Analysis of impurities in illicit methamphetamine

Forensti Science Intcrnutional, 56 (1992) 157 - 165 Elsevier Scientific Publishers Ireland Ltd.

ANALYSIS

OF IMPURITIES

IN ILLICIT

157

METHAMPHETAMINE

K. TANAKA, T. OHMORI and T. INOUE Nationul Research Institute of Police Scierm, 6 Sanban-chq Chiyodu-ku, Tokyo 102 (Japan) (Received March 25th, 1992) (Accepted May 27th, 1992)

Summary Impurity profiles of methamphetamine samples seized in Japan have been investigated. The samples are extracted with smal1 amounts of hexane under alkaline conditions and the extracts are analysed by gas chromatography (GC). Several impurity peaks are found in each chromatogram and the comparison of impurity profiles permits the establishment of common or different origins of methamphetamine seizures. The presence of ephedrine, which is a starting material for illegal methamphetamine preparations, is confirmed in al1 samples. In addition, methamphetamine dimer is newly found as an impurity and its structure is elucidated by the comparison of its retention time on GC and its mass spectrum with that .of the authentic compound synthesized by condensation of cis-1,2-dimethyl-3-phenyl asiridine and ( + )-methamphetamine. Key words: Methamphetamine; dimer

Impurities;

Ephedrine;

Gas chromatography;

Methamphetamine

Introduction Methamphetamine is one of the most popular abused drugs in Japan. It has been reported that the seized methamphetamine samples contain traces of starting materials and/or by-products of the reactions as their impurities [l - 181. Recently, the demand for an intimate knowledge of the composition of these impurities has increased in the forensic science field, as detailed impurity profiles can provide valuable information concerning illegal methods of manufacture. In addition, the comparison of such impurity profiles can aid in identifying the common origin of drug samples. In 1983, Strömberg reported a gas chromatographic method for the display of impurity profiles of Leuckart-synthesized methamphetamine and pointed out that the method permitted the establishment of common or different origins of methamphetamine seizures [ 131.

Correapondence to: Takako Inoue, National Research Chiyoda-ku, Tokyo 102 (Japan) 0379-0738/92/$05.00

0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

Institute

of Police Science, 6 Sanban-cho,

158

Kram et al. identified cy-benzyl-N-methylphenethylamine, N,N-di(@-phenethylisopropyl)amine, N,N-di@-phenethylisopropyl)methylamine and nine other compounds as impurities in methamphetamine synthesized by the Leuckart reaction [5] and Kishi et al. reported 1,2-dimethyl-3-phenyl aziridine, 1-phenyl-2-methylamino-1-propanone, ephedrine and 1-chloro-1-phenyl-2-methylaminopropane (chloroephedrine) as impurities in methamphetamine synthesized from ephedrine [12]. Furthermore, Cantrell et al. [14] and Skinner [18] elucidated the structures of two impurities, 1-benzyl-3-methylnaphthalene and 1,3-dimethyl-2phenylnaphtalene, in methamphetamine synthesized from ephedrine via reduction with hydroiodic acid. In the present studies, the structure of a newly found impurity in illicit methamphetamine samples seized in Japan, is identified and a gas chromatographic analytical method for impurities in methamphetamine preparations, which seem to be prepared from ephedrine, is described.

Experimental

Apparatus The gas chromatographic analysis was carried out on a Shimadzu GC-15A gas chromatograph equipped with a flame ionization detector. The column was a fused-silica wide-bore capillary column, DB-1 (15 m x 0.53 mm i.d., film thickness 1.5 Pm, J & W, CA, USA). The oven temperature was programmed as follows: 110°C for 1 min, 15”Clmin to 2OO”C, 2”CYmin to 208”C, lO”C/min to 300°C and then 300°C for 10 min. The injector and detector temperatures were 250°C and 27O”C, respectively. The helium carrier gas flow-rate was 10 ml/min and the injection port was the splitless mode. ‘H- and 13C-nuclear magnetic resonance (NMR) spectra were recorded on a Valian VXR-300 spectrometer in CDC13 and CD30D. Tetramethylsilane (TMS) was used as an internal standard. Gas chromatography-mass spectrometry (GC-MS) was performed on a JEOL SX-102 gas chromatograph-mass spectrometer. Gas chromatographic conditions were the same as described above. The following conditions were used for mass sepctrometry: ionization, chemical ionization (Cl) mode; ionization current, 300 PA; ionization voltage, 200 eV; reagent gas, isobutane. Melting points were determined on a Kofler-type apparatus- and uncorrected.

Sample extraction A sample (200 mg) of seized methamphetamine

sample was dissolved in 2 ml of 0.1 M phosphate buffer (pH 7.0). The solution was alkalized with 0.5 ml of 10% NazC03 and extracted by shaking for 10 min with 0.2 ml of n-hexane, containing tetratriacontane (0.1 mg/ml) as internal standard. After centrifugation the organic layer (top) was transferred to a smal1 glass tube with a disposable pipette and 4 ~1 of the extract was injected into a GC or GC-MS.

159

Cis- and trans-l,&dimethyl-S-phenyl azirìdine

Chloroephedrine hydrochloride (200 mg), which was prepared from (-)ephedrine and thionyl chloride [lg], was dissolved in 10% NaOH solution (2 ml) and refluxed for 2 h. After confirmation of the disappearance of the starting material by thin-layer chromatography (TLC, developing solvent: chloroformmethanol (95:5, vlv)), the reaction mixture was extracted three times with chloroform and the organic solutions were combined, dried over anhydrous NazS04 and evaporated in vacuo. The residue was purified by preparative-TLC (developing solvent: chloroform-methanol (95:5, v/v)) and 100 mg of cis-aziridine and 10 mg of trans-aziridine were obtained. Their identity was confirmed by ‘H-NMR [20] and CI-MS spectra. Cis-l,2-dimethyZ-3-phenyZaziridine. ‘H-NMR (6): 0.91 (3H, d, J = 6 Hz), 1.67 (lH, m, J = 6 Hz), 2.43 (lH, d, J = 6 Hz), 2.48 (3H, s), 7.15- 7.35 (5H, m). CI-MS (mlz): 148 (QM+). Trans-1,2-dim.ethyk?-phmyl azìridine. ‘H-NMR (6): 1.34 (3H, d, J = 6 Hz), 2.02-2.13 (2H, m), 3.55 (3H, s), 7.15-7.35 (5H, m). CI-MS (mlz): 148 (QM+). Cmpound

1

Anhydrous aluminum trichloride (136 mg) was added to a benzene solution (10 ml) of cis-aziridine (100 mg) and (+)-methamphetamine (201 mg). The reaction mixture was heated under reflux for 6 h. After cooling, the mixture was alkalized with 10 N KOH solution and extracted three times with ethyl acetate and the organic solutions were combined, dried over anhydrous NazS04 and evaporated in vacuo. The residue was purified by preparative-TLC (developing solvent: chloroform-methanol (95:5, v/v)) and compound 1 was isolated as a major product. The hydrochloride of the product was prepared in the usual way and the salt was recrystallized from methanol-ether solution. Compound 1. m.p. (hydrochloride): 149-153°C. ‘H-NMR (6): 0.60 (3H, d, J = 6.4 Hz), 0.74 (3H, d, J = 6.2 Hz), 2.19 (3H, s), 2.33 (3H, s), 2.34 (lH, dd, J = 6.9,13.1 Hz), 2.56 (lH, dd, J = 6.4, 13.1 Hz), 2.86 (lH, dd, J = 6.2, 9.6 Hz), 3.06 (lH, m), 3.40 (lH, d, J = 9.6 Hz), 7.08-7.34 (lOH, m). 13C-NMR(6): 16.3, 16.5, 32.2, 34.2, 41.2, 54.3, 56.9, 73.6, 125.8, 127.0, 128.0, 128.1, 129.2, 129.3, 138.3, 140.8. CI-MS (mlz): 297 (QM+), 238, 150, 148. coTnpound 2

Anhydrous aluminum trichloride (540 mg) was added to a benzene solution of trans-aziridine (200 mg) and (+)-methamphetamine (400 mg). The reaction mixture was reflued for 3 h. After cooling, the reaction mixture was alkalized with 10 N KOH solution and extracted three times with ethyl acetate. The organic solutions were combined, dried over anhydrous Na#O, and evaporated in vacuo. The product (compound 2) was isolated by repeated preparative-TLC using two developing solvent systems (chloroform saturated with ammonia and chloroform-methanol (90:10, v/v)). The hydrochloride of the product was

160

prepared in the usual way and the salt was recrystahized from methanol-ether solution. Compound 2. m.p. (hydrochloride): 193-197°C. ‘H-NMR (6): 0.81 (3H, d, J = 6.3 Hz), 0.87 (3H, d, J = 6.2 Hz), 2.19 (3H, s), 2.26 (3H, s), 2.40 (lH, dd, J = 7.2, 13.5 Hz), 2.79 (lH, dd, J = 6.6, 13.5 Hz), 2.98-3.08 (2H, m), 3.44 (lH, d, J = 6.3 Hz), 7.08-7.34 (lOH, m). 13C-NMR(6): 15.3, 16.5, 31.5, 34.1, 39.2, 55.2, 57.4, 72.2, 125.8, 127.3, 128.1, 129.1, 129.5, 138.5, 140.8. CI-MS (mlx): 297 (QM+), 238, 150, 148. Results and Discussion GC und GC-MS analysis of seìxed m-&hetamine

Fifty-nine methamphetamine samples seized at ten different places in Japan were analyzed by GC and GC-MS. Some typical gas chromatograms of extra& are shown in Fig. 1. Although Strömberg et al. [13] and Allen et al. [15] used the acidic extraction for analysis of impurities in methamphetamine, the acidic extract of methamphetamine seized in Japan showed no GC peaks. Peak 1 and 2, indicating the same retention times as methamphetamine and ephedrine, were confirmed to be methamphetamine (peak 1) and ephedrine (peak

?aC (1 tI peak2 J 111

region I ,

10

\

20

30 (min)

Fig. 1. Gas chromatograms of extracts of methamphetamine seizures. Peak 1, methamphetamine; peak 2, ephedrine; peak 3, compound 1.

161

150

238

238

LL

100

r

200

300

400

500 h Iz)

Fig. 2. Chemical ionization mass spectrum of peak 3 in Fig. 1.

2) by GC-MS analysis, respectively. The peak of ephedrine was found in al1meth-

amphetamine samples analyzed here. Kishi et al. also reported that ephedrine was detected in 11 of 14 methamphetamine samples seized in Japan [12] and it is wel1 known that methamphetamine abused in Japan is the (+)-isomer. These facts indicates that the methamphetamine abused in Japan is prepared from ephedrine. Peaks detected in region 1 (retention time 10- 18 min) were assumed to originate from impurities contained in methamphetamine preparations, as these peaks were not observed in the blank extract. These impurity profiles of methamphetamine prepared from ephedrine are simpler relative to those of methamphetamine synthesized from benzyl methyl ketone by the Leuckart reaction [13,17]. However, the peak patterns in this region were different from sample

dcH3 /

mH3 AKI3

cis -aziridine

e /

trans airidine

()%H,

AKI3

*

162

to sample depending on place of seizure. The comparison of these impurity profiles wil1permit the establishment of a common origin for the samples, since the reproducible preparation of methamphetamine in a clandestine laboratory is very difficult, thereby causing a great inter-batch variation in evidential drug samples. Structure of major impurìty (compound X)

Figure 2 shows the CI-mass spectrum of peak 3, which is the common and relatively intense peak in region 1 of Fig. 1 and the impurity giving this peak 3 is tentatively named as compound X. A quasi-molecular ion (QM‘) was observed at mlz 297 and diagnostic fragment ion peaks were detected at mlz 150 (base peak) and 238. The molecular weight of this compound (MW 296) coincided with double the weight of deprotonated methamphetamine (MW 148). The presence of the fragment ion at mix 238 (QM+-59) indicated that compound X had the CHsCH-NHCHa grouping in its structure. These results showed that the compound X might be a dimer of methamphetamine and that a carbon atom at the benzylic position of one methamphetamine moiety might be bound to a nitrogen atom of another methamphetamine moiety. Kishi et al. found 1,2-dimethyl-3-phenyl aziridine in methamphetamine samples synthesized from ephedrine [12]. Recently, Cantrell et al. reported a hypothesis about the aziridine formation in methamphetamine preparations from ephedrine with hydroiodic acid and phosphorus [16]. Thus, in the course of the illegal

a. a’

wm

c

1

i

7

signal I Y

signal II -

7

6

5

4

3

0

2 hm

Fig. 3. Proton-proton shift correlation spectrum of compound 1.

163

preparation of methamphetamine, the compound X seems to be formed by the condensation of 1,2-dimethyl-3-phenyl aziridine and methamphetamine. It is wel1 known that there are two stereoisomers in 1,2-dimethyl-3-phenyl aziridine, cis- and trans-aziridine [15,20,21]. Consequently, the configuration of the benzylic carbon of aziridine wil1 decide the configuration of compound X at the benzylic methine carbon adjacent to the amino group. For the structural elucidation of compound X, two dimers, compound 1 and 2, were synthesized by the condensation of cis- or trans-aziridine with (+)methamphetamine (Scheme 1). Confirmation of the structure of the synthesized compounds was performed by mass spectra1 analysis and ZD-NMR experiments. In CI-mass spectra, both synthesized compounds showed a similar mass spectrum with a QM + at mlz 297. The result of ‘H-lH shift correlation spectroscopy (COSY) experiments [22] of compound 1 is shown in Fig. 3. Signal 1 (6~ 2.86), the methine proton (proton e) adjacent to an amino grouping, coupled with the methyl proton (proton f, An 0.74) and the benzylic methine proton (proton d, Bn 3.40) adjacent to an amino grouping. Signal 11 (6n 3.06), the methine proton (proton b) adjacent to an amino grouping, coupled with the methyl protons (proton c, BH0.60) and the benzylic methylene protons (proton a and a’, bu 2.34 and 2.56). While compound 2 synthesized from the trans-aziridine showed the signal at Bn 2.98 - 3.08 (methine proton adjacent to an amino grouping) coupling with the methyl protons (6~ 0.81) and the benzylic methine proton adjacent to an amino grouping (6n 3.44) and the signal at 6n 2.98-3.08 (methine proton adjacent to an amino grouping) coupling with the methyl protons (6~ 0.87) and the benzilic methylene protons (6~ 2.40 and 2.79). These spectra1 data indicate that the structures of both synthesized compounds are formula 1 and 2 in Scheme 1, respectively. On GC and GC-MS analysis, the retention time of compound X contained in seized methamphetamine was consistent with that of the authentic sample prepared from the cis-aziridine and (+)-methamphetamine and mass spectra of both compounds coincided completely. From these results, the structure of compound X seems to be represented by formula 1. It seems reasonable that such a methamphetamine dimer is found as an impurity and that the amount of the dimer originating from the cis-aziridine is larger than that from the trans-aziridine, because ephedrine can easily convert to aziridine under acidic conditions and the cis-isomer is more stable than the transisomer. Identification of other impurities found on the gas chromatogram in this study is under investigation. Conclusion Impurity profiles of methamphetamine samples seized in Japan have been investigated, primarily aimed at establishing the common or different origin of the samples. Ephedrine, a starting material for illegal methamphetamine preparations, has been confirmed in al1 samples. In addition, a methamphetamine dimer

164

was found as an impurity and its structure was elucidated by the comparison of its retention time on GC and its mass spectrum with that of the authentic compound which was synthesized by condensation of &-1,2-dimethyl-3-phenyl aziridine and (+ )-methamphetamine. Gas chromatographic profiles of the basic extract from illicit methamphetamine have proved to be efficiently applicable to the establishment of a common or different origin for methamphetamine seizures. Acknowledgment

The authors wish to thank Dr. Sueshige Sets, Directer of our Department, for his helpful advice in the preparation of this paper. References

5

6 7 8 9 10 11

12 13 14

15

M. LeBelle, M. Sileika and M. Romach, Identification of a major impurity in methamphetamine. J. Pharm. SI_%.,62 (1973) 862. R.P. Barron, A.V. Kruegel, J.M. Moore and T.C. Kram, Identification of impurities in illicit methamphetamine samples. J. Assoc. Ofi An&. Chem., 57 (1974) 114’7- 1158. K. Bailey, J.G. Boulanger, P. Legault and S.L. Taillefer, Identification of an impurity in illicit amphetamine tahlets. J. Pharrn. Sci., 63 (1974) 1575- 1578. J.N. Lomonte, W.T. Lowry and I.C. Stone, The identification of impurities in illicit methamphetamine exhibits by gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy. J. Fowwic Sci., 21(1976) 575 - 582. T.C. Kram and A.V. Kruegel, Analysis of impurities in illicit methamphetamine exhibits. 111. Determination of methamphetamine and methylamine adulterant by nuclear magnetic resonance spectroscopy. J. Forensic Sci., 22 (1977) 40-52. T.C. Kram, Contaminants in illicit amphetamine preparations. J. Fwenaie Sci., 22 (1977) 508-514. A.M. v. d. Ark, A.B.E. Theeuwen and A.M.A. Verweij, Verunreinigungen in illegalem amphetamin. AT&. Kriminol., 162 (1978) 172 - 175. A.M. v. d. Ark, A.M.A. Verweij and A. Sinnema, Weakly basic impurities in illicit amphetamine. J. Fonmsic Sci., 23 (1978) 693- 700. T.C. Kram, Reidentification of a major impurity in illicit amphetamine. J. Fowxsic Sci., 24 (1979) 596-599. D.G. Sanger, I.J. Humphreys and J.R. Joyce, A review of analytical techniques for the comparison and characterization of illicit drugs. J. Fovvnsic Sci. Sec., 19 (1979) 65-71. J.H. Liu, W.W. Ku, J.T. Tsay, M.P. Fitzgerald and S. Kim, Approaches to drug sample differentiation. 111: A comparative study of the use of chiral and achiral capillary cohunn gas chromatography/mass spectrometry for the determination of methamphetamine enantiomers and possible impurities. J. Forensic Sci., 27 (1982) 39 - 48. T. Kishi, T. Inoue, S. Susuki, T. Yasuda, T. Oikawa and T. Niwaguchi, Analysis of impurities in methamphetamine. Eiwì Kagaku, 29 (1983) 400 - 406. L. Strömberg, H. Bergkvist and E.A. M.K. Edirisinghe, Comparative gas chromatographic analysis of narcotics IV. Methamphetamine hydrochloride. J. Chromatogr., 258 (1983) 65 - 72. M. Lambrechts, T. Klemetsrud, K.E. Rasmussen and H. J. Storesund, Analysis of leuckartspecific impurities in amphetamine and methamphetamine. J. Chromatop., 284 (1984) 499 - 502. A.C. Allen and W.O. Kiser, Methamphetamine from ephedrine: 1. Chloroephedrines and asiridines. J. Forensic Sci., 32 (1987) 953-962.

165 16

T.S. Cantrell, B. John, L. Johnson and A.C. Allen, A study of impurities found in methamphetamine synthesized from ephedrine. Forensti Sci. Int., 39 (1988) 39 - 53. 17 A.M.A. Verweij, Impurities in illicit drug preparations: amphetamine and methamphetamine. Forensic Sci. Reu., 1 (1989) 1- 11. 18 H.F. Skinner, Methamphetamine synthesis via hydriodic acidlred phosphorus reduction of ephedrine. Forensic Sci. Int., 48 (1990) 123 - 134. 19 H. Emde, Über Diastereomerie 111). Chlor- und Brom-ephedrine. Helv. Chim. Ada, 12 (1929) 384-399. 20 M. Tomie, H. Sugimoto and N. Yoneda, Studies on the steric inversion of alkamines. 1. On the reciprocal inversion between dl-ephedrine and dl-$-ephedrine. Chem. Pharm. Buil., 24 (1976) 1033 - 1039. 21 K. Tanaka, Synthesis of optically active prenylamine from (-)-norephedrine. Yakugaku Zasshi, 70 (1950) 212-216. 22 A. Bax, Two-Dimensionul NMR in Liquds, D. Reidel Publishing Co., The Netherlands, 1982.