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Appendix-2Final.Pdf 663.7 KB North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project Appendix 2 – Analytical methodologies Overview Urine samples were analysed using three methodologies. The first methodology (General Screen) was designed to cover a wide range of analytes (drugs) and was used for all analytes other than the synthetic cannabinoid receptor agonists (SCRAs). The analyte coverage included a broad range of commonly prescribed drugs including over the counter medications, commonly misused drugs and metabolites of many of the compounds too. This approach provided a very powerful drug screening tool to investigate drug use/misuse before and whilst in prison. The second methodology (SCRA Screen) was specifically designed for SCRAs and targets only those compounds. This was a very sensitive methodology with a method capability of sub 100pg/ml for over 600 SCRAs and their metabolites. Both methodologies utilised full scan high resolution accurate mass LCMS technologies that allowed a non-targeted approach to data acquisition and the ability to retrospectively review data. The non-targeted approach to data acquisition effectively means that the analyte coverage of the data acquisition was unlimited. The only limiting factors were related to the chemical nature of the analyte being looked for. The analyte must extract in the sample preparation process; it must chromatograph and it must ionise under the conditions used by the mass spectrometer interface. The final limiting factor was presence in the data processing database. The subsequent study of negative MDT samples across the North West and London and the South East used a GCMS methodology for anabolic steroids in addition to the General and SCRA screens. Official Sensitive (Commercial) Page 79 of 232 North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project Sample Preparation General Screen A 2ml portion of the urine sample was dispensed from the primary container. A 1ml aliquot of 1M pH 6.3 phosphate buffer containing D3 morphine glucuronide, D6 clozapine, D10 gabapentin and d3 EDDP was added and the mixture hydrolysed overnight at 45 oC using beta glucuronidase derived from Helix pomatia. The sample was then centrifuged prior to extraction using a solid phase extraction (SPE) methodology on an Agilent Nexus reversed phase polymer sorbent. The resulting elution from the cartridge was taken to dryness in a centrifugal evaporation system, reconstituted in LCMS mobile phase and submitted for analysis by full scan high resolution accurate mass LCMS SCRA Screen A 2ml portion of the urine sample was dispensed from the primary container. A 1ml aliquot of 1M pH 4.7 acetate buffer containing D5 hydroxypentyl JWH-018 was added and the mixture hydrolysed overnight at 45 oC using beta glucuronidase derived from Helix pomatia. The pH of the sample was then adjusted to pH 12 and a liquid/liquid extraction performed for 20 minutes. The sample was then centrifuged and the organic layer removed and taken to dryness in a centrifugal evaporation system, reconstituted in LCMS mobile phase and submitted for analysis by full scan high resolution accurate mass LCMS. Anabolic Steroid Screen (phase 2 of study) A 2.5ml portion of the urine sample was dispensed from the primary container. A 0.5ml aliquot of 2.5M pH 6.8 acetate buffer containing d3 morphine glucuronide and various anabolic steroid internal markers was added and the mixture hydrolysed overnight at 37 oC using beta glucuronidase derived from E. coli. The sample was extracted using a double SPE methodology. The first stage was performed on a Phenomenex Strata XC mixed mode cation exchange polymeric sorbent. A first elution contained neutral anabolic steroids and this was further purified using an anion exchange polymeric sorbent. The resulting eluent was taken to dryness in a centrifugal evaporator and reconstituted in a derivatising mixture before transfer to a GCMS vial. The capped vial was heated at 80C for 2 hours to form enol trimethylsilyl derivatives. The sample was then submitted for analysis by GCMS. A second elution was performed on the mixed mode cation exchange cartridge to remove basic compounds. This was combined with part of the first elution and then taken to drynesss in a centrifugal evaporation system. The sample was then reconstituted in LCMS mobile phase and submitted for analysis by full scan high resolution accurate mass LCMS using the general screen instrument conditions below. Instrumental analysis General Screen Samples were analysed on an Accela UPLC system interfaced to an LTQ Orbitrap Discovery High Resolution Accurate Mass mass spectrometer from Thermo operating in positive ion electrospray mode. Data were acquired in full scan mode operating at a mass resolution of Official Sensitive (Commercial) Page 80 of 232 North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project 30,000 across a mass range of 85-600 amu.. In addition, a second scan event using ‘in source fragmentation’ at a setting of 100V was acquired at a mass resolution of 15,000 across a scan range of 50-500 amu. Acquired data files were processed using Thermo Toxfinder software against a database containing NPS compounds augmented with compounds specifically requested by NOMS. The content of this database is listed in the database section at the end of the methods section. SCRA Screen Samples were analysed on an XRS UPLC system interfaced to a Q Exactive Focus High Resolution Accurate Mass mass spectrometer from Thermo operating in heated positive ion electrospray mode. Data were acquired in full scan mode operating at a mass resolution of 70,000 across a mass range of 240-550 amu.. In addition, a second scan event using ‘all ion fragmentation’ was performed with a stepped HCD setting of 37,45 at a mass resolution of 35,000 across a scan range of 95-500 amu. GCMS Screen for anabolic steroids Sample were analysed on an Agilent 5973 MSD GCMS instrument operating in windowed selected ion monitoring (SIM) mode. A SIM/SCAN acquisition method was used allowing targeted screening for ‘expected’ compounds and concurrent coverage for unexpected compounds in the same analysis. Data Processing General Screen Acquired data files were processed using Thermo Toxfinder software against a database containing NPS compounds augmented with compounds specifically requested by NOMS. The content of this database is listed in the database section at the end of the methods section. SCRA Screen Acquired data files were processed using Thermo Toxfinder software against a database containing SCRA compounds. The content of this database is listed in the database section at the end of the methods section. Data processing summary Data processing is based on the ability of the instrumentation to measure masses very accurately. Compounds with the same apparent molecular weight but different empirical formulae will actually have different accurate masses. This gives a much higher degree of selectivity when processing data, as mass windows of +/- 2 mDa (0.002 Da) can be used. The data processing software uses the accurate masses of the database analytes, the chromatographic retention time (Rt) of the database analytes, accurate mass qualifier ions where appropriate/available and a comparison of theoretical (derived from elemental composition) against actual isotope pattern. Where the search criteria are met, an identification is made. Manual data review is then performed to verify the findings. Where the identity of a finding was in doubt, further analysis by MS/MS techniques was performed to either confirm or rule out a finding. GCMS Anabolic Steroid Screen Official Sensitive (Commercial) Page 81 of 232 North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project The screening methodology for anabolic steroids by GCMS is a targeted test. Data processing is through the generation of hardcopy reports with extracted ion chromatograms for each anabolic steroid and associated metabolites. Data are reviewed manually by experienced/ trained laboratory personnel. Method capability General Screen – capability determined for major findings. As the analysis was qualitative and not quantitative, cut off levels were not used in the testing/reporting. The variations in sensitivity between analytes were due primarily to differences in extraction recovery, mass spectrometer ionisation efficiency and the analytical signal to noise for each analyte. Some compounds, had less interference from background material than others, hence better signal to noise, leading to better method capabilities. A comparison is given below between MDT screening cut-offs and LGC screening capabilities for the major findings in the urine analysis element of the study. Analyte LGC Screen Capability MDT screening cut-offs VDT (ng/ml) (ng/ml) 6-MAM 1 2 Amitriptyline 1 n/a Amphetamine 5 1000 Buprenorphine 1 5 Cannabis 250 50 Carbamazepine 2 n/a Chlorpromazine 2 n/a Citalopram 2 n/a Clonazepam 10 n/a Cocaine (BZE) 10 300 Codeine 5 300 Diazepam 10 200 Dihydrocodeine 10 300 Fluoxetine 5 n/a Gabapentin 100 n/a Ibuprofen >1000 n/a Lamotrigine 2 n/a MDMA 5 1000 Methadone 1 300 Mirtazapine 5 n/a Morphine 5 300 Nefopam 1 n/a Nitrazepam 5 n/a Olanzapine 5 n/a Paracetamol 25 n/a Pregabalin 100 n/a Official Sensitive (Commercial) Page 82 of 232 North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project Analyte LGC Screen Capability MDT screening cut-offs VDT (ng/ml) (ng/ml) Quetiapine 5 n/a Sertraline 10 n/a Sildenafil 5 n/a Stanozolol-3'OH 2 n/a Tramadol 5 n/a Trazodone 2 n/a Trenbolone 5 n/a Venlafaxine 1 n/a Zopiclone 10 n/a Initially the level of detection for cannabis was set much higher than for MDT, at 250 ng/ml. This was later adjusted to 25 ng/ml to provide a close comparison with MDT. The screening levels reported in the above table are based on a post study determination of the method capability.
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