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Successful Sample Preparation Strategies for LC/MS/MS Analysis of Drugs in Complex Biological Matrices for Forensic Toxicology Applications

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Successful Sample Preparation Strategies for LC/MS/MS Analysis of Drugs in Complex Biological Matrices for Forensic Toxicology Applications Thank you for joining us! Our session will begin shortly… Successful Sample Preparation Strategies for LC/MS/MS Analysis of Drugs in Complex Biological Matrices for Forensic Toxicology Applications Jonathan Danaceau, Ph.D. Senior Applications Chemist Waters Corporation ©2013 Waters Corporation 1 Friendly Reminders… Please use text chat functionality to submit your questions today. Poll Questions – Audience participation Providing ‘Live’ Technical Support during today’s event Upon conclusion, follow up information will be available: http://www.waters.com/Nov5 Recorded version of today’s presentation PDF Copy of today’s slides Product discount offers Product specific information and reference materials ©2013 Waters Corporation 2 Today’s Speaker Jonathan Danaceau, Ph.D. Senior Applications Chemist Consumable Business Unit Waters Corporation, Milford, MA USA Dr. Jonathan Danaceau is a Senior Applications Chemist at Waters Corp. He received his B.S. in Biology from Allegheny College (Meadville, PA) and his Ph.D. in Neuroscience from the University of Utah (Salt Lake City, UT). Jon has an extensive background in bioanalysis including experience in the pharmaceutical industry, forensic toxicology, and anti-doping analysis. Jon joined Waters’ Chemistry Applied Technology group in 2011 and currently focuses on sample preparation and chromatography solutions for various applications, including forensic toxicology and clinical research. He will highlight a number of methods today that he has developed directly. ©2013 Waters Corporation 3 Overview Goal of Sample Preparation Sample Preparation Options Application Examples – Opioids and metabolites in urine, whole blood and oral fluid – Synthetic cannabinoids in urine and whole blood – Synthetic cathinones “Bath Salts” in urine – THC and metabolites in whole blood Summary ©2013 Waters Corporation 4 Overview Goal of Sample Preparation Sample Preparation Options Application Examples – Opioids and metabolites in urine, whole blood and oral fluid – Synthetic cannabinoids in urine and whole blood – Synthetic cathinones “Bath Salts” in urine – THC and metabolites in whole blood Summary ©2013 Waters Corporation 5 Goal of Sample Preparation Provides the target analyte(s) in solution Provides the analyte(s) at a concentration appropriate for detection or measurement – Concentrating the analyte helps increase sensitivity and achieve lower limits of detection Removes interfering matrix elements (such as phospholipids, salts, proteins, nucleic acids, sugars, etc.) that alter the MS response or co-elute with the target analyte – Matrix effects result in ion suppression (loss of signal) or ion enhancement (gain in signal) – Matrix effects have a negative impact on the accuracy, precision, and robustness of the method; add to method variability ©2013 Waters Corporation 6 Importance of Clean Samples Having cleaner samples means: – Better chromatography – Lower limits of detection – Decreases assay variability; more robust assay o Reduced matrix effects o Fewer reanalyses o Less chance of false positives/negatives – Longer column lifetime – Less instrument downtime – Minimize costs in manpower and equipment maintenance Sample Prep makes your analytical lab more productive! ©2013 Waters Corporation 7 Sample Preparation: A Major Bottleneck Typically the most difficult and time-consuming step It is the single biggest time constraint that labs face ~75% of the work activity and operating cost in an analytical lab is spent processing and preparing samples for injection Choice of format can significantly improve workflow and decrease processing time Typically the least amount of effort is spent developing a rugged sample preparation method Magical Method ©2013 Waters Corporation 8 Sample Preparation Options Non- Technique Advantages Disadvantages Appropriate selective Matrices Dilution Simple No cleanup Urine Cheap No enrichment Easy to automate Non-selective Protein Simple Minimal selectivity; does not remove Whole blood, Precipitation Quick most matrix interferences plasma, serum Minimal method development No enrichment Substantial solvent evaporation may be needed Liquid-Liquid Offers better clean up than protein Less selective than SPE; does not Urine, plasma, Extraction precipitation remove endogenous phospholipids serum, oral fluid Can be optimized for different Cumbersome; requires user compound classes intervention Difficult to automate Not ideal for highly polar drugs and metabolites Solvent evaporation needed Lipid/protein Simple, universal method Minimal selectivity Whole blood, removal Quick No enrichment plasma, serum plates Minimal method development Substantial solvent evaporation may be needed Solid-Phase Best cleanup option May require method development to Urine, whole Highly Extraction Fast; easy to automate optimize the protocol blood, plasma, selective (SPE) Achieves the highest recovery and Perceived to be difficult and costly serum, oral fluid reproducibility Can be manipulated for optimum recovery and cleanup Variety of device formats and sorbent chemistries ©2013 Waters Corporation 9 Waters Alternative to LLE: OstroOstro™™9696--WellWell Sample Preparation Plate Cleanup of phospholipids and proteins in plasma and serum (also blood) – Fast, easy in-well protein precipitation; precipitated proteins and phospholipids are left behind in the wells – Significant time savings; protocol eliminates extract transfer and evaporation steps (also in plate format) – Generic protocol; no method development Extracts can be directly injected and analyzed Suitable for a wide variety of acidic, basic, and neutral compounds Pass-through method ©2013 Waters Corporation 10 Phospholipids Remaining in the Extract: Ostro vs. LLE and PPT 100 184.4 > 184.4 (Lipid 184) LLE with 5% MRM of m/z 184-184 2.00e8 2.29 2.60 2.88 NH 4OH in MTBE 2.21 2.72 2.78 % 2.10 1.90 0 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 100 184.4 > 184.4 (Lipid 184) LLE with MTBE 2.00e8 2.27 2.56 2.62 2.68 2.80 % 1.90 0 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 100 184.4 > 184.4 (Lipid 184) Ostro™ 2.00e8 % 1.90 1.77 1.96 0 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 100 184.4 > 184.4 (Lipid 184) PPT 2.00e8 1.38 1.42 1.63 1.75 1.96 2.21 2.84 1.51 % 1.32 0 Time 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 Ostro is superior to LLE and PPT for phospholipid removal ©2013 Waters Corporation 11 Phospholipid BuildBuild--upup Over Time: Ostro vs. PPT After 200 injections, no phospholipid build up in the system when injecting samples extracted with Ostro plate ©2013 Waters Corporation 12 SolidSolid--PhasePhase Extraction (SPE) SPE is gaining acceptance in clinical and forensic labs – Cleans up, concentrates, and produces a final sample that is in an appropriate solvent for further analysis Uses polymeric or silica-based chromatographic particles packed into a variety of formats – 96 -well plates, cartridges, etc. SPE is considered to be a very versatile sample preparation technique for various analytes in complex matrices – Blood, serum, plasma, oral fluid, tears, nasal fluid, CSF, urine, feces, meconium, postmortem samples, and many more! It’s the best technique for minimizing matrix interferences including proteins, phospholipids, salts, and other endogenous compounds ©2013 Waters Corporation 13 Oasis ®® Family of Sorbents: ReversedReversed--PhasePhase and MixedMixed--ModeMode Sorbent ALWAYS Charged (-) Sorbent ALWAYS Charged (+) Selective for Selective for Basic Acidic Compounds Compounds Selective for Selective for Strong Strong Acidic Basic Compounds Compounds For wide range of acidic, basic, and neutral compounds Sorbent charged (-) at high pH; Sorbent charged (+) at Low pH; unionized at low pH unionized at high pH ©2013 Waters Corporation 14 Oasis 2x4 Methodology A simple, logical approach to the selection of an SPE sorbent and protocol Two protocols and four sorbents – For extraction of acids, bases, and neutrals – Optimized to achieve high SPE recoveries while removing matrix components that may interfere with analysis Oasis ® 2x4 Method: 1. Characterize your analyte. 2. Select 1 of the 4 Oasis sorbents. Oasis sorbent selection tools are available 3. Apply the designated Protocol (1 of 2). in plate and cartridge formats for 4. Analyze SPE recoveries and matrix convenient method development. effects. ©2013 Waters Corporation 15 Waters SPE Device Formats Formats – 96-well plates (with 5, 10, 30, 60 mg of sorbent) – Syringe barrel cartridges – Glass cartridges – Online columns – µElution plates How to process samples? – Gravity – Pressure – Vacuum – Automation ©2013 Waters Corporation 16 Waters SPE Device Formats: Oasis µElution Plate Technology Patented plate design Ideal for SPE cleanup and analyte enrichment of small sample volumes (10 µL to 375 µL) Elute in as little as 25µL; up to 15X concentration No evaporation and reconstitution required –Eluates can be directly injected –Saves time –No evaporative loss Speed Narrow and Tall bed –96-well plate in <30 min, <20 sec/sample Compatible with most liquid handling robotic systems for automated high throughput SPE ©2013 Waters Corporation 17 Overview Goal of Sample Preparation Sample Preparation Options Application Examples – Opioids and Metabolites in Urine Summary ©2013 Waters Corporation 18 OOpioidspioids and Metabolites in Urine Assay Use Quantification of opioids and metabolites in urine Analytes
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