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25.04.2023 | Original Article

Analytical characterization and differentiation between threo- and erythro-4-fluoroethylphenidate

verfasst von: Miho Sakamoto, Toshinari Suzuki, Daisuke Teraoka, Kazue Tanaka, Yuki Saeki, Kiyoko Kishimoto, Machiko Nagashima, Jun’ichi Nakajima, Jin Suzuki, Akiko Inomata, Takako Moriyasu, Haruhiko Fukaya

Erschienen in: Forensic Toxicology | Ausgabe 2/2023

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Abstract

Purpose

Methylphenidate analogs appeared on the drug market during the last years. Its analogs contain two chiral centers and, thus, have potential varying configurations (i.e., threo and erythro forms). This study presents the analytical characterization of 4-fluoroethylphenidate (4-FEP) and its differentiation between threo- and erythro-4-FEP.

Methods

Analysis of the samples included high-performance liquid chromatography (HPLC), gas chromatography–electron ionization-mass spectrometry (GC–EI-MS), high-resolution mass spectrometry (HRMS) analyses, nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal structure analysis.

Results

NMR spectroscopic investigations confirmed the differences between threo- and erythro-4-FEP, and demonstrated that both isomers could be separated using HPLC and GC methods. Two samples obtained from one vendor in 2019 consisted of threo-4-FEP, whereas the other two samples obtained from a different vendor in 2020 consisted of a mixture of threo- and erythro-4-FEP.

Conclusions

Several analytical approaches including HPLC, GC–EI-MS, HRMS analyses, NMR spectroscopy and X-ray crystal structure analysis enabled the unambiguous identification of threo- and erythro-4-FEP. The analytical data presented in this article will be useful for identifying threo- and erythro-4-FEP included in illicit products.

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RITALIN^® (methylphenidate hydrochloride) tablets, for oral use, CII. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/010187s093lbl.pdf. Accessed 17 July 2022

Wall SC, Gu H, Rudnick G (1995) Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Mol Pharmacol 47:544–550PubMed

Challman TD, Lipsky JJ (2000) Methylphenidate: its pharmacology and uses. Mayo Clin Proc 75:711–721. https://doi.org/10.4065/75.7.711CrossRefPubMed

Szporny L, Görög P (1961) Investigations into the correlations between monoamine oxidase inhibition and other effects due to methylphenydate and its stereoisomers. Biochem Pharmacol 8(3):263–268CrossRef

FOCALIN^® (dexmethylphenidate hydrochloride) tablets for oral use, CII. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021278s029lbl.pdf. Accessed 17 July 2022

Urban KR, Gao W-J (2017) Psychostimulants as cognitive enhancers in adolescents: more risk than reward? Front Public Health 5:Article 260. https://doi.org/10.3389/fpubh.2017.00260

Normann C, Berger M (2008) Neuroenhancement: status quo and perspectives. Eur Arch Psychiatry Clin Neurosci 258(Suppl5):110–114. https://doi.org/10.1007/s00406-008-5022-2CrossRefPubMed

Finger G, da Silva ER, Falavigna A (2013) Use of methylphenidate among medical students: a systematic review. Rev Assoc Med Bras 59:285–289. https://doi.org/10.1016/j.ramb.2012.10.00CrossRefPubMed

International Narcotics Control Board (2021) List of Psychotropic Substances under International Control 32nd edition. https://www.incb.org/documents/Psychotropics/forms/greenlist/2021/Green_list_ENG_V21.pdf Accessed 17 July 2022

10.

Carlier J, Giorgetti R, Varì MR, Pirani F, Ricci G, Busardò FP (2019) Use of cognitive enhancers: methylphenidate and analogs. Eur Rev Med Pharmacol Sci 23(1):3–15. https://doi.org/10.26355/eurrev_201901_1674CrossRefPubMed

11.

DRUGS-FORUM (2016) Drug information 4f-EPH. https://drugs-forum.com/threads/4f-eph.291385/ Accessed 17 July 2022

12.

Bowden-Jones O (2017) RE: Further advice on methylphenidate-related NPS. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/598494/ACMD_s_further_advice_on_methylphenidate-related_NPS_Mar_17.pdf Accessed 17 July 2022

13.

SHERIFFDOM OF TAYSIDE, CENTRAL AND FIFE AT FALKIRK (2019) UNDER THE INQUIRIES INTO FATAL ACCIDENTS AND SUDDEN DEATHS ETC (SCOTLAND) ACT 2016. https://scotcourts.gov.uk/docs/default-source/cos-general-docs/pdf-docs-for-opinions/2018fai272ff469a7898069d2b500ff0000d74aa7.pdf?sfvrsn=0 Accessed 17 July 2022

14.

SWGDRUG (2018) 4-Fluoroethylphenidate. https://www.swgdrug.org/Monographs/4-Fluoroethylphenidate.pdf Accessed 17 July 2022

15.

National Forensic Laboratory, Slovenia (2016) 4F-EPH. https://www.policija.si/apps/nfl_response_web/0_Analytical_Reports_final/4F-EPH-ID-1563-16-report200616.pdf. Accessed 17 July 2022

16.

Tanaka K, Sakamoto M, Shioda H, Suzuki A, Shimizu S, Teraoka D, Saeki Y, Moteki Y, Kishimoto K, Takahashi M, Nagashima M, Urade T, Ito Y, Nakajima J, Suzuki T, Suzuki J, Inomata A, Moriyasu T (2021) Analytical results of new psychoactive substance-containing drugs purchased over the internet in April 2020-March 2021. Ann Rep Tokyo Metr Inst Pub Health 72:135–142

17.

CrysAlisPro; Rigaku Oxford Diffraction: Tokyo, Japan

18.

Dolomanov OV, Bourhis LJ, Gildea RJ, Howard JAK, Puschmann H (2009) OLEX2: a complete structure solution, refinement and analysis program. J Appl Cryst 42:339–341. https://doi.org/10.1107/S0021889808042726CrossRef

19.

Sheldrick GM (2015) SHELXT – Integrated space-group and crystal-structure determination. Acta Cryst A71:3–8. https://doi.org/10.1107/S2053273314026370CrossRef

20.

Sheldrick GM (2015) Crystal structure refinement with SHELXL. Acta Cryst C71:3–8. https://doi.org/10.1107/S2053229614024218CrossRef

21.

McLaughlin G, Morris N, Kavanagh PV, Power JD, Dowling G, Twamley B, O’Brien J, Hessman G, Murphy B, Walther D, Partilla JS, Baumann MH, Brandt SD (2017) Analytical characterization and pharmacological evaluation of the new psychoactive substance 4-fluoromethylphenidate (4F-MPH) and differentiation between the (±)-threo and (±)-erythro diastereomers. Drug Test Anal 9(3):347–357. https://doi.org/10.1002/dta.2167CrossRefPubMedPubMedCentral

22.

Klare H, Neudörfl JM, Brandt SD, Mischler E, Meier-Giebing S, Deluweit K, Westphald F, Laussmanna T (2017) Analysis of six ‘neuro-enhancing’ phenidate analogs. Drug Test Anal 9:423–435. https://doi.org/10.1002/dta.2161CrossRefPubMed

23.

Froimowitz M, Wu K-M, George C, VanDerveer D, Shi Q, Deutsch HM (1998) Crystal structures of analogs of threo-methylphenidate. Struct Chem 9(4):295–303CrossRef

24.

SWGDRUG (2005) METHYLPHENIDATE. https://www.swgdrug.org/Monographs/METHYLPHENIDATE.pdf Accessed 17 July 2022

25.

Kobayashi K, Sakamoto M, Nakajima J, Suzuki A, Saito Y, Uemura N, Suzuki I, Shimizu S, Teraoka D, Uchimoto K, Saeki Y, Nagashima M, Takahashi M, Shimizu M, Urade T, Suzuki J, Inomata A, Moriyasu T (2017) Analytical results of drug compounds found in illegal drugs purchased in the 2016 fiscal year. Ann Rep Tokyo Metr Inst Pub Health 68:79–84

26.

Casale JF, Hays PA (2011) Ethylphenidate: an analytical profile. Microgram J 8(2):58–61

27.

Flamm BL, Gal J (1975) The thermal decomposition of methylphenidate in the gas chromatograph mass spectrometer. Biomed Mass Spectrom 2:281–283. https://doi.org/10.1002/bms.1200020509CrossRef

28.

Tsujikawa K, Iwata YT, Inoue M, Higashibayashi S, Inoue H (2015) Comments on “Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, α-PHPP and α-POP, with 11 newly distributed designer drugs in illegal products.” Forensic Sci Int 251:e15–e17. https://doi.org/10.1016/j.forsciint.2015.04.008CrossRefPubMed

29.

Berezin DB, Mal’tsev IA, Semeikin AS, Bolotin VL (2005) Tautomeric transformations of singly inverted analogues of tetraphenylporphin. Russ J Phys Chem 79(12):1980–1986

30.

Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM (1996) Synthesis and pharmacology of potential cocaine antagonists. 2. structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs. J Med Chem 39:1201–1209. https://doi.org/10.1021/jm950697cCrossRefPubMed

31.

Gutman A, Zaltsman I, Shalimov A, Sotrihin M, Nisnevich G, Yudovich L, Fedotev I (2004) Process for the preparation of dexmethylphenidate hydrochloride. Patent US 20040180928 A1

32.

Dias LC, Maria A, Fernandes AP (2000) Short synthesis of methylphenidate and its p-methoxy derivative. Synth Commun 30:1311–1318. https://doi.org/10.1080/00397910008087153CrossRef

33.

Deutsch HM, Ye X, Shi Q, Liu Z, Schweri MM (2001) Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction. Eur J Med Chem 36:303–311. https://doi.org/10.1016/s0223-5234(01)01230-2CrossRefPubMed

34.

Thai DL, Sapko MT, Reiter CT, Bierer DE, Perel JM (1998) Asymmetric synthesis and pharmacology of methylphenidate and its para-substituted derivatives. J Med Chem 41(4):591–601. https://doi.org/10.1021/jm970620jCrossRefPubMed

35.

Luethi D, Kaeser PJ, Brandt SD, Krähenbühl S, Hoener MC, Liechti ME (2018) Pharmacological profile of methylphenidate-based designer drugs. Neuropharmacology 134(Pt A):133–140. https://doi.org/10.1016/j.neuropharm.2017.08.020CrossRefPubMed

Titel: Analytical characterization and differentiation between threo- and erythro-4-fluoroethylphenidate
verfasst von: Miho Sakamoto
Toshinari Suzuki
Daisuke Teraoka
Kazue Tanaka
Yuki Saeki
Kiyoko Kishimoto
Machiko Nagashima
Jun’ichi Nakajima
Jin Suzuki
Akiko Inomata
Takako Moriyasu
Haruhiko Fukaya
Publikationsdatum: 25.04.2023
Verlag: Springer Nature Singapore
Erschienen in: Forensic Toxicology / Ausgabe 2/2023
Print ISSN: 1860-8965
Elektronische ISSN: 1860-8973
DOI: https://doi.org/10.1007/s11419-023-00664-y

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Analytical characterization and differentiation between threo- and erythro-4-fluoroethylphenidate