GC-MS Analysis of Methamphetamine Impurities: Reactivity of (+)-or (-)-Chloroephedrine and cis- or trans-1,2-Dimethyl-3-phenylaziridine

Abstract

S-(+)-Methamphetamine is frequently found as the only isomer in urine specimens from methamphetamine abuseres. Enantiomerically pure S-(+)-methamphetamine can be synthesized from ephedrine or pseudoephedrine via chloroephedrine intermediates. These intermediates are unstable and capable of cyclizing to form cis- and trans-1,2-dimethyl-3-phenyl aziridine. Studies were done to determine if these intermediates could be detected when using a common gas chromatographic-mass spectrometric analytical method (derivatization with heptafluorobutyric anhydride, HFBA) for toxicological screening of methamphetamine. Analysis of (+)- or (-)-chloroephedrine after extraction into hexane and derivatization with HFBA indicated that both pseudoephedrine and ephedrine were the major compounds detected. Direct derivatization of a hexane solution of cis-1,2-dimethyl-3-phenyl aziridine yielded only the derivatives of ephedrine and pseudoephedrine, indicating that the aziridine intermediate is responsible for the formation of the ephedrine or pseudoephedrine. These studies indicate that the aziridine intermediates would not be detected in methamphetamine samples following HFBA derivatization.

Contribution of thermal desorption and liquid–liquid extraction for identification and profiling of impurities in methamphetamine by gas chromatography–mass spectrometry

“…N-acetylephedrine, N-formyl MA, and cis-and trans-1,2-dimethyl-3-phenylaziridine (AZ) were synthesized in our laboratory as previously reported [27][28][29][30][31][32]. All other chemicals were of analytical grade and were purchased from Wako Pure Chemical Co.…”

Analysis of the impurities in the methamphetamine synthesized by three different methods from ephedrine and pseudoephedrine

“…They can be classified mainly into two categories according to the precursors, 1-phenyl-2-propanone [4][5][6][7] and ephedrine compounds [8][9][10][11][12][13][14]. Both are generally used as precursors, and the latter is more widely used in the clandestine laboratories.…”

Irreversible Inhibition of CYP2D6 by (−)-Chloroephedrine, a Possible Impurity in Methamphetamine

“…Further studies would be needed to characterize this inhibition of CYP3A4/5 by (ϩ)-chloroephedrine in human liver microsomes, however, prior studies with rat microsomes on the metabolism of a mixture of cis-and trans-1,2-dimethyl-3-phenylaziridine reported their metabolism to cis-and trans-1-phenylpropene and nitrosomethane (Hata et al, 1976;Hata and Watanabe, 1994). The chemical instability of (Ϫ)-chloroephedrine as its free base and of the trans-1,2-dimethyl-3-phenylaziridine as the free base or in protonated form in water or organic solvents has been reported (Taguchi and Kojima, 1959;Allen and Kiser, 1987;Lekskulchai et al, 2000). Consistent with this instability was that in pH 7.4 buffer, (Ϫ)-chloroephedrine underwent total decomposition in 5 min, and addition of these decomposition products to the microsomes had no effect on the CYP2D6 activity.…”

“…1 and indicates that both diastereomeric ␤-halogenated intermediates are formed. These intermediates can cyclize to form cis-or trans-1, 2-dimethyl-3-phenylaziridine (Allen and Kiser, 1987;Lekskulchai et al, 2000). The occurrence of these intermediates in clandestinely synthesized methamphetamine has been documented (Noggle et al, 1986;Allen and Kiser, 1987;Cantrell et al, 1988;Skinner, 1990;Tanaka et al, 1992).…”

“…The goal of this study is to determine what effect, if any, a haloephedrine and/or its respective aziridine could have on human CYP2D6. (ϩ)-and (Ϫ)-Chloroephedrine HCl were chosen since they have been shown to be present in clandestinely synthesized methamphetamine, are stable as the HCl salt, and are capable of cyclizing to cis-and trans-1,2-dimethyl-3-phenylaziridine when present as the free base (Taguchi and Kojima, 1959;Noggle et al, 1986;Allen and Kiser, 1987;Lekskulchai et al, 2000). A computational approach using a 3D 1 molecular model of a xenobiotic binding site of a CYP2D6 (Modi et al, 1996) was used initially to evaluate the feasibility of the interaction.…”