Meunier L, Von Gunten U (2008) Water Res 42:121–128CrossRefGoogle Scholar
  6. 6.
    Miao H-F, Zhu X-W, Xu D-Y, Lu D-Y, Lu M-F, Huang Z-X, Ren H-Y, Ruan W-Q (2015) Chem Eng J 279:156–165CrossRefGoogle Scholar
  7. 7.
    Loos G, Scheers T, Van Eyck K, Hoebeke L, Van Schepdael A, Adams E, Van der Bruggen B, Cabooter D, Dewil R (2018) Sep Purif Rev 195:184–191CrossRefGoogle Scholar
  8. 8.
    Jia X-H, Feng L, Liu Y-Z, Zhang L-Q (2018) Chem Eng J 345:156–164CrossRefGoogle Scholar
  9. 9.
    El-taliawy H, Escola Casas M, Bester K (2018) J Hazard Mater 347:288–298CrossRefGoogle Scholar
  10. 10.
    Gómez MJ, Sirtori C, Mezcua M, Fernandez-Alba AR, Agüera A (2008). Water Res 42:2698–2706CrossRefGoogle Scholar
  11. 11.
    Lim L, Yan F, Bach S, Pihakari K, Klein D (2016) Int J Mol Sci 17:104CrossRefGoogle Scholar
  12. 12.
    Bade R, Rousis NI, Bijlsma L, Gracia-Lor E, Castiglioni S, Sancho JV, Hernandez F (2015) Anal Bioanal Chem 407:8979–8988CrossRefGoogle Scholar
  13. 13.
    Svan A, Hedeland M, Arvidsson T, Jasper JT, Sedlak DL, Pettersson CE (2016) J Mass Spectrom 51(3):207–218CrossRefGoogle Scholar
  14. 14.
    Yuan F, Hu C, Hu X, Qu J, Yang M (2009) Water Res 43:1766–1774CrossRefGoogle Scholar
  15. 15.
    Agúndez JAG, Martinez C, Martin R, Benitez J (1994) Ther Drug Monit 16:316–322CrossRefGoogle Scholar
  16. 16.
    Ahel M, Jeličic I, Daughton CG, Jones-Lepp TL (eds) (2001) Pharmaceuticals and personal care products in the environment, scientific and regulatory issues. American Chemical Society, Washington, D.C, pp 100–115CrossRefGoogle Scholar
  17. 17.
    Hollender J, Zimmermann SG, Koepke S, Krauss M, McArdell CS, Ort C, Singer H, Von Gunten U, Siegrist H (2009) Environ Sci Technol 43:7862–7869CrossRefGoogle Scholar
  18. 18.
    Wiegel S, Aulinger A, Brockmeyer R, Harms H, Löffler J, Reincke H, Schmidt R, Stachel B, Von Tumpling W, Wanke A (2004). Chemosphere 57:107–126CrossRefGoogle Scholar
  19. 19.
    Zuehlke, S, Duennbier, U, Heberer T (2004) J Chromatogr A 1050:201–209CrossRefGoogle Scholar
  20. 20.
    Gómez MJ, Martinez Bueno MJ, Lacorte S, Fernandez-Alba AR, Agüera A (2007) Chemosphere 66:993–1002CrossRefGoogle Scholar
  21. 21.
    Martinez Bueno MJ, Agüera A, Gómez MJ, Hernando MD, Garcia-Reyes JF, Fernandez-Alba A (2007) Anal Chem 79:9372–9384CrossRefGoogle Scholar
  22. 22.
    Feldmann DF, Zuehlke S, Heberer T (2008) Chemosphere 71:1754–1764CrossRefGoogle Scholar
  23. 23.
    Gyenge-Szabó Z, Szoboszlai N, Frigyes D, Záray G, Mihucz VG (2014) J Pharmaceut Biomed Anal 90:58–63CrossRefGoogle Scholar
  24. 24.
    Ternes TA, Stüber J, Herrmann N, McDowell D, Ried A, Kampmann M, Teiser B (2003) Water Res 37:1976–1982CrossRefGoogle Scholar
  25. 25.
    Evgenidou EN, Konstantinou IK, Lambropoulou DA (2015) Sci Total Environ 505:905–926CrossRefGoogle Scholar
  26. 26.
    Cai MQ, Wang R, Feng L, Zhang LQ (2015) Environ Sci Pollut 22:1854–1867CrossRefGoogle Scholar
  27. 27.
    Favier M, Dewil R, Van Eyck K, Van Schepdael A, Cabooter D (2015) Chemosphere 136:32–41CrossRefGoogle Scholar
  28. 28.
    Jedrychowski M, Huttlin E, Haas W, Sowa M, Rad R, Gygi S (2011) Molecular Cellular Proteomics 10:M111 009910CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical AnalysisKU LeuvenLeuvenBelgium

Personalised recommendations