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Chromatographia

, Volume 69, Supplement 2, pp 115–122 | Cite as

LC Stability Studies of Voriconazole and Structural Elucidation of Its Major Degradation Product

  • Andréa I. H. Adams
  • Grace Gosmann
  • Paulo H. Schneider
  • Ana M. Bergold
Original

Abstract

Voriconazole is a broad spectrum agent used to treat serious fungal infections. Stability studies conducted so far refer to the stability of the injectable formulation in different solvents, packaging materials and on storage but studies on the inherent chemical stability of the drug are not available. The purpose of this study was to evaluate the stability of the drug under stress conditions, in solution and in the solid state; isolate and elucidate the structure of the major degradation product and evaluate the antifungal activity of the degradation products. The quantification of the drug after exposure to degradation conditions was studied by a validated LC method. Among the conditions tested, it was found that the drug is more rapidly degraded in an alkaline medium, exposure to UVC radiation (254 nm) and elevated temperatures (60 °C). Degradation was greater under the first two conditions and in solution. Tablets exposed to UVC radiation for 14 days remained chemically and physically stable. For the isolation of the major degradation product, semi-preparative LC was employed and for the structural elucidation, spectroscopic techniques (1H and 13C NMR spectroscopy, IR spectroscopy and mass spectrometry) were used, and the major degradation product identified as 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone. The degraded samples were evaluated through microbiological assay and found to have no antifungal activity.

Keywords

Column liquid chromatography Voriconazole stability Stability studies Degradation products Antifungal activity 

Notes

Acknowledgments

The authors wish to thank the Laboratórios Cristália (Brazil) for the supply of the reference substance. Authors are also thankful to Laboratório de Produção de Padrões Secundários (LAPPS), Laboratório de Ensino e Pesquisa em Controle de Qualidade (LEPCQ) and Centro Bioanalítico de Medicamentos/UFRGS (CBIM).

References

  1. 1.
    Wingard JR, Leather H (2004) Biol Blood Marrow Transpl 10:73–90. doi: 10.1016/j.bbmt.2003.09.014 CrossRefGoogle Scholar
  2. 2.
    Maertens JA (2004) CMI 10(Suppl 1):1–10Google Scholar
  3. 3.
    Sabo JA, Abdel-Rahman SM (2000) Ann Pharmacother 34:1032–1043. doi: 10.1345/aph.19237 CrossRefGoogle Scholar
  4. 4.
    Stopher DA, Gage R (1997) J Chromatogr B Anal Technol Biomed Life Sci 691:441–448. doi: 10.1016/S0378-4347(96)00408-2 CrossRefGoogle Scholar
  5. 5.
    Gage R, Stopher DA (1998) J Pharm Biomed Anal 17:1449–1453. doi: 10.1016/S0731-7085(98)00004-1 CrossRefGoogle Scholar
  6. 6.
    Perea S, Pennick GJ, Modak A, Fothergill AW, Sutton DA, Sheehan DJ, Rinaldi MG (2000) Antimicrob Agents Chemother 44(5):1209–1213. doi: 10.1128/AAC.44.5.1209-1213.2000 CrossRefGoogle Scholar
  7. 7.
    Zhou L, Glickman RD, Chen N, Sponsel WE, Graybill JR, Lam KW (2002) J Chromatogr B Anal Technol Biomed Life Sci 776:213–220. doi: 10.1016/S1570-0232(02)00344-6 CrossRefGoogle Scholar
  8. 8.
    Pennick GJ, Clark M, Sutton DA, Rinaldi MG (2003) Antimicrob Agents Chemother 47(7):2348–2350. doi: 10.1128/AAC.47.7.2348-2350.2003 CrossRefGoogle Scholar
  9. 9.
    Pehourq F, Jarry C, Bannwarth B (2004) Biomed Chromatogr 18(9):719–722. doi: 10.1002/bmc.383 CrossRefGoogle Scholar
  10. 10.
    Hariprasad SM, Mieler WF, Holz ER, Gao H, Kim JE, Chi JD, Prince RA (2004) Arch Ophthal 122(1):42–47. doi: 10.1001/archopht.122.1.42 CrossRefGoogle Scholar
  11. 11.
    Keevil BG, Newmann S, Lockhart S, Howard SJ, Moore CB, Denning DW (2004) Ther Drug Monit 26(6):650–657. doi: 10.1097/00007691-200412000-00011 CrossRefGoogle Scholar
  12. 12.
    Egle H, Trittler R, König A, Kümmerer K (2005) J Chromatogr B Anal Technol Biomed Life Sci 814:361–367. doi: 10.1016/j.jchromb.2004.10.069 CrossRefGoogle Scholar
  13. 13.
    Wenk M, Droll A, Krähenbühl S (2006) J Chromatogr B 832:313–316. doi: 10.1016/j.jchromb.2006.01.015 CrossRefGoogle Scholar
  14. 14.
    Chhun S, Rey E, Tran A, Lortholary O, Pons G, Jullien V (2007) J Chromatogr B Anal Technol Biomed Life Sci 852:223–228. doi: 10.1016/j.jchromb.2007.01.021 CrossRefGoogle Scholar
  15. 15.
    Cheng S, Qiu F, Huang J, He JQ (2007) J Chromatogr Sci 45:409–414Google Scholar
  16. 16.
    Araujo BV, Conrado DJ, Palma EC, Dalla Costa T (2007) J Pharm Biomed Anal 44:985–990. doi: 10.1016/j.jpba.2007.03.026 CrossRefGoogle Scholar
  17. 17.
    Langman LJ, Boakye-Agyeman F (2007) Clin Biochem 40:1378–1385. doi: 10.1016/j.clinbiochem.2007.07.024 CrossRefGoogle Scholar
  18. 18.
    Eiden C, Mathieu O, Peyriere H, Hillaire-Buys D, Cociglio M (2008) Chromatographia 67:275–280. doi: 10.1365/s10337-007-0508-z CrossRefGoogle Scholar
  19. 19.
    Nakagawa S, Suzuki R, Yamazaki R, Kusuhara Y, Mitsumoto S, Kobayashi H, Shimoeda S, Ohta S, Yamato S (2008) Chem Pharm Bull (Tokyo) 56:328–331. doi: 10.1248/cpb.56.328 CrossRefGoogle Scholar
  20. 20.
    Michael C, Teichert J, Preiss R (2008) J Chromatogr B Anal Technol Biomed Life Sci 865:74–80. doi: 10.1016/j.jchromb.2008.02.009 CrossRefGoogle Scholar
  21. 21.
    Simmel F, Soukup J, Zoerner A, Radke J, Kloft C (2008) Anal Bioanal Chem 392:479–488. doi: 10.1007/s00216-008-2286-3 CrossRefGoogle Scholar
  22. 22.
    Crego AL, Gómez J, Marina ML, Lavandera JL (2001) Electrophoresis 22:2503–2511. doi: 10.1002/1522-2683(200107)22:12<2503::AID-ELPS2503>3.0.CO;2-5 CrossRefGoogle Scholar
  23. 23.
    Adams AIH, Bergold AM (2005) Chromatographia 62(7–8):429–434. doi: 10.1365/s10337-005-0629-1 CrossRefGoogle Scholar
  24. 24.
    Srinubabu G, Raju Ch AI, Sarath N, Kumar PK, Rao JVLNS (2007) Talanta 71:1424–1429. doi: 10.1016/j.talanta.2006.04.042 CrossRefGoogle Scholar
  25. 25.
    Huang XL, Qiu F, Cheng S (2008) Chromatographia 68:649–652. doi: 10.1365/s10337-008-0737-9 CrossRefGoogle Scholar
  26. 26.
    Prajapati AM, Patel SA, Patel NJ, Patel DB, Patel SK (2008) J AOAC Int 91:1070–1074Google Scholar
  27. 27.
    Adams AIH, Steppe M, Fröehlich PE, Bergold AM (2006) J AOAC Int 89(4):960–965Google Scholar
  28. 28.
    Babu GS, Raju CAI (2007) Asian J Chem 19(2):1625–1627Google Scholar
  29. 29.
    Ferretti R, Gallinella B, La Torre F, Zanitti L (1998) Chromatographia 47(11–12):649–654. doi: 10.1007/BF02467448 CrossRefGoogle Scholar
  30. 30.
    Couch P, Jacobson P, Johnson CE (1992) Am J Hosp Pharm 49:1459–1462Google Scholar
  31. 31.
    Hunt-Fugate AK, Hennessey CK, Kazarian CM (1993) Am J Hosp Pharm 50:1186–1187Google Scholar
  32. 32.
    Inagaki K, Takagi J, Lor E, Kum-Ja I, Nii L, Gill M (1993) Am J Hosp Pharm 50:1206–1208Google Scholar
  33. 33.
    Johnson C, Jacobson P, Pillen HA, Woycik CL (1993) Am J Hosp Pharm 50:703–706Google Scholar
  34. 34.
    Yamredeewong W, Lopez-Anaya A, Rappaport H (1993) Am J Hosp Pharm 50:2366–2367Google Scholar
  35. 35.
    Hoppe-Tichy T, Wenzel S, Gehrig AK, Nguyen H (2005) Pharmazie 60(1):77–78Google Scholar
  36. 36.
    Sahraoui L, Chiadmi F, Schlatter J, Toledano A, Cisternino S, Fontan JE (2006) Am J Health Syst Pharm 63(15):1423–1426. doi: 10.2146/ajhp050544 CrossRefGoogle Scholar
  37. 37.
    Cadrobbi J, Hecq JP, Lebrun C, Vanbeckbergen D, Jamrt J, Galanti L (2006) EJHO-P 12(3):57–59Google Scholar
  38. 38.
    Adams AIH, Morimoto LN, Meneghini LZ, Bergold AM (2008) Braz J Infect Dis 12:400–404CrossRefGoogle Scholar
  39. 39.
    ICH (1996) In: International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. Stability Testing: photostability testing of new drug substances and productsGoogle Scholar
  40. 40.
    ICH (2003) In: International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. Stability testing of new drug substances and productsGoogle Scholar
  41. 41.
    Kommanaboyina B, Rhodes CT (1999) Drug Dev Ind Pharm 25(7):857–868. doi: 10.1081/DDC-100102246 CrossRefGoogle Scholar
  42. 42.
    Tonessen HH (2001) Int J Pharm 225:1–14. doi: 10.1016/S0378-5173(01)00746-3 CrossRefGoogle Scholar
  43. 43.
    Watson DG (2005) Pharmaceutical analysis a textbook for pharmacy students and pharmaceutical chemists. Elsevier Churchill Livingstone, EdinburghGoogle Scholar
  44. 44.
    Butters M, Ebbs J, Green SP, Macrae J, Morland MC, Murtiashaw CW, Pettman AJ (2001) Org Process Res Dev 5:28–36. doi: 10.1021/op0000879 CrossRefGoogle Scholar
  45. 45.
    Cyr TD, Dawson BA, Neville GA, Shurvell HF (1996) J Pharm Biomed Anal 14:247–255. doi: 10.1016/0731-7085(95)01598-1 CrossRefGoogle Scholar
  46. 46.
    EMEA European Medicines Agency. 2004. Proc.No. EMEA/H/C/387/X/09. http://www.emea.europa.eu/humandocs/PDFs/EPAR/vfend/H-384-X-09.pdf

Copyright information

© Vieweg+Teubner | GWV Fachverlage GmbH 2009

Authors and Affiliations

  • Andréa I. H. Adams
    • 1
  • Grace Gosmann
    • 1
  • Paulo H. Schneider
    • 2
  • Ana M. Bergold
    • 1
  1. 1.Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de FarmáciaUniversidade Federal do Rio Grande do SulRio Grande do SulBrazil
  2. 2.Departamento de Química Orgânica, Instituto de QuímicaUniversidade Federal do Rio Grande do Sul Rio Grande do SulBrazil

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