Forensic Science International: Synergy 2 (2020) 194e205

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Forensic Science International: Synergy

journal homepage: https://www.journals.elsevier.com/
forensic-science-international-synergy/

A review of the newly identified impurity profiles in

methamphetamine seizures
Isaac Onoka a, *, Andrew Toyi Banyika a, Protibha Nath Banerjee a, John J. Makangara a,
Laurence Dujourdy b
a
Department of Chemistry, College of Natural and Mathematical Sciences, University of Dodoma, P.O Box 259, Dodoma, Tanzania
b ^t. Longelles 26 bd Dr Petitjean, BP
Agrosup Dijon, Department of Engineering and Process Science, Research Support Service Agrosup Dijon - DSIP - Ba
87999 21079, Dijon Cedex, France

a r t i c l e i n f o a b s t r a c t

Article history: Forensic intelligence of synthetic illicit drugs suffers a problem of continuous introduction of new
Received 1 May 2020 synthetic methods, modification of the existing routes of manufacture, and adulterations practiced by
Received in revised form criminal networks. Impurity profiling has been indispensable in methamphetamine intelligence based
21 June 2020
on precursors, synthetic routes, and chemical modifications during trafficking. Law enforcement au-
Accepted 22 June 2020
Available online 24 June 2020
thorities maintain the credibility and integrity of intelligence information through constant monitoring
of the chemical signatures in the illicit drug market.
Changes in the synthetic pattern result in new impurity profiles that are important in keeping valuable
Keywords:
Methamphetamine
intelligence information on clandestine laboratories, new synthetic routes, trafficking patterns, and
Impurity profiles geographical sources of illicit Methamphetamine.
Stable isotopes This review presents a critical analysis of the methamphetamine impurity profiles and more specif-
Synthetic route ically, profiling based on impurity profiles from Leuckart, Reductive amination, Moscow, Emde, Nagai,
Birch, Moscow route; a recent nitrostyrene route and stable isotope signatures. It also highlights the
discrimination of ephedrine from pseudoephedrine sources and the emerging methamphetamine
profiling based on stable isotopes.
© 2020 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction illicit drugs [15e17]. The method uses organic and inorganic im-
purities which are by-products of reactions in the final formulation
Methamphetamine is a schedule II controlled substance ac- of MA. It has successfully been used to establish intelligence in-
cording to the Single Convention on Narcotic drugs [1] and the formation in France [18,19], Australia [20,21], Thailand [22,23],
United Nations Convention against Illicit Traffic in Narcotic Drugs China [24], Philipines [25], Japan [22,26,27], USA [28], Spain [29],
and Psychotropic Substances, 1988 [2]. It is highly addictive drug Korea [30,31] and in many other places worldwide [7,19,32e35].
with a potent central nervous system (CNS) stimulant properties Recently, the emerging complementary profiling method based on
[3,4]. The United Nations Office on Drugs and Crime (UNODC) stable isotopes has drawn the interest of many researchers
report MA as the most abused drugs worldwide [3,5,6]. For the last [36e38]; its details will be included in this review.
two decades, the use of MA has been increasing in many countries The chemical analysis of illegal drugs provides valuable infor-
worldwide [3,6e10]. In Japan, about 15,000 drug arrests were from mation about the conspiracy links and trafficking routes, catego-
cases related to MA [11] accounting for 90% of all reported viola- rizing the seizures based on the signatures, thereby identifying
tions [12]. Previous studies have documented the prevalence of their origins [39,40]. As a complementary law enforcement inves-
methamphetamine over other synthetic drugs elsewhere [13,14]. tigative work, it provides a background intelligence information
The impurity profiling of MA provides the linkage of illicit drug concerning the number of sources of drugs, whether those sources
seizures based on the chemical signatures contained in the seized are within a country or are internationally based and also unveiling
the points of distribution and distribution networks. Similarly, the
impurity profiles identifies the emergence of new clandestine
* Corresponding author. laboratories and their associated synthetic methods, which, in turn,
E-mail address: [email protected] (I. Onoka).

https://doi.org/10.1016/j.fsisyn.2020.06.004
2589-871X/© 2020 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205 195

provides background intelligence information [41]. Chemical discriminating against their cooks.
profiling marks the principal purpose of the intelligence of illicit For quite a long time, the clandestine synthesis of MA employs
drugs by establishing a link between the clandestine laboratories, three major precursors, namely ephedrine, pseudoephedrine, and
suppliers, and users. The chemical information obtained from a the 1-phenyl-2-propanone (P2P) [55e59]. With P2P (Fig. 1), the
drug can indicate its synthetic method, adulterations during traf- Leuckart route (VI) and reductive amination are the most
ficking, and the operations of the criminal networks [42]. commonly used routes for the synthesis of MA [48,60]. In contrast,
Generally, the fundermental role of a forensic chemist in drug ephedrine/pseudoephedrine precursors (Fig. 2) convert to MA
profiling is extract the chemical signatures that can be used to through the Nagai (I) [52,61], Emde (II) [52,61], Hypo (III) [62],
establish the degree of commonality of seizures with their origins Moscow (IV) [63] Rosenmund (V) [64,65] and Birch/Nazi (VI)
or a specific group of other samples [6,43] as well as linking the pathways [66,67].
signatures with the possible synthetic methods, conditions, and As one of the main MA precursors, P2P reaction scheme involves
post-production modifications. A comprehensive examination and the reductive amination reactions Fig. 1 (IeV) and the Leuckart
comparison of the chemical signatures has found a growing (HCL/H2O). The reductive amination reaction of P2P to MA is ach-
application strategically at the macro level [6] and tactically at the ieved through Pd/H2/NH2CH3, NaBH4/NH2CH3, NaBH3CN/NH2CH3,
micro-level [35]. These advances have helped the police and HCl/H2O, Pt/H2/NH2CH3, and Hg/Al/NH2CH3, however, the
criminal investigators at both national and global scales to establish aluminum/mercury (Al/Hg) amalgam in a slightly acidic media
the dynamics of illicit drug markets, locate the drug traffickers, method is reported to be the most commonly used method in
establish conspiracies links between dealers and users [11,43,44]. Europe and USA [48]. Although the method has long history, 1-
In this decade, extensive number of research studies on the phenyl-2-propanol formed from the direct reduction the precur-
chemical profiling of MA and its derivatives are focusing on the sor, P2P, remains the potential intelligence impurity profile [48,68].
determination of organic and inorganic impurities [19,45], deter- Described by Verweij in 1989 [68], the Leuckart route (Fig. 1VI) is
mination of synthetic routes [46], synthesis of the impurities achieved by the addition of N-methylformamide, methylamine or
[17,46] identification of the impurities [17,39,40] concentration in formic acid followed by H2SO4 or HCl to form MA. By means of N-
body fluids [47] characterization [48] and the extraction and sep- methylformamide, the reaction result in a Leuckart route deter-
arations of the impurities [49,50]. minant; the N-formylmethamphetamine disputed by Qi et al. [20]
In this paper, we critically analyze the impurity profiles of MA and Barron et al. [69]; and non-synthetic route determinants
synthesized from ephedrine, pseudoephedrine, and 1-phenyl-2- namely dibenzylketone, R-benzyl-N-methylphenethylamine, and
propanone (P2P) precursors and subsequently analyze their po- N-methyldiphenethylamine [70]. The synthetic-route character of
tential use for intelligence perspective. N-formylmethamphetamine argumented by Barron et al. and Qi
et al. was resolved by the identification of a,a0 -dimethyldiphene-
1.1. The synthetic schemes of methamphetamine and the specific- thylamine and N, a,a0 -trimethyldiphenethylamine by Barron et al.
route impurities The two impurities were later confirmed by Vanitha et al. [48]
having identified them in Leuckart based MAs only.
The Forensic intelligence of illicit drugs is an exciting subject The Nagai route (Fig. 2(I)) is associated with the formation of
and very challenging. In totality, it embraces the determination, (2E)-N-methyl-3-phenyl-N-(1-phenylpropan-2-yl)prop-2-
identification, and characterization of the individual components in enamide, iodoephedrine, N-methyl-N-(a-methylphenyl)amino-1-
the final formulation of illicit drugs regarded in this review as the phenyl-2-propanone and (Z)-N-methyl-N-(a-methylphenylethyl)-
impurities, intermediates, and the contaminants. Depending on the 3-phenylpropanamide [65,71].The impurities are formed from the
level of operation of a clandestine laboratory, an illegal drug is an nucleophilic substitution reaction of eOH group of ephedrine/
assemblage of constituents carrying the information about the pseudoephedrine to form idoephedrine or iodopseudoephedrine.
synthetic route [16,32], condition-specifics [19], reagents [30], The intermediary iodine is liable to internal nucleophilic attack
adulterations during trafficking, synthetic batches and sometimes from the adjacent nitrogen to form cis- and trans-1,2-dimethyl-3-
the chemical process level of the cooks (purity) [40,51]. phenylaziridines which is reduced to MA or hydrolysed to P2P
Like in any other reaction, each synthetic scheme has by- [72]. In a prolonged acidic conditions, the latter undergo conden-
products emanating from the conversion of the precursors to MA. sation to form 1,3-dimethyl-2-phenylnaphthalene and 1-benzyl-3-
For instance, some constituents are by-products of the reaction methylnaphthalene reported to be the specific synthetic route
conditions; others are formed from the conversion of precursors to signatures [73,74].
intermediates and from intermediates to MA while others are The conversion of ephedrine/pseudoephedrine to MA via Emde
intentionally added as cutting agents for potency or weight [52] route is the dominant synthetic route in the South East Asia [73]. In
and as artifacts described by Broseus et al. [53]. Therefore, the final contrast to the Nagai route, the Emde reaction scheme is
formulation of MA is charceterized by a variation of the relative augmented by SN1 substitution (intramolecular nucleophilic
abundance of the major by-products, intermediates, and impurities displacement) or SN2 substitution (intermolecular displacement) of
that defines a chemical signature. the eOH in ephedrine/pseudoephedrine with chloride to form a
Although different MA seizures produced from the same pre- racemic mixture of (þ)-chloropseudoephedrine and (-)-chlor-
cursor, using similar route and the same reagents have related oephedrine of variable impurity concentrations [75,76]. The
impurity profiles; some intra and inter batch variations may still (þ)-chloropseudoephedrine and (-)-chloroephedrine can then un-
occur due to varying reaction conditions. This variation is essential dergo a cyclic ring closure to form cis-1,2-dimethyl-3-
to distinguish chemists (cooks) by attaching a specific profile to phenylaziridines and trans-1,2-dimethyl-3-phenylaziridines,
reaction conditions practiced by a particular clandestine laboratory. respectively. Accordingly, (þ)-norpseudoephedrine and (-)-nor-
Based on a certain probability of a link corresponding to the ephedrine alternative precursors undergo similar reaction to form
calculation of a threshold, two or more exhibits will have the same (þ)-chloromethylpseudoephedrine and (-)-chloromethylephe-
chemical profiles supporting the fact that they originate from the drine. These intermediates may eliminate the HCl to form 1-
same batch, with the strength of support increasing as profiles propenylbenzene and 2-propenylbenzene or can undergo a rear-
become more complex [54]. Otherwise, a range not meeting the rangement to form 1-dimethylamino-1-phenyl-2-chloropropane
threshold can only distinguish the samples rather than [77]. The route specific potential of the intermediary aziridines
196 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205

Fig. 1. Synthesis of MA from P2P routes: (I) Pd/H2/NH2CH3, (II) NaBH4/NH2CH3, (III) NaBH3CN/NH2CH3, (IV) Hg/Al/NH2CH3, (V) Pt/H2/NH2CH3 (VI) HCl/H2O.

Fig. 2. Ephredine/Pseudoephredine synthetic routes: (I) Nagai route, (II) Emde route, (III) Hypo route, (IV) Moscow route (V) Rosenmund and (VI) Nazi/Birch route.

was contradicted by Ko et al. [37] and Salouros et al. [59] having formylephedrine, N-acetylephedrine, N,O-diacetylephedrine and
identified 1-methylamino-1-phenyl-2-chloropropane as a vapour- N-acetylamphetamine.
phase nucleophilic product of the aziridine and N-methyl-1-(4- “Moscow” method Fig. 2(IV) is achieved by a reaction between
[2-(methylamino)propyl]phenyl)-1-phenylpropan-2-amine. The ephedrine/pseudoephedrine with red phosphorus and iodine in
latter was recogonized in “Moscow” and Nagai related methods and water [59]. Its mechanism is treasured in the regenerative role of
could not qualify as a route specific impurity for Emde route red phosphorus [79]. Skinner [73] as supported by NicDae id et al.
[63,78]. Ko et al. instead identified and proposed 1-methylamino-1- [45] proposed a scheme based on the oxidation of P by I2 to
phenyl-2-chloropropane (chloroephedrine/chloropseudoephe- diphosphorus tetraiodide (P2I4) followed by the decomposition of
drine as route specific impurity for the Emde method. Other non- P2I4 in water to form phosphoric acid and phosphonium iodide. The
route specific impurities include methyephedrine, N- mixture them converts to hydroiodic acid (HI) and phosphine (PH3)
 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205 197

upon heating. The former protonates the eOH of ephedrine/pseu- from pseudoephedrine decreased significantly since 2007 with
doephedrine to form aziridine intermediates which potentially increasing impurity profiles derived from P2P. This shift was asso-
reduce to MA as in the case of the Nagai route [73]. ciated with a spike in unknown synthetic route assignments and a
Birch/Nazi route (Fig. 2 (VI)) is a reduction reaction of ephed- sharp decrease (84%) in samples assigned to a P2P-based recipe in
rine/psedoephedrine using excess alkali metal e.g., lithium/sodium the first quarter of 2015 [82,91].
in liquid ammonia to form 1-(1ʹ,4ʹ-cyclohexadienyl)-2-
methylaminopropane (CMP) [54], notated as (S)eN-Methyl-1- 1.3. The emerging methamphetamine impurity profiles
(1,4-cyclohexadienyl)-2-propanamine [66]. The impurity is the
most commonly encountered MA impurity prepared by the Birch In response to the crackdown measures imposed on the pro-
route. Its reaction scheme is based on the role of alkali metals duction and trafficking of MA and its precursor chemicals, clan-
preferably lithium as a proton source for the eOH of ephedrine/ destine laboratories circumvent the law enforcement authorities by
pseudoephedrine. As lithium protonates the precursor, NH3 facili- deriving the precursors from uncontrolled substances such as
tate the reduction of the aromatic rings to form 1-(1,4- phenyl acetic Acid (PAA) [40], nitrostyren [82], and legal medicine
cyclohexadienyl)-2-methylaminopropane [80]. This primary im- [93] resulting into the emergence of new impurity profiles.
purity associated with the lithium - ammonia method normally The emergence of impurity profiles such as dimethylamphet-
results in high CMP:MA ratio limiting the isolation of the impurity. amine and p-methoxyamphetamine was recently documented by
Martinez et al. [81] proposed potassium permanganate and aquous Stojanovska et al. [54] and supported by a literature collection of
base for effective CMP isolation. impurity profiles and synthetic route of manufacture of methyl-
amphetamine, 3,4-methylenedioxymethylamphetamine, amphet-
1.2. A paradigm shift in methamphetamine precursor production amine, dimethylamphetamine, and p-methoxyamphetamine as
well as the recently identified less potent l-methamphetamine in
As a result of the crackdown measures taken against the pro- place of d-methamphetamine in the United States [57].
duction, trafficking and the availability of the P2P and ephedrine/ Since their identification in seized MA, several MA impurity
pesudoephedrine, access to the precursors has shifted to the illicit profiling [19,53,76,91] reveal profiles that are potentially important
manufacture of the precursors through readily available starting for strategic, tactical and operational intelligence of MA in the USA
materials with new routes leading to the emergence of new im- [57], France [18] Australia [20,44,94e96] Korea [30], Iran [97],
purity profiles [82e84]. China [24], Philipines [25], Japan [98] and Thailand [22].
For quite a long time, the synthesis of phenyl-2-propanone is
through a vast number of starting materials such as a-phenyl- 1.3.1. Impurities from metal catalytic hydrogenation
acetoacetonitrile [83,84], a-phenyl-b-methyleneglycol [85], a- Metal catalytic hydrogenation of ephedrine/pseudoephedrine
phenylisopropyl alcohol [86] phenylacylmalonic ester [87] phe- and P2P is one of the oldest MA synthetic methods [35,40,99e101].
nylacetyl chloride [88] a-methylstyrene with thallium nitrate, and Using ephedrine/pseudoephedrine, the clandestine laboratories
benzene via o,o-diprotonated nitro olefin [89], b-methyl-b-Nitro- often use palladium via the Rosenmund route [101], lithium/NH3
styrene, and phenylacetic acid (PAA). via Birch route, and nickel via Emde route [100]. The reaction in-
Although several P2P synthetic schemes were available in the volves the reduction of the C-X (X-halo, phosphate, and sulfate)
1980s, the illicit production of P2P was mainly through Phenyl- (Fig. 4) rather than the benzylic OH group to form methamphet-
acetic acid (PAA) via acetic anhydride and lead (II) acetate; and b- amine [100].
methyl-b-Nitrostyrene via Fe/Hþ [65]. Using P2P, an imine intermediate MA base is formed from a
A recent twist in the production of P2P has recently involved the reaction of between P2P with methylamine. The MA freebase is
nitrostyrene method (NTS) [82]. This emerging synthetic scheme then distilled and directly converted to hydrochloride salt [99,100].
results in nitrostyrene recently identified in MA samples seized in Fig. 5 represents a reductive amination for the conversion of P2P to
Mexico [55] and the USA [82]. The NTS method uses benzaldehyde MA hydrochloride.
and nitroethane in Knoevenagel reaction to form a nitrostyrene, Reaction (c) occurs through heterogeneous reactions with in-
yellow solid, which converts to P2P in the presence of iron powder ternal or external sources of hydrogen in the presence of Pd, Pd/C,
and hydrochloric acid [82e90]. Pd/BaSO4, Pt, Pt/C, CuO, CaSO4, BaSO4, Raney Nickel (Ni-Al) [100].
The evolution of the P2P clandestine chemistry is further Tracking the traces of metals in the final formulation of MA has
confirmed by the re-emergence of a new impurity profile in place of been used to determine the synthetic routes. MA manufactured
a-benzyl-N-methylphenethylamine and trans-N-methyl-4-methyl- from ephedrine/pseudoephedrine through the Emde and Nagai
5-phenyl-4-penten-2-amine from the usual foul-smelting of a methods was found to contain N-methyl-1-{4-[2-(methylamino)
crystalline PAA [82]. The synthesis of P2P from PAA (Fig. 3 (a)) propyl]phenyl}-1-phenylpropan-2-amine and (1S,2S)-1-
utilizes the then easily available ethyl phenylacetate (EtPA). How- methylamino-1-phenyl-2-chloropropane as route-specific impu-
ever, a recent decline of EtPA and its associated esters and amides rities [61]. Since their identification, they have been used as Emde
resulted in a shift in the P2P precursors (Fig. 3(b)) resulting in the route-specific signatures [61,76,77].
emergence of new characteristic impurities recently reported in the Furthermore, (1S,2S)-1-methylamino-1-phenyl-2-
in Australia [91] and observed in the USA [82]. chloropropane has recently been used as an additional route-
The P2P produced from the PAA method and nitrostyrene (NTS) specific marker impurity synthesized from ephedrine via chlor-
convert to MA with route-specific markers intelligently used to oephedrine by the Emde route (Fig. 6) [64]. The metal catalysis
trace the sources of P2P. reaction of (1R, 2S)-(þ)-ephedrine or (1S, 2S)-(þ)-pseudoephedrine
The dynamics of the operations of criminal MA networks is one results in the formation of chloroephedrine/chloropseudoephe-
of the exciting profiling topics appealing to close monitoring by drine which is hydrogenated to (S)-(þ)-Methamphetamine.
intelligence agencies. A recent Drug Enforcement Administration Recent profiling of reductive amination of P2P made from PAA/
(DEA) MA Profiling Program (MPP) done in the USA [82,92] recor- lead (II) based MA [102] elucidated trans-N-methyl-4-methyl-5-
ded trade-off impurity profiles assigned to pseudoephedrine route phenyl-4-penten-2-amine and a-benzyl-N-methylphenethyl-
to those assigned to P2P precursors. According to the MA impurity amine. Trans-N-methyl-4-methyl-5-phenyl-4-penten-2-amine
profiles documented by this program, the impurity profiles derived used as a route-specific marker was presumed acetone and P2P
198 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205

Fig. 3. A paradigm shift in MA precursor production: (a) PAA method,(b) nitrostyrene (NTS) method (c) 1e5 synthetic routes of P2P to MA.

Fig. 4. C-X reduction to form MA: X ¼ Cl-, SO-2

4 , H2PO4, and ClO4.

Fig. 5. Imine reduction to Methamphetamine: (I) P2P, (II) Methylamine, (III) Phenyl acetone methylimine (IV), Methamphetamine freebase, (V) Methamphetamine hydrochloride
salt. (a) Removal of water, (b) reduction of imine to amine, (c) addition of hydrogen chloride.

Fig. 6. Metal catalytic reduction of (1R, 2S)-(þ)-ephedrine or (1S, 2S)-(þ)-pseudoephedrine.

condensation product, however, this assumption could not explain Furthermore, an attempt to produce P2P using a Dakin-West
why the little amount of the impurity and its associated in- and lead (II) acetate conditions [102] were futile and could not
termediates produced even if the P2P was refluxed in acetone for a yield the expected trans-N-methyl-4-methyl-5-phenyl-4-penten-
long time. 2-amine as an impurity.
 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205 199

The best reasoning so far centers the argument on the role of a has been fundamental in tracking the P2P based MA synthesized by
low-level 4-carbon acetate unit as an intermediate. Since acetic the nitrostyrene chemistry.
acid undergoes decarboxylation in aqueous solution over a range of
temperatures, a route-specific marker impurity, trans-N-methyl-4-
1.3.2. Emerging impurity profiles from pharmaceutical compounds
methyl-5-phenyl-4-penten-2-amine results from an intra-
In response to the crackdown measures taken against controlled
molecular reaction of lead acetate with P2P via chelation controlled
substances, ephedrine, and pseudoephedrine, other adaptation
transition states followed by decarboxylation [102,103]. Fig. 7
strategies used by clandestine laboratories are co-ingredients of
shows the proposed mechanism for the formation of this route-
legal medicines, direct extraction from ephedra plants
specific marker.
[77,93,103,104] as well as direct synthesis from easily available
The reductive amination of P2P is also associated with the for-
starting materials [83,84]. Although Lee et al. [31] reports less
mation of a-benzyl-N-methylphenethylamine as a synthetic route
common MA crystals containing pharmaceutical impurities, Barker
characteristic impurity. The MPP identified the contaminant at the
and Antia [77] had a different opinion on the most common sources
DEA’s Special Testing and Research Laboratory [102].
of ephedrine and pseudoephedrine used to synthesize crystal MA.
The emergence of new impurity profiles in MA analysis sug-
The latter as supported by Liu et al. [93] who also considered me-
gests, possibly, a change in the synthetic route parameters or the
dicinal drugs as the most common sources of pseudoephedrine and
synthesis of precursor chemicals. The foul-smelting of a crystalline
ephedrine.
PAA results in new impurity profiles monitored in seized MA
Synthesis from legal medicines is the most common coping
samples. The impurities associated with the modified P2P synthetic
strategy practiced by clandestine laboratories to avoid strict mea-
pathway are a-benzyl-N-methylphenethylamine and trans-N-
sures from the law enforcement authorities [77]. The legal medi-
methyl-4-methyl-5-phenyl-4-penten-2-amine) [82]. They have
cines approach result in MA whose final formulation contains
been used to track MA synthesized from PAA.
pharmaceutical signatures that used to reflect the trends in pre-
The emergence of N-butylamphetamine and N-cyclo-
cursor chemicals, manufacturing sources, and the trafficking pat-
hexylamphetamine in seized MA has recently triggered the nitro-
terns organized by the criminal networks. Unlike by-products,
alkene chemistry. The two impurities result from a Knoevenagel
there is limited literature linking pharmaceutical impurities to the
reaction of benzaldehyde and nitroethane to form a nitrostyrene
synthetic route of MA.
[90].
More recently, the MA profiling based on synthetic pharma-
Toske et al. [82] referred to this method as a nitrostyrene
ceutical signatures has been done in Korea [31], Iran [97], China
method (NTS) or a nitropropene method. The catalytic activities of
[24], Japan [98] and Thailand [22]. several studies have been done
butylamine/cyclohexylamine influence the conversion of the P2P
in this field, more research is required to unveil the potential of
precursors. The catalysts react with benzaldehyde to form imine,
pharmaceutical impurities beyond their existence as sole impu-
which then reacts with the nitroalkane to form a nitrostyrene as an
rities into the final MA formulations. Tracking the by-products
intermediate [82]. The reaction mixture at this step contains
down to their origin and their point of entry may provide the po-
nitrostyrene and extractable cyclohexylamine/butylamine with a
tential of establishing synthetic routes using pharmaceutical
significant reaction potential. Based on a reaction proposed by Hass
contaminants.
et al. [90], nitrostyrene converts to P2P in the presence of iron
In a profiling program conducted in Korea between 2006 and
powder and hydrochloric acid. The extractable cyclohexylamine/
2011, Acetaminophen, Caffeine, Phenacetin, Ambroxol, Chlorphen-
butylamine can then react with P2P to form the stable N-buty-
iramine, Desloratadine, Barbital, Ketamine, Procaine, and Dime-
lamphetamine, and N-cyclohexylamphetamine elucidated in MA
thylsulfone were elucidated as characteristic pharmaceutical
seizures. Fig. 8(a) and (b) represents the formation of N-butylam-
impurities [31]. The profiling program linked these impurities with
phetamine and N-cyclohexylamphetamine.
cold medicines, cold relievers, ingredients of analgesic drugs [105],
Since 2015, the two impurities were detected in MA seizures
expectorant, and dietary supplements extracted together with
collected in the USA [82]. The identification of the two impurities
ephedrine/pseudoephedrine. In contrast, others added as

Fig. 7. The reaction mechanism for the formation of trans-N-methyl-4-methyl-5-phenyl-4-penten-2-amine.

200 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205

Fig. 8. Impurity profiles for NTS synthetic method. (a) N-Butylamphetamine synthetic route, (b) N-Clyclohexylamphetamine route.

adulterants during trafficking. While the pharmaceutical medicines

demonstrate growing intelligence phenomena, tracking the specific
legal drugs used in the MA production and the post-production
modifications is an area of utmost interest.
Interestingly, in 2010, chlorpheniramine was identified in both
Korea [31] and Iran [106], indicating a cross-border operation of the
criminal networks. The emergence of these impurities was a direct
indication of the use of legal medicines and their associated anal-
gesic and co-ingredients containing ephedrine or
pseudoephedrine.
Furthermore, Lee et al. [31] identified a pharmaceutical recipe
based dimethyl sulfone from seized MA in Korea. The impurity was
associated with the recipe used in medicinal drugs containing
ephedrine/pseudoephedrine as well as an adulterant used in cut-
ting MA. The impurity was previously identified in Korea
Fig. 9. A synthetic mechanism of N1,N1,N2-trimethyl-N2-(1-phenylpropaN-2-yl)
(1996e2003) and USA (1996e2003) [30,107] emerged in Australia ethane-1,2-diamine from diphenhydramine: (a) formation of methamphetamine, (b)
(1998e2002) [21], re-surfaced in (USA 2007) [108], Korea dissociation of diphenhydramine to imine and diphenyl methanol, (c) reaction be-
(2006e2011) [31] and Japan (2006e2007) [98]. The observed trend tween imine and methamphetamine to form N1,N1,N2-trimethyl-N2-(1-phenylpropan-
in the occurrence and re-emergence of dimethyl sulfone in the 2-yl)ethane-1,2-diamine. Source [93].

seized MA is potentially important in linking the operation of

criminals in the countries. Although the determination of homo-
dimethylethanamine as an intermediate and traces of diphenyl
geneity might be very challenging, linking the dimethyl sulfone to
methanol. The 2-iodo-N, N-dimethylethanamine then reacts with
its common source is essential for integrated intelligence.
MA to form N1, N1, N2-trimethyl-N2-(1-phenylpropan-2-yl)ethane-
Unlike other countries, a new profiling program based on
1,2-diamine as shown in Fig. 9.
pharmaceutical impurities conducted China recorded a new trend
In this reaction, the diphenhydramine is present as co-
of impurity profiles of MA synthesized from ephedrine/pseudoe-
ingredients of legal medicine used for the synthesis of ephedrine/
phedrine [93]. Liu et al. reported tablets with Theophylline-
pseudoephedrine. The control of such drugs is essential for moni-
Ephedrine, Ephedrine-Diphenhydramine, Pseudoephedrine, Dex-
toring and identification of illicit production of ephedrine/pseu-
tromethorphan, and Chlorpheniramine as a new set of legal med-
doephedrine from legal medicines.
icines commonly used as a source of ephedrine/pseudoephedrine.
These drugs contain alkaline substances such as chlortrimeton,
diphenhydramine, dextromethorphan, and triprolidine with the
1.3.3. Impurities discriminating ephedrine and pseudoephedrine
potential to form characteristic impurities. Their profiles informa-
synthetic routes
tion is not only used for monitoring the routine trends in precursor
Ephedrine and pseudoephedrine are the basic precursors
chemicals but also for the identification of the seized materials,
commonly used to synthesize MA beside the Phenyl-2-propanone
smuggling patterns, and the determination of the synthetic routes
[10,44,104,106]. A synthetic method using each of the precursor
[31,109].
chemicals is associated with specific impurities that can intelli-
Liu et al. systematically determined N1,N1, N2-trimethyl-N2-(1-
gently discriminate against the MA synthetic method. From a
phenylpropan-2-yl)ethane-1,2-diamine, which was assigned a
forensic chemist’s viewpoint, tracking the impurities down to the
characteristic impurity derived from pharmaceutical products
level of discrimination ephedrine and pseudoephedrine is an ulti-
containing ephedrine/pseudoephedrine and diphenhydramine.
mate goal. Many MA profiling methods based on ephedrine/pseu-
Unlike other pharmaceutical contaminants, the impurity is a
doephedrine end up with non-discriminatory results, deriving their
product of a reaction between MA and traces of diphenhydramine
conclusions from an unresolved analytical process.
derivative, which is co-extracted with ephedrine/pseudoephedrine.
Precursor discrimination based on identified impurities is
As a pharmaceutical co-extract of ephedrine/ephedrine derived
another interesting intelligence work. In a recent study by
diphenhydramine, the traces of the P2P precursor undergo band
Dujourdy et al. [19], 43 target impurities in MA were successfully
dissociation with HI in an I/P route to form 2-iodo-N, N-
characterized and discriminated using chemometric methods.
 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205 201

Through clustering, the impurities identified from ephedrine, complementary technique that can individualize illicit MA samples
pseudoephedrine, and benzylmethylketone. In their work, 1- based on the sources of their starting materials. Elsewhere, the
benzyl-3-methyl-naphthalene, and 1,3-dimethyl-2-phenyl-naph- method has successfully used in tracing studies in food [124,125],
thalene were used to signify a route associated with ephedrine identification of illegal migrants [126], past human activities [122],
precursor. and reconstruction of human diet [127].
Previously, N-formylmethamphetamine was considered a In forensic intelligence of illicit drugs, stable isotopes technique
route-specific impurity for Leuckart route based MA [69,110]; unveil the hidden intrinsic precursor signatures that break the
however, the impurity has recently been identified in reductive limits of the conventional impurity profiling by linking the seized
amination based route for MA [20,99]. MA and their batches to their synthetic origin [123]. Stable isotopes
A realization of this challenge was reported by Khajeamiri et al. add value to the intelligence of illicit drugs based on impurity
[106] in their work involving the reduction of ephedrine/pseu- profiling.
doephedrine with HI/red P. In their viewpoint, both ephedrine and MA produced by the same hidden laboratories, following the
pseudoephedrine react with HI/red P to form iodoephedrine, which same method with the same kind of a precursor but different
undergoes a ring-opening to form commonly used route-specific sources distinguished by examining their d13C and d15N values of
impurities; the cis and trans-1,2-dimethyl-3-phenylaziridine [73]. their precursors [104]. In this respect, the variation of stable iso-
Khajeamiri et al. articulated that 1,2-dimethyl-3- topes in seized MA can also trace the diversion of medicinal
phenylaziridine is derivatized into N-methylmethamphetamine, ephedrine for the illicit manufacture of MA.
N-ethylmethamphetamine, N-acetylmethamphetamine, acetic Illicit ephedrine based MA was initially produced through a
acid, N-benzyl-2-methylaziridine, methoxyphenyloxime ampheta- biosynthetic approach from the ephedra plant (Fig. 10(a)); however,
minil, d-proline-1-phenylmethyl-methylester N-for- a growing trend of total chemical synthesis (Fig. 10(b)) and semi-
mylmethamphetamine, and dextromethorphane. synthesis (Fig. 10(c)) have dominated the market.
Reporting N-benzyl-2-methylaziridine as an emerging impurity, The ephedrine produced through methods (a), (b) and (c) above
Khajeamiri et al. associated its formation with the conversion of will have different stable isotopic compositions used to track MA
1,2-dimethyl-3-phenylaziridine into N-benzyl-2-methylaziridine seizures. In principle, isotopic variation is due to different enrich-
during the formation of MA from ephedrine and pseudoephedrine. ment factors during the biochemical synthesis of raw materials for
Additionally, Khajeamiri et al. reported for the first time in 2012 the precursor chemicals as well as the isotopic fractionation during
the presence of Chlorpheniramine as a pharmaceutical-based im- the synthetic processes [60]. Although chemical synthesis a reliable
purity in MA. The impurity was later reported in Korea (2013) source of ephedrine, the extraction from natural sources is another
[31,49] and Iran [111]. The reports associated the impurity with potential source for clandestine laboratories [104]. Therefore, an
pharmaceutical tablets used to synthesize pseudoephedrine pre- integrated approach with intelligence information collected
cursors. Because chlorpheniramine is co-ingredient of pseudoe- beyond the starting materials is key to linking the operation of the
phedrine tables only [49], it discriminates ephedrine and criminal networks.
pseudoephedrine based MA. A complementary study on the use of stable isotopes techniques
in evaluating the links between different MA seizures was reported
1.3.4. Emerging signatures from stable isotopes by Iwata et al. [112] Benson et al. [36] and Billault et al. [123]. In a
Stable isotopes composition in a MA sample has recently been study by Billault et al., a variation of d13C and d15N was used to
used to profile MA seized in the USA [92] and Japan [112]. The cluster seized MA and successfully established a link between
technique employs natural abundance stable d13C, d12C, d15N, d14N, different MA cases. The study successfully discriminated against
d2H, d1H and, d16O, d17O, d18O and d32S, d33S, d34S, d36S compositions semi-synthetic ephedrine from bio-synthetic or synthetic ephed-
in samples to establish chemical signatures for evaluating the links rine by using d13C. However; based on the fact the d13C values of
between MA seizures and their production batches [113e116]. The acetaldehyde from sugar are more optimistic compared to C3-
isotopes have specific natural rations; however, compartmental photosynthetic plants or products derived from petroleum, it could
isotope ratios vary as per the geographical origin of the source [36] not differentiate biosynthetic ephedrine from synthetic ephedrine.
which is the basis for MA profiling based on stable isotopes. Recently, a stable isotopes technique was used to investigate the
The stable isotope ratio presented in delta values, d in per mill unique profiles of stable nitrogen isotopic composition in seized
where (“mil” ¼ 1000), written ‰). The calculation of delta value as MA samples [128]. In this work, the stable isotopes variation can be
proposed by Barrie [117] is shown in the equation below. due to the isotopic variations in the starting materials, isotopic
fractionation during the synthetic processes, and due to analytical
d ¼ 1000(Rsample-Rstandard)Rstandard [117] errors. It is therefore essential to draw a conclusion based on the
magnitude of the variation to eliminate the influence of isotopic
Where RSample represents the ratio of the heavy to the light isotope fractionation and analytical errors. A variation of 0.9‰ d15N evi-
measured for the sample while RStandard is the equivalent ratio for denced a difference in batches of production and subsequently,
the standard. different ephedrine sources used as starting materials for the pro-
Although the conventional analytical techniques through the duction of MA. Iwata et al. [128] further used the stable isotope
existing GC [98], HPLC [110], GC-MS [33], and LC-MS-MS, ICP-MS technique to classify the MA seizures based on their synthetic
[118e120], NMR [33,120] have been very effective in determining batches. Based on the criteria proposed by Iwata et al. [128],
the type of precursor chemicals [100,121] synthetic route [16], and Dd < 0.4‰ represents a significant variation in batches.
adulteration of illicit MA [28,48,54,122]; it has not been able to Interestingly, stable isotope technology is making an in-road
discriminate the precursors produced by different methods in the towards the discrimination of illicit synthetic/semi-synthetic
sense of identifying their origins. Furthermore, reductive amination illegal drugs based on their synthetic routes and their associated
routes usually have few impurity profiles that may not grant a reactions conditions beyond its conventional use in discriminating
successful impurity profiling [114]. The conventional techniques are the sources for MA. As a growing profiling method, it complements
also ineffective in traceability beyond sources of the starting ma- the impurity profiling by linking the synthetic routes to isotopes
terials [123]. ratios.
In such circumstances, stable isotope analysis is a Billault et al. reported startling scientific research that seems to
202 I. Onoka et al. / Forensic Science International: Synergy 2 (2020) 194e205

Fig. 10. Different sources of ephedrine: (a) extraction from ephedra plant, (b) chemosynthesis, (c) semi-synthesis.

confirm the use of stable isotopes in linking MA batches to their MA, drug markets, and the advances of the criminal networks,
respective synthetic routes. These results were the first to be re- future research is indispensable. Future research should focus on
ported in linking the d13C values of the precursors in distinguishing the diversity of both licit and illicit starting materials, com-
synthetic routes of seized MA and their derivatives. Having inves- plementing impurity profiling with stable isotopes, building
tigated the relationship between d13C and d15N of the precursors knowledge with regards to the newly identified MA profiles, and
and those of 45 samples of MDMA, the authors demonstrated how finally; coupling the methods with chemometric techniques.
the number of synthesis steps influenced the value of d13C in the
seized MA samples and consequently discriminated the synthetic CRediT authorship contribution statement
routes possessing more than one step.
Similarly, the discrimination of synthetic routes using stable Isaac Onoka: Conceptualization, Writing - original draft.
isotopes is established by comparing the d15N values of the origin Andrew Toyi Banyika: Writing - review & editing. Protibha Nath
precursors and the seized MA. The values of d15N in MA are Banerjee: Supervision. John J. Makangara: Supervision, Writing -
dependent on the source of nitrogen used, the route by which the review & editing. Laurence Dujourdy: Resources, Writing - review
MDMA is synthesized [114,115], and the experimental conditions & editing.
employed [116,123,129].
Previous work by Billault et al. discriminated MA based on their Declaration of competing interest
synthetic origins, synthetic routes as well a close variation of the
stable isotopes based reaction conditions of MA tested. The authors declare that there is no conflict of interest.

Acknowledgment
2. Conclusion
Thanks to the University of Dodoma, Tanzania for allowing the
In this review, we have discussed the impurities and stable
ongoing study on the profiling of methamphetamine. We would
isotopes signatures found in illicit MA. The signatures are critical in
also like to thank Dr. Mellony Manning for proofreading and
the intelligence of illegal drugs, linking the illegal drugs with their
checking the language.
sources, synthetic methods, synthetic batches, and their
geographical origin. Although stable isotopes have been influential
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