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Quantification of Drugs for Drug-Facilitated Crimes in Human Urine

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Quantification of Drugs for Drug-Facilitated Crimes in Human Urine Quantification of Drugs for Drug-Facilitated Crimes in Human Urine by Liquid Chromatography Tandem Mass Spectrometry Claudio De Nardi1, Anna Morando2, Anna Del Plato2 1Thermo Fisher Scientific, Dreieich, Germany; 2Ospedale “La Colletta”, Arenzano, Italy Overview TABLE 1. Concentrations of calibrators TABLE 3. Concentration range, intercept, slope and correlation factor (R2) Purpose: To implement a liquid chromatography tandem mass spectrometry method for forensic toxicology for the CAL CAL CAL CAL CAL CAL CAL Analyte Units Calibration quantification of drugs for drug-facilitated crimes in human 1 2 3 4 5 6 7 Analyte Intercept Slope R2 urine on a Thermo Scientific™ TSQ Access MAX™ triple stage Range Ketamine mass spectrometer; the method includes ketamine, its Ketamine 5 – 200 ng/mL -0.002 0.004 0.999 metabolites norketamine and dehydronorketamine, Norketamine phencyclidine and γ-butyrolactone (GBL); the method is also Norketamine 5 – 200 ng/mL 0.000 0.003 0.998 Dehydro ng/mL 5 10 20 50 100 200 N/A suitable for the detection of γ-hydroxybutyric acid (GHB) at norketamine Dehydronorketamine 5 – 200 ng/mL -0.001 0.002 0.999 physiological levels. Phencyclidine Phencyclidine 5 – 200 ng/mL 0.000 0.003 0.999 Methods: Following extraction using three volumes of GBL µg/mL 1 2 5 10 20 50 100 GBL 1 – 100 µg/mL -0.001 0.008 0.999 methanol containing 0.1% formic acid, samples were injected onto a Thermo Scientific™ Accela™ 600 HPLC system connected to a TSQ Access MAX triple stage mass Mass Spectrometry Figure 1. Calibration curve forGBL GBL spectrometer using a heated electrospray source. Data Y = -0.0006901+0.00760059*X R^2 = 0.9992 W: 1/X The LC system was connected to a TSQ Access MAX triple- acquisition was performed by selected reaction monitoring 0.8 stage quadrupole mass spectrometer; acquisition time ranges (SRM) and results were processed using Thermo Scientific™ were used for each analyte and the following MS conditions 0.7 Xcalibur™ software. were used: 0.6 Results: The analytical method proved to be linear for all the 0.5 analytes of interest in the calibration range 5-200 ng/mL for Heated electrospray ionization (HESI) in 0.4 Source type ketamine, its metabolites and phencyclidine and 1-100 µg/mL positive mode RatioArea 0.3 for GBL; the percentage bias between nominal and back- 0.2 calculated concentration for the calibrators was between - Vaporizer temp 325°C 10.6% and 12.3% and the correlation factor (R2) always above 0.1 Capillary temp 280°C 0.998. The method also proved to be able to detect GHB in 0.0 human urine above the endogenous level. 0 20 40 60 80 100 Spray voltage 4000 V ug/mL Sheath gas 35 AU Figure 2. Representative chromatograms of each analyte at the LOQ Introduction Sweep gas 0 AU C:\Users\...\DFC\PCP_KET\PCP_CC5_001 09/18/14 08:55:28 PCP_CC5_001 None A considerable increase in the number of reported drug- Auxiliary gas 10 AU RT: 6.30 - 7.30 RT: 6.30 - 7.30 RT: 6.30 - 7.30 RT: 6.30 - 7.30 RT: 6.78 RT: 6.78 RT: 6.75 RT: 6.78 facilitated crimes (DFC) has occurred in recent years. Drugs 100 100 100 100 that can induce a state of semi- or unconsciousness in the Data acquisition mode Selected reaction monitoring (SRM) 80 Ketamine 80 Norketamine 80 Dehydro- 80 Ketamine-D4 norketamine victims are most typically used in these cases; victims are 60 60 60 60 usually unable to fight off their attackers and report their Chrom filter peak width 5.0 s 40 40 40 40 inability to prevent the crime as it occurs. Sedative-hypnotic 6.32 6.71 Collision gas pressure 1.5 mTorr Relative Abundance Relative Abundance Relative Abundance Relative Abundance 20 20 20 6.79 20 drugs like norketamine, phencyclidine and GHB are among the 6.37 6.85 6.67 6.94 6.44 7.11 6.49 6.91 6.91 7.01 6.45 6.65 6.92 7.28 0 0 0 0 compounds most frequently involved in this kind of offences. c:\users\...\dfc\ghb_gbl\ghb_cc1_001c:\users\...\dfc\ghb_gbl\ghb_cc1_001 09/18/14 11:19:2109/18/14 11:19:21GHB_CC1_001 GHB_CC1_001 Cycle time 0.400 s 6.5 7.0 6.5 7.0 6.5 7.0 6.5 7.0 NoneNone We hereby report the implementation of an LC-MS/MS Time (min) Time (min) Time (min) Time (min) RT:RT:6.306.30 - 7.30 - 7.30 RT:RT:6.306.30 - 7.30 - 7.30 RT:RT:3.303.30 - 7.30 - 7.30SM: 15BSM: 15B RT:RT:3.303.30 - 7.30 - 7.30 analytical method for the quantification of ketamine and its Q1 (FWMH) 0.7 RT:RT: 6.83 6.83 RT:RT: 6.84 6.84 RT: 5.36 NL:RT: 2.55E4 5.36 RT: 5.37RT: NL:5.37 100100 100100 100100 100100 metabolites norketamine and dehydronorketamine, TIC F: + c ESI 2.42E6 SRM ms2 87.100 TIC F: + c ESI 80 80 80 80 GBL-D6 Q3 (FWMH) 0.7 80 80 80 [43.599-43.601, 80 SRM ms2 phencyclidine, GHB and its metabolite GBL in human urine. PCP PCP-D5 45.599-45.601] 93.100 60 60 60 60 6060 4.56MS ghb_cc1_001 6060 [49.599- SRM transitions See Table 2 49.601] MS 40 40 40 40 4040 4040 ghb_cc1_001 Relative Abundance Relative Abundance Relative Abundance Relative Abundance Relative Abundance Relative Abundance Relative Abundance Relative Abundance 20 20 20 20 2020 GBL 2020 7.197.19 Methods 6.676.67 6.88 6.61 6.43 6.766.76 6.976.977.14 4.15 TABLE 2. SRM transitions 0 0 0 0 0 0 0 0 Sample Preparation 6.5 6.5 7.07.0 6.56.5 7.07.0 5 4 6 4 4 6 6 TimeTime (min) (min) TimeTime (min) (min) Time (min)Time (min) Time (min)Time (min) A calibration curve covering the concentration range 5-200 ng/mL Start Stop Tube Precursor Product Collision was prepared by spiking blank human urine with methanolic Analyte Time Time Lens Ion Ion Energy solutions (50x) containing ketamine and its metabolites (min) (min) (V) (m/z) (m/z) (V) The method also proved to be able to detect GHB in human norketamine and dehydronorketamine and phencyclidine. 300 μL urine above the endogenous level; a signal-to-noise ratio above of a 100 ng/mL solution containing ketamine-D4 and Ketamine 6.0 8.0 70 238.0 125.1 28 400 was obtained for GHB in the three human urine samples phencyclidine-D5 in methanol with 0.1% formic acid were added Norketamine 6.0 8.0 70 224.0 125.1 24 analysed. A representative chromatogram for GHB in a real to 100 μL of each calibrator; a blank urine sample was also added. Dehydro 6.0 8.0 70 222.0 142.1 20 urine sample is reported in Figure 3. Due to the high concentrations involved, a calibration curve of norketamine GBL in methanol was prepared to cover the concentration range Ketamine-D4 6.0 8.0 70 242.0 129.1 26 Figure 3. Representative chromatogram of GHB from a 1,2 of 1-100 μg/mL; this range was based on the assumption of an 86.3 12 real urine sample endogenous level for GHB in urine of 10-50 μg/mL. 100 μL of Phenylcyclidine 6.0 8.0 40 244.1 91.2 28 RT: 0.00 - 8.00 SM: 11B each calibrator, including a blank, were added to 300 μL of a 50 RT: 2.30 NL: 4.88E5 μg/mL solution of GHB-D6 and GBL-D6 in water/methanol/formic 159.1 11 100 TIC F: + c ESI SRM ms2 105.100 [45.599-45.601, acid 33/67/0.1 (v/vv). 86.3 12 80 69.399-69.401, 87.299-87.301] M S GHB_URINE_SAM PLE_002 All samples from the two extracted calibration curves were vortex- Phenylcyclidine-D5 6.0 8.0 60 249.1 96.2 29 60 mixed, centrifuged and the supernatant injected onto an LC- 164.1 11 40 MS/MS system. 45.6 17 Relative Abundance 20 γ-Hydroxybutyric Nominal concentrations of calibrators are reported in Table 1. 1.0 5.0 25 105.1 69.4 10 acid 0 87.3 5 0 1 2 3 4 5 6 7 8 Liquid Chromatography γ-Hydroxybutyric Time (min) 1.0 5.0 45 111.1 93.3 5 The following LC conditions were used: acid-D6 43.6 10 Conclusion γ-Butyrolactone 3.0 7.0 60 87.1 Thermo Scientific™ Transcend™ I TLX-1 45.6 15 A liquid chromatography tandem mass spectrometry method for LC system system used in LX mode γ-Butyrolactone- forensic toxicology for the quantification of a panel of drugs for 3.0 7.0 60 93.1 49.6 15 D6 DFC and their metabolites in human urine has been developed Thermo Scientific™ Hypersil GOLD™ on a TSQ Quantum Access MAX. The instrument proved to Analytical column 150x2.1mm (3µ) @ RT have the sensitivity and linearity of response suitable to cover Data Analysis the necessary range of concentration for these drugs. Mobile phase A. 0.1% formic acid in water Data were quantitated using a linear regression and 1/x B. 0.1% formic acid in methanol weighing was used to build the calibration curves. A maximum percentage bias between nominal and calculated concentration Time Flow Rate A B References Gradient Profile of 15% was set as acceptance criterion for all calibrators.
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