Impurities in Illicit Drug Preparations: Amphetamine and Methamphetamine

REFERENCE: Verweij AMA: Impurities in illicit drug preparations: amphetamine and methamphetamine; Forensic Sci Rev 1:1; 1989.

ABSTRACT: In this review, attention is paid to chromatographic and mass spectral properties of already identified impurities found to be present in frequently abused drug preparations ofillegal origin of amphetamine and methamphetamine. The most commonly employed methods of synthesis of drugs of this type are briefly described. Special emphasis is given to the Leuckart route, found to be the preferred method, in the illicit production of amphetamine. Furthermore, some isolation and preconcentration methods for the contaminants are discussed. The importance of identifying impurities present in amphetamine or methamphetamine cannot be overestimated. These impurities originate mostly from the improper purification in the end stage of the different syntheses used in the clandestine manufacture of the substances; it is possible to differentiate between the several kinds of illegal drug preparations, synthesized by various methods, by means of so-called "route specific" impurities. Finally, a survey is given of the impurities already known to be present in amphetamine and methylamphetamine, together with their mass spectral and some chromatographic properties.

KEYWORD: Amphetamine, chromatography, contaminants, impurities, isolation, mass spectrometry, metham- phetamine.

I. INTRODUCTION it is related to the Leuckart reaction as the most popular method for the production of amphetamine in both the A recurrent theme in forensic drug analysis concerns western European countries and the U.S. [8,35]. the possibilities oflocating sources of supply and manu- In this review, the syntheses commonly used in the facture of illicit drugs by means of diagnostic chemical or clandestine preparation of amphetamine and metham- physical properties [17,38], Powder formulated drugs phetamine are discussed, followed by some remarks on and their potential accompanying substances can be the isolation of impurities from reaction mixtures and examined only on the basis of their chemical properties; final preparations. Lastly some chromatographic and whereas with tablets or capsules their visual appearance mass spectrometric data of the various impurities are and the nature of bulking, binding, lubricating, diluting .given. The impurities present in amphetamine and and coloring agents can play an important role. methamphetamine are accentuated here, since the con- In contrast to genuine drugs, illegal drug preparations taminants present can give important indications about are often contaminated. Impurities in these preparations the type of synthesis used. A contribution has been made largely depend on inadequate purification procedures, in improving the information content of the "signature" and they can originate from a variety of causes such as analysis of amphetamines. Today even the presence of imperfect chemical handling, starting materials, side, and "reaction specific" impurities can be established in the subsequent reactions, intermediate products, diluents, chromatographic profiles. laboratory dirt, and from handling and packing the drugs. Due to the scarcity of data, little attention can be given It stands to reason that chromatographic patterns obtained to inorganic impurities found in clandestine ampheta- from illegally produced drugs might contain valuable mine or methamphetamine originating from hydrogenat- information about the drug and its method of synthesis, ing catalysts. even if the identity of only a limited number of the chromatographic peaks is known. In general, only pat- n. SYNTHESES OF AMPHETAMINE terns are compared and, if possible, recognized in these so-called "chemical signature" analyses [38]. In recent Over the years the Leuckart reaction has remained the years some basic work has been done [23,35] regarding most popular method for synthesizing illicit ampheta- the nature of contaminations encountered in the different mine in the U.S. [8], the U.K. [32], and The Netherlands. syntheses of amphetamine or methamphetamine. Mostly The reductive amination of benzyl methyl ketone is im-

ForensicScienceReview • VolumeOne Number One • June 1989 3 portant [8,16], while in Sweden and the U.S., the nitro- propene route is incidentally used, like the phenyloxime route in the U.S. RO- ~OH [a] 0- "H. O~ h -CH.,-C-CIi:, + NH.OH -t ~ h :H~-C -CHJ --t ~-h CH,-{-CH. The following are some methods forthe production of [bl H amphetamine, in which the chemical handling is not dif- Hydroxylamine Benzyl methyl keioxime ficult and the necessary materials are easy to purchase. Many other production methods are known, but are of in which [a]: Na (amalgamated), Na (absolute ethanol), lesser importance in this context. For further information LiAlH4, or H2 and Raney Nickel, nickel, iron, nickel refer to reference [32]. plated zinc; [b]: 20-170 °C, 1-130 atm; Electrolytical reduction has also been reported. Great A. The Leuckart Rection differences have been described for the reaction condi- tions [18,27,31]. This reaction can be formulated by the following scheme: D. The Phenylnitropropene Route

Condensation of benzaldehyde withnitroethane yields l-phenyl-2-nitropropene [2,9]. Hydrogenation of the double bond and subsequent reduction of the nitro group Benzyl methyl Formamidc N·Fonnylamphetamine Amphetamine gives the amphetamine: ketone in which [a]: 180-190°C; [b]: H2SO/HCI (dilute); [c]: 90- 125°C. Reaction conditions can vary [29]. A trend [15] in recent years has been to replace form amide by ammo- nium formate [48] or a mixture of ammonia and formic Benzaldehyde Nitroethane Phen ylnitropropene acid [6]. in which [a]: LiAlH4' H2 and Raney Nickel or Pd/C; [b]: B. The Reductive Amination of Benzyl Methyl Ketone 20-100°C, 1-80 atm, CH30H, C2HsOH, H20/HCOOH, C H 0H. Reaction conditions vary widely [4,10]. 2 s Benzyl methyl ketone can react with ammonia in the following way [13]: III. SYNTHESES OF METHAMPHETAMINE

[al NH, F\ ~ R ~HJ-C -CH~ + N~ -> O-CH'-H~ -cu, [b] In contrast to the western European countries, in the Ammonia U.S. the illicit production of methamphetamine has pref- erence over clandestine amphetamine production. (In in which [a]: Raney Nickel, Pt,:-I2, Al powder in the The Netherlands, methamphetamine has rarely been presence ofHgC12, Nickel plated Zinc; [b]: 20-170 DC,1- produced up to the current time. Only once in the past 10 130 atm, ethanol, methanol. Reaction conditions can years has a high pressure reductive amination of benzyl differ widely [1,5,11,36]. (Only low pressure and low methyl ketone with methylamine been found [46], oper- temperature aminations have been encountered so far in ating under near-professional standards.) the Netherlands.) A. The Reductive Amination of Benzyl Methyl Ketone c. The Oxime Route Illicit methamphetamine is primarly produced in the Benzyl methyl ketone reacts with hydroxylamine to U.S. [8] by reductive amination, according to the follow- give the oxime, which can be hydrogenated to give the ing scheme: amphetamine [14]:

Verweij • Impurities in Illicit Amphetamine and Metamphetamine Preparations 4

IV. ISOLATION AND PRECONCENTRA TION OF THE IMPURITIES

For identification purposes, where the substances should be of a purity better than 95%, it turned out that, at Methylamine Methamphetamine best, crude reaction mixtures could be taken. A reliable extraction procedure started by diluting the reaction in which [a]: HgCl/Al, NaBH4 in slightly acid medium, mixture with water then adding enough tartaric acid to H/Pd, Na/ethanol, H , Raney Nickel; [b]: 25-160 DC, 1- 2 obtain a weakly acidic solution. Next, the solution was 200 atm, methanol, ethanol, ethyl ether. Reaction condi- extracted with diethyl ether. Then the ether layer was tions vary widely. extracted with 4N hydrochloric acid. An aliquot of the hydrochloric solution was made alkaline and extracted B. The Leuckart Reaction with chloroform to give fraction I (weak bases). A quantity of the ether layer was evaporated to give fraction In methamphetamine preparation, the following re- II (neutral substances). The tartaric acid fraction was action is of minor importance, compared with reductive made alkaline, and was extracted with chloroform to give amination. Schematically: fraction III (strong bases). With the help of repetitive preparative thin-layer Chromatography the compounds in question were iso- lated from the fractions I, II, III. The eluents hexane- acetone 50:50 or 80:20, hexane-ether 50:50 or 90: 10 were

N·Methylfonnamide N-Formylamphelamine suitable, with the best results obtained with hexane-ether 50:50. in which [a]: 170-190°C; [b]: H2S04 orHel; [c]: 120-170 By combining the evidence obtained in low resolu- "C. Instead of N-methylfonnamide, a mixture of methyl- tion mass spectrometry and 'H NMR, it appears that the amine and formic acid is sometimes used [23]. identification of the substances is straightforward. Of far lesser importance are the syntheses, in which Incidentally, 13C NMR and high resolution mass spec- ephedrine is used as the starting material. Several routes trometry seemed to be necessary. using ephedrine have been reported, including: (a) hydro- For routine profiling of illicit amphetamines, off line genating ephedrine [12] in acidic solutions using Pd/ extraction methods were developed [3,25]. An on line

BaS04 and H2 at elevated temperatures (100°C); (b) method is also described [26]. In the on line method, the reacting ephedrine with chlorine (from thionyl chloride or clandestine amphetamine was dissolved in a buffer and phosphorus pentachloride) and subsequent hydrogena- injected in the chromatograph without further pretreat- tion of the intermediate [20] 1-phenyl-l-chloro-2-meth- ment. The contaminations were enriched on a Cs pre- ylamino propane; (c) reducing of ephedrine with hydro- column, and amphetamine and other polar substances gen iodide and red phosphorus [20]. were washed out. Then the impurities were eluted from A typical example of thoughtless chemical handling the extraction column to the analytical CIS column, on is the reaction in which benzylmagnesium chloride is which the separation was done. refluxed with the condensation product of methylamine and acetaldehyde. Due to imperfect chemical handling the efforts to produce methamphetamine were fruitless V. SURVEY OF IMPURITIES [8]. A wide variety of methamphetamine syntheses are The impuri ties reported in the literature are given here known but oflesser importance. For further details, refer according to the sequence developed in the section (II) on to references [3,32]. the syntheses of amphetamine and methamphetamine.

Forensic Science Review • Volume One Number One • June 1989 5

Table 1. (continued) Table 1. Impurities found in amphetamine synthesized with the Leuckart reaction MW Formula Name and structural formula Remarks Ref.

2,4-Dimethyl-3,5-diphenylpyridine MW Formula Name and structural formula Remarks Ref. 259 Cl9Hl7N c [42]

45 CH3NO Fonnamide a /- '" c-, ~CI", 0 N H, He"_Nil, 259 Cl9Hl7N 2,6-Dimethyl-3,5- c [42] diphenylpyridine 46 CHP2 Formic acid a [24]

259 Cl9Hl7 4-Methyl-5-phenyl-2- c [42] (phenylmethyl)-pyridine 134 C9H1OO Benzyl methyl ketone a [24] (phenyl acetone, phenylpropanone) OOCH'-o

o~-~ h CH,-C -CHl

259 CI9H17N 2-Methyl-3-phenyl-6-(phenylmethyl)- c [42] pyridine 163 C1OHl3NON-Fonnylamphetamine b [24] CH, Q-cH?-~HC-NHH,-CHO QVH'-o

170 CIIHI~2 4-Methyl-5-phenylpyrimidine c,d [45] 267 Cl9HzsN N ,N-Di(~ -phenylisopropyl) c [24] methylamine o-~j CH, Q-cH'-C~--cHl

HCH~ 170 CI1HION2 4-Benzylpyrimidine c,d [45] Q-cH2-C~--cHl

273 C H N 2,4-Dimethyl-3-phenyl-6- c [44] 0- N~ 2o l9 ~ ;, CH,-U (phenylmethyl)-pyridine

210 ~-;, ~-1. H,-Q C1sHl4O Dibenzyl ketone e [24] 00CH, O~R-;,-oCH,-C-CH" ;, 277 Cl9Hl9NO 2-Methyl-2-phenylmethyl-5- c [43] phenyl-2,3-dihydropyrid-4-one

211 C1sH1,N cc-Benzylphenetylarnine c [22] (Dibenzylmethylamine) o-CH~OO H VH.-rH-CH,-o NH, 281 C19Hz3NON,N-Di(~-phenylisopropyl) c [23] fonnamide 253 Cl8H23N N,N-Di(~-phenylisopropyl)amine c [24]

Q-cH2-C~-CH~ OCH~-CH,,-CHl HH N-CHO Q-cH2--e;.-CHl OCH:rC:-CHl

'Starting material. bIntennediate product. CProduct of side reaction. d"Route specific" impurity. "Impurity in starting material.

Verwelj • Impurities in Illicit Amphetamine and Metamphetamine Preparations 6

Table 2. (continued) Table 2. Impurities found in amphetamine synthesized by the reductive amination of benzyl methyl ketone MW Formula Name and structural formula Remarks Ref.

MW Formula Name and structural formula Remarks Ref. 251 C1sH.IN N-(~ -PhenylisopropyJ)benzyl methyl b [40] ketimine

134 C9H1P Benzyl methyl ketone a [24] ~H, -<:H-eM, 'N (Phenyl acetone, phenyJpropanone) ~H,-C"--{;H'

~~~ /; HrC-CH) 253 C1sH23N N,N-Di(~ -phenylisopropyl)amine b [24]

177 C11H1sNON-Acetylamphetamine c [41] O-CH1-CH ,:-cH~ o /N" ~ h -CH,--cH -eH, 0~ ;;- CHrCMT-NHH~----C R --(;H~ 265 C1SHI9NO l-Oxo-l-phenyl-Ztf -phenylisopropyl- c [41] imino )propane

210 C1sHI4O Dibenzyl ketone e [24] Q-cH~--cH-CH3 'N ° cr",-g-CH,-o 0~ /,-~-c /-eM/ , ° 268 ClsH2002 2A-Dihydroxy-l,5-diphenyl-4- c [16]

223 CI6H17N N-(~-Phenylisopropyl)benzaldimine b [40] methylpentene-l

o-CH1-CH,-CH~ (}c"=rC",-i~"'-oH, 0~ /,/" c':" 'S tarting material. bIntermediate product. "Product of side reaction. dURoutespecific" impurity. "Impurity in starting material.

Table 3. Impurities found in amphetamine synthesized by Table 4. Impurities found in methamphetamine synthe- the oxime route and the phenylnitropropene route sized by the reductive amination of benzyl methyl ketone

MW Formula Name and structural formula Remarks Ref. MW Formula Name and structural formula Remarks Ref.

133 CgHlIN 2-Phenylmethylaziridine c [21] 134 C9H1P Benzyl methyl ketone a [24]

OCH,-CHVCH, OR~ /, -CH,,-C-CH, " Amphetamine 135 CgH13N c [46] 133 2-Methyl-3-phenylaziridine C9HIIN c [21] ~ ;, CH,-9CH, 0" N", ~H-CH-CH - \/ ' N " 136 C9HI2O I-Phenyl-propanol-2 b [46] 149 C9H11NO Benzyl methyl ketoxime b [8] (}c7~ /, H2-9--<.'H, OH

o~ /, HrCNo~113H 163 C11H17N N,N' -Dimethylarnphetamine c [46]

163 C HgN0 Phenyl nitropropene b,f [8] Q-cH,-yH-CHJ 9 2 N / -, .CHl CH,

(fH=~:" 210 C1sH14O Dibenzyl ketone e [24]

Q~ -cRrIt QH,-C-CH ~ /, 'Starting material. bIntermediate product. "Product of side reaction. dURoutespecific" impurity. ·Impurity in starting material. !'found in the 'Starting material. bIntermediate product. phenylnitropropene "Product of side reaction. d"Route specific" impurity. route only. "Impurity in starting material.

Forensic Science Review • Volume One Number One • June 1989 7

Table 5. (continued) Table 5. Impurities found in methamphetamine synthe- sized by the Leuckart reaction MW Formula Name and structural formula Remarks Ref.

MW Formula Name and structural formula Remarks Ref. 267 Cl91\sN N,N-Di(~ -phenylisopropyl) c [24] methylamine 31 Methylamine a [24]

'')tarting material. bIntennediate product. 46 CI\02 Formic acid a [24] C i-roduct of side reaction: d"Route specific" impurity. "Impurity in starting material.

HCOOH

59 a [24] Table 6. Impurities found in methamphetamine synthe- sized wi th ephedrine

MW Formula Name and structural formula Remarks Ref. a [24] Benzyl methyl ketone a [24] (Phenyl ace ton, phenyl propanone)

c [24]

147 C1oH13N 1.2-Dimethyl-3-phenylaziridine c [20]

163 CllHI7N N,N'-Dimethylamphetamine c [24]

163 C1oH13NO I-Phenyl-2-methylamino-propanone b [20]

b [24]

a [20] 177 C11H1SNON-Fonnylmethylamphetamine d [24]

1\" CH, ~_j'y•...tH-NH-C~ 0"

e [24] 183 C1oHl4NCl l-Chloro-l-phenyl-2- b [20] methy larnino-propane

~1H-eH\"-NH-CHs 9'"

CI 225 Cl6HI9N a-Benzyl-N-methylphenetylamine c [24]

if", 'Starting material. bIntennediate product. (}!:~-NH-CH' "Product of side reaction. d"Route specific" impurity. eImpurity in starting material. 253 C1Sl\3N N.N-Di( ~-phenylispropyl)amine c [24]

Verwelj • Impurities in Illicit Amphetamine and Metamphetamlne Preparations 8

5 7

TIC 7' i

6 6' 2

4

A A fL UJL .i II 1 - ~ ~ J t. l1 h h "- ----7 RT Figure 1. Computer reconstructed ion chromatogram (TIC) of impurities in amphetamine synthesized by the Leuckart reaction. Chromatographic conditions: (a) gas chromatograph, Varian 3700; (b) column, 50-m fused silica C Sil5, 0.32-mm i.d.; (c) injector temperature, 270°C; split ratio, l: 10;(d) oven temperature, 50-250°C, 5 °C/min; (e~carrier gas, helium, 2 mL/min. Chromatographic peak identities: (1) amphetamine; (2) 4-methyl-5-phenylpyrim- idine; (3) 4-benzylpyrimidine; (4) N-formylamphetamine; (5) N,N-di(~-phenylisopropyl)amine; (6) N,N-di(~- phenylisopropyl)methylamine; (6-a) stereoisomer of (6); (7) N,N-di(~-phenylisopropyl)formamide; (7-a) stereoi- somer of (7).

VI. CHROMATOGRAPHIC AND MASS SPECTROMETRIC PROPERTIES OF THE IMPURITIES Table 7. Mass spectral data of impurities found in As mentioned, thin-layer chromatography with pre- amphetamine synthesized by the Leuckart reaction coated silica gel plates and hexane-ether 50:50 as the eluent gave the best results. Staining was done with MW' Fragments" Ref. iodoplatinate reagent or with 1% p-dimethylaminoben- 45 18 45 28 29 17 44 27 [7] zaldehyde in 50% sulfuric acid followed by heating the 46 46 29 45 18 28 44 17 [37] plate at 100°C in a drying box. 134 91 134 92 43 65 77 89 [24] Gas chromatography could be carried out with 2-m 163 72 44 118 91 65 [24] columns packed with Apiezon®jKOH 10% in Chromo- 170 170 169 102 115 116 171 51 [45] 170 170 [45] sorb" G DCMS (80-100 mesh). In Figure 1, a chromato- 169 91 115 142 65 116 210 91 65 39 119 92 63 89 [24] gram of a mixture of different impurities is given, on a 50- 211 120 91 42 77 102 65 51 [47) m, 0.32 mm i.d., C SH@5 on fused silica column. Tem- p 253 91 44 162 119 65 70 [24] perature of the oven was programmed. 259 259 260 244 115 215 202 116 [42] HPLC analysis [25,26] of the various contaminations 259 259 260 115 244 101 202 215 [42] in illicit amphetamine can be done on a reverse phase C 259 258 259 243 244 260 115 91 [42] I8 259 258 259 180 244 260 182 115 [44] column with an acetonitrile-water gradient as the mobile 267 91 58 176 119 42 41 56 [23] phase. Peaks can be detected at 220 and 254 nm. From 273 272 273 258 55 57 71 79 [44] these studies it appears that the impurities are present in 277 186 91 158 143 187 65 115 [43) the final products in quantities often less than 0.1 % of the 281 91 190 119 72 191 41 44 [23] total amount of the drug. Tables 7 through 12 give the mass spectral data for the "These compounds are listed in the same sequence as listed in Table 1. different impurities. Most data rely on 70 eV electron bIons are listed in decreasing order of intensity, with the base peak listed energy. first.

Forensic Science Review • Volume One Number One • June 1989 9

Table 10. Mass spectral data of impurities found in amphetamine synthesized by the reductive amination of VIT. CONCLUSIONS benzyl methyl ketone The mass spectral data given in Tables 7-12 together MW' Fragments" Ref. with the information in Tables 1-6 open possibilities for adequate identification of the various impurities, espe- 134 91 134 92 43 65 77 89 [24] cially when chromatographic parameters are taken into 135 44 91 43 42 65 39 45 [7] account. On the basis of the number and combination of 136 105 106 77 79 91 103 136 [7] 163 72 44 42 91 56 70 65 [7] impurities present in the drug preparation and in the case 210 91 65 39 119 92 63 89 [24] of Leuckart amphetamine c.q. methamphetamine of "reaction specific" impurities, we can trace the synthesis "These compounds are listed in the same sequence as listed in Table 4. of amphetamine or methamphetamine followed by the "Ions are listed in decreasing order of intensity. with the base peak listed illegal producers. Furthermore it is possible to decide first. (based on the similarity of impurity patterns) that illicit

Verweij • Impurities in Illicit Amphetamine and Metamphetamine Preparations 10

amphetamine preparations originate from the same pro- REFERENCES duction batch [34]. In the cited study on the Leuckart 1. Alexander ER, Misegades ML: A low pressure reductive reaction of amphetamine, the effects of the reaction alkylation method for the conversion of ketones to primary conditions on the production of known impurities were amines; J Arn Chern Soc 70:1315; 1948. investigated and the possibilities examined for different 2. Alles GA: dl-Beta-Phenylisopropylamines; J Arn Chern chemists to produce amphetamine with the same impurity Soc 54:271; 1932. profile by rigidly following the same detailed synthetic 3. Clandestinemanufacture of substancesunder international control, United Nations, Vienna; 1987; ST/NAR/lO. directions. Strong support was found in this study for the 4. Commercial Solvents Corporation: Catalytic Reduction of above stated assumption. Nonetheless the assumption of Nitro Olefins; United States Patent 2.647.930; 1953. the equality of batches is tied to the presence of quite a lot 5. CouturierPL:Actiondesderivesorganomagnesiensmixtes; of impurities, in which the Leuckart reaction excels, be- Ann Chirn 10: 559; 1938. cause of its condensation character, where numerous re- 6. CrossleyFS, Moore ML: Studies on the Leuckart reaction; J Org Chern 9:5291; 1944. action pathways can be followed. With other types of syn- 7. Eight Peak Peak Index of Mass Spectra; The Mass Spec- theses, impurity signatures can give less information trometry Data Centre, The Royal Society of Chemistry: content, as fewer impurities can be present, due to the Nottingham; 1983. possibilities for a given reaction. The meaning of equality 8. Frank RS: The clandestine drug laboratory situation in the of profiles under such circumstances should, of course, be United States; J Forensic Sci 28:18; 1983. approached by another standard of value than in Leuckart 9. Gairaud CB,Lapin, GR: The synthesis of co-nitrostyrenes; J Org Chern 18:1; 1953. type synthesis of amphetamine. 10. Great Lakes Carbon Corporation: Reduction of Arylnitro- The fact that the identity of the impurities are known alkenes; United States Patent 3.458.576; 1969. will stimulate studies in other unexplored areas, for in- 11. Groot-Wassink BH, Duyndam A, Jansen ACA: Synthesis stance, the acute toxicity of a-benzyl-N-methylpheneth- of amphetamine; J Chern Ed 51:671; 1974. 12. Haley TJ: Desoxyephedrine - a review of literature; J ylamine and a-benzylphenethylamine [30]. The (X- PharrnAss Sci Ed 36:161; 1947. benzyl components appeared to have a greater CNS 13. HaskelbergL: Aminativereduction ofketones; J Am Chem stimulation at the brain stem and cord levels than am- Soc 70:2811; 1948. phetamine. Further studies in this field are expected to 14. Hey DH: dl-~-Phenylisopropy1amine and related appear in due time. compounds; J Chern Soc 18; 1930. Recent interest has been focused on the nature and 15. Huizer H, Brusee H, Poortman-van der Meer AJ: Di( ~- phenylisopropyl) amine in illicit amphetamine; J Forensic level of inorganic trace impurities present in the final Sci 30:427; 1985. product of the methamphetamine synthesis. By using 16. Huizer H, Theeuwen ABE, Verweij AMA, Sinnema A, vd inductively coupled plasma mass spectrometry (lCP-MS) ToornJM: Impurities in illicitamphetamine;J Forensic Sci or a combination of ion chromatography and ICP-MS Soc 21:225; 1981. [19,39] several inorganic trace impurities inmethamphet- 17. Humphreys U: The work ofthe Drugs IntelligenceLabora- amine were detected. It appeared even possible to differ- tory, Home Office Forensic Science Service;Bull Narcot- ics 36:33; 1984. entiate in this way between two methods of synthesizing 18. JaegerFM, van DijkJA:Preparation of2-phenylisopropy1- methamphetamine. It is expected that further develop- amine (benzedrine) the isomeric 1-phenylpropylamineand ments in this aspect will take place in due time. 3-phenyl-1,2-propanediamine and the resolution of these bases into their optical antipods; in Proceeding of the ACKNOWLEDGEMENTS Section of Sciences of the Koninklijke academie van Weten- schappen; Amsterdam; 44:26; 1941. 19. Kishi T: Analysis of trace elements in methylamphetamine The author wishes to thank Mrs. A.M. v.d. Ark, F.H. hydrochloride by inductively coupled plasma-mass spec- v. Dijk, A. Sinnema, A.B.E. Theeuwen and J.M. v.d. trometry; J Res Natl Bur Stand (U.S.) 93:469; 1988. Toom. Their help made the publication of this review 20. KishiT,InoueT,SuzukiS, YasudaT,Oikawa T,Niwaguchi possible. T: Analysis of impurities in methamphetamine; Eisei Kagaku 29:400; 1983. 21. Kotera K, Okada T, Miyazaki S: Aziridine formation by reduction of ketoximes with lithiumaluminiumhydride. Dibenzylketoximeand its O-substituted derivations;Tetra- hedron 24:6177; 1968. 22. Kram TC: Identification of an impurity in illicit ampheta- mine tablets; J Pharm Sci 66:443; 1977. 23. Kram TC: Reidentification of a major impurity in illicit amphetamine; J Forensic Sci 24:596; 1979.

Forensic Science Review • Volume One Number One • June 1989 11

24. Kram TC, Kruegel AV: The identification of impurities in ture Analyses of Drugs; in Proceedings of the International illicit methamphetamine exhibits by gas chromatography/ SymposiumonI nstrumental Applications inF orensicDrug mass spectrometry and nuclear magnetic resonance spec- Chemistry; United States Department ofJ ustice: Washing- troscopy; J Forensic Sci 22:40; 1977. ton, DC; p. 202; 1978. 25 .. Lambrechts M, Rasmussen KE: Use of bonded-phase silica 39. Suzuki S, Tsuchihashi H, Nakajima K, Matsushita A, sorbents for rapid sam pIing of impurities in illicit ampheta- Nagao T: Analysis of impurities in methamphetamine by mine for high-performance liquid chromatographic analy- inductively coupled plasma-mass spectrometry and ion ses; J Chromatogr 331:339; 1985. chromatography; J Chromatogr 437:322; 1988. 26. Lambrecht M, Tonnesen F, Rasmussen KE: Profiling of 40. Theeuwen ABE, Verweij AMA: Impurities in illicit am- impurities in illicit amphetamine samples by high perform- phetamine 7. Identification of benzyl methyl ketone phen- ance liquid chromatography using column switching; J ylisopropylimine and benzyl methyl ketone benzylimine in Chromatogr 369:365; 1986. amphetamine; Forensic Sci Int 15:237; 1980. 27. Larsen E: Notiz uber die Reduktion von Oximen mit 41. Theeuwen ABE, Verweij AMA: Verunreinigungen in ille- Lithiumaluminiumhydrid; Svensk Kem Tid 61:242; 1949. galem Amphetamin 9. Identifizierung von N-Acetylam- 28. LomonteJN, LowryWT, Stone IC: Contaminants in illicit phetamin und 1-0xo-l-phenyl-2-(phenyl isopropyl amphetamine preparations; J Forensic Sci 21:575; 1976. imino)propan; Archiv Krim 168:23; 1981. 29. Moore ML: The Leuckart reaction; in Adams R (ed): 42. v.d. Ark AM, Sinnema A, Theeuwen ABE, v.d. Toorn JM, Organic Reaction, Vol V; John Wiley: New York; p. 301; Verweij AMA: Impurities in illicit amphetamine 3. Isola- 1949. tion and identification of2,4-dimethyl-3,5-diphenyl pyri- 30. Noggle Jr TF, Clark RC, Davenport TW, Coker ST: Syn- dine, 2,6-dimethyl-3,5-diphenyl pyridine and 4-methyl-5- thesis, identification, and acute toxity of o-benzylphene- phenyl-2-(phenyl-meythyl)pyridine;Pharm Weekbll13:41; tylamine and o-benzy I-N-methylphenethylamine, Contami- 1978. nants in clandestine preparation of amphetamine and 43. v.d. Ark AM, Sinnema A, v.d. Toom JM, Verweij AMA: methamphetamine; J Assoc Off Anal Chem 68: 1213; 1985. Impurities in illicit amphetamine 2. Isolation and identifi- 31. Purdue Research Foundation: Processfor the Reduction of cation of 2-benzyl-2-methyl-5-phenyl-2,3-dihydropyrid- Arylnitroalkenes; United States Patent 2.233.823; 1939. 4-one; Pharm WeekbI1l2:980; 1977. 32. Recommended Methods for Testing Amphetamine and 44. v.d. Ark AM, Sinnema A, v.d. Toom JM, Verweij AMA: Methamphetamine; United Nations: Vienna; 1987; ST/ Impurities in illicit amphetamine 4. Isolation and identifi- NAR/9. cation of2-methy 1-3-pheny 1-6-(phen ylmethy l)pyridine and 33. Sanger DG, Humphreys IJ, Ardrey RE: Internal Report 2,4-dimethyl-3-phenyl-6-(phenylmethyl)pyridine; Pharm 258; Home Office Central Research Establishment: Alder- WeekbI113:341; 1978. maston; 1978. 45. v.d. Ark AM, Theeuwen ABE, Verweij AMA: Impurities 34. Sanger DG, Humphreys, IJ, Patel AC, Japp M, Osborne, in illicit amphetamine 1. Isolation and identification of RGL: The significance of gas chromatographic impurity some pyrimidines; Pharm WeekbI1l2:977; 1977. patterns obtained from illicitly produced amphetamine; 46. v.d. Ark AM, Theeuwen ABE, Verweij AMA: Verunre- Forensic Sci Int 28:7; 1985. inigungen in illegalem Amphetamin, Identifizierung von 35. Sinnema A, Verweij AMA: Impurities in illicit ampheta- Phenylpropanol-2, Amphetamin und N,N'·Dimethylam- mine, a review; Bull Narcotics 33:37; 1981. phetamin in Methylamphetamin; Archiv Krim 162:171; 36. Schwoegler EJ, Adkins H: Preparation of certain amines; J 1978. Am Chem Soc 61:3499; 1939. 47. v.d. Ark AM, Verweij AMA, Sinnema A: Weakly basic 37. Stenhagen E, Abrahamson A, McLafferty FW: Atlas of impurities in illicit amphetamine: J Forensic Sci 23:693; Mass Spectral Data Vol I; Interscience: New York; 1969. 1978. 38. Stromberg L, Maehly AC: Advances of Chemical Signa- 48. Wallach 0: Uber Methylamin; Ber 24:3992; 1891.

ABOUT THE AUTHOR A.M.A. Verweij

Dr. Anthonie M.A. Verweij is senior chemist in the mass spectrometric service group at the National Forensic Science Laboratory of the Ministry of Justice. He studied chemistry atthe Free University of Amsterdam, where he received his Ph.D. in organic chemistry in 1970. His research interests center on studies of the syntheses of illicitly prepared drugs and on the structure elucidation of impurities found in them.

Verweij • Impurities in Illicit Amphetamine and Metamphetamine Preparations