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Determination of Benzodiazepines in Oral Fluid Using LC/MS/MS

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Determination of Benzodiazepines in Oral Fluid Using LC/MS/MS Determination of Benzodiazepines in Oral Fluid Using LC/MS/MS Application Note Forensic Toxicology Authors Introduction Christine Moore, Cynthia Coulter, and Katherine Crompton Benzodiazepines are the most commonly pre- Immunalysis Corporation scribed class of drugs in the USA for the treatment 829 Towne Center Drive of anxiety and insomnia, particularly in the elderly Pomona, CA 91767 [1]. They are also used as muscle relaxants and USA anticonvulsants. They are commonly detected in incidents of driving under the influence of drugs Michael Zumwalt (DUID), often in combination with other medica- Agilent Technologies, Inc. tions [2,3]. Oral fluid is becoming increasingly used 9780 S. Meridian Blvd. as a specimen in many areas of forensic interest, Englewood, CO 80112 including collection at the roadside during traffic USA stops. Its ease of collection, difficulty of adulteration, and applicability to routine testing Abstract has promoted its use as a valid test specimen. However, the detection of benzodiazepines in particular in oral fluid is not without difficulty A rapid, simple, highly sensitive procedure for the simul- since the saliva:plasma ratio for most of the drug taneous analysis of 14 benzodiazepines in oral fluid, using class is low. the Agilent 6410 Triple Quadrupole Mass Spectrometer (QQQ) in electrospray mode, is described. Sample prepa- One of the main issues with the quantitation of ration includes solid-phase extraction, evaporation of the drugs in oral fluid is the difficulty of collection in final eluent to dryness, and reconstitution in mobile phase terms of specimen volume. Many of the currently for injection into the LC/MS/MS system. To our knowl- available devices do not give an indication of how edge, the procedure is the first to include the simultane- much oral fluid is collected, thereby rendering any ous monitoring of a qualifying ion, which is required to be quantitative results meaningless without further present within a specific ratio to the primary ion for manipulation in the laboratory [4,5]. Further, acceptable identification. The unique features of the Agi- devices incorporating a pad or material for the lent software allow the transitions to be monitored and saliva collection do not always indicate how much automatically calculated into ratios, which must fall of each drug is recovered from the pad before within the range of the calibration standards in order to analysis, again calling into question any quantita- be considered positive. While monitoring a qualifying ion tive result. The drug concentration reported is naturally inhibits the sensitivity of the assay, the addi- dependent on the collection procedure used [6]. tional confidence in the result is a critical factor in foren- sic analysis. This work employs the Quantisal oral fluid collec- tion device, which collects a known amount of neat oral fluid. The efficiency of recovery of the benzo- diazepines from the collection pad into the trans- portation buffer is determined, in order to Experimental increase confidence in the quantitative value. Materials and Methods Several publications have addressed the issue of the analysis of benzodiazepines in oral fluid. Oral Fluid Collection Devices Quintela et al. [7] determined nine benzodi- azepines in neat oral fluid using an LC/MS proce- Quantisal devices for the collection of oral fluid dure. They included lormetazepam and specimens are obtained from Immunalysis Corpo- tetrazepam, which were not in our profile; how- ration (Pomona, CA). The devices contain a collec- ever, clonazepam, chlordiazepoxide, nordiazepam, tion pad with a volume adequacy indicator, which temazepam, oxazepam, flurazepam, and turns blue when one milliliter of oral fluid (± 10%) nitrazepam were not included. has been collected. The pad is then placed into transport buffer (3 mL), allowing a total specimen A recent publication from Oiestad et al reported volume available for analysis of 4 mL (3 mL buffer the screening of oral fluid using tandem LC mass + 1 mL oral fluid). This is specifically advanta- spectrometry for several drugs, including benzodi- geous in cases where the specimen is positive for azepines [8]. They analyzed fenazepam and some more than one drug and the volume of specimen benzodiazepine metabolites, which we did not available for analysis may be an issue. The oral include (see below); but they did not include the fluid concentration is diluted 1:3 when using prescribed drugs triazolam, temazepam, Quantisal collection devices, and drug concentra- midazolam, flurazepam, or chlordiazepoxide. tions detected were adjusted accordingly. Smink et al. [9] analyzed urine and oral fluid for 33 benzodiazepines using LC/MS/MS. With the Standards and Reagents exception of diazepam, where a limit of quantita- tion (LOQ) of 0 ng/mL was reported, the lower Deuterated internal standards: D5-diazepam; D5- limit of quantitation for the other analytes was sig- temazepam; D5-alprazolam and D4-clonazepam, as nificantly higher than in our application. In their well as unlabeled drug standards: bromazepam; study, five oral fluid samples were found to be pos- clonazepam; nitrazepam; triazolam; alprazolam; itive; two for oxazepam (concentrations of 18 and flunitrazepam; flurazepam; lorazepam; midazolam; 1,659 ng/mL) and three for alprazolam (concentra- chlordiazepoxide; diazepam, oxazepam, nor- tions of 5, 6, and 9 ng/mL). diazepam, temazepam were purchased from Ceril- liant (Round Rock, TX). Mixed-mode solid-phase In our research, we did not include the metabolites extraction columns (CSDAU020) were purchased such as 7-aminoflunitrazepam, 7-aminoclon- from United Chemical Technologies (Bristol, PA) azepam, 7-aminonitrazepam, α-hydroxy alprazo- α lam, -hydroxytriazolam, or desalkylflurazepam All solvents were of HPLC grade or better; all because the parent drug is more often in higher reagents were ACS grade and purchased from concentration than metabolites in oral fluid. We Spectrum Chemical (Gardena, CA). did, however, include metabolites such as nor- diazepam, temazepam, lorazepam, and oxazepam. Calibrators and Controls Calibration standards and controls were prepared from synthetic oral fluid and diluted with Quanti- sal transportation buffer. Throughout the develop- ment of the assay, multiple Quantisal collection devices were selected from different lots. In this experiment, the drug concentration used to fortify the synthetic oral fluid was adjusted according to the dilution factor for all calibration standards and controls. In this way, the final result obtained from the instrument did not need to be recalculated for dilution factors. For each analysis, a four-point cal- ibration curve (1, 10, 20, and 40 ng/mL) was run with each batch; the internal standard concentra- tion was 100 ng/mL. 2 Extraction Procedure Analytical Procedure Instrument: Agilent 1200 Series RRLC; 6410 LC Triple Quantisal buffer (1 mL) was measured and the cal- Quadrupole Mass Spectrometer ibration curve was prepared at the following con- LC Conditions centrations: Column: ZORBAX Eclipse XDB C18 4.6 x 50 mm x 1.8 µm Negative: 100 µL of deuterated stock solution (PN: 922795-902) (100 ng/mL) A 2.1-mm id column is optimal for a 0.2 mL/min 0.5 ng/mL: 100 µL of deuterated stock solution flow rate, but a 1 mL/min column flush is used (100 ng/mL) at the end of the run. 12.5 µL of 10 ng/mL stock solution Column 1 ng/mL: 100 µL of deuterated stock solution temperature: 35°C (100 ng/mL) Injection volume: 5 µL 5 µL of 10 ng/mL stock solution Solvent flow rate: 0.2 mL/min 10 ng/mL: 100 µL of deuterated stock solution (100 ng/mL) Isocratic pump 25 µL of 100 ng/mL stock solution program: A = 20 mM ammonium formate (pH = 8.6) B = Acetonitrile 20 ng/mL: 100 µL of deuterated stock solution 50:50 v,v (100 ng/mL) 50 µL of 100 ng/mL stock solution Time (minutes) Flow rate (mL/min) 40 ng/mL: 100 µL of deuterated stock solution 0 0.2 (100 ng/mL) 6.5 0.2 100 µL of 100 ng/mL stock solution 81 Sodium phosphate buffer (0.1 M, pH 6.0, 1 mL) was 10 0.2 added to the buffer and the samples were mixed. Post time: 4.5 min Extraction tubes were placed onto the vacuum Mass Spectrometer Conditions manifold and conditioned with methanol (3 mL), Operation: Electrospray ESI positive mode using Agilent deionized water (3 mL), and 0.1 M phosphate G1948B ESI source buffer (pH 6.0, 2 mL). The column bed was not Gas temperature: 300 °C allowed to dry. Each sample was poured through the column and allowed to dry, then rinsed with Gas flow (N2): 6 L/min deionized water (3 mL) and 0.1 M phosphate Nebulizer buffer pH 6.0: acetonitrile (80:20; 2 mL) and pressure: 15 psi (pressure of 30 to 40 psi recommended) allowed to dry. Hexane was allowed to flow Capillary voltage: 4,500 V through the column (1 mL). Finally, the drugs were eluted in ethyl acetate + 2% ammonium hydroxide The precursor and product ions, along with opti- (2 mL). The eluates were evaporated to dryness mized fragmentor and collision energy (CE) volt- under nitrogen (20 psi /37 °C) and reconstituted in ages, are shown in Table 1. Values pertaining to water (50 µL) for analysis. qualifier ions are in parentheses. Table 1. Benzodiazepine Acquisition Parameters Drug Recovery from the Collection Pad Compound Precursor Product Fragmentor CE ion ion (V) (V) Extraction efficiency of the collection system for Segment 1 benzodiazepines was determined. Oral fluid was (time = 0 min) fortified with all the drugs at the concentration of Bromazepam 316 288 (209) 160 20 (30) 10 ng/mL (n = 6). A collection pad was placed into Segment 2 the fluid until the volume adequacy indicator (time = 4.1 min) turned blue, showing that 1 mL (±10%) of oral fluid D4-Clonazepam 320 274 120 25 had been absorbed.
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