Forensic Toxicology

, Volume 37, Issue 1, pp 145–153 | Cite as

Simultaneous chiral impurity analysis of methamphetamine and its precursors by supercritical fluid chromatography–tandem mass spectrometry

  • Hiroki SegawaEmail author
  • Yuko T. Iwata
  • Tadashi Yamamuro
  • Kenji Kuwayama
  • Kenji Tsujikawa
  • Tatsuyuki Kanamori
  • Hiroyuki Inoue
Original Article



Impurity profiling of seized illicit methamphetamine (MA) provides information on MA manufacturing methods in clandestine laboratories, and this drug intelligence supports formulation of strategies to control MA abuse. In the present study, we developed a simultaneous chiral analysis method for MA and its precursors using supercritical fluid chromatography–tandem mass spectrometry equipped with an enantioselective stationary phase.


Chromatographic conditions were optimized by systematic investigation of the flow rate, temperature, back pressure, co-solvent, additive, and mobile phase composition. The ability of the developed method was evaluated using standard and authentic illicit MA.


The use of a chiral selector in the stationary phase allowed for simultaneous chiral differentiation of MA and its precursors including ephedrine, norephedrine, chloropseudoephedrine, methylephedrine, dimethylamphetamine, and amphetamine. Sufficient limit of detection, repeatability of retention time, and linearity were achieved. A switching valve interfacing a chromatograph and a mass spectrometer enabled analyzing large amounts of MA directly. The application to the authentic illicit MA samples was achieved and revealed the existence of impurities, which was not detected by conventional gas chromatography–mass spectrometry.


The developed supercritical fluid chromatography–tandem mass spectrometry method could be a powerful analytical tool for MA impurity profiling.


Methamphetamine Supercritical fluid chromatography Mass spectrometry Impurity profiling 



This study was supported by Brandenberger–Matsumoto Award 2018 from the Japanese Association of Forensic Toxicology, and the content will be presented at The International Association of Forensic Toxicologist 2018 meeting in Ghent, Belgium. This study was also supported in part by the Japan Society for the Promotion of Science KAKENHI Grant-in Aid for Young Scientists (B) (Grant Number JP17K12994). We thank Gabrielle David, PhD from Edanz Group ( for editing a draft of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies involving human participants or animals performed by any of the authors.

Supplementary material

11419_2018_446_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1061 kb)


  1. 1.
    United nations office on drugs and crime, word drug report 2018. Available at: Accessed 27 Jun 2018
  2. 2.
    Inoue H, Kanamori T, Iwata YT, Ohmae Y, Tsujikawa K, Saitoh S, Kishi T (2003) Methamphetamine impurity profiling using a 0.32 mm i.d. nonpolar capillary column. Forensic Sci Int 135:42–47. CrossRefGoogle Scholar
  3. 3.
    Qi Y, Evans ID, McCluskey A (2006) Australian federal police seizures of illicit crystalline methamphetamine (‘ice’) 1998–2002: impurity analysis. Forensic Sci Int 164:201–210. CrossRefGoogle Scholar
  4. 4.
    Stojanovska N, Fu S, Tahtouh M, Kelly T, Beavis A, Kirkbride KP (2013) A review of impurity profiling and synthetic route of manufacture of methylamphetamine, 3,4-methylenedioxymethylamphetamine, amphetamine, dimethylamphetamine and p-methoxyamphetamine. Forensic Sci Int 224:8–26. CrossRefGoogle Scholar
  5. 5.
    Ko BJ, Suh S, Suh YJ, In MK, Kim S-H (2007) The impurity characteristics of methamphetamine synthesized by Emde and Nagai method. Forensic Sci Int 170:142–147. CrossRefGoogle Scholar
  6. 6.
    Lee JS, Han EY, Lee SY, Kim EM, Park YH, Lim MA, Chung HS, Park JH (2006) Analysis of the impurities in the methamphetamine synthesized by three different methods from ephedrine and pseudoephedrine. Forensic Sci Int 161:209–215. CrossRefGoogle Scholar
  7. 7.
    Remberg B, Stead A (1999) Drug characterization/impurity profiling, with special focus on methamphetamine: recent work of the United Nations International Drug Control Programme. Bull Narc 51:97–117Google Scholar
  8. 8.
    Kunalan V, Nic Daéid N, Kerr WJ, Buchanan HAS, McPherson AR (2009) Characterization of route specific impurities found in methamphetamine synthesized by the Leuckart and reductive amination methods. Anal Chem 81:7342–7348. CrossRefGoogle Scholar
  9. 9.
    Qi Y, Evans I, McCluskey A (2007) New impurity profiles of recent Australian imported ‘ice’: methamphetamine impurity profiling and the identification of (pseudo)ephedrine and Leuckart specific marker compounds. Forensic Sci Int 169:173–180. CrossRefGoogle Scholar
  10. 10.
    Toske SG, McConnell JB, Brown JL, Tuten JM, Miller EE, Phillips MZ, Vazquez ER, Lurie IS, Hays PA, Guest EM (2015) Isolation and characterization of a newly identified impurity in methamphetamine synthesized via reductive amination of 1-phenyl-2-propanone (P2P) made from phenylacetic acid/lead (II) acetate. Drug Test Anal 9:453–461. CrossRefGoogle Scholar
  11. 11.
    Puthaviriyakorn V, Siriviriyasomboon N, Phorachata J, Pan-ox W, Sasaki T, Tanaka K (2002) Identification of impurities and statistical classification of methamphetamine tablets (Ya-Ba) seized in Thailand. Forensic Sci Int 126:105–113. CrossRefGoogle Scholar
  12. 12.
    Tsujikawa K, Kuwayama K, Miyaguchi H, Kanamori T, Iwata YT, Inoue H (2013) Chemical profiling of seized methamphetamine putatively synthesized from phenylacetic acid derivatives. Forensic Sci Int 227:42–44. CrossRefGoogle Scholar
  13. 13.
    Chinaka S, Tanaka S, Takayama N, Komai K, Ohshima T, Ueda K (2000) Simultaneous chiral analysis of methamphetamine and related compounds by capillary electrophoresis. J Chromatogr B Biomed Sci Appl 749:111–118. CrossRefGoogle Scholar
  14. 14.
    Iwata YT, Inoue H, Kuwayama K, Kanamori T, Tsujikawa K, Miyaguchi H, Kishi T (2006) Forensic application of chiral separation of amphetamine-type stimulants to impurity analysis of seized methamphetamine by capillary electrophoresis. Forensic Sci Int 161:92–96. CrossRefGoogle Scholar
  15. 15.
    Iwata YT, Kanamori T, Ohmae Y, Tsujikawa K, Inoue H, Kishi T (2003) Chiral analysis of amphetamine-type stimulants using reversed-polarity capillary electrophoresis/positive ion electrospray ionization tandem mass spectrometry. Electrophoresis 24:1770–1776. CrossRefGoogle Scholar
  16. 16.
    Liau A-S, Liu J-T, Lin L-C, Chiu Y-C, Shu Y-R, Tsai C-C, Lin C-H (2003) Optimization of a simple method for the chiral separation of methamphetamine and related compounds in clandestine tablets and urine samples by β-cyclodextrine modified capillary electrophoresis: a complementary method to GC–MS. Forensic Sci Int 134:17–24. CrossRefGoogle Scholar
  17. 17.
    Tagliaro F, Manetto G, Bellini S, Scarcella D, Smith FP, Marigo M (1998) Simultaneous chiral separation of 3,4-methylenedioxymethamphetamine (MDMA), 3-4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDE), ephedrine, amphetamine and methamphetamine by capillary electrophoresis in uncoated and coated capillaries with native β-cyclodextrin as the chiral selector: preliminary application to the analysis of urine and hair. Electrophoresis 19:42–50. CrossRefGoogle Scholar
  18. 18.
    Cody JT (1992) Determination of methamphetamine enantiomer ratios in urine by gas chromatography–mass spectrometry. J Chromatogr B Biomed Sci Appl 580:77–95. CrossRefGoogle Scholar
  19. 19.
    Hensley D, Cody JT (1999) Simultaneous determination of amphetamine, methamphetamine, methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA), and methylenedioxyethylamphetamine (MDEA) enantiomers by GC-MS. J Anal Toxicol 23:518–523. CrossRefGoogle Scholar
  20. 20.
    Jirovský D, Lemr K, Ševčı́k J, Smysl B, Stránský Z (1998) Methamphetamine—properties and analytical methods of enantiomer determination. Forensic Sci Int 96:61–70. CrossRefGoogle Scholar
  21. 21.
    LeBelle MJ, Savard C, Dawson BA, Black DB, Katyal LK, Zrcek F, By AW (1995) Chiral identification and determination of ephedrine, pseudoephedrine, methamphetamine and metecathinone by gas chromatography and nuclear magnetic resonance. Forensic Sci Int 71:215–223. CrossRefGoogle Scholar
  22. 22.
    Tao QF, Zeng S (2002) Analysis of enantiomers of chiral phenethylamine drugs by capillary gas chromatography/mass spectrometry/flame-ionization detection and pre-column chiral derivatization. J Biochem Biophys Methods 54:103–113. CrossRefGoogle Scholar
  23. 23.
    Płotka JM, Biziuk M, Morrison C, Namieśnik J (2014) Pharmaceutical and forensic drug applications of chiral supercritical fluid chromatography. Trends Anal Chem 56:74–89. CrossRefGoogle Scholar
  24. 24.
    Segawa H, Iwata YT, Yamamuro T, Kuwayama K, Tsujikawa K, Kanamori T, Inoue H (2017) Enantioseparation of methamphetamine by supercritical fluid chromatography with cellulose-based packed column. Forensic Sci Int 273:39–44. CrossRefGoogle Scholar
  25. 25.
    Toribio L, Bernal JL, Martín MT, Bernal J, Nozal MJ (2014) Effects of organic modifier and temperature on the enantiomeric separation of several azole drugs using supercritical fluid chromatography and the Chiralpak AD column. Biomed Chromatogr 28:152–158. CrossRefGoogle Scholar
  26. 26.
    Segawa H, Iwata YT, Yamamuro T, Kuwayama K, Tsujikawa K, Kanamori T, Inoue H (2017) Differentiation of ring-substituted regioisomers of amphetamine and methamphetamine by supercritical fluid chromatography. Drug Test Anal 9:389–398. CrossRefGoogle Scholar

Copyright information

© Japanese Association of Forensic Toxicology and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Hiroki Segawa
    • 1
    Email author
  • Yuko T. Iwata
    • 1
  • Tadashi Yamamuro
    • 1
  • Kenji Kuwayama
    • 1
  • Kenji Tsujikawa
    • 1
  • Tatsuyuki Kanamori
    • 1
  • Hiroyuki Inoue
    • 1
  1. 1.National Research Institute of Police ScienceKashiwaJapan

Personalised recommendations