Profiling of synthesis‐related impurities of the synthetic cannabinoid Cumyl‐5F‐PINACA in seized samples of e‐liquids via multivariate analysis of UHPLC−MSⁿ data

Abstract

Vaping of synthetic cannabinoids via e‐cigarettes is growing in popularity. In the present study, we tentatively identified 12 by‐products found in a pure sample of the synthetic cannabinoid Cumyl‐5F‐PINACA (1‐(5‐fluoropentyl)‐N‐(2‐phenylpropan‐2‐yl)‐1H‐indazole‐3‐carboxamide), a prevalent new psychoactive substance (NPS) in e‐liquids, via high‐resolution mass spectrometry fragmentation experiments (HRMS/MS). Furthermore, we developed a procedure to reproducibly extract this synthetic cannabinoid and related by‐products from an e‐liquid matrix via chloroform and water. The extracts were submitted to flash chromatography (F‐LC) to isolate the by‐products from the main component. The chromatographic impurity signature was subsequently assessed by ultra‐high‐performance liquid chromatography coupled to mass spectrometry (UHPLC–MS) and evaluated by automated integration. The complete sample preparation sequence (F‐LC + UHPLC–MS) was validated by comparing the semi‐quantitative signal integrals of the chromatographic impurity signatures of five self‐made e‐liquids with varying concentrations of Cumyl‐5F‐PINACA [0.1, 0.2, 0.5, 0.7 and 1.0% (w/w)], giving an average relative standard deviation of 6.2% for triplicate measurements of preparations of the same concentration and 10.5% between the measurements of the five preparations with different concentrations. Lastly, the chromatographic signatures of 14 e‐liquid samples containing Cumyl‐5F‐PINACA from police seizures and Internet test purchases were evaluated via hierarchical cluster analysis for potential links. For the e‐liquid samples originating from test purchases, it was found that the date of purchase, the identity of the online shop, and the brand name are the critical factors for clustering of samples.

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

“…It seems that SCRAs have now come to acquire a market of their own, distinct from other NPS, particularly amongst marginalized population groups, including homeless and incarcerated individuals. Apart from the highly informative work of Pütz and co‐workers regarding the synthesis and chemical impurity profiling of indole or indazole SCRAs, little if any information is currently available regarding the clandestine manufacture of newly emerging azaindole, γ‐carbolinone, or carbazole SCRAs. Consequently, the continued chemical and pharmacological investigation of SCRAs is evidently pivotal to our further improved understanding of this ever‐evolving class of structurally heterogenous new psychoactive substance (NPS).…”

“…Amide impurity 41 has been proposed to form via amidation of ethyl acetate (a potential solvent used in the manufacture of 5F‐MDMB‐P7AICA [ 25 ]). Although significant developments regarding the impurity profiling of indole‐ and indazole‐type SCRAs have been made by Pütz and co‐workers, the impurity profiles of newly emerging heterocyclic SCRAs still remain largely unknown.…”

Shape matters: The application of activity‐based in vitro bioassays and chiral profiling to the pharmacological evaluation of synthetic cannabinoid receptor agonists in drug‐infused papers seized in prisons

“…The use of nonchiral impurity profiling has previously been applied to illicitly produced drugs including heroin, 29–31 cocaine, 31–34 MDMA, 35,36 and fentanyl 37 . Münster‐Müller et al describes a novel stable isotope analysis and impurity‐profiling workflow, using the SCRAs MDMB‐CHMICA (2) and Cumyl‐5F‐PINACA [1‐(5‐fluoropentyl)‐ N ‐(2‐phenylpropan‐2‐yl)‐1 H ‐indazole‐3‐carboxamide] (9) , for the detection of synthesis precursor/by‐product impurities in seized herbal materials and potential source attribution 38–41 . Chiral profiling has been applied previously to illicitly produced drugs including amphetamine and methamphetamine for intelligence purposes, 42–44 although the methodology is rarely routinely employed in forensic drug testing laboratories.…”

Metabolic profiling of synthetic cannabinoid 5F‐ADB and identification of metabolites in authentic human blood samples via human liver microsome incubation and ultra‐high‐performance liquid chromatography/high‐resolution mass spectrometry

“…chemical impurities, degradants and pyrolysis products) may contribute to certain toxicities observed in users. [17][18][19][20][21][22] 5F-ADB ( Figure 1 14 Member States had controlled 5F-ADB. 24 In 2018, 5F-ADB was internationally controlled by the UNODC.…”

“…It is important to note, however, that other substances (e.g. chemical impurities, degradants and pyrolysis products) may contribute to certain toxicities observed in users 17–22 …”