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