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With synthetic cannabinoid receptor agonist (SCRA) use still prevalent across Europe and structurally advanced generations emerging, it is imperative that drug detection methods advance in parallel. SCRAs are a chemically diverse and evolving group, which makes rapid detection challenging. We have previously shown that fluorescence spectral fingerprinting (FSF) has the potential to provide rapid assessment of SCRA presence directly from street material with minimal processing and in saliva. Enhancing the sensitivity and discriminatory ability of this approach has high potential to accelerate the delivery of a point-of-care technology that can be used confidently by a range of stakeholders, from medical to prison staff. We demonstrate that a range of structurally distinct SCRAs are photochemically active and give rise to distinct FSFs after irradiation. To explore this in detail, we have synthesized a model series of compounds which mimic specific structural features of AM-694. Our data show that FSFs are sensitive to chemically conservative changes, with evidence that this relates to shifts in the electronic structure and cross-conjugation. Crucially, we find that the photochemical degradation rate is sensitive to individual structures and gives rise to a specific major product, the mechanism and identification of which we elucidate through density-functional theory (DFT) and time-dependent DFT. We test the potential of our hybrid "photochemical fingerprinting"approach to discriminate SCRAs by demonstrating SCRA detection from a simulated smoking apparatus in saliva. Our study shows the potential of tracking photochemical reactivity via FSFs for enhanced discrimination of SCRAs, with successful integration into a portable device.

Rapid analysis of surrendered or seized drug samples provides important intelligence for health (e.g. treatment or harm reduction), and custodial services. Herein, three in-situ techniques, GC-MS, 1H NMR and FT-IR spectroscopy, with searchable libraries, are used to analyse 318 samples qualitatively, using technique specific library-based searches, obtained over the period 24th – 29th August 2019. 259 samples were identified as consisting of a single component, of which cocaine was the most prevalent (n = 158). Median match scores for all three techniques were ≥ 0.84 and showed agreement except for metformin (n = 1), oxandrolone (identified as vitamin K by IR (n = 4)), diazepam (identified as zolpidem by FT-IR (n = 2)) and 2-Br-4,5-DMPEA (n = 1), a structural isomer of 2C-B identified as a polymer of cellulose (cardboard) by FT-IR. 51 samples were found to consist of two or more components, of which 49 were adulterated cocaine samples (45 binary and 4 tertiary samples). GC-MS identified all components present in the 49 adulterated cocaine samples, whereas IR identified only cocaine in 88 % of cases (adulterant only = 12 %). The breakdown for 1H NMR spectroscopy was all components identified (51 %), cocaine only (33 %), adulterant only (10 %), cocaine and one adulterant (tertiary mixtures only, 6 %).

Amphetamine and cathinone derivatives are abused recreationally due to the sense of euphoria they provide to the user. Methodologies for the rapid detection of the drug derivative present in a seized sample, or an indication of the drug class, are beneficial to law enforcement and healthcare providers. Identifying the drug class is prudent because derivatisation of these drugs, to produce regioisomers, for example, occurs frequently to circumvent global and local drug laws. Thus, newly encountered derivatives might not be present in a spectral library. Employment of benchtop nuclear magnetic resonance (NMR) could be used to provide rapid analysis of seized samples as well as identifying the class of drug present. Discrimination of individual amphetamine-, methcathinone-, N-ethylcathinone and nor-ephedrine-derived fluorinated and methylated regioisomers is achieved herein using qualitative automated 1 H NMR analysis and compared to gas chromatography-mass spectrometry (GC-MS) data. Two seized drug samples, SS1 and SS2, were identified to contain 4-fluoroamphetamine by 1 H NMR (match score median = 0.9933) and GC-MS (RRt = 5.42-5.43 min). The amount of 4-fluoroamphetamine present was 42.8%-43.4% w/w and 48.7%-49.2% w/w for SS1 and SS2, respectively, from quantitative 19 F NMR analysis, which is in agreement with the amount determined by GC-MS (39.9%-41.4% w/w and 49.0%-49.3% w/w). The total time for the qualitative 1 H NMR and quantitative 19 F NMR analysis is ~10 min. This contrasts to ~40 min for the GC-MS method. The NMR method also benefits from minimal sample preparation. Thus, benchtop NMR affords rapid, and discriminatory, analysis of the drug present in a seized sample.

This study describes the first reported development of a rapid, generic gradient Ultra-High Performance Liquid Chromatography (UHPLC) methodology with targeted triple quadrupole MS/MS using electrospray positive ionisation to detect and unambiguously confirm the identity of 33 substituted 1, 2-diarylethamine (or diphenidine) derivatives in solid drug samples. The in-house synthesised library included a range of derivatives possessing either electron donating/withdrawing substituents, commonly included in combinatorial libraries, of varying size and lipophilicity on the phenyl ring. These test probes were used to investigate if their order of elution and that of their regioisomers were dependent on the position and type of the substituent on the phenyl ring. In addition, investigations into the retention mechanism of the diphenidines under reverse-phase UHPLC conditions were undertaken. Common adulterants found within seized bulk samples were assessed to prove that the methodology was specific, and the developed UHPLC-MS/MS (t G = 10 min) protocol was applied to confirm the identity of the psychoactive components within four seized bulk samples provided by law enforcement.

Rapid analysis of surrendered or seized drug samples provides important intelligence for health (e.g. treatment or harm reduction), and custodial services. Herein, three in-situ techniques, GC-MS

Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC50, 11.5 nM and ADB-4en-PINACA (EC50, 11.6 nM) are similar to that of MDMB-4en-PINACA (EC50, 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation. Funding Agencies|Linkopings Universitet; Dubai Police Force [2427681]; Leverhulme TrustLeverhulme Trust [RC-2015-01]; Scottish Prison Service [01865]; Linkoping University; VINNOVAVinnova [2019-03566]; European CommissionEuropean CommissionEuropean Commission Joint Research Centre [E! 113377]

According to the World Drugs Report (2019) from the United Nations on Drugs and Crime there were over half a million drug related deaths, 35 million people were treated for drug use disorders across the globe, and it is estimated that more than 270 million people used drugs during 2017. Lab-on-a-Chip (LOC) technology is an increasingly popular choice of detection method for drugs of abuse. We systematically reviewed the published literature available on LOC methods for the detection of drugs of abuse including New Psychoactive Substances (NPS) from January 1999 to March 2021 and identified 45 publications. A total of 28 different drugs of abuse were investigated, with cocaine the most widely studied (58%). The LOC devices were capable of accepting a wide range of biological and non-biological samples. A total of 18 countries have been involved in LOC research into detection of drugs of abuse, with locations generally following local trends in drug use. LOC devices employed a range of detection methods with immunoassays most commonly incorporated (34%). Recommendations are made for expanding the use of real-world samples, improved validation and further analysis of practicality (in terms of providing information on cost, speed of analysis and ease of use). More than a third of all the publications included in this review were published since 2019, representing a recent increase in research using LOC devices for the detection of drugs of abuse. There is currently an extensive range of LOC approaches available offering potential for these devices as cost-effective, rapid and portable detection systems.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via 19Fluorine magnetic resonance spectroscopy (19F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver 19F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via

Fentanyl, also known as ‘jackpot’, is a synthetic opiate that is 50–100 times more potent than morphine. Clandestine laboratories produce analogues of fentanyl, known as fentalogues to circumvent legislation regarding its production. Three pyridyl fentalogues were synthesized and then hyperpolarized by signal amplification by reversible exchange (SABRE) to appraise the forensic potential of the technique. A maximum enhancement of ‐168‐fold at 1.4 T was recorded for the ortho pyridyl 1H nuclei. Studies of the activation parameters for the three fentalogues revealed that the ratio of ligand loss trans to hydride and hydride loss in the complex [Ir(IMes)(L)3(H)2]+ (IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene) ranged from 0.52 to 1.83. The fentalogue possessing the ratio closest to unity produced the largest enhancement subsequent to performing SABRE at earth's magnetic field. It was possible to hyperpolarize a pyridyl fentalogue selectively from a matrix that consisted largely of heroin (97 : 3 heroin:fentalogue) to validate the use of SABRE as a forensic tool., No more hiding for pyridyl fentalogues! The hyperpolarization technique SABRE (signal amplification by reversible exchange) is utilised for the successful enhancement of 1H NMR signals of pyridyl functionalised fentalogues. We further demonstrate the successful selective polarization of one the fentalogues against a strong background‐signal of heroin.

The emergence of a new class of novel psychoactive substances, N-benzyl-substituted phenethylamine derivatives so-called “NBOMes” or “Smiles”, in the recreational drug market has forced the development of new sensitive analytical methodologies for their detection and quantitation. NBOMes’ hallucinogenic effects mimic those of the illegal psychedelic drug lysergic acid diethylamide (LSD) and are typically sold as LSD on blotter papers, resulting in a remarkable number of fatalities worldwide. In this article, four halide derivatives of NBOMe, namely, 2-(4-fluoro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine, 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2- methoxybenzyl)ethan-1-amine, and 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine, were detected and quantified simultaneously using a high-performance liquid chromatographic method, and two detection systems were compared: photodiode array detection (detection system I) and amperometric detection via a commercially available impinging jet flow-cell system incorporating embedded graphite screen-printed macroelectrodes (detection system II). Under optimized experimental conditions, linear calibration plots were obtained in the concentration range of 10−300 and 20−300 μg mL−1 , for detection systems I and II, respectively. Detection limit (limit of detection) values were between 4.6−6.7 and 9.7−18 μg mL−1, for detection systems I and II, respectively. Both detectors were employed for the analysis of the four NBOMe derivatives in the bulk form, in the presence of LSD and adulterants commonly found in street samples (e.g. paracetamol, caffeine, and benzocaine). Furthermore, the method was applied for the analysis of simulated blotter papers, and the obtained percentage recoveries were satisfactory, emphasizing its advantageous applicability for the routine analysis of NBOMes in forensic laboratories.

[Image: see text] An automated approach to the collection of (1)H NMR (nuclear magnetic resonance) spectra using a benchtop NMR spectrometer and the subsequent analysis, processing, and elucidation of components present in seized drug samples are reported. An algorithm is developed to compare spectral data to a reference library of over 300 (1)H NMR spectra, ranking matches by a correlation-based score. A threshold for identification was set at 0.838, below which identification of the component present was deemed unreliable. Using this system, 432 samples were surveyed and validated against contemporaneously acquired GC–MS (gas chromatography–mass spectrometry) data. Following removal of samples which possessed no peaks in the GC–MS trace or in both the (1)H NMR spectrum and GC–MS trace, the remaining 416 samples matched in 93% of cases. Thirteen of these samples were binary mixtures. A partial match (one component not identified) was obtained for 6% of samples surveyed whilst only 1% of samples did not match at all.

Mirfentanil, a fentanyl derivative that is a μ-opioid partial agonist, is hyperpolarised via Signal Amplification By Reversible Exchange (SABRE), a para-hydrogen-based technique. [Ir(IMes)(COD)Cl] (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene, COD=cyclooctadiene) was employed as the polarisation transfer catalyst. Following polarisation transfer at 6.5 mT, the pyrazine-protons were enhanced by 78-fold (polarisation, P=0.04 %). The complex [Ir(IMes)(H) (mirfentanil) (MeOH)] is proposed to form based on the observation of two hydrides at δ −22.9 (trans to mirfentanil) and −24.7 (trans to methanol). In a mixture of mirfentanil and heroin, the former could be detected using SABRE at concentrations less than 1 % w/w. At the lowest concentration analyzed, the amount of mirfentanil present was 0.18 mg (812 μM) and produced a signal enhancement of −867-fold (P=0.42 %). following polarisation transfer at 6.5 mT. 2 2 +

Amphetamine and cathinone derivatives are abused recreationally due to the sense of euphoria they provide to the user. Methodologies for the rapid detection of the drug derivative present in a seized sample, or an indication of the drug class, are beneficial to law enforcement and healthcare providers. Identifying the drug class is prudent because derivatisation of these drugs, to produce regioisomers, for example, occurs frequently to circumvent global and local drug laws. Thus, newly encountered derivatives might not be present in a spectral library. Employment of benchtop nuclear magnetic resonance (NMR) could be used to provide rapid analysis of seized samples as well as identifying the class of drug present. Discrimination of individual amphetamine-, methcathinone-, N-ethylcathinone and nor-ephedrine-derived fluorinated and methylated regioisomers is achieved herein using qualitative automated

Supercritical Fluid Chromatography (SFC-UV) employing a carbon dioxide (CO 2) and 10 mM ammonium acetate in MeOH-water (95:5 v/v) gradient provides a rapid analysis (t G

Fluorinated fentanyl regioisomers have become increasingly common in forensic casework. This study reports the synthesis of eight fluorinated fentanyl derivatives as pure reference materials and their complete NMR, infrared and mass spectral characterisation. Presumptive colour tests and TLC results are presented as an initial screening method for these compounds. The fully validated GC–MS method (employing SIM mode) allows the quantification of the target analytes (LOD = 9 – 20 ng/mL, LOQ = 31 – 67 ng/mL), fentanyl, heroin, acetaminophen and caffeine, within 13 minutes. In most cases, the regioisomeric fluorofentanyls were resolved from each other except for the 3’- and 4’-fluorinated derivatives (5b and 5c). To achieve full separation, an orthogonal benchtop 19F NMR method allows the identification and quantification of target analogues (LOD = 74 – 400 μg/mL, LOQ = 290 – 1340 μg/mL). The 19F NMR method allows the detection of fluorinated fentanyl analogues at a low concentration (2.4% w/w) in heroin.

Synthetic cannabinoid receptor agonists (SCRAs) elicit many of their psychoactive effects via type‐1 human cannabinoid (CB1) receptors. Enantiomer pairs of eight tert‐leucinate or valinate indole‐ and indazole‐3‐carboxamide SCRAs were synthesized and their CB1 potency and efficacy assessed using an in vitro β‐arrestin recruitment assay in a HEK239T stable cell system. A chiral high‐performance liquid chromatography method with photodiode array and/or quadrupole‐time of flight mass spectrometry detection (HPLC‐PDA and HPLC‐PDA‐QToF‐MS) was applied to 177 SCRA infused paper samples seized in Scottish prisons between 2018 and 2020. In most samples, SCRAs were almost enantiopure (S)‐enantiomer (>98% of total chromatographic peak area), although in some (n=18), 2 to 16% of the (R)‐enantiomer was detected. (S)‐enantiomers are consistently more potent than (R)‐enantiomers and often more efficacious. The importance of SCRA‐CB1 receptor interactions in the ‘head’ or ‘linked group’ moiety is demonstrated, with the conformation of the ‘bulky’ tert‐leucinate group greatly affecting potency (by up to a factor of 374), significantly greater than the difference observed between valinate SCRA enantiomers. (S)‐MDMB‐4en‐PINACA, (S)‐4F‐MDMB‐BINACA and (S)‐5F‐MDMB‐PICA are currently the most prevalent SCRAs in Scottish prisons and all have similar high potency (EC50, 1‐5 nM) and efficacy. Infused paper samples were compared using estimated intrinsic efficacy at the CB1 receptor (EIECB1) to evaluate samples with variable SCRA content. Given their similar potency and efficacy, any variation in CB1‐receptor mediated psychoactive effects are likely to derive from variation in dose, mode of use, pharmacokinetic differences and individual factors affecting the user, rather than differences in the specific SCRA present.

Recreational MDMA use is a worldwide problem. Tablet dosage varies, thus entailing a requirement for quantitative analysis. The quantification of MDMA in tablets using benchtop 1H NMR spectroscopy via either linear regression (‘manual’ method) or partial least square regression (‘automated’ method) approaches are reported, without the need for an internal standard, and compared against contemporaneously obtained GC–MS data. Twenty samples were evaluated of which 15 were proven to contain MDMA, via qualitative NMR (hit score ≥ 0.97) and GC–MS (Rt = 5.6 min) analysis. Quantitative NMR analysis showed that the mean value of MDMA content was 42.6% w/w by the manual method and 45.9% w/w by the automated method. The mean value obtained from GC analysis was 44.0% w/w. A substantial proportion (n = 9) of the tablets tested possessed > 190 mg of MDMA (range 133–223 mg, average of all techniques’ calculations for each tablet). This value is higher than the reported average MDMA content of tablets by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), which was ca. 125 mg of MDMA per tablet in 2016.

Over recent years there has been a progressive increase in the adulteration of common illicit street drugs, such as heroin and cocaine, with fentanyl and its derivatives (fentalogues) being the cause of over doses ending with fatal repercussions. Consequently, there is a need for the development of sensitive, selective and reliable analytical protocols for their separation and quantification. Herein, we report for the first time, a combination of high-performance liquid chromatography with a dual-diode array and electrochemical (amperometric) detector achieved for the simultaneous detection and quantification of heroin (HRN), fentanyl and ten fentalogues; the amperometric detection is achieved using a commercially available impinging jet flow-cell that incorporates in-house screen-printed graphite macroelectrodes (SPEs). Both protocols are analytically compared and contrasted in terms of their experimental parameters and chromatographic conditions with the separation and quantification being optimized, with these protocols demonstrating a high sensitivity and reproducibility. The proposed methods were successfully applied for the analysis of the investigated drugs of abuse, in the presence of common adulterants (e.g. caffeine, paracetamol and benzocaine), co-formulated excipients (starch, lactose, aerosil 200, etc.) and simultaneously within seized street samples.

In this communication, we present the first developed Molecularly Imprinted Polymers (MIPs) for the specific detection of a New Psychoactive Substance (NPS); namely, methoxphenidine (MXP) and its regioisomers. Selectivity of the MIP towards MXP is studied by analysing mixtures and an acquired street sample with High Performance Liquid Chromatography coupled to UV detection. The study demonstrates that the engineered polymers selectively extract MXP from heterogeneous samples, which makes for a very powerful diagnostic tool that can detect traces of MXP in complicated NPS samples.

Synthetic cannabinoid receptor agonists (SCRAs) are a continually evolving family of illicit drugs, with novel analogues frequently being detected. This paper reports the detection of a new N-hexyl-1H-indazole derivative, ADB-HINACA, within a herbal sample seized by law enforcement for the first time in the United Kingdom. The identity of the compound was confirmed via the synthesis of a pure ADB-HINACA reference standard and direct spectral comparison by 1H NMR and GC-EI-MS analysis. A full analytical profiling of ADB-HINACA by nuclear magnetic resonance (NMR), attenuated total reflection Fourier-transform infrared (FTIR) spectroscopy and gas chromatography-electron ionisation-mass spectrometry (GC-EI-MS) is reported and shows good concordance between the seized sample and the reference standard. A validated GC-EI-MS method for the routine quantification of the cannabinoid in seized samples (LOD: 1.7 μg/mL, LOQ: 5.8 μg/mL) was also developed and using this method, the seized herbal sample was determined to contain 4.9% w/w ADB-HINACA.

Background On 26 May 2016, the UK introduced the Psychoactive Substances Act. The Act made it an offence to produce, supply, or offer to supply, any psychoactive substance likely to be used for its psychoactive effects. While a Home Office review of the Act in 2018 proclaimed that the Act had been successful in achieving its main goal of preventing the open sale of psychoactive substances, significantly, the review acknowledged that high levels of synthetic cannabinoid use remain amongst vulnerable user groups, in particular the homeless population. Methods The research adopted an innovative interdisciplinary approach drawing on sociology and chemistry. The sociological element involved 82 face-to-face qualitative semi-structured interviews with 37 homeless synthetic cannabinoid users, 45 stakeholders, and over 100 h of fieldwork observations. The chemical analysis element involved the testing (using Gas Chromatography-Mass Spectrometry) of 69 synthetic cannabinoid street samples obtained by a local police force. Results The introduction of the Act was associated with a number of significant changes to the synthetic cannabinoid market, including the integration of synthetic cannabinoids into the existing illicit street market, new dealers, the adoption of more targeted and aggressive supply practices, and variability in the content and potency of synthetic cannabinoids. Combined, these changes have increased the risk of harm to homeless users and homeless sector staff and resulted in a concomitant increase in the demand on emergency services. Conclusion The foreseen concerns that the Act would result in detrimental market changes and increased harms to vulnerable user groups have been manifested in the homeless population. The failure of the Act to reduce synthetic cannabinoid use within this group, combined with the increased risk of individual and societal harm, highlights the importance of reducing the demand for synthetic cannabinoids.

© 2016 Elsevier B.V. Remarkable advances have been made in the development of an environmentally-friendly approach for the rapid and simple construction of the Active Pharmaceutical Ingredient (API) Fluoxetine (1). These include the use of ball milling and microwave irradiation as greener alternatives − compared to conventional heating − to provide the energy needed for the chemical transformations.

Piperazine-based drugs, such as N-benzylpiperazine (BZP), became attractive in the 2000s due to possessing effects similar to amphetamines. Herein, BZP, in addition to its pyridyl analogues, 2-, 3- and 4-pyridylmethylpiperidine (2-PMP, 3-PMP and 4-PMP respectively) were subjected to the hyperpolarisation technique SABRE (Signal Amplification By Reversible Exchange) in order to demonstrate the use of this technique to detect these piperazine-based drugs. Although BZP was not hyperpolarised via SABRE, 2-PMP, 3-PMP and 4-PMP were, with the ortho- and meta-pyridyl protons of 4-PMP showing the largest enhancement of 313-fold and 267-fold respectively in a 1.4 T detection field, following polarisation transfer at earth's magnetic field. In addition to the freebase, 4-PMP.3HCl was also appraised by SABRE and was found not to polarise, however, the addition of increasing equivalents of triethylamine (TEA) produced the freebase, with a maximum enhancement observed upon the addition of three equivalents of TEA. Further addition of TEA led to a reduction in the observed enhancement. SABRE was also employed to polarise 4-PMP.3HCl (ca. 20% w/w) in a simulated tablet to demonstrate the forensic application of the technique (138-fold enhancement for the ortho-pyridyl protons). The amount of 4-PMP.3HCl present in the simulated tablet was quantified via NMR using D2 O as a solvent and compared well to complimentary GC-MS data. Exchanging D2 O for CD3 OD as the solvent utilised for analysis resulted in a significantly lower amount of 4-PMP.3HCl being determined, thus highlighting safeguarding issues linked to drug abuse in relation to determining the amount of active pharmaceutical ingredient present.

© 2020 John Wiley & Sons, Ltd. Drug misuse in prisons contributes to increased disruption and violence and negatively impacts prisoner safety, rehabilitation, and recovery. Synthetic cannabinoid receptor agonists (SCRAs), colloquially known as “spice”, are infused into papers and are of particular concern in a prison setting where they are commonly vaped. Methods for the qualitative and quantitative analysis of SCRA infused papers, including impurity profiling, were developed using gas chromatography–mass spectrometry (GC–MS) with qualitative confirmation by ultra high pressure liquid chromatography with photodiode array and quadrupole time of flight mass spectrometry detection (UPLC-PDA-QToF-MS) and applied to 354 individual seized paper samples originating from 168 seizures from three Scottish prisons. Of these samples, 41% (146 samples from 101 seizures) contained at least one SCRA and multiple SCRAs were detected on 23% of these papers. Concentrations ranged from < 0.05–1.17 mg/cm2 paper, representing the first reported quantitative data for SCRA infused papers. An evolution in the SCRAs detected was demonstrated; 5F-MDMB-PINACA (5F-ADB) predominated until late 2018, after which time 5F-MDMB-PICA and 4F-MDMB-BINACA became increasingly more prevalent, followed by the arrival of MDMB-4en-PINACA in June 2019. Concentration mapping data from two seized paper samples demonstrated that SCRA concentrations across larger papers were highly variable (0.47–2.38 mg/cm2 paper) making consistent dosing by users, and representative sampling by laboratory analysts, difficult. Near real-time qualitative and quantitative information on SCRAs circulating in prisons acts as an early warning system for SCRAs emerging on the wider illicit market, inform the methods used to detect them and limit supply, and provide information to support harm reduction measures.

4-methylmethcathinone (mephedrone) has emerged in drug seizures as a new psychoactive substance (NPS) causing a public health risk of global concern. Currently, there are no commercial microfluidic devices for the selective detection of mephedrone and so this study presents a simple, low-cost and portable paper-based Lab-on-a-Chip (LOC) device with colorimetric detection to fill this gap. Limits of detection for mephedrone in spiked urine and dissolved powder (aqueous) samples are clinically relevant at 4.34 ng mL−1 and 2.51 ng mL−1 respectively. No cross-reactivity for commonly encountered cutting agents, interferents and adulterants were detected. Mephedrone and its main metabolite were detectable in aqueous and urine samples within 3 min. Stability and reproducibility measurements showed no significant difference in signal intensity over eight weeks and no significant difference within or between devices. The proposed device has the potential to provide cost-effective, rapid, on-site testing within forensic or clinical settings and therefore has wide global applicability.

The emergence of a wide variety of fentanyl analogues has become a problem for the identification of seized drug samples. While chemical databases are largely reactive to the emergence of new analogues, efforts should focus on the development of predictive models which can discern how new analogues differ from the parent drug. Principal component analysis (PCA) was performed on mass spectral data from 54 fentanyl analogues. Hierarchical clustering was used to group these analogues into meaningful classes. The model was able to classify 67 analogues not previously included in the model with high accuracy, based on the nature and position of the chemical modification.

The constant and persistent synthesis and abuse of new psychoactive substances have sparked the requirement for rapid, on-site, sensitive analytical protocols for their sensing and quantification. Mephedrone (4-MMC) is currently one of the most popular legal highs among recreational drug abusers and imposes a serious public health problem. In this paper, the electrochemical sensing of two metabolites of 4-MMC, namely, nor-mephedrone (4-methylcathinone, 4-MC) and dihydromephedrone (4-methylephedrine, 4-MMC-R), utilizing screen-printed graphite electrodes is performed. The accessible linear ranges by cyclic voltammetry were found to correspond to 40–300 μg mL–1 for 4-MC in both phosphate buffer solution (PBS, pH 7.0) and spiked diluted human urine, whereas in the case of 4-MMC-R, the linearity ranges are 15–300 μg mL–1 (PBS, pH 3.0) and 25–300 μg mL–1 (spiked diluted human urine). To maximize the assay sensitivity, differential pulse voltammetry (DPV) was performed toward the sensing of 4-MC, which exhibited a linear response over the range 10–250 and 10–300 μg mL–1 in PBS pH 7.0 and spiked diluted human urine, respectively. However, 4-MMC-R demonstrated slightly higher sensitivity over the range 5–300 μg mL–1 in both PBS pH 3.0 and spiked diluted human urine. Using DPV, the limits of detection (3σ) were calculated and found to correspond to ca. 3.97 and 3.64 μg mL–1 for 4-MC and 4-MMC-R (PBS, pH 7.0 and 3.0), respectively, and ca. 6.34 and 3.87 μg mL–1 for 4-MC and 4-MMC-R (spiked diluted human urine), respectively. The potential interference of adulterants’ metabolites commonly found in NPS street samples was also explored (at both pH 7.0 and 3.0). The electrochemical approach reported herein provides a novel laboratory tool for the identification and quantification of synthetic cathinone metabolites and has potential for the basis of a portable analytical sensor for their fast, cheap, reliable, and accessible determination in the field.

MDMA (3,4-methylenedioxymethamphetamine) is a Class A substance that is usually found in a tableted form. It is only observed in one orthorhombic polymorph under ambient conditions. It shows slight positional disorder around the methlyenedioxy ring which persists during compression up to 6.66 GPa. The crystal quality deteriorates above 6.66 GPa where the hydrostatic limit of the pressure-transmitting medium is exceeded. The structure undergoes anisotropic compression with thea-axis compressing the greatest (12%cf.4 and 10% for theb- andc-axes, respectively). This is due to the pattern of the hydrogen bonding which acts like a spring and allows the compression along this direction.

Purpose The detection of a novel psychoactive substance, 2F-MT-45, a fluorinated analogue of the synthetic opioid MT-45, was reported in a single seized tablet. MT-45, 2F-, 3F- and 4F-MT-45 were synthesised and reference analytical data were reported. The in vitro and in vivo metabolisms of MT-45 and 2F-MT-45 were investigated. Method The reference standards and seized sample were characterised using nuclear magnetic resonance spectroscopy, ultra-performance liquid chromatography–quadrupole time of flight mass spectrometry, gas chromatography–mass spectrometry, attenuated total reflectance-Fourier transform infrared spectroscopy and Raman spectroscopy. Presumptive tests were performed and physicochemical properties of the compounds determined. Metabolite identification studies using human liver microsomes, human hepatocytes, mouse hepatocytes and in vivo testing using mice were performed and identified MT-45 metabolites were confirmed in authentic human urine samples. Results Metabolic pathways identified for MT-45 and 2F-MT-45 were N-dealkylation, hydroxylation and subsequent glucuronidation. The major MT-45 metabolites identified in human in vitro studies and in authenticated human urine were phase I metabolites and should be incorporated as analytical targets to existing toxicological screening methods. Phase II glucuronidated metabolites were present in much lower proportions. Conclusions 2F-MT-45 has been detected in a seized tablet for the first time. The metabolite identification data provide useful urinary metabolite targets for forensic and clinical testing for MT-45 and allows screening of urine for 2F-MT-45 and its major metabolites to determine its prevalence in case work. Electronic supplementary material The online version of this article (10.1007/s11419-018-0413-1) contains supplementary material, which is available to authorized users.

© 2018 Elsevier B.V. A detailed investigation into the chromatographic retention behaviour and separation of the three regioisomers of the Novel Psychoactive Substance (NPS) methoxphenidine (i.e. 2-, 3- and 4-MXP isomers) has revealed the ionization state of the analyte and stationary phase, to be the controlling factor in dictating which retention mechanism is in operation. At low pH, poor separation and retention was observed. In contrast, at intermediate pH, enhanced retention and separation of the three MXP isomers was obtained; it appeared that there was a synergistic effect between the electrostatic and hydrophobic mechanisms. At high pH, the MXP isomers were retained by hydrophobic retention. Accurate retention time predictions ( < 0.5%) were achievable using non-linear retention models (3 × 3). This allowed the optimization of the gradient separation of the MXP isomers using a two-dimensional gradient and temperature design space. Prediction errors for peak width and resolution were, in most cases, lower than 5%. The use of linear models (2 × 2) still afforded retention time and resolution accuracies of < 2.3 and 11% respectively. A rapid and highly sensitive LC–MS friendly method (i.e. R smin > 5 within 4 min) was predicted and verified. The developed methodology should be highly suitable for the rapid, specific and sensitive detection and control of MXP regioisomers.

African animal trypanosomosis is arguably the most important animal disease impairing livestock agricultural development in sub-Saharan Africa. In addition to vector control, the use oftrypanocidal drugs is important in controlling the impact of the disease on animal health and production in most sub-Saharan countries. However, there are no internationally agreed standards (pharmacopoeia-type monographs or documented product specifications) for the quality control of these compounds. This means that it is impossible to establish independent quality control and quality assurance standards for these agents. An international alliance between the Food and Agriculture Organization of the United Nations, the International Federation for Animal Health, the Global Alliance for Livestock Veterinary Medicines, the University of Strathclyde and the International Atomic Energy Agency (with critical support from the World Organisation for Animal Health) was established to develop quality control and quality assurance standards for trypanocidal drugs, with the aim of transferring these methodologies to two control laboratories in sub-Saharan Africa that will serve as reference institutions for their respective regions. The work of the international alliance will allow development of control measures against sub-standard or counterfeit trypanocidal drugs for treatment of trypanosome infection. Monographs on diminazene aceturate (synonym: diminazene diaceturate), isometamidium chloride hydrochloride, homidium chloride and bromide salts and their relevant veterinary formulations for these agents are given in the annex to this paper. However, the authors do not recommend use of homidium bromide and chloride, because of their proven mutagenic properties in some animal test models and their suspected carcinogenic properties.

This chapter gives a concise overview of the synthetic and supramolecular chemistry of cucurbit[n]uril (CB[n]) family of macrocycles and expands it to hemicucurbit[n]urils (HemCB[n]) and bambus[n]urils (BU[n]). The application of microwave-assisted synthesis to access these macrocycles is reviewed. Several extensive papers describing the synthesis, physical and recognition properties and applications of CB[n]s have been published and the reader is directed to these key sources throughout this chapter.

We demonstrate that the electrochemical signa- tures of graphene screen-printed electrodes towards hy- drazine are not due to the reported benefits of graphene per se but rather it is the metallic impurities which can.

The electrochemical sensing of new psychoactive substance(s) (NPSs), synthetic cathinone derivatives also termed "legal highs", are explored with the use of metallic modified screen-printed electrochemical sensors (SPES). It is found that no significant electrochemical enhancement is evident with the use of either in situ bismuth or mercury film modified SPES compared to the bare underlying electrode substrate. In fact, the direct electrochemical reduction of the cathinone derivatives mephedrone (4-methylmethcathinone; 4-MMC) and 4'-methyl-N-ethylcathinone (4-methylethcathinone; 4-MEC) is found to be possible for the first time, without heavy metal catalysis, giving rise to useful voltammetric electroanalytical signatures in model aqueous buffer solutions. This novel electroanalytical methodology is validated toward the determination of cathinone derivatives (4-MMC and 4-MEC) in three seized street samples that are independently analyzed with high-performance liquid chromatography (HPLC) wherein excellent agreement between the two analytical protocols is found. Such an approach provides a validated laboratory tool for the quantification of synthetic cathinone derivatives and holds potential for the basis of a portable analytical sensor for the determination of synthetic cathinone derivatives in seized street samples.

In order to assess the effect of silica gel structure on retention in hydrophilic interaction chromatography, a test system was developed which used quaternary ammonium ions as probes with tetramethylammonium acetate (TMAA) as the counter-ion competing against the interaction of the test probes with ionised silanols in the stationary phase. Four silica gel columns and a silica hydride column were examined. Retention times were obtained for the test probes at 20, 40, 60, 80 and 90 % acetonitrile (ACN) with all the mobile phase mixtures containing 10-mM TMAA buffer at pH 6.0. All phases gave “U”-shaped plots for log k against percentage of ACN with the steepest rise in retention occurring between 80 and 90 % ACN. Benzyltrimethylammonium, the smallest quaternary ammonium ion, was the most strongly retained probe at 90 % ACN and was most retained on a high surface area 60 A Kromasil column and least retained on a 300 A ACE silica gel column. The ionic strength of the mobile phase was varied at 80 and 90 % ACN and plots of log k against the inverse of buffer strength followed by fitting of second-order polynomial curves allowed an assessment of the contribution from HILIC to the mixed HILIC/ion-exchange retention mechanism. Toluene and pentylbenzene were used to assess the decrease in accessible pore volume due to water absorption in HILIC mode.

This paper describes a methodology for the modification of phase transition temperatures using (±)-4′-methylmethcathinone solid solutions as an exemplar. This method serves to show that by varying the composition of the halide ion one can systematically alter the temperatures at which phase transitions can occur in order to evade the possibility of interconversion between polymorphs during processing or storage of materials.

The prevalence of so-called 'legal high' drugs in forensic science drug casework has increased markedly in recent years. This has given rise to both legal and analytical challenges in the identification of these substances. The requirement for validated, reliable and rapid testing methodologies for these compounds is obvious. This work reports the analysis of sixteen synthesised cathinone derivatives encountered in casework using presumptive testing, thin layer chromatography and gas chromatography-mass spectrometry (GC-MS).