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Rosscarrde2017.Pdf (4.959Mb) THE UNIVERSITY OF CENTRAL OKLAHOMA Edmond, OK Jackson College of Graduate Studies Method Development and Validation for Drug Identification and Confirmation by LC/MS-MS for Limited-specimen Cases A THESIS SUBMITTED TO THE GRADUATE FACULTY In partial fulfillment of the requirements For the degree of MASTER OF SCIENCE By Danielle Ross-Carr Edmond, Oklahoma 2017 DRUG IDENTIFICATION AND CONFIRMATION BY LC/MS-MS iii Acknowledgements I would like to express my appreciation to the Oklahoma State Bureau of Investigation Forensic Science Center and Andrea Swiech for allowing me the opportunity to complete this project and providing all necessary materials. A special thank you to Robert Weston for guiding me through the validation requirements and taking the time to work with me every step of the way. Thank you to Melissa Windham and Kourtney Heard for assisting with the required extractions and to Matt Stillwell for reviewing the completed data. To my committee chair, Dr. Thomas Jourdan, I would like to thank you for your support and guidance throughout the entirety of this project and for your feedback during the writing process. I would like to acknowledge my committee members, Dr. Wayne Lord and Dr. John Bowen for challenging me to think critically and preparing me to defend my project. To my family, friends, and co-workers, I would like to express my gratitude for all of your support and encouragement through this entire process. I cannot say thank you enough for your understanding and constant reassurance that I would make it to this point. Finally, to my wife, Kayla, for your unwavering support in everything that I do. Thank you for helping with my late night editing sessions and nearly endless rewrites. We did it! DRUG IDENTIFICATION AND CONFIRMATION BY LC/MS-MS iv Table of Contents Acknowledgements.........................................................................................................................iii List of Tables ....................................................................................................................................v List of Figures ..................................................................................................................................vi Abstract........................................................................................................................................... 1 Introduction .......................................................................................................................... 2 Literature Review................................................................................................................ 2 Materials and Methods ....................................................................................................... 17 Chemicals and Reagents ................................................................................................... 17 Preparation of Standard Solutions.................................................................................... 17 LC/MS-MS Conditions ....................................................................................................... 18 Sample Preparation .......................................................................................................... 23 Method Development and Validation .............................................................................. 24 Results ................................................................................................................................ 50 Discussion and Future Research........................................................................................... 56 References .................................................................................................................................... 59 Appendices.................................................................................................................................... 62 DRUG IDENTIFICATION AND CONFIRMATION BY LC/MS-MS v List of Tables 1. Gradient Used in Current Study........................................................................................ 19 2. Parameters For Each Drug in the Current Study .............................................................. 20 3. Drugs of Interest and Low Positive Control Concentration.............................................. 27 4. Assessed Validation Parameters....................................................................................... 40 5. Extraction Possibilities for 100 µL Method....................................................................... 43 6. Peak Areas For Key Compounds for 100 µL Method........................................................ 43 7. Compound Table Associated With Figure 20.................................................................... 49 8. Results of Comparison Study Between GC/MS and LC/MS-MS Methods........................ 52 DRUG IDENTIFICATION AND CONFIRMATION BY LC/MS-MS vi List of Figures Cocaine Spectrum ..................................................................................................................... 3 Benzodiazepine Chemical Structures........................................................................................ 9 Amphetamine Chemical Structures........................................................................................ 10 Opioid Chemical Structures .................................................................................................... 12 Miscellaneous CNS Depressant Structures............................................................................. 13 Antihistamine Chemical Structure.......................................................................................... 14 TCA Chemical Structures......................................................................................................... 14 Psychotropic Drug Chemical Structures ................................................................................. 15 PCP Chemical Structure .......................................................................................................... 16 Micro-centrifuge Tube ............................................................................................................ 24 Step 1 of Optimization, Determination of Parent Ion ............................................................ 29 Step 2 of Optimization, Determination of Q1 Voltage ........................................................... 30 Step 3 of Optimization, Determination of Collision Energy Voltage ...................................... 31 Step 4 of Optimization, Selection of Most Common Product Ions......................................... 32 Step 5 of Optimization, Determination of Q3 Voltage ........................................................... 33 Results of Optimization........................................................................................................... 34 Schematic of a LC/MS-MS. Based on Schimadzu (n.d.) .......................................................... 35 Coelution of Methamphetamine and Phentermine............................................................... 36 Separation of Methamphetamine and Phentermine ............................................................. 36 Low Positive Control for 100 µL Extraction ............................................................................ 45 DRUG IDENTIFICATION AND CONFIRMATION BY LC/MS-MS vii Close Up of Front Third of Figure 20....................................................................................... 46 Close Up of Middle Third of Figure 20 .................................................................................... 47 Close Up of Last Third of Figure 20 ......................................................................................... 48 Oxycodone Peak in Association With Figure 20 ..................................................................... 50 DRUG IDENTIFICATION AND CONFIRMATION BY LC/MS-MS 1 Abstract Driving under the influence of drugs (DUID) cases represent the largest portion of cases handled in most forensic toxicology laboratories. Blood is a commonly used specimen and is often analyzed using gas chromatography-mass spectrometry (GC/MS). A common extraction for this method requires two milliliters of blood. If more than one extraction is necessary, a larger volume of blood is required. Recently, laboratories have started using liquid chromatography-mass spectrometry (LC/MS) to obtain a lower limit of detection and extractions which require less blood to complete. Currently, the Oklahoma State Bureau of Investigation (OSBI) Laboratory operates LC-based extractions which require 250 to 500 microliters (µL) of sample to complete, but these are limited to specific drug classes. A general drug screen for forty drugs has been developed and validated using 250 microliters of blood. Even with this reduction of volume requirements, there are still instances in which less than one milliliter (mL) of blood is available for use by the analyst. An additional validation has been completed which required 100 microliters of sample to confirm the presence of thirty-nine drugs. A comparison between these methods was completed to verify the sensitivity of the 100 microliter method. DRUG IDENTIFICATION AND CONFIRMATION BY LC/MS-MS 2 Introduction Breath and blood are commonly encountered specimens associated with the assessment of driving under the influence of alcohol or drugs, hereinafter referred to as DUI cases,
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