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Forensic Science International 224 (2013) 826

Contents lists available at SciVerse ScienceDirect

Forensic Science International


journal homepage: www.elsevier.com/locate/forsciint

Review article

A review of impurity proling and synthetic route of manufacture of


methylamphetamine, 3,4-methylenedioxymethylamphetamine, amphetamine,
dimethylamphetamine and p-methoxyamphetamine
Natasha Stojanovska a, Shanlin Fu a,*, Mark Tahtouh b, Tamsin Kelly c, Alison Beavis a, K. Paul Kirkbride b
a
b
c

Centre for Forensic Science, University of Technology, Sydney, PO Box 123, Broadway, NSW 2007, Australia
Australian Federal Police, 110 Goulburn St, Sydney, NSW Australia
National Centre for Forensic Studies, Faculty of Applied Science, University of Canberra, ACT 2601, Australia

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 9 March 2012
Received in revised form 19 October 2012
Accepted 30 October 2012
Available online 24 November 2012

Amphetamine-type substances (ATS), like other synthetically derived compounds, can be produced by a
multitude of synthetic pathways using a variety of precursors and reagents, resulting in a large number
of possible contaminants (by-products, intermediates and impurities). This review article describes the
common contaminants found in preparations of methylamphetamine (MA), 3,4-methylenedioxymethylamphetamine (MDMA), amphetamine (AP), N,N-dimethylamphetamine (DMA) and p-methoxyamphetamine (PMA) synthesised via common synthetic pathways including reductive amination,
Leuckart method, Nagai method, Emde method, Birch reduction, Moscow method, Wacker process,
Nitrostyrene method and the Peracid oxidation method.
Contaminants can facilitate identication of the synthetic route, origin of precursors and may suggest
information as to the location of manufacture of these illicit drugs. Contaminant proling can provide
vital intelligence for investigations in which linking seizures or identifying the synthetic pathway is
essential. This review article presents an accessible resource; a compilation of contaminants resulting
from a variety of manufacturing methods used to synthesise the most common ATS. It is important for
research in this eld to continue as valuable information can be extracted from illicit drug samples,
increasing discrimination amongst ATS, and in turn, leading to an increase in evidential value and
forensic drug intelligence from forensic drug samples.
2012 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Methylamphetamine
3,4-Methylenedioxymethylamphetamine
Amphetamine
N,N-Dimethylamphetamine
p-methoxyamphetamine
Impurity proling

Contents
1.
2.
3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Common synthetic methods in the manufacture of ATS . . . . . . . . . . . . . . . . . . . . . . . .
Common methods for the synthesis of precursors. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Phenyl-2-propanone (P-2-P). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Pseuedoephedrine and ephedrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
3,4-Methylenedioxyphenyl-2-propanone and 4-methoxyphenyl-2-propanone .
3.3.
Characteristic ATS impurities, intermediates and by-products . . . . . . . . . . . . . . . . . . .
Methylamphetamine (MA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
The Nagai, Moscow and Hypo methods . . . . . . . . . . . . . . . . . . . . .
4.1.1.
The Emde method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.2.
4.1.3.
The Leuckart method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The Birch reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.4.
Reductive amination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.5.
Impurities found in seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.6.

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* Corresponding author at: PO Box 123, Broadway, NSW 2007, Australia. Tel.: +61 2 9514 8207; fax: +61 2 9514 1460.
E-mail addresses: natasha.stojanovska@student.uts.edu.au (N. Stojanovska), shanlin.fu@uts.edu.au (S. Fu), mark.tahtouh@afp.gov.au (M. Tahtouh),
Tamsin.Kelly@canberra.edu.au (T. Kelly), alison.beavis@uts.edu.au (A. Beavis), Paul.Kirkbride@afp.gov.au (K.P. Kirkbride).
0379-0738/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.forsciint.2012.10.040

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.. 9
. 10
. 13
. 13
. 13
. 13
. 14
. 14
. 15
. 15
. 17
. 17
. 17
. 18

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

4.2.

5.
6.
7.
8.

3,4-Methylenedioxymethamphetamine (MDMA) . . .
The Leuckart method. . . . . . . . . . . . . . . . . .
4.2.1.
Reductive amination . . . . . . . . . . . . . . . . . .
4.2.2.
Impurities found in seizures . . . . . . . . . . . .
4.2.3.
Amphetamine (AP) . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
The Leuckart method. . . . . . . . . . . . . . . . . .
4.3.1.
Nagai, Moscow, Hypo, Emde and Birch
4.3.2.
Reductive amination . . . . . . . . . . . . . . . . . .
4.3.3.
4.3.4.
Impurities found in seizures . . . . . . . . . . . .
N,N-Dimethylamphetamine (DMA) . . . . . . . . . . . . . .
4.4.
p-Methoxyamphetamine (PMA) . . . . . . . . . . . . . . . . .
4.5.
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adulterants and cutting agents . . . . . . . . . . . . . . . . . . . . . . .
Intelligence methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction
Recreational use of non-medically accepted drugs is a
phenomenon that has been apparent for many years. The
amphetamine-type substances (ATS) such as amphetamine (AP),
methylamphetamine (MA), 3,4-methylenedioxyamphetamine
(MDA), and 3,4-methylenedioxymethylamphetamine (MDMA)
are particularly popular drugs of abuse [1]. ATS are sometimes
collectively referred to as phenethylamines due to a common
structural moeity.
According to the United Nations Ofce on Drugs and Crime
(UNODC), ATS are rmly established on the illicit drug market,
with global use continuing to exceed that of cocaine and heroin
combined [2]. In Australia, ATS are the second most commonly
used illicit drugs, only after cannabis [1]. In East and South-East
Asia, as well as in the Middle East, consumption of ATS, particularly
MA, is increasing [1].
Proling of ATS, based upon the presence of traces of byproducts, intermediates and impurities can provide useful
information in criminal investigations and, specically, on drug
trafcking routes, sources of supply, and relationships between
seizures [3]. In this article the word by-product will be used to
describe compounds that arise from reactions that compete with
the formation of the desired product (i.e. products of a side
reaction). This includes reactions where the desired product,
once it has been formed, undergoes reaction with starting
materials. By-products will therefore arise in a synthetic method
no matter how pure the reagents or precursor are. Of particular
importance are the so-called route specic by-products that
suggest the particular method used in the synthesis of the drug. It
should be pointed out, however, that the research leading to the
identication of a number of route-specic by-products has been
relatively limited in scope. For example, the nding was made
that certain naphthalenes are route-specic by-products in the
Nagai reaction for the production of MA simply by conducting
the reaction under controlled conditions and identifying that the
naphthalenes were present after the reaction was completed,
rather than by searching for the presence of these naphthalenes
in a wide range of different MA syntheses. As is indicated below,
naphthalenes can be produced when a key precursor, phenyl-2propanone (P-2-P), is heated in the presence of acid, therefore
rather than being route-specic certain by-products should
perhaps be considered condition-specic. Several articles are
cited below where the concept of route-specic by-products is
being challenged.
In some syntheses the product is produced as a result of two
consecutive steps, where the precursor is converted into a
compound that is in turn converted into the product; in this

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18
18
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20
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22
22
23
23
24
24

article the word intermediate will be used to describe the product


of the rst step.
Many precursors and reagents contain additional compounds,
that is, they are not absolutely pure. The word impurities will be
used to describe these additional compounds, or products arising
from reactions of these compounds, that appear in the desired
product of the synthesis. Clearly if starting materials are rigorously
puried then the nal product will not contain impurities but it can
contain by-products. The word contaminant will be used as a
collective term for by-products, intermediates and impurities (i.e.
anything detected in nal product other than the desired
compound).
ATS may be produced by numerous synthetic pathways using a
variety of precursors and reagents, resulting in a vast number of
possible contaminants. Furthermore, Sanger et al. [4], established
that variation in proles (i.e. the relative abundance of the major
by-products, intermediates and impurities) are observed, even
when the same synthetic reaction is strictly followed by different
chemists. Prole variations are also obtained by the same chemist
following the same procedure to produce more than one batch. For
each stage of a reaction, varying the reaction conditions leads to a
change in the prole. Therefore, when a number of illicit drug
samples are found with similar proles there is support for the
hypothesis that they came from the same batch, with the strength
of support increasing as proles become more complex [4]. While
inter-batch variation can be used to distinguish two samples, it
cannot be used to determine whether the same chemist or
different chemists were involved in the manufacture.
The detection of route-specic by-products or intermediates
can be used to determine the route of manufacture, that through
fusion with other forms of intelligence, might allow linking of
batches to the cook that synthesised the drugs. This is beyond the
scope of this study.
This review provides an overview of the characteristic byproducts, intermediates and impurities resulting from the
manufacture of AP, MA, MDMA, N,N-dimethylamphetamine
(DMA) and p-methoxyamphetamine (PMA) and their key precursors via some common synthetic routes. Fig. 1 depicts the most
common manufacturing routes for the production of MA, including
the Leuckart method [5], reductive aminations [5], Nagai method
[6], Moscow method [7], Birch reduction (also known as Nazi
method) [8,9], and Emde method [6]. The manufacture of MDMA,
AP, DMA, and PMA (Figs. 25) follow similar reaction pathways
when suitably substituted precursors are used, which can be
prepared via synthetic methods such as the Wacker process [10]
and peracid oxidation [11].
It is important to note that this article does not present an
exhaustive list of compounds found in all ATS preparations nor

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

10

Fig. 1. Common synthetic routes of MA manufacture.

does it cover every published synthetic route to ATS, just the more
common ones (see Table 1 for a list of the most characteristic
compounds and see also Supplementary data: Tables S1S5 for a
comprehensive list of all the by-products, intermediates and
impurities mentioned in this article).

2. Common synthetic methods in the manufacture of ATS


The Leuckart reaction is very important in the synthesis of ATS
because it is a method that is generally applicable to the synthesis
of a wide range of amphetamines from starting materials that can

Table 1
Characteristic contaminants corresponding to synthetic route of manufacture and compound of interest.
Compound

Synthetic route

Characteristic contaminants

MA (refer to Fig. 6)

Reductive
amination
Nagai

1-Phenyl-2-propanol A1, amphetamine A2, 1,3-diphenyl-2-methylaminopropane A3,


N-cyanomethyl-N-methyl-1-phenyl-2-propylamine A4
(2E)-N-Methyl-3-phenyl-N-(1-phenylpropan-2-yl)prop-2-enamide (cis-cinnamoyl
derivative of MA) B1, iodoephedrine B2, N-methyl-N-(a-methylphenyl)amino-1-phenyl-2-propanone B3,
(Z)-N-methyl-N-(a-methylphenylethyl)-3-phenylpropanamide B4
Chloroephedrine/chloropseudoephedrine C1, methylephedrine C2, N-formylephedrine C3, N-acetylephedrine
C4, N,O-diacetylephedrine C5, N-acetylamphetamine C6
1-(1,4-Cyclohexadienyl)-2-methylaminopropane D1
a-Benzyl-N-methylphenethylamine F1, a,a0 -dimethyldiphenethylamine F2, N-a,a0 -trimethyldiphenylamine F3

Emde
Birch
Leuckart
MDMA (refer to Fig. 7)

Reductive
amination

Leuckart
Wacker
oxidation
Peracid
oxidation

3,4-Methylenedioxy-N-methylbenzylamine A5, 4-methyl-5-(3,4-methylenedioxyphenyl)-[1,3]-dioxolan-2-one A6,


N-methyl-2-methoxy-1-methyl-2-(3,4-methylenedioxyphenyl)-ethanamine A7, N-cyclohexylacetamine A8,
1,2-methylenedioxy-4-(2-N-methyliminopropyl)benzene A9, N-cyanomethyl-N-methyl-1-(3,4-methylenedioxyphenyl)2-propylamine A10, N,N-di-[1-(3,4-methylenedioxy)phenyl-2-propyl]methylamine (MDMA dimer) A11
p-Bromotoluene F4, N-ethylamphetamine F5, N-ethylmethamphetamine F6, N-formylamphetamine F7,
N-formyl-MDMA F8, 5-(1,3-benzodioxol-5-ylmethyl)pyrimidine F9, 3,4-bis-(1,3-benzodioxol-5-ylmethyl)pyridine F10
1-(3,4-Methylenedioxyphenyl)-1-methoxypropan-2-one G1, methyl-3-(3,4-ethylenedioxyphenyl)-propanoate G2,
1-(3,4-methylenedioxyphenyl)-1,3-dimethoxypropane G3, 3-(3,4-ethylenedioxyphenyl)-1,1-dimethoxypropane G4,
1-(3,4-methylenedioxyphenyl)-1-methoxypropane G5
2,4-Dimethyl-3,4-bis(3,4-methylenedioxyphenyl)tetrahydrofuran H1, 1-(3,4-dimethoxyphenyl)-2-propanone H2
1-(3,4-methylenedioxyphenyl)-1-propanone H3, 2,2,4-trimethyl-5-(3,4-methylenedioxyphenyl)-[1,3]-dioxolane H4,
1-(3,4-methylenedioxyphenyl)- 1,2-propanedione H5, 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-propanol H6

AP (refer to Fig. 8)

Emde
Birch
Leuckart

Chloronorpseudoephedrine/chloronorephedrine C7
1-(1,4-Cyclohexadienyl)-aminopropane D2
a-Benzylphenylethylamineformamide F11, 4-benzylpyrimidine F12, 4-methyl-5-phenyl-pyrimidine F13,
2,4-dimethyl-3,5-diphenylpyridine F14, 2,6-dimethyl-3,5-diphenylpyridine F15

DMA (refer to Fig. 9)

Nitrostyrene
Nagai
Emde
Birch

(2-Nitroprop-1-enyl)benzene I1, benzyl methyl ketoxime I2, N-(b-phenylisopropyl)benzaldime I3


1-Propenylbenzene B5, 2-propenylbenzene B6
Chloromethylephedrine/chloromethylpseudoephedrine C8, 1-dimethylamino-1-phenyl-2-chloropropane C9
1-(1,4-Cyclohexadienyl)-2,2-dimethylaminopropane D3

PMA (refer to Fig. 10)

Leuckart

4-(4-Methoxybenzyl)pyrimidine F16,4-methyl-5-(4-methoxyphenyl)pyrimidine F17,


2,4-dimethyl-3,5-di-(4-methoxyphenyl)pyridine (F18), 2,6-dimethyl-3,4-di-(4-methoxyphenyl)pyridine
4-Methoxyphenol H7

Peracid
oxidation

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

11

Fig. 2. Common synthetic routes of MDMA manufacture.

be readily sourced by legal or illegal means (i.e. P-2-P and its


analogues). The reaction was rst described by Leuckart in 1885
[12], who used ammonium formate or formamide, and was then
elaborated upon in 1893 by Wallach [13] who used ammonium
formate in the presence of excess formic acid. The former reaction
is called the Leuckart reaction and the latter the LeuckartWallach
reaction; it is common in the literature for the LeuckartWallach
reaction and another variant where formamide is used to be

referred to simply as the Leuckart reaction and that convention will


be followed here. Landmark publications in 1944 [14] and 1949
[15] provided discussions as to the mechanism of the reductive
alkylation, although debate as to the exact detail of the mechanism
was still taking place in 1963 [16] and 1999 [17]. In the context of
ATS synthesis the Leuckart reaction is dened as a reductive
alkylation (with P-2-P or one of its analogues being the alkylating
agent) of an amine (ammonia or methylamine) with formic acid

Fig. 3. Common synthetic routes of AP manufacture.

12

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

Fig. 4. Common synthetic routes of DMA manufacture.

acting as the reducing agent. The reaction product is a formylamphetamine that is hydrolysed in aqueous acid to produce the
corresponding amphetamine.
Reductive amination is also a generally applicable reaction that
involves the treatment of one of the ketones listed above with an
amine (e.g. methylamine or ammonia) to form a hemiaminal
species that is then converted to an intermediate imine. Reducing
agents such as sodium cyanoborohydride, sodium borohydride or
aluminium in the presence of mercury chloride catalyst are used to
reduce the imine to the corresponding ATS (Figs. 15). Although it
is an old reference, the review of synthetic reductions by Allen et al.
[18] is still relevant.
Several variations of the reduction of l-ephedrine or dpseudoephedrine to MA via iodoephedrine or iodopseudoephedrine

exist; these include the Nagai method, Moscow method, and the
Hypo method (Fig. 1). The Nagai method employs hydriodic acid
and red phosphorus [19,20], whereas the others generate hydriodic
acid in situ using iodine and red phosphorus (Moscow method
[21]) or iodine and either hypophosphorous acid or phosphoric acid
(Hypo method [22]). These methods are popular due to their
ability to produce end products that are enantiomerically pure, i.e.
the more potent d-MA.
The dissolving metal reductions, sometimes called the Birch
reduction [23], were rst described as being used in clandestine
laboratories by Ely and McGrath [9]. Since that time the use of this
method has become increasingly common for the synthesis of MA.
In this method, a metal such as metallic lithium or metallic sodium
is reacted with l-ephedrine or d-pseudoephedrine (or, as indicated

Fig. 5. Common synthetic routes of PMA manufacture.

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

by Ely and McGrath [9] and Barker and Antia [24], their
desmethylated or methylated analogues) in the presence of liquid
ammonia to produce the amine (e.g. MA, AP or DMA) (Figs. 1, 3 and
4). Metallic lithium is more commonly used in place of metallic
sodium as the former can be easily extracted from lithium batteries
while the latter is more difcult to source and is more dangerous.
The solution of metal in ammonia provides an electron to form an
ephedrine or pseudoephedrine radical anion, which through loss of
hydroxyl and acceptance of another electron is converted into an
intermediate carbanion and nally the resulting amine.
The Emde method [25] consists of a two-step reaction in which
l-ephedrine or d-pseudoephedrine is reacted with thionyl chloride
to produce the chloro-substituted intermediate (i.e. chloroephedrine or chloropseudoephedrine), followed by a hydrogenation
reaction in the presence of a catalyst (usually palladium and
barium sulfate) to yield MA (or AP if norpseudoephedrine or
norephedrine are used as the starting material, or DMA if
methylephedrine or methylpseudoephedrine are used) (Figs. 1, 3
and 4). In place of thionyl chloride other chlorinating agents such
as phosphorus pentachloride, phosphorus oxychloride or phosphorus trichloride can be used.
Another less common synthetic route employed in the
synthesis of ATS is the Nitrostyrene method. Benzaldehyde (or
analogue, such as piperonal or anisaldehyde) and nitroethane react
in the presence of acid or base to yield a nitrostyrene intermediate,
which is then reduced using electrolysis, hydrogenation or various
reducing agents (lithium aluminium hydride or sodium borohydride to yield the ATS (Fig. 3). Ref. [26] cites a number of the
original references to these methods and patents.

3. Common methods for the synthesis of precursors


3.1. Phenyl-2-propanone (P-2-P)
P-2-P is a key precursor that is usually prepared from either
phenyacetic acid or benzaldehyde, although allyl benzene or even
benzene can be used. In the former case, phenylacetic acid is
treated either with lead acetate at high temperature or a mixture of
acetic anhydride and sodium acetate or pyridine at reux [18,27].
In the case of benzaldehyde, it is treated with nitroethane to
produce b-methyl-b-nitrostyrene that is then either directly
reduced to P-2-P using iron and hydrochloric acid [28] or partially
reduced to phenyl-2-propylketimine that is hydrolysed to P-2-P
[29].
The reaction between phenylacetic acid and acetic anhydride is
complex but is well described by Allen et al. [18]. Although Allen
et al. do postulate a mechanism for the lead acetate conversion of
phenylacetic acid into P-2-P [18], the exact mechanism is obscure.
In any event, the complexity of both of these synthetic procedures
ensures that many competing side reactions take place and as a
result a multitude of by-products are produced. Allen et al. [18]
indicate that route-specic by-products that could be detected in
illicit P-2-P or crude reaction mixtures are the E- and Z-isomers of
P-2-P enol acetate for the method using acetic anhydride and
bibenzyl and diphenylmethane for the method using lead acetate.
A range of non route-specic olens (E- and Z-1-phenyl-2-benzyl1-propene and 1-phenyl-2-benzyl-2-propene) [18,30] and other
aromatics [18] have also been described in the synthesis of P-2-P
from phenylacetic acid but of particular relevance is the
production of dibenzyl ketone as a by-product. This ketone is
difcult to separate from P-2-P therefore non-commercial P-2-P
will most likely contain dibenzyl ketone and it will undergo the
same reactions as P-2-P to form 1,3-diphenyl-2-aminopropane in
the case of AP synthesis or 1,3-diphenyl-2-methylaminopropane
(structure A3) in the case of MA synthesis.

13

3.2. Pseuedoephedrine and ephedrine


By far the largest source of pseudoephedrine and ephedrine in
the illicit manufacture of MA is commercial material, either
diverted in its pure form or extracted from medications such as
cold and u tablets [31]. Ultimately the sources of this commercial
material are the Ephedra plant or by the biotransformation of
benzaldehyde. Clandestine syntheses of ephedrine/pseudoephedrine are encountered less regularly due to lengthy procedures
needed resulting in racemic mixtures of ephedrine/pseudoephedrine subsequently requiring enantiomeric purication prior to
conversion to their illicit end-product.
The extraction of pseudoephedrine from medications is
straightforward but the process will also extract other active
ingredients that can be carried through the subsequent chemistry
used to convert pseudoephedrine into MA. In addition, Pigou [32]
found that the use of ethanol or methanol in the extraction of
pseudoephedrine from medications leads to the formation of Nethyl- and N-methyl-ephedrine, respectively, when the Hypo
method is used.
Barker and Antia [24] discuss the illicit extraction of Ephedra
plants and indicate that as well as ephedrine and pseudoephedrine
the related congeners methylephedrine, methylpseudoephedrine,
norephedrine and norpseudoephedrine are extracted. These
behave analogously to ephedrine and pseudoephedrine in MAforming reactions to form DMA and AP, respectively (Figs. 4 and 3).
The use of the biotransformation process in clandestine
laboratories has only been reported once [33]. Fermentation of
glucose with yeast leads to pyruvic acid and then acetaldehyde,
which in the presence of benzaldehyde condenses to form 1hydroxy-1-phenylpropanone (also known as L-phenylacetylcarbinol or L-PAC). This hydroxyketone is converted into ephedrine and
pseudoephedrine upon treatment with methylamine and sodium
borohydride. 1-Phenyl-1,2-propanedione and 2-hydroxy-1-phenyl-1-propanone by-products are formed in the fermentation and
these are carried through to 1-phenyl-1,2-diaminopropane (two
diastereoisomers) and 1-phenyl-1-amino-2-hydroxypropane (also
two diastereoisomers), respectively, upon reductive amination
(each by-product was unambiguously identied by independent
synthesis). When ephedrine and pseudoephedrine contaminated
with these compounds are subjected to the Hypo method the
expected impurities are detected in the MA product, as described
in more detail below.
Armellin et al. [34] detailed the synthesis of ephedrine or
pseudoephedrine through the bromination of propiophenone. The
resulting 2-bromo-1-phenylpropan-1-one is then reacted with
methylamine to form 2-(methylamino)-1-phenylpropan-1-one
that is subsequently reduced to produce a racemic mixture of
ephedrine and pseudoephedrine. With an increase in distance
between the nal product and precursor comes less regulation of
the precursor. However, lengthy synthetic processes will inevitably result in lower yields and slower production of nal product.
Further to this, the racemic mixture obtained for ephedrine and
pseudoephedrine will require resolution if d-MA is the target.
These drawbacks possibly indicate why few instances of the
conversion of propiophenone into MA have been reported.
3.3. 3,4-Methylenedioxyphenyl-2-propanone and 4-methoxyphenyl2-propanone
Peracid or chromate oxidation of isosafrole or anethole has been
used in the synthesis of 3,4-methylenedioxyphenyl-2-propanone
(3,4-MDP-2-P) and 4-methoxyphenyl-2-propanone (PMP-2-P)
(Figs. 2 and 5). The olens are converted into intermediate diols,
which undergo pinacol-type rearrangement under acidic conditions to produce the ketones [11].

14

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

Gimeno et al. [35] reported that 3,4-methylenedioxybenzaldehyde and 1-(3,4-methylenedioxyphenyl)-1-propanone (structure


H3) were signicant by-products in 3,4-MDP-2-P prepared using
both oxidative methods together with two reduction products
(dihydrosafrole and 3,4-methylenedioxymethanol) and two methoxylated compounds, 1-(4-methoxyphenyl)-2-propanone and 1(3,4-dimethoxyphenyl)-2-propanone (structure H2). The latter
methoxylated compound and 3,4-methylenedioxypropiophenone
(structure H3) were not detected in 3,4-MDP-2-P prepared by
oxidation/hydrolysis of 3,4-methylenedioxyphenylnitropropene
(see below) and therefore appear to be specic to the peracid or
chromate oxidation of isosafrole. Gimeno took the crude 3,4-MDP2-P prepared by the oxidation of isosafrole and subjected it to
reductive aminations. As expected the dimethoxyketone (structure
H2) yielded a secondary amine but the structure for the product
(structure 8meth) drawn by Gimeno is not correct, although it is
named correctly. The intermediate diol was rarely detected in 3,4MDP-2-P. In the same article Gimeno et al. also examined the fate
of contaminants present in commercial isosafrole and that sourced
from sassafras oil. They found 1-methoxy-4-(1-propenyl)benzene,
safrole and 1,2-dimethoxy-4-(1-propenyl)benzene to be present in
both forms of isosafrole and these were oxidised in a manner
analogous to that of isosafrole to produce 1-(4-methoxyphenyl)-2propanone and 1-(3,4-dimethoxyphenyl)-2-propanone (structure
H2) impurities in the nal material. Unambiguous assignment of
these structures through independent synthesis was not described.
Swist et al. [36] agreed with Gimeno et al. [35] that 3,4methylenedioxypropiophenone (structure H3) is an important
contaminant in the oxidation of isosafrole. However, they did not
report the presence of either of the methoxylated ketones described
by Gimeno et al. Swist et al. also reported the presence of other
signicant compounds (unambiguous assignment of these structures through independent synthesis was not described); these were
1-(3,4-methylenedioxyphenyl)-1-methoxypropan-2-one (structure
G1), 2,2,4-trimethyl-5-(3,4-methylenedioxyphenyl)-[1,3]dioxolane
(structure H4), 1-(3,4-methylenedioxyphenyl)-1,2-propanedione
(structure H5), 1-(3,4-methylenedioxyphenyl)-1-propanone (structure H3), 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-propanol
(structure H6) and 4-methyl-5-(3,4-methylenedioxyphenyl)[1,3]dioxolan-2-one (structure A6) as route-specic by-products.
Swist et al. [36] conducted their oxidation using acetone as solvent,
which would account for the formation of the dioxolanone and the
dioxolane that were not detected by Gimeno et al. [35]. Although it
was reported that the dioxolane readily converts into 3,4-MDP-2-P
and does not tend to carry-through subsequent chemistry the
dioxolanone does. Swist et al. [36] also analysed their (commercial)
isosafrole for contaminants and detected terpineol, thymol, 1,7dimethyl-7-(4-methyl-3-pentenyl)-tricyclo[2.2.1.02,6]heptane, 2,6dimethyl-6-(4-methyl-3-pentenyl)-bicyclo[3.1.1]hept-2-ene and
3,4-methylenedioxbenzaldehyde. Under the oxidative conditions
that are used to form 3,4-MDP-2-P the unsaturated moiety in 1,7dimethyl-7-(4-methyl-3-pentenyl)-tricyclo[2.2.1.02,6]heptane was
found to react to form 1-(2,3-dimethyltricyclo[2.2.1.02,6]hept-3-yl)4-methylpentan-3-one.
In a study conducted by Cox et al. [37], the chemical markers for
the peracid oxidation of isosafrole have been identied (Fig. 2). It
was found that 2,4-dimethyl-3,5-bis(3,4-methylenedioxyphenyl)tetrahydrofuran (structure H1) is produced as a mixture of three
diastereomeric isomers. The most abundant stereoisomer formed
contains a 2,3-cis, 3,4-trans, 4,5-trans conguration, while the next
most abundant diastereoisomer contains the all trans conguration.
Waumans et al. [38] reported upon the peracid oxidation of
anethole present in anise oil to yield PMP-2-P. These authors mention
the detection of the intermediate glycol and its formate ester but do
not mention the presence of any by-product compounds analogous
to those reported by Cox et al. [37]. Waumans et al. did however

report a number of impurities arising from the anise oil starting


material, especially 4-methoxyphenol (which conrmed the earlier
detection of this compound in illicit PMA tablets by Coumbaros et al.
[39]) and its formate ester. The authors postulated that 4methoxyphenol (Fig. 10, structure H7) arises from the Baeyer
Villiger oxidation of 4-methoxybenzaldehyde, which is present in
anise oil as an impurity. This hypothesis is supported in the literature
by Godfrey et al. [40], who converted a number of methoxybenzaldehydes into methoxyphenols using m-chloroperbenzoic acid.
Waumans et al. also report that whilst anise oil contains 4methoxybezaldehyde it does not contain 4-methoxyphenol; star
anise oil contains both the aldehyde and the phenol. Both types of oils
contain a multitude of other natural products like limonene, borneol,
camphor, etc. that would be detected in crude PMP-2-P derived from
anise oil. It would appear that 4-methoxyphenol is difcult to remove
from 4-methoxyphenyl-2-propanone because it has been identied
as an impurity in illicit PMA tablets [39].
Gimeno et al. [35] studied the production of 3,4-MDP-2-P from
the oxime of 3,4-MDP-2-P, which in turn was produced by iron/acetic
acid reduction of the condensation product between 3,4-methylenedioxybenzaldehyde and nitroethane (i.e. 3,4-methylenedioxyphenylnitropropene). Even though the oxime is an intermediate in
this reaction Gimeno et al. reported that it is rarely detected in the
nal product. The authors found that the only difference between
3,4-MDP-2-P synthesised from the nitrostyrene and that produced
by oxidation of isosafrole is that 3,4-methylenedioxypropiophenone
(structure H3) and 1-(3,4-dimethoxyphenyl)-2-propanone (structure H2) are not by-products of the oxidation/hydrolysis route. Swist
et al. [36] also studied the 3,4-methylenedioxyphenylnitropropene
route to 3,4-MDP-2-P and used acetic acid and cyclohexylamine to
catalyse the condensation. They indicated that 3-methyl-6,7methylenedioxy-isoquinoline-1,4-dione, 3-methyl-6,7-methylenedioxy-3,4-dihydroisoquinolin-1(2H)-one, 2-methyl-(6,7-methylenedioxyphenyl)-3-methylmorpholine and N-cyclohexylacetamine
(structure A8) are important contaminants in 3,4-MDP-2-P. It was
acknowledged that the latter amide is route-specic only in the
particular case when acetic acid and cyclohexylamine are used in the
condensation; replacement of the amine with others would yield
other amides. Origins of the isoquinolinone, the isoquinolinedione
and the morpholine were not discussed.
A less common synthetic process for the production of 3,4-MDP2-P is the Wacker reaction [41]. In this process safrole is treated with
palladium chloride and methanol in the presence of p-benzoquinone
to yield the ketone (Fig. 2). In a study conducted by Cox and Klass
[10], it was found that 1-(3,4-methylenedioxyphenyl)-1-methoxypropan-2-one (structure G1), methyl-3-(3,4-ethylenedioxyphenyl)-propanoate (structure G2), 1-(3,4-methylenedioxyphenyl)1,3-dimethoxypropane (structure G3), 3-(3,4-ethylenedioxyphenyl)-1,1-dimethoxypropane (structure G4) and 1-(3,4-methylenedioxyphenyl)-1-methoxypropane (structure G5) are produced
during the Wacker oxidation of safrole but the ester can only be
detected in the crude reaction mixture, not in the nished ketone.
These authors also report that ethanol is a viable alternative to
methanol and in this case ethoxy substituted by-products are
produced. Interestingly, Cox and Klass [10] reported that pbenzoquinone was found to produce p-methoxyphenol (a compound reported in the synthesis of PMA [38,39]) but it was detected
only in the reaction mixture, not in the extracted ketone.
4. Characteristic ATS impurities, intermediates and byproducts
4.1. Methylamphetamine (MA)
Methylamphetamine remains, by far, the most widely manufactured ATS worldwide [42]. Several articles describe the most

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

common synthetic methods employed in the manufacture of MA,


the precursor materials used and the reaction markers associated
with these syntheses [4350]. The multitude of synthetic pathways utilised in the manufacture of MA are summarised in Fig. 1.
The most popular synthetic routes employed by clandestine
laboratories in Australia are the iodine/phosphorus methods
(Fig. 1) [31,51] with the Birch reduction of lesser prominence
[31,52]. It has been reported that nearly all MA produced in the
USA is prepared by one of two methods, either from P-2-P with the
mercury amalgam reductive amination method or from the
reduction of ephedrine or pseudoephedrine. With P-2-P scheduled
in the USA and in other parts of the world as a schedule II drug,
syntheses tend towards the use of ephedrine or pseudoephedrine
as precursor materials. However, with the recent increased
restrictions on the sale of ephedrine/pseudoephedrine there
may be a resurgence of the synthetic methods utilising P-2-P.
The main synthetic routes of MA manufacture in Europe have been
reported as being reductive amination and the Leuckart route [43
48].
4.1.1. The Nagai, Moscow and Hypo methods
Discussions of the mechanism of the Nagai preparation of MA
from ephedrine or pseudoephedrine and its stereochemistry can be
found in references [1821]. In short, the hydroxyl group in the
starting material undergoes nucleophilic substitution with iodide
to form either iodoephedrine or iodopseudoephedrine. In both of
these intermediates iodide can be displaced by internal nucleophilic attack from the adjacent nitrogen to form cis- and trans-1,2dimethyl-3-phenylaziridines. These aziridines can undergo two
reactions: reduction to yield MA; and hydrolysis to yield P-2-P.
Under the acidic conditions P-2-P can undergo condensation to
yield 1,3-dimethyl-2-phenylnaphthalene and 1-benzyl-3-methylnaphthalene. Of this multitude of possible by-products only the
two naphthalenes are reported to be route specic. However, it is
important to bear in mind that the naphthalene arises simply
because P-2-P has been heated in the presence of acid for a length
of time and other conditions that duplicate these could also lead to
the formation of the naphthalenes.
The important feature of the Nagai reaction is that nucleophilic
attack never takes place on the carbon atom in the 2-position on
the propane chain, therefore the conguration about that centre
(S)- is preserved and the potent d-MA is exclusively formed. Barker
and Antia [24] subjected methylephedrine, methylpseudoephedrine, norephedrine and norpseudoephedrine to the Nagai,
Moscow and Hypo methods. The desmethyl compounds
reacted as expected to produce cis- and trans-3-phenyl-2methylaziridines and P-2-P but in addition (b-phenylisopropyl)benzylmethylketimine arose from the condensation between P-2P and amphetamine. As expected, methylephedrine and methylpseudoephedrine reduced to yield DMA (Fig. 5), but in addition 1propenylbenzene and 2-propenylbenzene were detected (as
indicated below, these olens are also produced in the Emde
reaction of methylephedrine and methylpseudoephedrine).
Iodoephedrine (structure B2), iodopseudoephedrine and the
aziridines are all vulnerable to nucleophilic attack and MA can act
as a nucleophile. It is therefore not surprising that the methylamphetamine dimer is found as a by-product of the Nagai
reaction; Tanaka [53] was the rst to identify this compound.
Windahl et al. [21] also examined the Nagai method. They were not
able to nd the dimer reported by Tanaka but identied the
presence of N-methyl-N-(a-methylphenyl)-amino-1-phenyl-2propanone (Fig. 6, structure B3) and cis-cinnamoyl MA (structure
B1), with the structures conrmed by independent synthesis.
Windahl et al. did not conjecture as to how B3 or B1 form but did
provide evidence to indicate that they arise from reaction between
1,2-dimethyl-3-phenylaziridine and MA. Iodoephedrine (structure

15

B2) is also considered a characteristic marker compound for MA


produced via the Nagai method.
Ko et al. [6] examined a modied Nagai preparation of MA
(using red phosphorus and hydrochloric acid). Although they did
not detect the aziridines, they did detect 1-phenyl-2-propanone,
N-formylmethamphetamine, N-acetylmethamphetamine, 1,3-dimethyl-2-phenylnaphthalene, 1-benzyl-3-methylnaphthalene, Nmethyl-N-(a-methylphenethyl)amino-1-phenyl-2-propane
(structure B3) and (Z)-N-methyl-N-(a-methylphenethyl)-3-phenylpropenamide (structure B4).
4.1.2. The Emde method
The Emde method has been found to be the most widely used
method in large-scale syntheses in South East Asia in the
production of MA [54]. The Emde method proceeds via a pathway
similar to the Nagai method inasmuch as ephedrine or pseudoephedrine are halogenated and then hydrogenated with preservation of the stereochemistry around the carbon bearing nitrogen.
One difference in the Emde method, however, is that hydroxyl in
the starting material can be replaced by chloride via either
intramolecular nucleophilic displacement (a so-called SNi substitution) or intermolecular displacement (SN2 substitution). The
work of Lekskulchai et al. [55] and Allen and Kiser [56] are at
variance in regards to the relative contributions of the two
pathways when thionyl chloride is used. Allen and Kiser indicate
that ()-ephedrine yields a 99:1 mixture of (+)-chloropseudoephedrine and ()-chloroephedrine and that (+)-pseudoephedrine
yields a 60:40 mixture whereas Lekskulchai et al. report no
difference in the products of chlorination of (+)-pseudoephedrine
and ()-ephedrine (approximately 50:50 mixtures of the chlorides). Barker and Antia [24], in their examination of the Emde
reaction applied to extracts of Ephedra, agreed with Allen and Kiser
and, through examination of the chlorination products of ()norephedrine, (+)-norpseudoephedrine, ()-methylephedrine and
(+)-methylpseudoephedrine, established that the SNi substitution
reaction becomes more dominant as the level of methylation on
the nitrogen atom increases. Both Allen and Kiser [56] and Barker
and Antia [24] used nuclear magnetic resonance spectroscopy
(NMR) and gas chromatographymass spectrometry (GCMS) to
analyse reaction products. It was found that the higher temperature used in GCMS encouraged the chlorinated products to ringclose and produce mixtures containing 1,2-dimethyl-3-phenylaziridines. As (+)-pseudoephedrine yields a mixture of (+)chloropseudoephedrine and ()-chloroephedrine and ()-ephedrine yields essentially pure (+)-chloropseudoephedrine, and as GC
MS causes (+)-chloropseudoephedrine to cyclise to cis-1,2dimethyl-3-phenylaziridines and ()-chloroephedrine to cyclise
to trans-1,2-dimethyl-3-phenylaziridines, GCMS analysis can be
used to infer whether (+)-pseudoephedrine or ()-ephedrine
starting material was used. As (+)-norpseudoephedrine and ()norephedrine chlorinate to yield similar mixtures of the chlorides
and neither (+)-chloromethylpseudoephedrine nor ()-chloromethylephedrine can cyclise to yield aziridines, GCMS cannot be
used to infer the identity of the starting material in these cases
[24]. GCMS analysis was found by Barker and Antia to cause (+)chloromethylpseudoephedrine and ()-chloromethylephedrine to
eliminate HCl and produce 1-propenylbenzene and 2-propenylbenzene and to rearrange to produce 1-dimethylamino-1-phenyl2-chloropropane (tentative identications). Ko et al. [6] examined
the Emde method for the production of MA. In addition to the
aziridines they detected trace amounts of two unidentied
compounds one with a base peak at 120 Da and one with a
molecular weight of 239 Da. The former was present in all
chloroephedrine samples and therefore was felt to be an important
contaminant but the authors did not rule out the possibility of it
being a GC injection artefact. The latter was reported to be a

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N. Stojanovska et al. / Forensic Science International 224 (2013) 826

Fig. 6. Characteristic contaminants in the manufacture of MA by synthetic routes: Reductive amination (A1A4); Nagai method (B1B4); Emde method (C1C6); Birch
method (D1); Leuckart method (F1F3).

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

contaminant arising, by means unknown, from the hydrogenolysis


step. In later work, Ko et al. [57] identied the injection artefact to
be 1-methylamino-1-phenyl-2-chloropropane, which is produced
by vapour-phase nucleophilic attack of chloride upon the aziridine.
They also conrmed that the identity of the other unknown was Nmethyl-1-(4-[2-(methylamino)propyl]phenyl)-1-phenylpropan-2
-amine, as reported by Salouros et al. [58]. The conclusion drawn
by Ko et al. was that the presence of aziridines in mixtures cannot
be used to differentiate between the involvement of the Nagai or
Emde methods; 1-methylamino-1-phenyl-2-chloropropane (chlo
-roephedrine/chloropseudoephedrine, structure C1) on the other
hand is route-specic for the Emde process. Compounds C2C6 are
also produced by the Emde method.
As indicated above, Salouros et al. [58] identied N-methyl-1(4-[2-(methylamino)propyl]phenyl)-1-phenylpropan-2-amine in
MA prepared using the Emde route and also detected two isomers
of N0 -dimethyl-3,4-diphenylhexane-2,5-diamine. The identity of
both of these compounds was veried by independent synthesis. In
agreement with Lee et al. [7] and Ko et al. [6], Salouros [58] et al.
also detected N-methyl-1-(4-[2-(methylamino)propyl]phenyl)-1phenylpropan-2-amine in material produced by the Moscow and
Nagai methods, therefore this amine is not route specic. The
origin of N0 -dimethyl-3,4-diphenylhexane-2,5-diamine and Nmethyl-1-(4-[2-(methylamino)propyl]phenyl)-1-phenylpropan2-amine is the homolysis of the CCl bond of chloroephedrine or
chloropseudoephedrine by hydrogen atoms to form a delocalised
radical that can either pick up a hydrogen atom to form MA or
dimerise through the benzylic position to form N-dimethyl-3,4diphenylhexane-2,5-diamine or through the para position to form
N-methyl-1-(4-[2-(methylamino)propyl]phenyl)-1-phenylpropan-2-amine [58].
4.1.3. The Leuckart method
In the preparation of MA by the Leuckart method the key
intermediate is N-formylmethylamphetamine. Kram and Kruegel
[59] indicate that N,N-di-(b-phenylisopropyl)methylamine and Nformylmethylamphetamine are encountered in illicit MA prepared
by the Leuckart reaction; it was suggested that the former might
not be route-specic while the latter is. Sanger et al. [60] have
written that N-formylmethylamphetamine is route-specic for the
Leuckart reaction and this is unequivocal if substantial quantities
of that amide are present. However, Qi et al. [61] and groups after
them [5,32] have evidence that N-formylmethylamphetamine is
found, albeit at very low levels, in MA synthesised by methods
other than the Leuckart. Qi et al. found that the presence of Nformylmethylamphetamine was correlated with the presence of Nacetylmethamphetamine, which in turn was said to have arisen
from reaction between MA and ethyl acetate. Several years before
Qi et al. detected N-acetylmethamphetamine, Conn et al. [62] were
the rst to document its presence in illicit MA and attributed its
presence to the usage of propylacetate to azeotropically dessicate
MA that had been salted-out using aqueous hydrogen chloride.
Sasaki and Makino [63] indicate that the abundance of both Nformyl- and N-acetyl-methamphetamine increases with increasing injection port temperature and surmised that they arise from
thermal decomposition of an unknown compound (or compounds)
that are seen to decrease with increasing temperature. In any
event, the presence of N-formylmethylamphetamine at the trace
level in illicit MA might require cautious interpretation.
Kram and Kruegel [64] also report that a compound of MW
239 Da, tentatively identied as N-methyldiphenethylamine, was
detected in illicit MA produced by the Leuckart reaction. In a later
article Kram [65] indicates that the actual identity of this
compound was di-(1-phenylisopropyl)formamide.
Unlike the situation when the Leuckart method is used for the
production of primary amphetamines, where condensations

17

involving formamide lead to the production of a multitude of


heterocyclic by-products (see below), side reactions leading to
analogous heterocycles cannot take place in the Leuckart
preparation of MA because the N-methyl group effectively blocks
them [66].
Kunalan et al. [5] compared by-products from the Leuckart
preparation of MA with those from a reductive amination and
concluded that a,a0 -dimethyldiphenylamine (structure F2) and Na,a0 -trimethyldiphenethylamine (structure F3), in this context at
least, are route-specic for the Leuckart reaction.
If impure P-2-P, methylamine, or N-methylformamide (which
may contain dibenzylketone, ammonia and formamide, respectively) are used in the Leuckart reaction then a-benzylphenethylamine,
N-formyl-a-benzylphenethylamine,
a-benzyl-Nmethylphenethylamine (structure F1), amphetamine and formylamphetamine impurities can be detected in MA [50,59]. In
addition to the above, Kunulan [5] detected in MA prepared by the
Leuckart method the presence of bibenzyl, 3,4-diphenyl-3butenone, benzylmethamphetamine, N-b-(phenylisopropyl)benzyl methyl ketimine, N-benzoylmethamphetamine, benzylamphetamine, N-benzoylamphetamine, and several pyridines associated
with the Leuckart preparation of AP (the latter desmethylated byproducts were presumed to have arisen from the presence of
formamide in the N-methylformamide used in the reaction).
4.1.4. The Birch reduction
Although the chemistry involved in the Birch reduction of
ephedrine or pseudoephedrine is somewhat exotic, there is only
one major contaminant in the nal product reported; 1-(1,4cyclohexadienyl)-2-methylaminopropane (structure D1) [8]. If the
starting material is not pure then other materials can undergo
reduction as well. Barker and Antia [24] describe the situation
when extracts of plants of the genus Ephedra are used as starting
material. The methyl and desmethyl analogues of ephedrine and
pseudoephedrine (e.g. methylephedrine and norephedrine) are
reduced, as expected, to AP and DMA and the main by-products are
desmethyl and methyl analogues of 1,4-cyclohexadienyl-2methylaminopropane (structures D2 and D3, not conrmed by
independent synthesis). As might be expected, the 1,4-cyclohexadienyl moiety in 1-(1,4-cyclohexadienyl)-2-methylaminopropane (and presumably its analogues D2 and D3) is prone to
aromatisation to form MA. Pal et al. [67,68] report that this
aromatisation takes place rapidly in soil, chiey by processes that
do not involve microorganisms. The implication is that residues
from clandestine laboratories, especially those retrieved from soil
but also those that might have had sufcient time and appropriate
conditions to oxidise, might not contain 1-(1,4-cyclohexadienyl)2-methylaminopropane even if it was once there. Similarly, the
presence of MA might be due to oxidation of the diene rather than
it being initially present in the residue.
4.1.5. Reductive amination
Verweij [50] reviewed the reductive aminations of P-2-P in the
presence of both ammonia and methylamine and cites his own
earlier publication in German. A by-product, common to both not
surprisingly, was 1-phenyl-2-propanol (structure A1), which arises
from the reduction of starting ketone. The alcohol was reported to
be a route-specic by-product.
In a paper dealing chiey with the reductive amination of 3,4MDP-2-P, Salouros et al. [69] mention in passing that the reductive
amination of P-2-P with methylamine produces the by-product Ncyanomethyl-N-methyl-1-phenyl-2-propylamine (structure A4),
which is likely to be route-specic.
Kunulan et al. [5] compared the contaminants in MA prepared
by the Leuckart and reductive amination routes. They conrmed
the nding by Verweij [50] that 1-phenyl-2-propanol was a

18

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

route-specic by-product of their reductive amination (methylamine in the presence of amalgamated aluminium in methanol).
They also reported that 1-phenyl-2-propanol was not recovered by
extraction of the reaction mixture at basic pH. Kunulan et al. also
report many other contaminants detected in the reductive
amination product that were also present in the Leuckart reaction
mixture such as AP, DMA (that could have arisen from impurities in
methylamine) and their formyl, benzoyl and benzyl derivatives,
bibenzyl and pyridines.
4.1.6. Impurities found in seizures
Many articles deal with the analysis of seized MA where it is not
known exactly which particular method might have been used in
manufacture or even if the seizures actually contain material from
more than one batch or method. Many of these articles deal more
with developing processes for comparing seizures rather than
proving the identity and origin of the contaminants.
Impurities such as AP (structure A2), DMA and P-2-P were
among the rst to be described as commonly occurring in illegal
MA [59] suspected to have been produced by the Leuckart reaction.
AP has also been seen in illicit MA preparations via the reductive
amination route.
In a study conducted by Puthaviriyakorn et al. [70] ten
contaminants were identied in Ya Ba tablets. These compounds
are 1,2-dimethyl-3-phenylaziridine, ephedrine, methylephedrine,
N-formylmethamphetamine, N-acetylmethamphetamine, N-formylephedrine, N-acetylephedrine, N,O-diacetylephedrine, methamphetamine dimer and a newly identied impurity trans-3,4dimethyl-5-phenyl-2-oxazolidone. The dimer was rst reported
by Tanaka [53], who identied it in MA seized in Japan.
Dayrit and Dumlao [71] found MA samples suspected to be
synthesised by the Leuckart method to contain the impurities pbromotoluene, N-benzylamphetamine, N-ethylamphetamine, Nethylmethamphetamine as well as P-2-P, DMA, and N-formylamphetamine.
N-benzoylamphetamine has been reported [61,72] to be an
impurity in illicit MA but its origin is obscure.
Between 1998 and 2002, the Australian Federal Police seized
and analysed 19 crystalline MA ice samples [73] and found 36
separate contaminants, six of which could not be identied. Of note
were the presence of 1-phenyl-2-propanol (Fig. 6, structure A1),
which is indicative of these samples being synthesised via the
reductive amination route, benzyl chloride, bibenzyl and benzyl
alcohol.
4.2. 3,4-Methylenedioxymethamphetamine (MDMA)
4.2.1. The Leuckart method
Verweij [49] reviewed three methods for the production of
MDMA and MDA: the Leuckart reaction; reductive amination; and
the bromopropane route (a route not discussed herein). Unfortunately only the production of MDA was discussed with regards to
the Leuckart route and Vervweij indicated that N-formyl-MDA was
a route specic by-product. He also reported upon the presence of
di-[1-(3,4-methylenedioxy)phenyl-2-propyl]amine (MDA dimer),
an expected by-product, and di-[1-(3,4-methylenedioxy)phenyl2-propyl]methylamine (MDMA dimer, Fig. 7, structure A11) an
unexpected contaminant, presumably arising from N,N-dimethylformamide impurity in the formamide used. Additional compounds, also presumably impurities rather than by-products, were
safrole, isosafrole, 1,2-(methyelendioxy)-4-propylbenzene and
isosafrole glycol.
Renton et al. [74] reported that the only contaminant in MDMA
prepared by the N-methylformamide/formic acid reaction was
N,N-dimethyl-3,4-MDA, which presumably arises as a result of
N,N-dimethylformamide impurity in the N-methylformamide.

Surprisingly, in the same article while discussing the Leuckart


formation of MDMA in boiling N-methylformamide, Renton et al.
tentatively identied the 3,4-methylenedioxy pyridine (3,4-bis(1,3-benzodioxol-5-ylmethyl)pyridine, structure F10) and pyrimidine (5-(1,3-benzodioxol-5-ylmethyl)pyrimidine, structure F9).
Whether this was due to a demethylation step during condensation or as a result of formamide impurity in N-methylformamide
was not discussed.
Cheng et al. [75] reported on tablets containing MDMA thought
to be prepared by the Leuckart method. Their ndings mirror those
of Verweij [49] above in that dimers, pyridines and 4-methyl-5(3,4-methylenedioxyphenyl)pyrimidine were detected (tentatively). However, in this instance, because the drug present was MDMA
rather than MDA, the expected by-product was the MDMA dimer
(structure A11) and the pyridines, the pyrimidine and MDA dimer
were unexpected products.
As discussed in the next section, both Swist et al. [36] and Cheng
et al. [75] have some evidence that N-formyl-MDMA (structure F8)
is associated with the synthesis of MDMA via reductive aminations
as well as via the Leuckart reaction. Compounds F4F7 have also
been identied as route-specic markers in MDMA production via
this route.
4.2.2. Reductive amination
Verweij [76] examined reductive amination of 3,4-MDP-2-P
using aluminium amalgam and methylamine in boiling ethanol
and identied 12 contaminants in the nal product. One of these,
3,4-MDP-2-propanol, is a reaction by-product and another, 1,2(methylenedioxy)-4-(2-N-methyliminopropyl)benzene (structure
A9), is the reaction intermediate. The other 10 compounds
included MDA, N,N-dimethylMDA, N-methyl-N-ethylMDA (originating from impurities in methylamine), safrole and isosafrole, the
hydrogenation product of safrole (1,2-(methylenedioxy-4-propylbenzene), 1,2-(dimethoxy)-4-propenylbenzene, 3,4-methylenedioxybenzaldehyde and 1,2-(methylenedioxy)-4-methylbenzene
all of which would have been contaminants in the 3,4-MDP-2-P
starting material. In a later review [49], Verweij also indicates that
3,4-(methylenedioxy)benzyl-N-methylamine is present in the
reductive amination product.
Other common reductive aminations for the production of
MDMA involve the use of sodium borohydride (NaBH4) or sodium
cyanoborohydride as the reducing agent (Fig. 2) [77]. Swist et al.
[78] prepared MDMA salt using all three of the above reductive
aminations (and the Leuckart reaction) and examined the
contaminants that could be extracted from the salt under basic
conditions. The authors concluded that 1,2-(methylenedioxy)-4(2-N-methyliminopropyl)benzene (structure A9) is a route specic
by-product for the three reductive aminations but also noted that
it might not be present if the reduction has been efcient. Also
detected were 3,4-(methylenedioxy)benzyl-N-methylamine, 3,4(methylenedioxy)benzyl-N,N-dimethylamine, N-(30 ,40 -methylenedioxybenzyl)MDMA and N-methyl-2-methoxy-1-methyl-2-(3,4methylenedioxyphenyl)-ethaneimine (structure A7, this being an
impurity carried through from 3,4-MDP-2-P prepared from
isosafrole by oxidation). These compounds were also detected in
the Leuckart preparation. It was also suggested by Swist et al. [78]
that
2-(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphenyl)-propanenitrile is a route-specic by-product in the sodium
cyanoborohydride reductive amination but later work by Salouros
et al. [69] unambiguously identied this by-product as Ncyanomethyl-N-methyl-1-(30 ,40 -methylenedioxyphenyl)-2-propylamine (structure A10).
In slightly later work [77] Swist et al. examined basic and
neutral impurities extracted from MDMA salt prepared using the
three reductive amination methods. In addition to the compounds
listed above in this work Swist et al. also reported the presence of

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

19

Fig. 7. Characteristic contaminants in the manufacture of MDMA by synthetic routes: Reductive amination (A5A11); Leuckart route (F4F10); Wacker oxidation (G1G5);
Peracid oxidation (H1H6).

3,4-methylenedioxyphenyl-2-propanol but only in reductions


conducted using sodium borohydride. When 3,4-MDP-2-P was
prepared from 3,4-methylenedioxybenzaldehyde via the nitrostyrene 3-methyl-6,7-methylenedioxyisoquinoline-1,4-dione, Ncyclohexylacetamide and 5-(30 ,40 -methylenedioxyphenyl)-3,4-

dimethyloxazolidine impurities were detected. As indicated above,


this particular amide only arises when cyclohexylamine is used to
catalyse the formation of the nitrostyrene. It was indicated that
extraction under basic conditions was much more effective than
extraction under neutral conditions.

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N. Stojanovska et al. / Forensic Science International 224 (2013) 826

Gimeno et al. [35] also examined contaminants arising from the


three reductive aminations. In addition to the compounds
described previously by Verweij et al. [49], Gimeno et al. also
detected 1,3-benzodioxazole, PMA, 3,4-(methylenedioxy)benzyl
alcohol and 3,4-(methylenedioxy)benzyl chloride. As indicated
above, Gimeno et al. also report the presence of 3,4-dimethoxymethamphetamine (which they call 8meth) but published an
incorrect structure for that compound. Gimeno et al. concluded
that it was not possible to use contaminant proles to deduce
which of the three reductive amination methods were used in the
preparation of MDMA.
4.2.3. Impurities found in seizures
An impurity found in MDMA samples seized and analysed in
France was N-formyl-MDMA (structure F8). This impurity, present
in 25% of the samples is said to be specic to the Leuckart reaction
[79]. In addition to the compounds discussed above, ketamine,
DMA, 3,4-methylenedioxybenzaldehyde, PMA, 3,4-methylenedioxybenzyl alcohol and 3,4-methylenedioxyethylamphetamine
have been detected and used for proling, however they are not
specic to a particular synthetic route.
Gimeno et al. [80] proled 10 MDMA seizures and identied
(presumably by mass spectrometry alone) 26 different compounds of
which benzaldehyde, 1,3-benzodioxole, 3,4-methylenedioxytoluene,
AP, 1,2-dimethyl-3-phenylaziridine, safrole, 3,4-methylenedioxyphenylpropane, 3,4-methylenedioxybenzaldehyde, methcathinone,, 3,4methylenedioxybenzyl chloride, isosafrole, 3,4-methylenedioxy-Nmethylbenzylamine (structure A5), 3,4-methylenedioxy-N,Ndimethylbenzylamine, 3,4-methylenedioxybenzyl alcohol, PMA
3,4-methylenediox-N-ethyl-N-methylamphetamine, N,N-dimethyl(1,2-methylenedioxy)4-(2-aminopropyl)benzene, N-methyl-1-[1,2dimethoxy-4-(2-aminopropyl)benzene,
N-ethyl-N-methyl-(1,2methylenedioxy)-4-(2-aminopropyl)benzene and N-methyl-(1,2methylenedioxy)-4-(1-ethyl-2-aminopropyl)benzene can be classied as impurities arising from various sources. This article includes a
wealth of mass spectral data.
4.3. Amphetamine (AP)
4.3.1. The Leuckart method
Due to its simplicity, the Leuckart reaction is the preferred
synthetic route employed for the illicit manufacture of AP [81]. As
the Leuckart preparation of AP involves the production of Nformylamphetamine as an intermediate, the latter can be
encountered in the nal product if hydrolysis is incomplete
[60]. As indicated by Blachut [82], if formamide is used in the
Leuckart preparation then condensations can occur between it and
P-2-P to yield a number of route-specic heterocyclic by-products.
The rst mention of these was by Sinnema and Verweij [83] who
tentatively identied ve pyridines, one pyridone and two
pyrimidines. Later the structures of the pyrimidines (4-methyl5-phenylpyrimidine and 4-benzylpyrimidine) [84] and two
pyridines (2,4-dimethyl-3,5-diphenylpyridine and 2,6-dimethyl3,5-diphenylpyridine) [82] were unambiguously assigned (structure F12F15). As formamide can be contaminated with Nmethylformamide the product of Leuckart preparation of AP can
also include MA but this impurity is not route specic. Similarly, if
P-2-P contaminated with dibenzylketone is used in the Leuckart
reaction then a-benzylphenethylamine [85] and a-benzylphenylethylamineformamide (Fig. 8, structure F11) [65] will be formed,
the latter being route-specic but the former not.
4.3.2. Nagai, Moscow, Hypo, Emde and Birch methods
In a study conducted by Barker and Anita [24], six main marker
compounds were identied in the synthesis of AP from norephedrine/norpseudoephedrine via the Nagai route (hydrogen iodide

and red phosphorus). The six by-products were cis- and trans-2methyl-3-phenylaziridine, P-2-P, 1,3-dimethyl-2-phenylnaphthalene, 1-benzyl-3-methylnaphthalene, and N-(b-phenylisopropyl)
benzyl methyl ketimine.
By-products resulting from the metal catalysed hydrogenation
of norephedrine/norpseudoephedrine (the Emde method) in the
production of AP closely parallel those found in the manufacture of
MA. The by-products identied for AP include chloronorpseudoephedrine/chloronorephedrine (structure C7), and cis- and trans-2methyl-3-phenylaziridine [24]. Although both the Emde and Nagai
(and related) methods produce the same aziridines as by-products
it is not correct to infer that illicit material containing them must
have originated from one of these two methods. Reduction of P-2-P
ketoxime by lithium aluminium hydride, for example, also
produces these aziridines [86].
The Birch reduction of norephedrine/norpseudoephedrine to
form AP gives rise to one characteristic marker, 1-(10 ,40 -cyclohexadienyl)-aminopropane (Fig. 8, structure D2), as described by
Barker and Anita [24].
4.3.3. Reductive amination
The presence of the compounds (2-nitroprop-1-enyl)benzene
(structure I1)), benzyl methyl ketoxime (structure I2), N-(bphenylisopropyl)benzaldime (structure I3), and 2-methyl-3-phenylaziridine [43] in a sample may be indicative of the Nitrostyrene route being employed in the conversion of P-2-P to AP (Fig. 8).
Theeuwen and Verweij [87] identied unambiguously the
presence of benzyl methyl ketone phenylisopropylimine and
benzyl methy lketone benzylimine by-products in the reductive
amination of P-2-P using ammonia, Raney nickel and hydrogen.
The authors surmised that the by-products are detected only when
hydrogenation is incomplete and the water that is produced by
condensation side-reactions is removed from the reaction mixture.
These imines arise as a result of condensation between AP and P-2P and AP and benzaldehyde, respectively. Although N,N-di-(bphenylisopropyl)amine (the hydrogenated product of benzyl
methyl ketone phenylisopropylimine) is commonly detected in
illicit AP [83], the corresponding product of hydrogenation of
benzyl methyl ketone benzylimine (i.e. N-benzylamphetamine) is
not. Possibly this compound undergoes hydrogenolysis under the
reaction conditions to yield AP and 1-phenylpropane. Allen and
Cantrell [26] indicate that if an excess of ammonia is not used in
the reductive amination then a competing side-reaction, reduction
of P-2-P, takes place with the production of phenyl-2-propanol.
Verweij [50] indicates that other by-products and impurities found
in illicit AP prepared by reductive amination are N-acetylamphetamine (origin not explained) and dibenzyl ketone (presumably
arising from contaminated P-2-P). Huizer et al. [88] report that
reductive amination using ammonia and ammonium chloride
yielded a thermally labile by-product (tentatively identied as 2,4dihydroxy-1,5-diphenyl-4-methylpent-1-ene) that decomposed
into cis- and trans-1,5-diphenyl-2-methyl-4-oxopent-1-ene and
cis- and trans-1,5-diphenyl-2-methyl-4-oxopent-2-ene. In addition, the presence of 3,4-dihydro-2-benzyl-2-methyl-4-oxo-5phenyl-2h-pyrrole was tentatively identied at a trace level. With
the possible exception of these latter olens and the pyrrole, which
surprisingly do not appear to have been detected in any other
synthetic pathways to AP from P-2-P, none of the above
compounds can be considered to be route-specic for the reductive
amination of P-2-P.
4.3.4. Impurities found in seizures
Nevescanin et al. [72] reported that N-benzoylamphetamine
together with many of the compounds listed above were detected
in AP seized in Serbia. Although the origin of this amide was not
discussed it could be an impurity arising from the reaction

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

21

Fig. 8. Characteristic contaminants in the manufacture of AP by synthetic routes: Emde route (C7); Birch reduction (D2); Leuckart route (F11); Nitrostyrene route (I1I3).

between AP and benzoic acid (itself an impurity in benzaldehyde).


Other impurities that have been identied in AP samples include
N-benzylamphetamine, N,N-di-(b-phenylisopropyl)methylamine,
1,3-diphenyl-2-propylamine, 4-benzylpyrimidine, N-formylamphetamine, N,N-di-(b-phenylisopropyl)amine, N,N-di-(b-phenylisopropyl)formamide, and 2,4-dimethyl-3,5-diphenylpyridine
[43,61,84,89].
4.4. N,N-Dimethylamphetamine (DMA)
The precursor chemicals commonly employed in the
production of DMA are methylephedrine and methylpseudoe-

phedrine. The conversion of these precursor compounds to


DMA via the Nagai method results in two characteristic marker
compounds, 1-propenylbenzene (Fig. 9, structure B5) and 2propenylbenzene (structure B6), and a less specic marker
compound, P-2-P [24].
The metal catalysed hydrogenation (Emde route) of methylephedrine/methylpseudoephedrine results in the production of the
by-products chloromethylpseudoephedrine/chloromethylephedrine (structure C8), and 1-dimethylamino-1-phenyl-2-chloropropane (structure C9) in the manufacture of DMA [24]. Although
these by-products may not be route specic, they may suggest the
route of manufacture of DMA.

Fig. 9. Characteristic contaminants in the manufacture of DMA by synthetic routes: Nagai method (B5B6); Emde (C8C9); Birch reduction (D3).

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

22

The Birch reduction of methylephedrine or methylpseudoephedrine to DMA commonly results in one characteristic compound, 1(10 ,40 -cyclohexadienyl)-2,2-dimethylaminopropane (Fig. 9, structure D3) [24].

[38]. Coumbaros et al. also tentatively identied the presence of 4methoxyphenyl-2-propanol, which was likely to have originated
from PMP-2-P. Blachut et al. [90] also reported the presence of 4hydroxymethamphetamine, N,N-dimethylPMA and N-ethylPMA in
illicit tablets.

4.5. p-Methoxyamphetamine (PMA)


The only synthesis of PMA to be described in the literature is the
Leuckart preparation from PMP-2-P. 4-methyl-5-(4-methoxyphenyl)pyrimidine (Fig. 10, structure F17) and 4-(4-methoxybenzyl)pyrimidine (structure F16) were unambiguously identied as byproducts in the Leuckart preparation of PMA [84] and, as they are
derived from the condensation between formamide and PMP-2-P,
are likely to be route-specic for the Leuckart preparation. Blachut
et al. [90] detected these two pyrimidines and tentatively
identied the presence of at least six pyridines of molecular
weight 319 or 333 Da in crude products from the reaction. In later
work the same authors [82] positively identied two pyridines
with molecular weight 319 Da, namely 2,4-dimethyl-3,5-di-(40 methoxyphenyl)pyridine and 2,6-dimethyl-3,5-di-(40 -methoxyphenyl)pyridine (structures F18F19). It was found that the
presence of these pyridines at signicant levels was indicative of
the use of formamide in the reaction mixture rather than
ammonium formate and furthermore it was found that abundant
2,6-dimethyl-3,5-di-(40 -methoxyphenyl)pyridine compared to
2,4-dimethyl-3,5-di-(40 -methoxyphenyl)pyridine indicated that
formic acid was present.
In a manner analogous to that observed for the production of AP
by the Leuckart reaction the imine by-products and their reduction
products
N-(b-4-methoxyphenylisopropyl)-4-methoxybenzyl
methyl ketimine, 1-(4-methoxyphenyl)-N-(2-(4-methoxyphenyl)-1-methylethyl-2-propanamine and N-(b-4-methoxyphenylisopropyl)-4-methoxybenzaldimine are detected in the Leuckart
synthesis of PMA but as they arise from the condensation of PMA
and PMP-2-P they are therefore not route-specic by-products.
In regards to impurities found in illicit PMA preparations,
Coumbaros et al. [39] detected the two route-specic pyrimidines
and 4-methoxyphenol (Fig. 10, structure H7) the origin of which, as
described earlier, was found to be the Bayer-Villiger oxidation of 4methoxybenzaldehyde present in the anise oil starting material

5. Summary
It is not uncommon to see different synthetic routes sharing the
same by-product formation. One common by-product, P-2-P, is
sometimes thought to be a characteristic marker, however, due to
its presence as a by-product in multiple reactions or even as
unreacted precursor, it should be classied as a common byproduct. P-2-P is found in MA synthesised via reductive amination
and the Nagai method, also in MDMA synthesised via the Leuckart
reaction and in AP and DMA synthesised via the Nagai method.
Similarly, cis- and trans-1,2-dimethyl-3-phenylaziridine are
common by-products of MA synthesised via the Nagai method and
also the Emde method. The by-product N-(b-phenylisopropyl)
benzyl methyl ketimine has been described as a characteristic byproduct in the production of AP via reductive amination [61].
However, it has also been found in the synthesis of AP via the Nagai
method, suggesting that this marker compound is not characteristic to the reductive amination method. 1,3-Dimethyl-2-phenylnaphthalene has been reported as a by-product in the production
of MA and AP via the Nagai method.
Table 1 summarises the characteristic contaminants resulting
from the manufacture of MA, MDMA, AP, DMA and PMA (Figs. 610
that provide the chemical structures of the characteristic
contaminants for each ATS). It is evident that the number of
characteristic by-products varies amongst different synthetic
routes and also amongst different drug compounds. This can be
explained by the nature of the synthetic route itself, since the
varying reaction pathways may have a greater or lesser likelihood
of by-products resulting. However, a more logical explanation
could be that the most common synthetic routes, i.e. reductive
amination and the Leuckart methods, are the most frequently used
and thus the most researched methods, which in turn leads to the
determination and identication of the greatest number of

Fig. 10. Characteristic contaminants in the manufacture of PMA by synthetic routes: Leuckart method (F12F13); Peracid oxidation (H7).

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

characteristic by-products. This suggests that further research is


needed in the area of proling and drug intelligence.
By-product and impurity proling can be a very useful tool in
identifying the method of manufacture; however, great care must
be taken in interpreting the signicance of by-products and
impurities present in an illicit sample. Marker compounds are of
most signicance when accurately identifying the synthetic
method; i.e. when they are route-specic or precursor-specic.
With this knowledge in mind, it is possible to achieve great
discrimination in identifying these ATS and the different precursors used and the synthetic routes of manufacture.
6. Adulterants and cutting agents
Adulterants are added to illicit drugs in order to modify the
physiological properties of preparations. Cutting agents can be
inert substances that are added solely to increase product bulk.
Some common adulterants and cutting agents used in the
production of MA and other ATS include dimethylsulfone, N,Ndimethylamphetamine hydrochloride, ephedrine hydrochloride,
sodium thiosulfate, sodium chloride, sodium glutamate, caffeine,
sodium benzoate, diphenylhystamine, ethyl vanillin and procaine
[70,91,92]. MA samples seized in Thailand were also found to
contain traces of acetylcodeine, monoacetylmorphine and diacetylmorphine and are thought to have originated from contamination due to MA synthesis overlapping with areas of illicit heroin
production [70]. Some common adulterants and cutting agents
used in the production of MDMA include caffeine, ketamine,
paracetamol, aspirin, dimethylsulfone, palmitic acid, stearic acid,
atropine and sometimes other amphetamines are also used
[79,92,93]. Some common adulterants and cutting agents used
in the production of AP include creatine, ephedrine, salicylamide,
paracetamol, phenazone and sugar [43]. The presence of adulterants and cutting agents may further aid in discriminating or linking
drug samples as some batches may contain the same adulterants
and cutting agents, suggesting that they came from the same
manufacturer or supplier. Although the presence of common
adulterants or cutting agents themselves may suggest a link
between seizures, unless a complex or unusual mixture of them is
involved, greater evidential value of a link is provided by
contaminant proling. However, assessment of both contaminant
and adulterant/cutting agent proles can be informative. For
example, if two seizures exhibit different adulterant/cutting agent
proles yet exhibit identical contaminant proles the likely
situation is that two batches of product were produced using a
single source of drug, either from a single clandestine laboratory or
from different ones.
7. Intelligence methods
One of the tasks of the European project entitled Collaborative
Harmonisation of Methods for Proling of Amphetamine Type
Substances (CHAMP) was to develop a harmonised methodology
for MA and MDMA proling and the creation of a common
database in a drug intelligence perspective. This project involves
two separate parts: Part I includes the analysis of organic
impurities formed during synthesis in order to highlight potential
links between samples; Part II focuses on physical characteristics
of the tablets. Correlation coefcients were used to distinguish
between populations of linked samples (from the same seizures)
and unlinked samples (from different seizures) [94,95].
Australian efforts in the area of drug proling are comparatively
recent. Following research and development work between 1991
and 1995 the National Heroin Signature Program (NHSP) was
established in 1997 [31]. In 2003, the NHSP was expanded to
become the Australian Illicit Drug Intelligence Program (AIDIP)

23

[31]. The objective of the AIDIP was to consolidate work completed


on heroin and expands into other major drug types. The AIDIP
developed signature programmes for heroin, cocaine and the ATS
such as MA and MDMA. The AIDIP has two major arms: chemical
proling and physical proling, which are designed to complement
each other. Chemical proling involves an in-depth chemical
analysis of the drugs to provide information that may complement
intelligence previously acquired by law enforcement [31].
Aalberg and co-workers [43,44] focused on the development of
a harmonised method for the proling of AP. They synthesised a
number of standards i.e. by-products found in illicit AP. Following
this they conducted a study focusing on the stability of 22 AP
impurities dissolved in six organic solvents in order to nd the
most inert, and most suitable, solvent for AP proling. The study
proved to be essential due to the fact that unstable compounds can
have a negative inuence on the comparison of proles.
Anderson et al. [45,46] developed a GCMS method for the
analysis of target compounds found in AP synthesised by the
Leuckart method, reductive amination of benzyl methyl ketone,
and the Nitrostyrene method. Anderson et al. [48] subsequently
developed a procedure involving partial least squares discriminant
analysis (PLS-DA) to evaluate the effects of various pre-treatment
methods on the separation of AP batches synthesised by the
Leuckart reaction, reductive amination of benzyl methyl ketone
and the Nitrostyrene method. A Pearson correlation was applied
in order to successfully differentiate AP samples synthesised from
different batches.
Dayrit et al. [71] described a GCMS and gas chromatography
ame ionisation detector (GCFID) method for the detection and
impurity proling of impurities found in illicit MA samples seized
in the Philippines. This method was successful in identifying
impurities present in samples synthesised via the Leuckart
method. Lee et al. [7] developed a method for the analysis of
organic impurities present in MA samples synthesised from
ephedrine and pseudoephedrine by the Emde, Nagai and
Moscow methods using GCMS and GCFID. Following a cluster
analysis of the characteristic peaks detected, samples were able to
be differentiated into four main groups. Tanaka and Inoue et al.
[53,99] conducted studies on the impurity proling of MA seized in
Japan using GC. Impurity proles containing ephedrine and MA
dimer were used to establish links between MA seizures.
In 2006, Kuwayama et al. [100] developed a GCMS method
using headspace solid phase microextraction (HS-SPME) for the
detection and proling of impurities in MA samples. MA from
nine different origins were analysed and the compounds
detected were discriminated by means of logarithmic conversion and cosine distance calculations in order to classify the
MA samples into groups. In 2007, a new capillary zone
electrophoresis method for the simultaneous chiral determination of the enantiomers of DMA, MA, ephedrine, pseudoephedrine and methylephedrine (obtained from drug seizures
in Hong Kong) was developed [101]. The results suggested that
all the samples were not racemic mixtures. This indicated that
DMA and MA samples were unlikely to be synthesised through
reductive amination of achiral precursor P-2-P, rather DMA and
MA in samples were more probably prepared from methylephedrine and pseudoephedrine or ephedrine, respectively
[101]. In 2008, Lee et al. [91] were able to link MA samples
seized in Japan to those seized in Korea by means of analysing
impurities and additives present in MA seizures using GCMS
and GCFID. Puthaviriyakorn et al. [70] reported GCMS
analysis of MA tablets seized in Thailand. Nine compounds
were identied as impurities in the MA samples and these were
subjected to multivariate analysis which was successful in
characterising and classifying 250 exhibits into ve groups.
Studies utilising GCMS for the impurity proling of MDMA

24

N. Stojanovska et al. / Forensic Science International 224 (2013) 826

tablets seized in the Netherlands and Hong Kong have also


been reported [75,102].
Another important aspect of drug intelligence is the determination of the enantiomeric purity of a drug. All manufacturing
methods starting from l-ephedrine or d-pseudoephedrine produce
d-MA as the single product, which is at least twice (in some
publications reported to be up to ten times) as potent as the
racemic mixture [81]. The identication of an enantiomerically
pure sample of MA therefore suggests that l-ephedrine/dpseudoephedrine was used as starting material, however, a
successful attempt at separation of a racemic mixture cannot be
ruled-out. If equal amounts of l- and d-MA are present this suggests
that P-2-P or some other achiral or racemic compounds were used
as the starting material. Some seized samples in Australia have
been found to contain unequal amounts of l- and d-MA, which may
suggest that two or more samples synthesised from P-2-P,
ephedrine or pseudoephedrine have been combined to produce
the end product making identication of the route of manufacture
complicated. Alternatively, a partially effective enantiomeric
purication may have been attempted. In these cases the
observation of an unusual mixture of by-products, intermediates
or impurities would add weight to the hypothesis that a mixed
product is involved.
The source of ephedrine (synthetic/natural) is an important
aspect in determining origin of manufacture of a drug. There have
been more than 30 different species of Ephedra found, in Europe,
Asia and America [24]. However, only a few of these species
contain ephedrine related alkaloids at any signicant level.
Kurashima et al. [96] reported the origin of ephedrine based on
the carbon and nitrogen stable isotope ratio values analysed by
means of isotope ratio mass spectrometry (IRMS). The various
origins of ephedrine (biosynthetic, semi-synthetic derived from
molasses, or synthetic) could be discriminated clearly by using
these values. In 2009, Kurashima et al. [97] expanded on their
previous IRMS work by utilising the hydrogen stable isotope ratio
measurement for establishing the origin of ephedrine and
pseudoephedrine. The low deuterium content of biosynthetic
ephedrines allows a clear distinction from synthetic ephedrines,
semi-synthetic ephedrines derived from pyruvic acid and semisynthetic ephedrines derived from molasses. Matsumoto et al. [98]
established a method for the quantitative analysis of the
deuterium contents (D/H) at the phenyl, methine, benzyl, Nmethyl and methyl groups of l-ephedrine hydrochloride (HCl), dpseudoephedrine HCl and MA HCl by NMR. By comparison of the 5
position-specic D/H values of l-ephedrine HCl and d-pseudoephedrine HCl prepared by three methods (chemical synthesis,
semi-chemical synthesis, and biosynthesis) it was possible to
differentiate between chemically synthesised ephedrines and
semi-synthetic ephedrines. The classication of several MA
samples seized in Japan in terms of the D/H values at these two
positions clearly illustrated that the MA samples had been
synthesised from biosynthetic or semi-synthetic ephedrines but
not from synthetic ephedrine [98].
8. Conclusion
In this review, the contaminants found in MDMA, MA, AP, DMA,
and PMA preparations have been described. These contaminants
are increasingly important as they are essential in determining
possible routes of manufacture and illustrating links between
seizures. This review illustrates the large diversity of impurities/
intermediates/by-products found in illicit ATS resulting from
common synthetic routes and methods in proling these
compounds. The variety of characteristic compounds encountered
suggests that signicant discrimination between seizures of
different origins is possible. Future research is necessary to

address knowledge gaps in regards to the manufacture of drugs of


current interest, to identify new developments in the synthesis of
these drugs (i.e. the identity of new precursors or new synthetic
methods) and to develop knowledge in regards to newly emerging
drugs.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.forsciint.2012.10.040.
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