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A Fast Analytical LC/MS/MS Method for the Simultaneous Analysis of Barbiturates and 11-Nor-9-Carboxy-Δ9- Tetrahydrocannabinol (THC-A) in Urine

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Application Note Clinical Research A Fast Analytical LC/MS/MS Method for the Simultaneous Analysis of Barbiturates and 11-nor-9-carboxy-Δ9- tetrahydrocannabinol (THC-A) in Urine Using ESI negative ionization mode and alternating column regeneration Authors Abstract Andre Szczesniewski and Most of the compounds in large drug panels are analyzed using positive ionization Carrie J. Adler mode. However, barbiturates and 11-nor-9-carboxy-Δ9-THC (THC-A) perform better Agilent Technologies, Inc. using electrospray ionization (ESI) in negative mode with the mobile phase pH favorable for negative ionization. This work developed a fast analytical method combining eight barbiturates and THC-A in a single analysis using alternating column regeneration (ACR) to increase sample throughput. Moving the analytes preferring negative ionization into a separate test increases the analytical sensitivity of the compounds, allowing for greater research capabilities. The simple sample preparation techniques used provided rapid analysis, good analytical sensitivity, and quantitation over a wide dynamic range. This analysis used an Agilent 6470 triple quadrupole mass spectrometer with Agilent Jet Stream technology in ESI negative ionization mode and an Agilent Infinity II 1290 UHPLC system. A second pump and 2-position 10-port switching valve were added to facilitate use of the ACR. A 100 µL aliquot of human urine was used for the analysis of barbiturates and THC-A. Chromatographic separation of the analytes was achieved in less than 3 minutes using a gradient method composed of a H2O:acetonitrile mixture with 5 mM ammonium acetate and two Agilent Poroshell 120 EC-C18, 2.1 × 100 mm, 1.9 μm columns. Quantitative analysis was performed using multiple reaction monitoring (MRM) transition pairs for each analyte and an internal standard in the negative ionization mode. The isobaric pair, amobarbital and pentobarbital, were not separated under these chromatographic conditions. Good linearity and reproducibility were obtained for the concentration range from 5 to 1,000 ng/mL with a coefficient of determination >0.995 for all analytes. Excellent reproducibility was observed for all analytes (CV <15 %). A fast, specific, and accurate quantitative LC/MS/MS analytical method was developed and verified for the simultaneous measurement of barbiturates and THC-A in urine. Introduction Compounds in large drug panels are O O O O O O O O O O analyzed using positive ionization mode. However, barbiturates and HN NH HN NH HN NH HN NH HN N 11-nor-9-carboxy-Δ9-THC (THC-A) O O O O O perform better in negative ionization Amobarbital Butabarbital Butalbital Methohexital Pentobarbital mode using a separate assay with the mobile phase pH favorable for negative O ionization. Included in the analysis were NH OH eight barbiturates and THC-A (Figure 1). O O O O O H3C barbiturates included: amobarbital, O O HN NH N HN NH OH butabarbital, butalbital, methohexital, CH pentobarbital, phenobarbital, O 3 O O hexobarbital, and secobarbital. This Phenobarbital Hexobarbital Secobarbital 11-nor-9-Carboxy-∆9-THC work developed a fast analytical method Figure 1. Analyte structures. combining barbiturates and THC-A in a single analysis using alternating column regeneration (ACR) to increase Experimental sample throughput. This analytical method used the ability of LC/MS/MS LC Configuration and parameters to detect compounds over a wide range Configuration of concentrations simultaneously. The Pump Two Agilent 1290 Infinity II binary pumps (p/n G7120A) calibration concentrations ranged from Multisampler Agilent 1290 Infinity II multisampler (p/n G7167A) 0.1 ng/mL to 5,000 ng/mL. The standard Agilent 1290 Infinity thermostatted column compartment with a 2-position 10 port valve Column compartment curve preparation was generated using (p/n G7116B) matrix-matched standards, diluting 1:10 Needle wash 50:20:20:10 IPA:MeOH:ACN:H2O and injecting into the LC/MS/MS system. Autosampler temperature 10 °C The methodology was developed on an Injection volume 10 µL Agilent 1290 Infinity II UHPLC and an Analytical column 2 Agilent Poroshell 120 EC-C18, 2.1 × 100 mm, 1.9 µm, LC columns (p/n 695775-902) Agilent 6470 LC/TQ mass spectrometer Column temperature 55 °C with a 5-minute analytical gradient. ACR Mobile phase A 5 mM Ammonium acetate in water reduced the analysis time by 26 %, to Mobile phase B Acetonitrile 3.7 minutes injection to injection. Flow rate 0.35 mL/min Eluent pump Regeneration pump Time (min) %B Time (min) %B 0.00 35 0.00 98 Gradient 1.60 45 1.40 98 1.61 98 1.50 35 3.00 98 3.01 45 3.59 45 Stop time Eluent pump: 3.65 minutes Regeneration pump: no limit 0.00 minutes Current position Valve position 3.59 minutes Next position 2 Chemicals and reagents Column 2 Human urine used for matrix-matched Valve (V1) position 1 calibrators was purchased from Golden West Biologicals, Inc, (Temecula, CA). 1 10 29 Standards and internal standards were Eluent pump Autosampler Waste bought from Cerillant Corporation 38 (Round Rock, TX). Sample preparation V1 47 and LC solvents were acquired from Regeneration Detector Honeywell (Muskegon, MI). pump 56 Sample preparation Standards were spiked into drug-free Column 1 human urine solution (10 %). The calibration curve was created by serial dilution following a pattern of Column 2 1:2:2:2.5. Concentrations ranged from Valve (V1) position 2 0.5 to 5,000 ng/mL. Internal standards were added to a final concentration of 1 10 29 200 ng/mL. Then, 10 μL were injected Eluent pump Autosampler Waste onto the LC/MS system. 38 V1 Data analysis 47 Regeneration Data acquisition was performed using Detector pump Agilent MassHunter Acquisition Software 56 (B.08.00). MS/MS transitions were obtained using Agilent MassHunter Acquisition optimizer software to Column 1 determine optimal parent and product Figure 2. Alternating column regeneration (ACR) valve configuration. ions, fragmentor voltages, and collision energies. Data were analyzed using Gradient run Agilent MassHunter Quantitative Analysis Rinse Eluent pump Software (B.08.00) and Qualitative V1 column 1 %B 0.6 minutes Analysis Software (B.07.00). 3 minutes Regeneration Column wash pump Column equilibration %B 1.4 minutes column 1 2.2 minutes ACR Analysis cycle time = 3.65 minutes Overlapped Draw and inject injection 0.85 minutes Figure 3. Graphical timeline for ACR analysis. 3 Results and discussion LC/TQ Mass spectrometer configuration and parameters Configuration Chromatography Instrument Agilent 6470 triple quadrupole mass spectrometer with Agilent Jet Stream The main emphasis of this work was MS/MS mode MRM increased throughput. Therefore, under Ionization mode Negative these chromatographic conditions, the Drying gas temperature 150 °C isobars amobarbital and pentobarbital Drying gas flow 11 L/min did not separate, and are reported as Nebulizer pressure 30 psi a single peak (Figure 4). If separation Sheath gas temperature 350 °C between amobarbital and pentobarbital Sheath gas flow 11 L/min is required, adjust the gradient and the Nozzle voltage 2,000 V run time to achieve baseline separation Capillary voltage 6,000 V between those isobars, as shown in Delta EMV 800 V Figure 6. Q1/Q2 resolution Unit/Unit Dwell time 50 ms Cell accelerator voltage 4 V MS/MS Compound information for analytes and internal standards Precursor ion Product ion Fragmentor Collision energy Compound ISTD? (m/z) (m/z) RT (min) (V) (V) Amo/Pentobarbital 225.1 182 1.78 105 12 Amo/Pentobarbital 225.1 42 1.78 105 24 AmoPentobarbital-D5 230.1 42 1.78 105 24 Butabarbital 211.1 168 1.32 165 12 Butabarbital 211.1 42 1.32 165 40 Butalbital 223.1 180 1.45 165 8 Butalbital 223.1 42 1.45 165 36 Butalbital-D5 228.1 42 1.45 165 36 Hexobarbital 235.1 42 1.85 85 20 Methohexital 261.1 42 2.66 65 20 Phenobarbital 231.1 188 1.17 140 8 Phenobarbital 231.1 42 1.17 140 36 Phenobarbital-D5 236.1 42 1.17 140 36 Secobarbital 237.1 194 2.02 170 12 Secobarbital 237.1 42 2.02 170 36 Secobarbital-D5 242.1 42 2.02 170 36 THC-A 343.2 299.2 2.88 125 24 THC-A 343.2 245 2.88 125 36 THC-A-D9 352.2 254.1 2.88 125 32 4 ×105 2.6 2.4 2.2 Hexobarbital 2.0 THC-A 1.8 1.6 1.4 1.2 Counts Amo/pentobarbital 1.0 Butalbital 0.8 Phenobarbital 0.6 Butabarbital Secobarbital Methohexital 0.4 0.2 0 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0 Acquisition time (min) Figure 4. dMRM Chromatogram showing elution of the nine compounds at 500 ng/mL. 2 ×102 ×102 ×102 ×10 Phenobarbital Butabarbital Butalbital 9 Amo/pentobarbital 7 5 ng/mL 5 pg OC* 6 5 ng/mL 5 pg OC 6 5 ng/mL 5 pg OC 8 0.5 ng/mL 500 fg OC 6 1,106.16 5 987.33 5 7 5 987.80 6 1,651.10 4 4 4 5 3 3 4 Counts 3 Counts Counts Counts 3 2 2 2 2 1 1 1 1 0 0 0 0 1.0 1.1 1.2 1.3 1.2 1.3 1.4 1.5 1.3 1.4 1.5 1.6 1.7 1.8 1.6 1.7 1.8 1.9 Acquisition time (min) Acquisition time (min) Acquisition time (min) Acquisition time (min) ×103 ×102 ×102 ×103 2.4 Hexobarbital 7 Secobarbital 6 Methohexital THC-A 2.4 2.0 0.5 ng/mL 500 fg OC 6 5 ng/mL 5 pg OC 5 5 ng/mL 5 pg OC 50 pg/mL 50 fg OC 2.0 1.6 5 4,093 3,409.85 888.02 4 604.16 1.6 4 1.2 3 1.2 Counts 3 Counts Counts Counts 0.8 2 2 0.8 0.4 1 1 0.4 0 0 1.7 1.8 1.9 2.0 1.9 2.0 2.1 2.2 2.5 2.6 2.7 2.8 2.5 2.6 2.7 2.8 Acquisition time (min) Acquisition time (min) Acquisition time (min) Acquisition time (min) Figure 5.
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