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TN-0143 APPLICATIONS Designer and Pharmaceutical Benzodiazepine Analysis from Urine using In-Well Hydrolysis Solid Phase Extraction (SPE) and LC-MS/MS Brittany LeBlanc Phenomenex, Inc., 411 Madrid Ave., Torrance, CA 90501 USA Overview Sample Preparation Designer benzodiazepines are a rapidly increasing threat as an alternative to prescription benzodiazepines and due to their com- Pre-treatment plex structures and sample matrices, clean-up techniques can Combine 100 μL spiked urine, 30 μL IMCS Room Temp buffer, be difficult to develop. Designer benzos provide many analytical 270 µL water, and 10 μL of IMCSzyme RT onto the plate. Incu- challenges due to the limited knowledge of their metabolites and bate for 15 minutes at room temperature. the similarities to traditional pharmaceutical benzodiazepines, such as Diclazepam and its metabolite, Lorazepam. This can Solid Phase Extraction Method make clean-up and separation a problematic step in the method 96-Well Plate: Strata-X Drug B Plus, 30 mg/well development process. Part No.: 8E-S128-TGB-P Condition: Not required Equilibration: Not required In traditional sample preparation methods, the hydrolysis step Load: After incubation time is up, switch vacuum manifold on quickly to facilitate must be performed prior to the extraction step and analytes must flow through the SPE sorbent be converted back to their non-conjugated form, which often re- Wash 1: 1 mL of 1.0 % Formic acid in Water Wash 2: 1 mL of Water/Methanol (70:30) quires long wait time and high temperatures by either ovens or Dry: 10 minutes at high vacuum water baths. Once the hydrolysis has been performed, samples Elute: 2x 0.5 mL 5 % Ammonium hydroxide in Methanol/Acetonitrile (50:50) must be transferred to an extraction product which could cause Dry Down: To dryness at 40 °C under a gentle stream of Nitrogen Reconstitute: 100 µL 0.1% Formic acid in Water/0.1% Formic acid in Methanol (85:15) cross-contamination or loss of sample in the transfer step. By utilizing a room temperature beta-glucuronidase enzyme that is designed for fast hydrolysis without the need of high tempera- tures and by using solid phase extraction (SPE), this can save HPLC Conditions ® significant time in the sample preparation workflow. Strata -X Column: Kinetex® 2.6 µm Biphenyl Drug B Plus is a mixed-mode polymeric SPE product with in- Dimensions: 100 x 3.0 mm well hydrolysis capabilities, saving significant sample process- Part No.: 00D-4622-Y0 Mobile Phase: A: 0.1% Formic acid in Water ing time and additional lab equipment needs. Utilizing Strata-X B: 0.1% Formic acid in Methanol Drug B Plus as a SPE solution also does not require condition Gradient: Time (min) % B or equilibration steps, further reducing the time spent on sample 0 60 1 60 preparation while not sacrificing high recoveries of analytes or 2 70 removal of matrix interferences. 5 95 6 95 The objective of this project was to develop a fast and complete 6.1 60 8 60 quantitative liquid chromatography-tandem mass spectrometry Flow Rate: 0.6 mL/min (LC-MS/MS) method utilizing a room temperature hydrolysis Injection Volume: 1 µL combined with an advanced SPE product for the analysis of de- Temperature: 40 °C ® signer and pharmaceutical benzodiazepines in urine. System: Agilent 1260 Detection: MS/MS (SCIEX® Triple Quad™ 4500, ESI+) Detector: 6500 QTRAP® (SCIEX) Backpressure: ~160 bar (250 bar at max) Materials and Methods Reagents and Chemicals Alprazolam, N-desmethylclobazam, Clonazepam, 7-amino- clonazepam, Clonazolam, Diazepam, Estazolam, Etizolam, Flualprazolam, Flubromazepam, Flubromazolam, Flunitrazol- am, Lorazepam, Nordiazepam, Oxazepam, Phenazepam, and Temazepam reference standards as well as Diazepam-D5, Nordiazepam-D5, Oxazepam-D5, Temazepam-D5 deuterated internal standards were purchased from Cayman Chemical (Ann Arbor, MI). Clobazam and Deschloretizolam reference standards and Clobazam-13C6 internal standard were purchased from Cerilliant® Corporation (Round Rock, TX). Optima LC-MS grade formic acid, water, and methanol were ordered from Fisher Scien- tific (Pittsburgh, PA). Beta-glucuronidase enzyme was purchased from IMCS Inc. (Irmo, SC). Certified drug free urine was sourced from UTAK (Valencia, CA). Have questions or want more details on implementing this method? We would love to help! Visit www.phenomenex.com/Chat to get in touch with one of our Technical Specialists Page 1 of 5 APPLICATIONS Table 1. MS/MS Conditions Analyte Retention Times Q1 Mass Q3 Mass Time ID DP EP CE CXP Analyte Name Retention Time (min) (Da) (Da) (msec) (Volts) (Volts) (Volts) (Volts) 7-Aminoclonazepam 1.47 286.1 121 50 7-Aminoclonazepam (1) 85 10 35 12 Alprazolam+ 5.15 286.1 222.2 50 7-Aminoclonazepam (2) 85 10 35 16 Alprazolam-D5 5.15 309.1 205.1 50 Alprazolam (1) 0 10 55 6 Clobazam* 4.79 309.1 281.1 50 Alprazolam (2) 85 10 30 10 Clobazam-13C6 4.79 313 314.2 50 Alprazolam-D5 85 10 10 6 Clonazepam 4.21 301.1 259.1 50 Clobazam 80 10 35 8 Clonazolam 4.51 307 265 50 Clobazam-13C6 80 10 25 20 Deschloretizolam+ 5.66 316.2 270.2 50 Clonazepam (1) 75 10 35 20 Diazepam 5.56 316.2 214.2 50 Clonazepam (2) 70 10 50 6 Diazepam-D5 5.52 354 308 50 Clonazolam (1) 80 10 35 20 Diclazepam 5.33 354 280 50 Clonazolam (2) 85 10 45 18 Estazolam 5.00 309.1 280.1 50 Deschloretizolam (1) 80 10 30 10 Etizolam 5.57 309.1 225.1 50 Deschloretizolam (2) 85 10 45 12 Flualprazolam 4.83 285.3 193.2 50 Diazepam (1) 40 10 40 12 Flubromazepam 4.49 285.3 154.2 50 Diazepam (2) 80 10 35 10 Flubromazolam 5.01 290.2 154.2 50 Diazepam-D5 85 10 40 12 Flunitrazolam 4.31 319 227 50 Diclazepam (1) 85 10 40 16 Lorazepam 3.93 319 154 50 Diclazepam (2) 85 10 40 10 N-Desmethylclobazam^ 4.03 295 205 50 Estazolam (1) 50 10 45 14 Nordiazepam 4.71 295 267.1 50 Estazolam (2) 45 10 35 10 Nordiazepam-D5 4.67 343.1 314.1 50 Etizolam (1) 85 10 30 10 Oxazepam^ 4.21 343.1 138.2 50 Etizolam (2) 80 10 40 10 Oxazepam-D5 4.18 327 299 50 Flualprazolam (1) 85 10 30 10 Phenazepam 4.67 327 223 50 Flualprazolam (2) 40 10 50 14 Temazepam* 5.08 333 226 50 Flubromazepam (1) 0 10 35 14 333 206 50 Flubromazepam (2) 0 10 50 10 Legend: * Isomeric Pair 333 184 50 Flubromazepam (3) 40 10 50 12 + Isobaric Pair 371 292.1 50 Flubromazolam (1) 85 10 35 10 ^ Isomeric Pair 371 223 50 Flubromazolam (1) 80 10 35 14 338 292 50 Flunitrazolam (1) 45 10 35 10 338 264 50 Flunitrazolam (2) 40 10 45 14 321.3 275.3 50 Lorazepam (1) 0 10 35 14 321.3 229.1 50 Lorazepam (2) 70 10 40 14 287 245 50 N-Desmethylclobazam 80 10 25 8 271.3 140.3 50 Nordiazepam (1) 0 10 40 10 271.3 164.9 50 Nordiazepam (2) 40 10 35 12 276.3 140.1 50 Nordiazepam-D5 65 10 35 10 287.1 241.1 50 Oxazepam (1) 75 10 30 12 287.1 246.3 50 Oxazepam (2) 75 10 20 10 292.3 246.3 50 Oxazepam-D5 65 10 20 12 351 179 50 Phenazepam 70 10 55 12 301.3 255.2 50 Temazepam (1) 70 10 30 8 301.3 177.1 50 Temazepam (2) 40 10 50 6 Parameter Setting Curtain Gas (CUR) 20 psi Collision Gas (CAD) 6 psi IonSpray Voltage (IS) 4500 V Temperature (TEM) 550 °C Ion Source Gas 1 (GS1) 40 psi Ion Source Gas 2 (GS2) 60 psi Page 2 of 5 Page PB of 5 APPLICATIONS Figure 1. Figure 2. Representative Chromatogram, 400 ng/mL Neat Standard Oxazepam (1,000 ng/mL) and N-desmethylclobazam (50 ng/mL) in Urine 1.09e6 1.9e5 1.05e6 1.8e5 1.00e6 9.50e5 1.7e5 9.00e5 1.6e5 8.50e5 1.5e5 8.00e5 1.4e5 7.50e5 1.3e5 7.00e5 1.2e5 6.50e5 1.1e5 6.00e5 1.0e5 5.50e5 9.0e4 5.00e5 4.50e5 8.0e4 Intensity, cps Intensity, cps 4.00e5 7.0e4 3.50e5 6.0e4 3.00e5 5.0e4 2.50e5 4.0e4 2.00e5 3.0e4 1.50e5 2.0e4 1.00e5 App ID 26067 1.0e4 App ID 26072 5.00e4 0.00 0.0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 min 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 min Figure 3. Figure 4. Clobazam (10 ng/mL) and Temazepam (25 ng/mL) in Urine Oxazepam (1,000 ng/mL) and N-desmethylclobazam (50 ng/mL) in Urine 1.8e5 9.9e4 1.7e5 9.5e4 1.6e5 9.0e4 1.5e5 8.5e4 8.0e4 1.4e5 7.5e4 1.3e5 7.0e4 1.2e5 6.5e4 1.1e5 6.0e4 1.0e5 5.5e4 9.0e4 5.0e4 8.0e4 4.5e4 Intensity, cps 7.0e4 4.0e4 Intensity, cps 6.0e4 3.5e4 5.0e4 3.0e4 4.0e4 2.5e4 2.0e4 3.0e4 1.5e4 2.0e4 App ID 26070 1.0e4 App ID 26071 1.0e4 0.14 5000.0 0.0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 min 0.0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 min Time, min Table 2.
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    S1 Table. List of Medications Analyzed in Present Study Drug

    S1 Table. List of medications analyzed in present study Drug class Drugs Propofol, ketamine, etomidate, Barbiturate (1) (thiopental) Benzodiazepines (28) (midazolam, lorazepam, clonazepam, diazepam, chlordiazepoxide, oxazepam, potassium Sedatives clorazepate, bromazepam, clobazam, alprazolam, pinazepam, (32 drugs) nordazepam, fludiazepam, ethyl loflazepate, etizolam, clotiazepam, tofisopam, flurazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, brotizolam, quazepam, loprazolam, zopiclone, zolpidem) Fentanyl, alfentanil, sufentanil, remifentanil, morphine, Opioid analgesics hydromorphone, nicomorphine, oxycodone, tramadol, (10 drugs) pethidine Acetaminophen, Non-steroidal anti-inflammatory drugs (36) (celecoxib, polmacoxib, etoricoxib, nimesulide, aceclofenac, acemetacin, amfenac, cinnoxicam, dexibuprofen, diclofenac, emorfazone, Non-opioid analgesics etodolac, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, (44 drugs) ketoprofen, ketorolac, lornoxicam, loxoprofen, mefenamiate, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, pranoprofen, proglumetacin, sulindac, talniflumate, tenoxicam, tiaprofenic acid, zaltoprofen, morniflumate, pelubiprofen, indomethacin), Anticonvulsants (7) (gabapentin, pregabalin, lamotrigine, levetiracetam, carbamazepine, valproic acid, lacosamide) Vecuronium, rocuronium bromide, cisatracurium, atracurium, Neuromuscular hexafluronium, pipecuronium bromide, doxacurium chloride, blocking agents fazadinium bromide, mivacurium chloride, (12 drugs) pancuronium, gallamine, succinylcholine