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Synthetic Drugs Comprehensive and Confident Identification of Narcotics, Steroids and Pharmaceuticals in Urine David E. Alonso1, Petra Gerhards2, Charles Lyle1 and Joe Binkley1 | 1LECO Corporation, St. Joseph, MI; 2LECO European LSCA Centre, Moenchengladbach, Germany Introduction Experimental Sample A (Traditional Drugs) Sample B (Synthetic Drugs) Monitoring of patients in hospitals and clinics has traditionally relied on Samples Representative Compounds Representative Compounds targeted methods of analysis. These screening methods are not Peak # Name Formula R.T. (s) Area Similarity Mass Delta (mDa) MA (ppm) 1 Creatinine ME C5H9N3O 210 1326229 800 -0.05 -0.43 • Obtained from a collaborating European hospital 3.5e6 3.0e6 Peak # Name Formula R.T. (s) Area Similarity 2 o-Ethynylaniline C8H7N 219 167436 893 0.07 0.63 1 Indole C8H7N 213 2744171 917 comprehensive and result in an incomplete picture of a patient’s 3 2-Methoxy-4-vinylphenol C H O 223 65764 805 0.11 0.73 52 patient monitoring samples 9 10 2 2 Creatinine ME C5H9N3O 216 613318 651 • 2.5e6 4 Nicotine C10H14N2 234 3249121 898 -0.21 -1.29 3 Pyridine, 2-(1-methyl-2-pyrrolidinyl)- C10H14N2 230 24869771 899 activities. Gas chromatography high resolution time-of-flight mass 3.0e6 5 Hordenin C10H15NO 274 949734 775 -0.14 -0.84 4 Parabanic acid, 1-methyl- C4H4N2O3 233 434278 764 Sample preparation 5 Cotinine C10H12N2O 336 27810908 918 • 6 Methylecgonine C10H17NO3 276 104640 835 -0.22 -1.1 spectrometry (GC-HRT) provides a fast and convenient method for 2.0e6 5 6 Caffeine C8H10N4O2 371 3753598 797 2.5e6 7 4-(3-Pyridyl-tetrahydrofuran-2-one C9H9NO2 313 93817 849 -0.11 -0.68 3,4 7 1-methyl-7H-xanthine C6H6N4O2 437 4868196 850 analysis of urine samples. The objective of this study was to develop a 8 6-Methoxycoumaran-7-ol-3-one C9H8O4 321 161718 727 0.02 0.12 8 1,3,7,9-Tetramethyluric acid C9H12N4O3 460 562206 795 1.5e6 9 Cotinine C10H12N2O 339 5866842 870 -0.07 -0.38 9 Androsterone (-H2O) C H O 467 3154663 893 comprehensive, fast and accurate method for compound 11 19 28 2.0e6 10 3-Hydroxycotinine C10H12N2O2 364 2087294 899 0.05 0.24 10 1H-Phenanthro[9,10-d]imidazole C15H10N2 487 2252140 770 11 Caffeine C8H10N4O2 374 1179748 880 0.07 0.35 1.0e6 11 Androstan-17-one, 3-hydroxy- C19H30O2 520 2661266 859 characterization and effective molecular profiling of urine samples. 12 1'-Naphthoyl Indole C H NO 613 1056803 879 Fig. 3: SPE * *12 Theobromine C7H8N4O2 383 261387 743 0.12 0.65 19 13 13 N-[4-Hydroxy-3-(methylthio)phenyl]-acetamide C H NO S 393 1382915 888 0.17 0.89 Urine Sample 1.5e6 9 11 2 12 5.0e5 14 Proline anhydride C10H14N2O2 397 441603 872 0.04 0.2 8-10 Preparation. 1,2 6 9 15 4-Methyl-5H-carboline C12H10N2 406 109887 757 -0.01 -0.06 7 17-19 16 Acridine, 9-methyl- C H N 408 253214 860 0.2 1.06 1.0e6 14 11 0.0e0 Why Urine? Time (s) 200 300 400 500 600 700 800 17 1-Methyl-6-(phenylethynyl)-1H-indole C17H13N 488 6799 808 -0.16 -0.71 AIC Fig. 12: Peak True (Top) and Library Mass Spectra 10 18 5H-benzo[f]pyrido[4,3-b]indole C15H10N2 490 50619 839 -0.03 -0.15 Fig. 11: AIC and Table Listing Compounds in Sample B. Used since ancient times for medical diagnosis (Urology 2,3 12 • 5.0e5 19 Phenylalanylproline lactam C14H16N2O2 492 53239 835 0.04 0.15 (Bottom) for 3-(1-Naphthoyl)indole in Sample B. 4 11 13 1 20 Cholesterol C27H46O 617 38109 723 0.27 0.71 Synthetic Drugs 7,8 Urinalysis) 5,6 14,15 * 20 * 2.0e4 Naphthoyl Indole 0.0e0 C) Spectra Table T ime (s) 200 300 400 500 600 700 800 900 Ave.|ppm| = 0.57 In ancient times considered “a divine fluid and window to the body” AIC • 1.8e4 A) XIC Acquisition Parameters Fig. 5: Analytical Ion Chromatogram (AIC) – Sample A. Table 1: Compounds in Sample A. 1.5e4 1.3e4 194.07989 1.0e4 1000 Peak True •+ Formula Expected m/z Observed m/z MA (ppm) 900 M 67.02909 7.5e3 C H O 386.35432 386.35459 0.71 800 0.35 ppm 27 46 Synthetic Drug 700 5.0e3 C26H43O 371.33084 371.33056 -0.77 or Metabolite? 600 O N N C27H44 368.34375 368.34348 -0.75 2.5e3 500 109.06342 400 N C26H41 353.32028 353.32002 -0.73 0.0e0 55.04170 N Time (s) 590 600 610 620 630 640 650 660 670 300 82.05260 XIC(270.0950±0.0005) XIC(357.1360±0.0005) C22H37 301.28898 301.28912 0.48 200 O A Cornucopia of 97.03957 C H 275.27333 275.27354 0.78 69.99247 136.05050 20 35 100 94.04013 165.07716 178.06264 dance) 0 Accurate Mass Ions! C11H13 145.10118 145.10135 1.23 Library Hit - Similarity: 880 - Library: DD2013 - Caffeine, Abundance 207.03243 Name Formula Expected194 m/z Observed m/z Mass Delta (Da) MA (ppm) 55.05427 1000 B) Peak True •+ 1000 M Library: 880/1000 Caffeine C H N O 194.07983 194.07989 0.00006 0.35 1000 386.35459 900 8 10 4 2 105.06983 Peak True •+ 900 900 M 800 C23H19NO3 81.06977 145.10135 700 270.09173 0.02 ppm Fig. 1: A Physician Examining Urine through a Matula (Left). A Urine Color Chart (Right). 800 800 0.71 ppm HO 600 91.05430 700 700 230.08144 500 281.05106 Accurate Mass Ion: 357.13595 JWH 073 N-Butanoic Acid Metabolite 69.06988 127.05444 o 600 600 275.27354 400 109 119.08559 150.12819 301.28912 500 500 159.11668 300 Formula Search (Spectra Table) 357.13595 55.01794 133.10129 59.01281 o 191.00108 200 254.09675 368.34348 55 Urine-based measurements exhibit advantages over other 400 213.16405 400 • 67 100 Result: C23H19NO3, 0.02 ppm 353.32002 255.21118 300 300 173.13215 o 82 0 199.14769 200 231.17431 Launch Database Search 200 42 biological fluids: 40 o 100 53 165 100 136 70 94 0 0 Fig. 13: An XIC showing an unknown synthetic drug or metabolite not present in the NIST or Wiley libraries (A). Peak True mass spectrum for the unknown (B). The M/Z 50 75 100 125 150 175 200 225 250 ® • Samples are easily collected in large quantities ChromaTOF-HRT Spectra Table (C) showing the formula C23H19NO3 for m/z = 357.13595 (mass accuracy = 0.02 ppm) and the initiation of a spectral database search Fig. 6: Peak True, Deconvoluted (Top) and Library Mass Fig. 7: Peak True Mass Spectrum and Table of resulting in the potential hit: 4-(3-(1-naphthoyl)1H-indol-1-yl, a JWH 073 N-butanoic acid metabolite. • Contain relatively high concentrations of pharmaceuticals, illicit Spectra (Bottom) for Caffeine in Sample A. Accurate Mass Ions for Cholesterol in Sample A. drugs, and steroids Sample C (Amphetamine + Pharmaceuticals + Metabolites) Traditional Drugs • Compounds are typically detectable over extended periods of 1.6e7 Peak Name Formula R.T. (s) Area Similarity MA(ppm) Peak Name Formula R.T. (s) Area Similarity MA(ppm) * Amphetamine C H N 170 9913299 841 -0.14 17 Hexahydropyrrolizin-3-one C H NO 302 2541535 730 -0.10 time XIC(194.0573±0.0005) XIC(327.1466±0.0005) 9 13 7 11 1.4e7 XIC(341.1626±0.0005) XIC(285.1358±0.0005) 1 3-Pyridinol C H NO 183 6185856 812 -0.09 Results: Illustrative Urine Samples: 5 5 18 4-(3-Pyridyl-tetrahydrofuran-2-one C9H9NO2 317 1453261 862 -0.95 XIC XIC(283.0639±0.0005) XIC(299.1516±0.0005) XIC(248.1884±0.0005)*Constant(5.000000) Peak Name Formula R.T. (s) Area Similarity MA(ppm) 2 Dihydrothymine C H N O 187 621464 746 0.73 ® D 5 8 2 2 19 Cotinine C10H12N2O 343 23921315 865 -0.91 1.2e7 3 N,2-Dimethylimidazole C5H8N2 188 178643 813 -0.47 20 methyl 1H-indole-3-acetate C H NO 371 1792478 792 -0.85 Instrument: LECO Pegasus GC-HRT 4.0e5 A Meconin C10H10O4 350 2826248 870 -0.39 11 11 2 4 Ethanol, 2-phenoxy- C8H10O2 194 4463665 809 -0.68 21 Hydroxycotinine C H N O 382 63335156 795 -0.57 10 12 2 2 3.5e5 Lupanine C H N O 463 84876 791 0.46 5 Octanoic acid, 2-methyl- C9H18O2 204 3662983 726 -0.29 B 15 24 2 1.0e7 22 Theobromine C7H8N4O2 397 5447784 790 -0.31 High Quality Spectral Data 6 Dihydrobenzofuran C8H8O 208 399549 737 0.00 • 23 Proline anhydride C10H14N2O2 401 5113606 854 -0.52 3.0e5 C Codeine C18H21NO3 502 1778096 915 0.04 3.5e6 7 Creatinine ME C5H9N3O 218 36375929 773 -0.92 24 Acridine, 9-methyl- C14H11N 410 519170 707 -0.47 8.0e6 *Amphetamine + ? Sample A 2.5e5 D (-)-Morphine C H NO 521 16361201 906 -0.43 8 o-Ethynylaniline C8H7N 221 3330816 792 -0.19 • Comprehensive 17 19 3 25 Imidazo[2,1-a]isoquinoline C11H8N2 419 1196366 741 -0.13 3.0e6 10 30,31 9 5-methylhydantoin C4H6N2O2 232 24651088 793 -0.46 (Traditional Drugs) Acetylcodeine C H NO 524 151719 749 1.43 26 Hydroxyandrostene C19H30O 461 1102975 824 -0.81 2.0e5 E 20 23 4 6.0e6 10 Nicotin C10H14N2 237 43628594 889 -1.04 2.5e6 20,21 27 Trimepramine C20H26N2 463 8095369 783 -0.47 • Search Against Well-Established Databases (e.g., NIST, Wiley) 11 1H-Indole, 3-methyl- C H N 249 1481839 808 -1.11 Heroin 6-Monoacetylmorphine C H NO 529 1268450 868 0.41 7-9 9 9 1.5e5 F 19 21 4 26,27 28 Androsta-5,16-dien-3-ol C19H28O 478 541953 813 0.22 2.0e6 A 19 12 2-(Methylmercapto)benzonitrile C8H7NS 255 5421426 868 -0.74 C 4.0e6 F 14,15 29 Cyclo (Phe-Pro) C14H16N2O2 492 1442590 747 -1.17 32 13 Creatinine, 1-acetyl- C6H9N3O2 276 1017562 767 -0.13 • Excellent Mass Accuracy Values (<1 ppm) = Robust Formulas for 1.0e5 1.5e6 12 22,23 30 Androsterone C19H30O2 526 252420 834 0.06 14 Methyl 4-hydroxyphenylacetate C9H10O3 288 1417270 738 -0.68 ∆9 16-18 31 Androstenediol C H O 529 798453 736 0.06 Cocaine -THC 5.0e4 2.0e6 1-6 28,29 19 30 2 E 13 24,25 15 2,3,5-Trimethyl-6-ethylpyrazine C9H14N2 292 207732 734 -0.91 Fragment, Molecular & Adduct Ions 1.0e6 3.5e6 B 32 Cholesterol C27H46O 619 799390 909 -0.35 * 16 4 - vinyl - syringol C10H12O3 298 219900 764 0.44 0.0e0 11 5.0e5 3.0e6 Time (s) 300 350 400 450 500 550 600 0.0e0 TM TM Time (s) 200 300 400 500 600 700 Ave.|ppm| = 0.51 • High Resolution Deconvolution (HRD ) AIC 0.0e0 2.5e6 T ime (s) 200 300 400 500 600 700 800 900 AIC AIC Fig.
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