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Identification of New Amphetamine-Related Designer Drugs Using Exactive High Resolution Accurate Mass Spectrometry Giampietro Frison

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Identification of New Amphetamine-Related Designer Drugs Using Exactive High Resolution Accurate Mass Spectrometry Giampietro Frison 2011 Joint SOFT-TIAFT Meeting San Francisco, California, USA Thermo Scientific Workshop 28 September 2011 Identification of New Amphetamine-Related Designer Drugs Using Exactive High Resolution Accurate Mass Spectrometry Giampietro Frison Laboratory of Environmental Hygiene and Forensic Toxicology Department of Prevention Azienda ULSS 12 Veneziana, Mestre (Venezia), Italy Forensic Toxicology Use Only Forensic toxicology at the LIATF Seized drugs • Determination of active ingredients, adulterants, diluents in seized material for Police and Court Biological samples • Determination of alcohol, psychoactive drugs, other drugs of toxicological interest in biofluids • Driving under the influence of alcohol and drugs • Post-mortem toxicology • Drug-facilitated crimes • Other forensic toxicology applications Forensic Toxicology Use Only The flood of new designer drugs Indane analogues of Ecstasy’s (MDAI, MDMAI) Tetraline analogues of Ecstasy’s (2-AT, MDAT) Tryptamines Cannabinomimetics (JWH-18, JWH-073, JWH-200, JWH-250,CP-47,497, ... ) Beta-keto-amphetamines (designer cathinones) Piperazines Forensic Toxicology Use Only New A-R drugs encountered at LIAFT Mephedrone 4-MEC 4-FA MDPV Methylone Cl-Ph-Pip propyl Propylone Forensic Toxicology Use Only The flood of new designer drugs ? ? ?? ? The LIAFT experience with new designer drugs Increasing number of police seizures and/or intoxication cases Need to promptly obtain their structural characterization , in spite of poor availability of reference (p/m) standards Forensic Toxicology Use Only Analytical strategy to obtain the structural characterization of new A-R drugs GC-MS GC-MS + der UHPLC-HRMS underiv. drugs with 3ClEtClfor (Orbitrap) Poor chromatography Improved GC properties Accurate mass measurements at 100.000 resolv. power Non-specific EI MS Distinctive MS behav. Study of MH + collision- Highly inform. EI MS induced product ions Comparison of exp. and calc. MH + isotopic clusters Study of isotopic fine structure of M+1, M+2, M+3 clusters Forensic Toxicology Use Only GC/MS - Mephedrone Rel. Ab. 6.31 Mephedrone (4-Methyl-Meth-Cathinone) Methanolic solution (b.p. 64.5 °C) 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 Time GC/MS Agilent 7890 II - 5975 Agilent HP-5MS Ultra Inert column Full Scan EI (40-450 u) 30 m x 0.25 mm x 0.25 µm Inj. 1 µl, 250C, split / splitless (1 min) 50C (0.5 min), 200C a 30C/min, 300C (5 min) a 10C/min Carrier gas (He), 1 ml/min Interf. 280C, EMV + 300 V Forensic Toxicology Use Only GC/MS - Mephedrone Rel. Ab. 58 MW 177 56 65 91 119 162 0 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 m/z GC/MS Agilent 7890 II - 5975 Agilent HP-5MS Ultra Inert column Full Scan EI (40-450 u) 30 m x 0.25 mm x 0.25 µm Inj. 1 µl, 250C, split / splitless (1 min) 50C (0.5 min), 200C a 30C/min, 300C (5 min) a 10C/min Carrier gas (He), 1 ml/min Interf. 280C, EMV + 300 V Forensic Toxicology Use Only Mephedrone deriv. with 3ClEtClfor + Cl CO O CH 2 CCl 3 50 µL 2,2,2 - 3ClEtClfor : Ethyl acetate 3 : 7 MW 177 80 °C, 15 min, to dryness Residue reconst. with 50 µL Ethyl acetate CH 3 C O CH 2 CCl 3 O MW 351 Forensic Toxicology Use Only GC/MS of Mephedrone - 3ClEtClfor Rel. Ab. 11.08 Mephedrone – 3ClEtClfor 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 Time GC/MS (same instrument, same conditions) Agilent 7890 II - 5975 Agilent HP-5MS Ultra Inert column Full Scan EI (40-450 u) 30 m x 0.25 mm x 0.25 µm Inj. 1 µl, 250C, splitless (1 min) 50C (0.5 min), 200C a 30C/min, 300C (5 min) a 10C/min Carrier gas (He), 1 ml/min Interf. 280C, EMV + 300 V Forensic Toxicology Use Only GC/MS of Mephedrone - 3ClEtClfor . 91 + CH 3 Cl 351 353 Cl 355 C O CH 2 C Cl O 131 232 204 133 316 119 234 135 318 236 Rel. Ab. 232 234 58 91 119 131 236 133 65 135 351 160 316 204 353 318 355 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 m/z Forensic Toxicology Use Only U-HPLC/HR-Orbitrap-MS and A-R drugs Why choosing the Orbitrap technology r z k ω = m / z φ Non-targeting approach (Full Scan) and “all ions” MS/MS Retrospective detection of analytes without new MS runs High resolving power: 100.000 at m/z 200 High mass accuracy: < 5ppm (e.c.), < 2ppm (i.c.) High mass accur. for M+0 and M+1, M+2, ....ions: EC assign. with high confidence 100.000 RP: full separation of 15 N from M+1 C isotope, and 34 S from M+2 C isotope Forensic Toxicology Use Only U-HPLC/HR-Orbitrap-MS and A-R drugs U-HPLC Thermo Scientific LC: U-HPLC Thermo Scientific Accela 1250 Exactive HCD MS Injection: 10 µL Column: Thermo Scientific Hypersil Gold 50 x 2.1 mm x 1.9 mcm Phase A: H2O, 0,05% HCOOH, 5 mM HCOONH 4,pH 5 Phase B: ACN, 0,05% HCOOH Analytical Conditions Flow: 400 µL/min Gradient: 2% B, to 30% B in 5 min, to 98% B in 5 min, maint. 2 min, to 2% B in 4 min, maint. 2 min. Temp.: Column 40 °C, samples 15 °C HR-Orbitrap-MS Mass detect.: Thermo Scientific “Exactive” Orbitrap HRMS Source: HESI-II Ion Max Spray volt.: 2,5 KV Sheath gas: N2 set to 45 a. u. Aux. gas: N2 set to 5 a. u. Cap.Temp.: 290 °C HESI Temp.: 260 °C Polarity Pos Mass range: 50-800 u Mass resol.: 25.000 (HCD on, 25 eV) or 100.000 (HCD off), No Lock Mass Forensic Toxicology Use Only U-HPLC / HR-Orbitrap-MS analytical strategy 1. High chromatographic resolution of analytes 2. Accurate mass measurements of MH + ionic species in full scan conditions 3. Study of MH + collision-induced product ions obtained in MS/MS experiments 4. Comparison of experimental and calculated MH + isotopic clusters 5. Examination of the isotopic fine structure (IFS) of the (M+1), (M+2), (M+3) isotopic peaks relative to the monoisotopic (M+0 ) peaks Forensic Toxicology Use Only U-HPLC / HR-Orbitrap-MS analytical strategy 1. High chromatographic resolution of analytes “Classic” amphetamines New A-R drugs RT: 2.36 - 6.07 SM: 3B RT: 2.48 - 6.03 SM: 3B RT: 3.42 NL: 4.01E5 RT: 4.28 NL: 1.09E6 AA: 1367658 m/z= 136.1110-136.1124 F: FTMS AA: 3172486 m/z= 178.1217-178.1235 F: FTMS 100 100 {1,1} + p ESI Full ms [100.00-800.00] {1,1} + p ESI Full ms [100.00-800.00] Amphetamine MS ICIS MIX Mephedrone MS ICIS MIX 50 amf-amfsimili-jwh-metilon-propilon 50 amf-amfsimili-jwh-metilon-propilon 0 0 RT: 3.79 NL: 1.62E6 RT: 5.18 NL: 1.55E6 AA: 5728285 m/z= 150.1265-150.1281 F: FTMS AA: 4319203 m/z= 276.1580-276.1608 F: FTMS 100 100 {1,1} + p ESI Full ms [100.00-800.00] {1,1} + p ESI Full ms [100.00-800.00] MS ICIS MIX MS ICIS MIX 50 Methamphetamine amf-amfsimili-jwh-metilon-propilon 50 MDPV amf-amfsimili-jwh-metilon-propilon 0 0 RT: 3.70 NL: 2.77E5 RT: 4.73 NL: 2.77E6 AA: 891805 m/z= 180.1005-180.1023 F: FTMS AA: 7724451 m/z= 192.1373-192.1393 F: FTMS 100 100 {1,1} + p ESI Full ms [100.00-800.00] {1,1} + p ESI Full ms [100.00-800.00] MS ICIS MIX MS ICIS MIX amf-amfsimili-jwh-metilon-propilon 4-MEC Propylone amf-amfsimili-jwh-metilon-propilon 50 MDA 50 0 0 RT: 3.95 NL: 1.61E6 RT: 3.81 NL: 5.02E5 AA: 5218248 m/z= 194.1161-194.1181 F: FTMS AA: 1744924 m/z= 154.1019-154.1035 F: FTMS 100 100 {1,1} + p ESI Full ms [100.00-800.00] {1,1} + p ESI Full ms [100.00-800.00] MS ICIS MIX 4-FA MS ICIS MIX 50 MDMA amf-amfsimili-jwh-metilon-propilon 50 amf-amfsimili-jwh-metilon-propilon 0 0 RT: 4.33 NL: 2.37E6 RT: 4.94 NL: 1.98E5 AA: 7126059 4.60 m/z= 208.1317-208.1337 F: FTMS AA: 559381 m/z= 197.0830-197.0850 F: FTMS 100 100 {1,1} + p ESI Full ms [100.00-800.00] {1,1} + p ESI Full ms [100.00-800.00] MS ICIS MIX MS ICIS MIX 50 MDEA amf-amfsimili-jwh-metilon-propilon 50 Cl-Ph-Pip amf-amfsimili-jwh-metilon-propilon 2.47 2.94 3.18 3.85 4.114.76 5.03 5.62 5.79 0 0 RT: 4.60 NL: 2.37E6 RT: 3.30 NL: 1.91E6 4.33 AA: 6351417 m/z= 208.1317-208.1337 F: FTMS AA: 8608603 m/z= 208.0956-208.0976 F: FTMS 100 100 {1,1} + p ESI Full ms [100.00-800.00] {1,1} + p ESI Full ms [100.00-800.00] MBDB MS ICIS MIX MS ICIS MIX 50 amf-amfsimili-jwh-metilon-propilon 50 Methylone amf-amfsimili-jwh-metilon-propilon 2.47 2.94 3.18 3.85 4.114.76 5.03 5.62 5.79 0 0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 Time (min) Time (min) Forensic Toxicology Use Only U-HPLC / HR-Orbitrap-MS analytical strategy 2.
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