Analysis of fragmentation pathways of fentanyl derivatives by electrospray ionisation high‐resolution mass spectrometry

Abstract

Rationale During the last decade there has been a large increase in the availability of new synthetic opioids on the European drug market. Fentanyl analogues accounted for a significant proportion of these compounds. When there is a rapid introduction of new compounds from a given chemical class onto the market, a computer‐assisted library search is not recommended and the spectra have to be interpreted individually. Therefore, the knowledge of how different groups of new psychoactive substances are fragmented can be very helpful in identifying new compounds. Methods In this study, the fragmentation patterns of 33 fentanyl derivatives were investigated using electrospray ionisation (ESI). The analyses were conducted using liquid chromatography quadrupole time‐of‐flight mass spectrometry (LC/QTOFMS). Based on measurements carried out under various conditions, the fragmentation pathways of the tested compounds that were divided into groups due to their chemical structure were established. Results The performed study allowed for the determination of characteristic ions that were formed during the fragmentation of fentanyl derivatives using ESI. Due to the high mass accuracy of the LC/ESI‐QTOFMS technique, it was proved that the cleavage of the tested molecules occurred mostly on the bonds adjacent to the nitrogen atoms. Based on the proposed fragmentation scheme, the general structure for fentanyls, and the presence of some characteristic ions, it is possible, after applying simple mathematical operations, to calculate the masses of individual substituents in the formulas of the new fentanyl analogues, which may appear on the drug market. Furthermore, based on the exact masses, it is possible to determine the formulas of these substituents. Conclusions Knowledge of the specific fragments generated under ESI conditions can be used in forensic laboratories to determine the structures of novel compounds from the group of fentanyl derivatives.

Software‐assisted automated detection and identification of “unknown” fentanyl analogues

“…The latter are known product ions in fentanyl analogues. 27,28 In addition to these two distinct product ions, an additional product ion of m/z 188.1440 is well known for phenethylamine fentanyl analogues but is absent in this spectrum. In the case of F8, presented above, the product with m/z 202.1591 is the m/z 188.1440 equivalent, with the addition of a methylene moiety.…”

Identifying reliable ions for the statistical differentiation of structurally similar fentanyl analogs

“…TA B L E 5 Effect of spectral intensity on statistical comparison of mass spectra of valeryl fentanyl, isovaleryl fentanyl, and pivaloyl fentanyl. For the comparisons of valeryl fentanyl to pivaloyl fentanyl, eight of the 10 lowest-ranked ions were also the most frequently occurring discriminating ions, appearing in at least 13 4). Two less frequently occurring discriminating ions (m/z 244 and m/z 177) were also among the 10 lowest-ranked ions for these comparisons (Table 4).…”

“…The recognition of such challenges has resulted in the development of new instrumental methods and data analysis tools to assist with the characterization and definitive identification of fentanyl analogs [6][7][8][9][10][11][12][13][14]. Several researchers have employed different GC ionization modes, multiple stages of mass analysis, and high-resolution mass spectrometry (HRMS) methods for the characterization, identification, and distinction of fentanyl analogs and isomers [7][8][9][13][14][15].…”

Trace residue identification, characterization, and longitudinal monitoring of the novel synthetic opioid β‐U10, from discarded drug paraphernalia

“…[36][37][38][39][40] When coupled with high-resolution accurate mass spectrometry and MS/MS techniques, the identification and characterization of unexpected or novel drug substances may potentially be achieved using these approaches, via assignment of the molecular formulae of the observed ions and by similarities in MS/MS fragmentation behavior compared with structurally homologous known substances within an established drug class. [41][42][43][44] Recently, we described the development and application of a DART-MS and -MS/MS approach for rapid and high-throughput trace residue sampling and analysis of discarded drug packaging samples (DPS) as part of an early warning monitoring system for illicit drug use at large public events. This approach was shown to be applicable for the identification and characterization of a wide range of illicit drugs and adulterant substances, including numerous NPS and complex poly-drug mixtures, using laboratory-based instrumentation as well as in "close-to-real-time" applications using a transportable mass spectrometer housed within a mobile analytical laboratory.…”