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Research ArticleRESEARCH

N-nitrosamines as “Special Case” Leachables in a Metered Dose Inhaler Drug Product

Daniel L. Norwood, James O. Mullis, Thomas N. Feinberg and Letha K. Davis
PDA Journal of Pharmaceutical Science and Technology July 2009, 63 (4) 307-321;
Daniel L. Norwood
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  • For correspondence: daniel.norwood@boehringer-ingelheim.com
James O. Mullis
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Thomas N. Feinberg
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Letha K. Davis
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References

  1. 1.↵
    Product Quality Research Institute (PQRI), Leachables and Extractables Working Group. Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products; Product Quality Research Institute: Arlington, VA, 2006.
    Google Scholar
  2. 2.↵
    1. Ball D.,
    2. Blanchard J.,
    3. Jacobson-Kram D.,
    4. McClellan R.,
    5. McGovern T.,
    6. Norwood D. L.,
    7. Vogel M.,
    8. Wolff R.,
    9. Nagao L.
    Development of safety qualification thresholds and their use in orally inhaled and nasal drug product evaluation. Toxicol. Sci. 2007, 97 (2), 226.
    OpenUrlAbstract/FREE Full TextGoogle Scholar
  3. 3.↵
    1. Norwood D. L.,
    2. Paskiet D.,
    3. Ruberto M.,
    4. Feinberg T.,
    5. Schroeder A.,
    6. Poochikian G.,
    7. Wang Q.,
    8. Deng T. J.,
    9. DeGrazio F.,
    10. Munos M. K.,
    11. Nagao L. M.
    Best practices for extractables and leachables in orally inhaled and nasal drug products: an overview of the PQRI recommendations. Pharm. Res. 2008, 25 (4), 727.
    OpenUrlPubMedGoogle Scholar
  4. 4.↵
    1. Willoughby B. G.,
    2. Scott K. W.
    Nitrosamines in Rubber; Rapra Technology Ltd.: Shawbury, UK, 1997.
    Google Scholar
  5. 5.↵
    1. Krauss M.,
    2. Hollender J.
    Analysis of nitrosamines in wastewater: exploring the trace level quantification capabilities of a hybrid linear ion trap/orbitrap mass spectrometer. Anal. Chem. 2008, 80 (3), 834.
    OpenUrlPubMedGoogle Scholar
  6. 6.↵
    1. Liu X.,
    2. Zhao Y. Y.,
    3. Chan K.,
    4. Hrudey S. E.,
    5. Li X. F.,
    6. Li J.
    Analysis of nitrosamines by capillary electrospray-high field asymmetric waveform ion mobility spectrometry-MS with programmed compensation voltage. Electrophoresis 2007, 28 (9), 1327.
    OpenUrlPubMedGoogle Scholar
  7. 7.↵
    1. Andrews-Tate C.,
    2. Echarte M. C.,
    3. Liarakos J.,
    4. Cheng R. C.
    Optimizing nitrosamine analysis by solid phase extraction. Preprints of Extended Abstracts presented at the ACS National Meeting, American Chemical Society, Division of Environmental Chemistry 2004, 44 (1), 283.
    Google Scholar
  8. 8.↵
    1. Soares de Oliverira R. T.,
    2. Salazer-Banda G. R.,
    3. Machado S. A. S.,
    4. Avaca L. A.
    Electroanalytical determination of N-nitrosamines in aqueous solution using a boron-doped diamond electrode. Electroanalysis 2008, 20 (4), 396.
    OpenUrlGoogle Scholar
  9. 9.↵
    1. Grebel J.,
    2. Suffet I. H.
    Nitrogen-phosphorus detection and nitrogen chemiluminescence detection of volatile nitrosamines in water matrices: optimization and performance comparison. J. Chromatogr., A 2007, 1175 (1), 141.
    OpenUrlPubMedGoogle Scholar
  10. 10.↵
    1. Yoo L. J.,
    2. Fitzsimmons S.,
    3. Wehner M.
    Performance based analytical method for determination of 8 nitrosamines in aqueous samples. Proceedings—Water Quality Technology Conference and Exposition, 2006.
    Google Scholar
  11. 11.↵
    1. Li Y.,
    2. McCarty C. L.,
    3. Whitaker J. S.,
    4. Davis W. E., II
    Challenges in the analysis of nitrosamines in drinking water. Proceedings—Water Quality Technology Conference and Exposition, 2006.
    Google Scholar
  12. 12.↵
    1. Jurado-Sanchez B.,
    2. Ballesteros E.,
    3. Gallego M.
    Comparison of the sensitivities of seven N-nitrosamines in pre-screened waters using an automated preconcentration system and gas chromatography with different detectors. J. Chromatogr., A 2007, 1154 (1–2), 66.
    OpenUrlPubMedGoogle Scholar
  13. 13.↵
    1. Cheng R. C.,
    2. Hwang C. J.,
    3. Andrews-Tate C.,
    4. Guo Y. C.,
    5. Carr S.,
    6. Suffet I. H.
    Alternative methods for the analysis of NDMA and other nitrosamines in water. J. Am. Water Works Assoc. 2006, 98 (12), 82.
    OpenUrlGoogle Scholar
  14. 14.↵
    1. Zhao Y. Y.,
    2. Boyd J.,
    3. Hrudey S. E.,
    4. Li X. F.
    Characterization of new nitrosamines in drinking water using liquid chromatography tandem mass spectrometry. Environ. Sci. Technol. 2006, 40 (24), 7636.
    OpenUrlPubMedGoogle Scholar
  15. 15.↵
    1. Grebel J. E.,
    2. Young C. C.,
    3. Suffet I. H.
    Solid-phase microextraction of N-nitrosamines. J. Chromatogr., A 2006, 1117 (1), 11.
    OpenUrlPubMedGoogle Scholar
  16. 16.↵
    1. Fields J.,
    2. Andrews-Tate C.,
    3. Cheng R. C.
    Optimization of SPE and GC/CI-MS/MS as analytical methods for extraction and detection of NDMA. Proceedings—Water Quality Technology Conference and Exposition, 2004.
    Google Scholar
  17. 17.↵
    1. Perez-Ruiz T.,
    2. Martinex-Lozano C.,
    3. Tomas V.,
    4. Martin J.
    Automated solid-phase extraction and high-performance liquid chromatographic determination of nitrosamines using post-column photolysis and tris (2,2′-bipyridyl) ruthenium (III) chemiluminescence. J. Chromatogr., A 2005, 1077 (1), 49.
    OpenUrlPubMedGoogle Scholar
  18. 18.↵
    1. Charrois J. W. A.,
    2. Arend M. W.,
    3. Froese K. L.,
    4. Hrudey S. E.
    Detecting N-nitrosamines in drinking water at nanogram per liter levels using ammonia positive chemical ionization. Environ. Sci. Technol. 2004, 38 (18), 4835.
    OpenUrlPubMedGoogle Scholar
  19. 19.↵
    1. Grebel J. E.,
    2. Suffet I. H.
    Dual column gas chromatographic method for analysis of eight nitrosamines with a nitrogen phosphorus detector or a nitrogen chemiluminescence detector. Preprints of Extended Abstracts presented at the ACS National Meeting, American Chemical Society, Division of Environmental Chemistry, 2004, 44 (1), 273.
    Google Scholar
  20. 20.↵
    1. Juardo-Sanchez B.,
    2. Ballesteros E.,
    3. Gallego M.
    Gas chromatographic determination of N-nitrosamines in beverages following automatic solid-phase extraction. J. Agric. Food Chem. 2007, 55 (24), 9758.
    OpenUrlPubMedGoogle Scholar
  21. 21.↵
    1. Sanches Filho P. J.,
    2. Rios A.,
    3. Valcarcel M.,
    4. Soares Melecchi M. I.,
    5. Bastos Caramao E.
    Method of determination of nitrosamines in sausages by CO2 supercritical fluid extraction (SFE) and micellar electrokinetic chromatography (MEKC). J. Agric. Food Chem. 2007, 55 (3), 603.
    OpenUrlPubMedGoogle Scholar
  22. 22.↵
    1. Andrade R.,
    2. Reyes F. G. R.,
    3. Rath S.
    A method for the determination of volatile N-nitrosamines in food by HS-SPME-GC-TEA. Food Chem. 2004, 91 (1), 173.
    OpenUrlGoogle Scholar
  23. 23.↵
    1. Byun M. W.,
    2. Ahn H. J.,
    3. Kim J. H.,
    4. Lee J. W.,
    5. Yook H. S.,
    6. Han S. B.
    Determination of volatile N-nitrosamines in irradiated fermented sausages by gas chromatography coupled to a thermal energy analyzer. J. Chromatogr., A 2004, 1054 (1–2), 403.
    OpenUrlPubMedGoogle Scholar
  24. 24.↵
    1. Mahapatra S.,
    2. Tripathi R. M.,
    3. Bhalke S.,
    4. Sadasivan S.
    GC-MS in combination with solid phase microextraction for determination of N-nitrosamines in environmental and food matrices. BARC Newsletter 2003, 237, 103.
    OpenUrlGoogle Scholar
  25. 25.↵
    1. Sanches Filho P. J.,
    2. Rios A.,
    3. Valcarcel M.,
    4. Zanin K. D.,
    5. Bastos Caramao E.
    Determination of nitrosamines in preserved sausages by solid-phase extraction-micellar electrokinetic chromatography. J. Chromatogr., A 2003, 985 (1–2), 503.
    OpenUrlPubMedGoogle Scholar
  26. 26.↵
    1. Cardenes L.,
    2. Ayala J. H.,
    3. Gonzalez V.,
    4. Afonso A. M.
    Fast microwave-assisted dansylation of N-nitrosamines. Analysis by high-performance liquid chromatography with fluorescence detection. J. Chromatogr., A 2002, 946 (1–2), 133.
    OpenUrlPubMedGoogle Scholar
  27. 27.↵
    1. Komarova N. V.,
    2. Velikanov A. A.
    Determination of volatile N-nitrosamines in food by high-performance liquid chromatography with fluorescence detection. J. Anal. Chem. 2001, 56 (4), 359.
    OpenUrlGoogle Scholar
  28. 28.↵
    1. Eerola S.,
    2. Otegui I.,
    3. Saari L.,
    4. Rizzo A.
    Applications of liquid chromatography-atmospheric pressure chemical ionization mass spectrometry and tandem mass spectrometry to the determination of volatile nitrosamines in dry sausages. Food Addit. Contam. 1998, 15 (3), 270.
    OpenUrlPubMedGoogle Scholar
  29. 29.↵
    1. Sen N. P.,
    2. Seaman S. W.,
    3. Page D. B.
    Rapid semi-quantitative estimation of N-nitrosodibutylamine and N-nitrosodibenzylamine in smoked hams by solid-phase microextraction followed by gas chromatography-thermal energy analysis. J. Chromatogr., A 1997, 788 (1–2), 131.
    OpenUrlPubMedGoogle Scholar
  30. 30.↵
    1. Goldman R.,
    2. Shields P. G.
    Food mutagens. J. Nutr. 2003, 133 (3S), 965S.
    OpenUrlAbstract/FREE Full TextGoogle Scholar
  31. 31.↵
    1. Jakszyn P.,
    2. Agudo A.,
    3. Ibanez R.,
    4. Garcia-Closas R.,
    5. Pera G.,
    6. Amaino P.,
    7. Gonzalez C. A.
    Development of a food database of nitrosamines, heterocyclic amines, and polycyclic aromatic hydrocarbons. J. Nutr. 2004, 134 (8), 2011.
    OpenUrlAbstract/FREE Full TextGoogle Scholar
  32. 32.↵
    1. Skrypec D. J.,
    2. Gray J. I.,
    3. Mandagere A. K.,
    4. Booren A. M.,
    5. Pearson A. M.,
    6. Cuppett S. L.
    Effect of bacon composition and processing on N-nitrosamine formation. Food Technology 1985, 39 (1), 74.
    OpenUrlGoogle Scholar
  33. 33.↵
    1. Johnson D. E.,
    2. Millar J. D.,
    3. Rhoades J. W.
    Nitrosamines in Tobacco Smoke. National Cancer Institute Monograph 1968, No. 28, 181.
    Google Scholar
  34. 34.↵
    1. Hoffmann D.,
    2. Brunnermann K. D.,
    3. Adams J. D.,
    4. Rivenson A.,
    5. Hecht S. S.
    N-nitrosamines in tobacco carcinogenesis. Banbury Report (Nitrosamine Hum. Cancer) 1982, 12, 211.
    OpenUrlGoogle Scholar
  35. 35.↵
    1. Havery D. C.,
    2. Chou H. J.
    N-nitrosamines in cosmetics products. An overview. Cosmetics and Toiletries 1994, 109 (5), 53.
    OpenUrlGoogle Scholar
  36. 36.↵
    1. Wang L. H.,
    2. Hsia H. C.,
    3. Wang C. C.
    Simultaneous determination of five volatile and non-volatile N-nitrosamines in biological fluids and cosmetic products by liquid chromatography with photodiode array detection. J. Liq. Chromatogr. Relat. Technol. 2006, 29 (12), 1737.
    OpenUrlGoogle Scholar
  37. 37.↵
    1. Spiegelhandler B.,
    2. Preussmann R.
    Nitrosamines and rubber. IARC Scientific Publication 41 1982, 231.
    OpenUrlGoogle Scholar
  38. 38.↵
    1. Havery D. C.,
    2. Fazio T.
    Estimation of volatile N-nitrosamines in rubber nipples for babies' bottles. Food Chem. Toxicol. 1982, 20 (6), 939.
    OpenUrlPubMedGoogle Scholar
  39. 39.↵
    1. Gray J. I.,
    2. Stachiw M. A.
    Gas chromatographic-thermal energy analysis method for determination of volatile N-nitrosamines in baby bottle rubber nipples: A collaborative study. J. AOAC Int. 1987, 70 (1), 64.
    OpenUrlPubMedGoogle Scholar
  40. 40.↵
    1. Incavo J. A.,
    2. Schafer M. A.
    Simplified method for the determination of N-nitrosamines in rubber vulcanizates. Anal. Chim. Acta 2006, 557 (1–2), 256.
    OpenUrlGoogle Scholar
  41. 41.↵
    1. Reche F.,
    2. Garrigos M. C.,
    3. Marin M. L.,
    4. Jimenez A.
    Determination of N-nitrosamines in latex by sequential supercritical fluid extraction and derivatization. J. Chromatogr., A 2002, 976 (1–2), 301.
    OpenUrlPubMedGoogle Scholar
  42. 42.↵
    1. Reche F.,
    2. Garrigos M. C.,
    3. Marin M. L.,
    4. Canto A.,
    5. Jimenez A.
    Optimization of parameters for the supercritical fluid extraction in the determination of N-nitrosamines in rubbers. J. Chromatogr., A 2002, 963 (1–2), 419.
    OpenUrlPubMedGoogle Scholar
  43. 43.↵
    1. El Assaf Z.,
    2. Pellerin F.,
    3. Hamon M.
    Detection of nitrosamines in elastomers of pharmaceutical and food significance. Ann. Pharm. Fr. 1984, 42 (4), 301.
    OpenUrlPubMedGoogle Scholar
  44. 44.↵
    1. Chakrabarti J.,
    2. Bloodworth B. C.,
    3. Harn C. S.,
    4. Siang Y. T.
    Occurrence of volatile N-nitrosamines in baby bottle nipples and pacifiers in Calcutta markets. J. Food Sci. Technol. 1998, 35 (4), 375.
    OpenUrlGoogle Scholar
  45. 45.↵
    1. Dawson B. A.,
    2. Lawrence R. C.
    Analysis of selected drug formulations for volatile nitrosamines. J. AOAC Int. 1987, 70 (3), 554.
    OpenUrlPubMedGoogle Scholar
  46. 46.↵
    1. Abdul-Baki A.,
    2. Lauven-Wetje A. K.,
    3. Roth H. J.
    Nitrosamine formation from drugs, 3. Differential pulse polarographic determination of N-nitrosodimethylamine (NDMA) from promethazine hydrochloride and nitrous acid. Archiv der Pharmazie 1978, 311 (9), 775.
    OpenUrlPubMedGoogle Scholar
  47. 47.↵
    1. Kim J. S.,
    2. Rhoades M. G.,
    3. Shea P. J.
    Formation and fate of N-nitrosamines from pharmaceuticals at physiological pH. Abstracts of Papers, 232nd ACS National Meeting, American Chemical Society 2006.
    Google Scholar
  48. 48.↵
    1. Dawson B. A.,
    2. Lawrence R. C.
    Analysis of piperazine drug formulations for N-nitrosamines. J. AOAC Int. 1987, 70 (5), 840.
    OpenUrlPubMedGoogle Scholar
  49. 49.↵
    AOAC Official Method 987.05. N-nitrosamines in Baby Bottle Rubber Nipples, Gas Chromatographic Method. In AOAC Official Methods of Analysis; Chapter 48, 2000, 7.
    Google Scholar
  50. 50.↵
    TEA® is a registered trademark of Thermoelectron Corporation.
    Google Scholar
  51. 51.↵
    1. Norwood D. L.,
    2. Nagao L.,
    3. Lyapustina S.,
    4. Munos M.
    Application of modern analytical technologies to the identification of extractables and leachables. American Pharmaceutical Review 2005, 8 (1), 78.
    OpenUrlGoogle Scholar
  52. 52.↵
    1. Norwood D. L.,
    2. Granger A. T.,
    3. Paskiet D. M.
    Extractables and Leachables in Drugs and Packaging. In Encyclopedia of Pharmaceutical Technology, 3rd Edition, Dekker Encyclopedias (a product line from Taylor and Francis Books): New York, 2006; p 1693.
    Google Scholar
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PDA Journal of Pharmaceutical Science and Technology
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July/August 2009
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N-nitrosamines as “Special Case” Leachables in a Metered Dose Inhaler Drug Product
Daniel L. Norwood, James O. Mullis, Thomas N. Feinberg, Letha K. Davis
PDA Journal of Pharmaceutical Science and Technology Jul 2009, 63 (4) 307-321;
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N-nitrosamines as “Special Case” Leachables in a Metered Dose Inhaler Drug Product
Daniel L. Norwood, James O. Mullis, Thomas N. Feinberg, Letha K. Davis
PDA Journal of Pharmaceutical Science and Technology Jul 2009, 63 (4) 307-321;

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