Synthetic origin of illicit methylamphetamine in Australia: 2011-2020.

The National Measurement Institute's Methylamphetamine Profiling Program has evolved over the last 15 years to address analytical challenges faced with changes in illicit methylamphetamine production. The program involves organic and inorganic analysis of methylamphetamine to determine the precursors and synthetic route used in manufacture. This paper discusses changes in the methylamphetamine chemical profile for samples received at this laboratory during January 2011 to December 2020. In particular, changes observed in the methylamphetamine purity, potency, synthetic route, precursor and precursor synthetic origin are discussed. Over 13,180 samples were analysed during this period consisting of samples seized on the streets and the Australian border. This paper shows correlations between methylamphetamine seizures at the Australian border with international clandestine laboratory and precursor seizures trends. As the illicit drug landscape changes so too must our approach to chemical profiling if we are to confidently determine the synthetic origin of methylamphetamine.

Investigations into the stable isotope ratios of 1-phenyl-2-propanone.

Stable isotope ratio mass spectrometry (IRMS) can be used to determine the precursor and precursor origin of methylamphetamine drug samples. Previous work has shown that methylamphetamine samples can be distinguished as derived from different sources of (pseudo)ephedrine or phenyl-2-propanone (P2P) through the use of IRMS alongside conventional chemical profiling techniques. To date, limited research has been conducted to investigate whether methylamphetamine samples of differing P2P origins can be distinguished through drug profiling. This was investigated by synthesising methylamphetamine in-house in a three-step process. Two 'preprecursors' were used in this study, phenylacetic acid (PAA) and α-phenylacetoacetonitrile (α-PAAN). Using a combination of profiling techniques, it was found that methylamphetamine samples of PAA preprecursor origin and methylamphetamine samples of α-PAAN preprecursor origin can be distinguished.

Authenticity and geographic origin of global honeys determined using carbon isotope ratios and trace elements.

Honey is the world's third most adulterated food. The addition of cane sugar or corn syrup and the mislabelling of geographic origin are common fraudulent practices in honey markets. This study examined 100 honey samples from Australia (mainland and Tasmania) along with 18 other countries covering Africa, Asia, Europe, North America and Oceania. Carbon isotopic analyses of honey and protein showed that 27% of commercial honey samples tested were of questionable authenticity. The remaining 69 authentic samples were subject to trace element analysis for geographic determination. One-way ANOVA analysis showed a statistical difference (p < 0.05) in trace element concentrations of honey from Australian regions and different continents. Principal component analysis (PCA) and canonical discriminant analysis (CDA) coupled with C5.0 classification modelling of honey carbon isotopes and trace element concentrations showed distinct clusters according to their geographic origin. The C5.0 model revealed trace elements Sr, P, Mn and K can be used to differentiate honey according to its geographic origin. The findings show the common and prevalent issues of honey authenticity and the mislabelling of its geographic origin can be identified using a combination of stable carbon isotopes and trace element concentrations.

Enantiomeric resolution of methylamphetamine and ephedrine: Does this affect the δ13 C, δ15 N, and δ2 H stable isotope ratios of the product?

The use of stable isotope ratio mass spectrometry (IRMS) as a profiling tool for methylamphetamine has evolved over the last decade. Stable isotope ratios of carbon (δ13 C), nitrogen (δ15 N), and hydrogen (δ2 H) of methylamphetamine are useful in determining the precursor used to manufacture methylamphetamine, and in many cases the synthetic origin of the methylamphetamine precursor. More recently, samples of seized methylamphetamine show that a resolution step is being employed in the manufacturing process. We sought to determine whether the δ13 C, δ15 N, and δ2 H values were affected by either a resolution performed on racemic methylamphetamine or a resolution on racemic ephedrine, a commonly used precursor to methylamphetamine. We found that for the types of resolution studied, IRMS is still able to provide useful information on the provenance of a methylamphetamine sample.

Profiling ephedrine prepared from N-methylalanine via the Akabori-Momotani reaction.

Novel methods for synthesising methylamphetamine precursors are appearing in clandestine laboratories within Australia. One such laboratory involved the synthesis of ephedrine from N-methylalanine and benzaldehyde via the Akabori-Momotani reaction. This article presents chiral and stable isotope ratios of ephedrine synthesised via this method, along with a chemical profile of methylamphetamine produced from this ephedrine. Based on the chiral results and the δ13 C, δ15 N, and δ2 H values, it is possible to distinguish ephedrine made via the Akabori-Momotani reaction from ephedrine of a "natural", "semi-synthetic", or "fully-synthetic" origin. Methylamphetamine and ephedrine samples synthesised from benzaldehyde having an enriched δ2 H value (ie, > 0‰), via the Akabori-Momotani reaction, had an isotopic profile which set them apart from all other methylamphetamine samples. It was noted, however, that using stable isotope ratios alone to determine the precursor of methylamphetamine is limited; they could not with confidence differentiate between methylamphetamine and ephedrine synthesised from benzaldehyde having a depleted δ2 H value (ie, <0‰) from other ephedrine sources and phenyl-2-propanone based methylamphetamine samples profiled.

Identification and characterization of N-tert-butoxycarbonyl-MDMA: a new MDMA precursor.

In September 2015, 80 litres of a viscous, light-red liquid, described as hair product, was seized by the Australian Border Force (ABF). Initial testing by ABF indicated that the liquid was the 3,4-methylenedioxymethamphetamine (MDMA) precursor chemical safrole and custody of the material was transferred to the Australian Federal Police (AFP) who coordinated all subsequent investigations. Initial gas chromatography-mass spectrometry (GC-MS) analysis by the AFP indicated that the material was not safrole and samples of the liquid were transferred to the National Measurement Institute Australia (NMIA) for identification. Using a combination of nuclear magnetic resonance spectroscopy (NMR), GC-MS, infrared spectroscopy, and synthesis, the unknown substance was identified as N-tert.-butoxycarbonyl-MDMA (t-BOC-MDMA). The substance was also converted in high yield to MDMA (aqueous HCl, 80 °C, 30 min). The possibility that the t-BOC-MDMA may act as a pro-drug following ingestion was explored by exposure to simulated gastric juice (pH 1.5) and monitored by NMR (37 °C) at various intervals. The majority of t-BOC-MDMA was converted to MDMA after 305 min, which suggested that this derivatized form might serve as a pro-drug in vivo. An investigation into the chemistry of potential pro-drugs showed that t-BOC derivatives of methamphetamine, pseudoephedrine and 4-methylmethcahtinone (mephedrone) could also be prepared using di-tert.-butyl dicarbonate. The appearance of t-BOC-derivatives on the drug market requires further monitoring. © 2016 Commonwealth of Australia. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.

Cathinones: Isotopic profiling as an aid to linking seizures.

The number of cathinone derivatives available to the street market has increased steadily since 2008. Many of these compounds have proven to be potent psychostimulants and fatalities have occurred through their recreational use. The method of manufacture is essentially the same for each cathinone, i.e., (i) selection of the appropriate ß-ketoarylalkane, (ii) bromination alpha to the keto group, followed by (iii) amination using the desired amine. The cathinone derivatives are usually prepared at a very high purity and little information is available from an organic manufacturing by-products profile because the product is so pure. To provide law enforcement agencies with a tool that would enable links to be identified between samples from the same production batch, the carbon, hydrogen, and nitrogen stable isotope ratios in a number of cathinones were investigated. The aim was to determine if sufficient diversity existed in the light element stable isotope ratios of cathinones to allow the isotopic ratios to be used to discriminate between different seizures and to assist in linking samples from the same seizure. Careful measurement of the δ(13) C, δ(15) N, and δ(2) H values in each sample revealed that the stable isotope ratios for a particular cathinone analogue vary from one seizure to another. In the seizures studied, carbon, hydrogen, and nitrogen stable isotope ratios were found to vary from -32.8‰ to -26.1‰, -152‰ to +72‰, and -16.6‰ to -2.7‰, respectively. Copyright © 2015 John Wiley & Sons, Ltd.

A review of some recent studies on the stable isotope profiling of methylamphetamine: Is it a useful adjunct to conventional chemical profiling?

This paper reviews a body of work published by the authors over a number of years aimed at providing a complementary "signature" to conventional chemical profiling of methylamphetamine. The work, beginning in 2009, was undertaken because of the changing nature of clandestine methylamphetamine manufacture which has seen a dramatic rise in production and a major shift to a higher quality product. As manufacturing methods changed and methylamphetamine purity increased some conventional drug profiling techniques became less useful as an intelligence tool. For instance, the value of the organic impurity profile, a mainstay of conventional profiling, decreases as there are fewer impurities present in seized samples. However, whilst many seizures may contain less conventional chemical intelligence another property of the methylamphetamine molecule is always available, i.e. the light element stable isotope ratios. The stable isotope ratios of carbon, hydrogen and nitrogen are an integral part of the methylamphetamine molecule itself. This review describes previous work by the authors and by researchers in other national laboratories to investigate and implement the use of stable isotope ratios as an everyday methylamphetamine profiling tool. It also looks at how powerful this technique can be when used to compare samples from different seizures.

Measurement of stable isotope ratios in methylamphetamine: a link to its precursor source.

The illicit drug methylamphetamine is often prepared from the precursor ephedrine or pseudoephedrine, which in turn are obtained by three processes: extraction from the Ephedra plant ("natural"), via fermentation of sugars ("semi-synthetic"), and by a "fully synthetic" route from propiophenone. We report the first method to differentiate between the three industrial routes used to produce the precursors ephedrine and pseudoephedrine by measurement of stable isotope ratios of nitrogen (δ(15)N), hydrogen (δ(2)H), and carbon (δ(13)C). Analysis of 782 samples of seized methylamphetamine allowed classification into three groups using k-means clustering or the expectation-maximization algorithm applied to a Gaussian mixture model. By preparation of 30 samples of ephedrine by the "fully synthetic" industrial process and measuring their δ(15)N, δ(2)H, and δ(13)C values, we observed that (15)N becomes significantly depleted compared to the methylamine starting material. Conversion of ten ephedrine samples to methylamphetamine showed that this depletion is maintained in the final drug product, of which the δ(15)N, δ(13)C, and δ(2)H values were distinct from those of ephedrine and methylamphetamine samples of a semi-synthetic (fermentation pathway) origin. Combining modeling analysis with the new experiments and published information on the values of δ(2)H gave a definitive assignment of the three model groups, and equations to obtain probabilities for the precursor origin of any new sample. A simple rule of thumb is also presented. Making an assignment using delta values is particularly useful when no other chemical profiling information is available.

Methylamphetamine synthesis: does an alteration in synthesis conditions affect the δ(13) C, δ(15) N and δ(2) H stable isotope ratio values of the product?

Conventional chemical profiling of methylamphetamine has long been employed by national forensic laboratories to determine the synthetic route and where possible the precursor chemicals used in its manufacture. This laboratory has been studying the use of stable isotope ratio mass spectrometry (IRMS) analysis as a complementary technique to conventional chemical profiling of fully synthetic illicit drugs such as methylamphetamine. As part of these investigations the stable carbon (δ(13) C), nitrogen (δ(15) N), and hydrogen (δ(2) H) isotope values in the precursor chemicals of ephedrine and pseudoephedrine and the resulting methylamphetamine end-products have been measured to determine the synthetic origins of methylamphetamine. In this study, results are presented for δ(13) C, δ(15) N, and δ(2) H values in methylamphetamine synthesized from ephedrine and pseudoephedrine by two synthetic routes with varying experimental parameters. It was demonstrated that varying parameters, such as stoichiometry, reaction temperature, reaction time, and reaction pressure, had no effect on the δ(13) C, δ(15) N, and δ(2) H isotope values of the final methylamphetamine product, within measurement uncertainty. Therefore the value of the IRMS technique in identifying the synthetic origin of precursors, such as ephedrine and pseudoephedrine, is not compromised by the potential variation in synthetic method that is expected from one batch to the next, especially in clandestine laboratories where manufacture can occur without stringent quality control of reactions.

delta(13)C and delta(2)H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane.

Previous work in these laboratories and by Butzenlechner et al. and Culp et al. has demonstrated that the delta(2)H isotope value of industrial benzaldehyde produced by the catalytic oxidation of toluene is profoundly positive, usually in the range +300 per thousand to +500 per thousand. Synthetic routes leading to amphetamine, methylamphetamine or their precursors and commencing with such benzaldehyde may be expected to exhibit unusually positive delta(2)H values. Results are presented for delta(13)C and delta(2)H isotope values of 1-phenyl-2-nitropropene synthesized from an industrial source of benzaldehyde, having a positive delta(2)H isotope value, by a Knoevenagel condensation with nitroethane. Results are also presented for delta(13)C and delta(2)H isotope values for amphetamine prepared from the resulting 1-phenyl-2-nitropropene. The values obtained were compared with delta(13)C and delta(2)H isotope values obtained for an amphetamine sample prepared using a synthetic route that did not involve benzaldehyde. Finally, results are presented for samples of benzaldehyde, 1-phenyl-2-nitropropene and amphetamine that had been seized at a clandestine amphetamine laboratory.

Isolation and identification of three by-products found in methylamphetamine synthesized by the Emde route.

This article describes the isolation and structural elucidation of three compounds produced during the synthesis of methylamphetamine by the so-called "Emde" procedure. The "Emde" procedure involves the preparation of the intermediate chloropseudoephedrine or chloroephedrine from ephedrine or pseudoephedrine, respectively. The intermediates are then reduced to methylamphetamine with hydrogen under pressure in the presence of a catalyst. The by-product compounds were isolated from methylamphetamine by column chromatography and liquid chromatography (LC). Proton nuclear magnetic resonance spectroscopy ((1)H NMR), carbon nuclear magnetic resonance spectroscopy ((13)C NMR), and nanospray quadrupole-time of flight-mass spectrometry (Q-TOF-MS) were used to identify them as two stereoisomers of the compound N, N'-dimethyl-3,4-diphenylhexane-2,5-diamine and N-methyl-1-{4-[2-(methylamino)propyl]phenyl}-1-phenylpropan-2-amine.

Delta(13)C, delta(15)N and delta(2)H isotope ratio mass spectrometry of ephedrine and pseudoephedrine: application to methylamphetamine profiling.

Conventional chemical profiling of methylamphetamine has been used for many years to determine the synthetic route employed and where possible to identify the precursor chemicals used. In this study stable isotope ratio analysis was investigated as a means of determining the origin of the methylamphetamine precursors, ephedrine and pseudoephedrine. Ephedrine and pseudoephedrine may be prepared industrially by several routes. Results are presented for the stable isotope ratios of carbon (delta(13)C), nitrogen (delta(15)N) and hydrogen (delta(2)H) measured in methylamphetamine samples synthesized from ephedrine and pseudoephedrine of known provenance. It is clear from the results that measurement of the delta(13)C, delta(15)N and delta(2)H stable isotope ratios by elemental analyzer/thermal conversion isotope ratio mass spectrometry (EA/TC-IRMS) in high-purity methylamphetamine samples will allow determination of the synthetic source of the ephedrine or pseudoephedrine precursor as being either of a natural, semi-synthetic, or fully synthetic origin.

N-cyanomethyl-N-methyl-1-(3',4'-methylenedioxyphenyl)-2-propylamine: an MDMA manufacturing by-product.

This paper describes the structural elucidation of a compound produced during the synthesis of 3,4-methylenedioxymethylamphetamine (MDMA) via the reductive amination of 3,4-methylenedioxyphenyl-2-propanone (3,4-MDP-2-P) with methylamine and sodium cyanoborohydride. The compound was isolated from MDMA by column chromatography, proton and carbon nuclear magnetic resonance spectroscopy, LC/mass spectrometry, and total synthesis were used to identify the compound as N-cyanomethyl-N-methyl-1-(3',4'-methylenedioxyphenyl)-2-propylamine. This compound has been identified as a potential synthetic route marker for the reductive amination of 3,4-MDP-2-P with methylamine and sodium cyanoborohydride and as such it should prove valuable to forensic scientists engaged in profiling illicit drugs. Profiling MDMA can provide useful information to law enforcement agencies relating to synthetic route, precursor chemicals and reagents employed and may be used for comparative analyses of different drug seizures. This paper also describes the structural elucidation of the analogous methylamphetamine synthetic route marker compound, N-cyanomethyl-N-methyl-1-phenyl-2-propylamine, produced during the reductive amination of phenyl-2-propanone using methylamine and sodium cyanoborohydride.