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Presented to the Graduate Council of the University of North Texas in Partial Fulfillment of the Requirements for the Degree Of 3-7? CHEMICAL IONIZATION (CI) GC/MS ANALYSIS OF UNDERIVATIZED AMPHETAMINES FOLLOWED BY CHIRAL DERIVATIZATION TO IDENTIFY d AND 1-ISOMERS WITH ION TRAP MASS SPECTROMETRY THESIS Presented to the Graduate Council of the University of North Texas in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE (Pharmacology) By John A. Tarver B.S.,B.A. May, 1991 Tarver, John A. Chemical Ionization (CI) GC/MS Analysis of Underivatized Amphetamines Followed by Chiral Derivatiza- tion to Identify d and 1-Isomers with Ion Trap Mass Spectro- metry. Master of Science (Biomedical Sciences), May, 1991, 26 pp., 9 figures, bibliography, 20 titles. An efficient two step procedure has been developed using CI GC/MS for analyzing amphetamines and related compounds. The first step allows the analysis of underiv- atized amphetamines with the necessary sensitivity and specificity to give spectral identification, including differentiation between methamphetamine and phentermine. The second step involves preparing a chiral derivative of the extract to identify d and 1-isomeric composition. TABLE OF CONTENTS Page LIST OF ILLUSTRATIONS.......... ... .. .. .......... iv INTRODUCTION .1........................... EXPERIMENTAL MATERIALS ...--- - - - - ----... -....-..... 15 METHODS --------------------.---...... 15 RESULTS AND DISCUSSION ...-..-..................... 17 CONCLUSION - - - - - -- - - - - --- - --- . - . 23 APPENDIX......... ---. -----....-.-. ----.. -........ 24 REFERENCES ----------------------------.. --. ...---.. 28 iii LIST OF ILLUSTRATIONS Figure Page 1. Full scan chromatogram and mass spectra of amphetamine obtained in the electron impact mode....................... ........... 2. Full scan chromatogram and mass spectra of methamphetamine obtained in the electron impact mode.....................................8 3. Full scan chromatogram and mass spectra of amphetamine obtained in the chemical ioniza- tion mode........................................ 9 4. Full scan chromatogram and mass spectra of meth- amphetamine obtained in the chemical ionization mode............................................10 5. Possible stereoisomers produced by derivatiz- ing methamphetamine with trifluoro-l-prolyl chloride........................................14 6. CI analysis of a 10 ng/ml urine standard extract showing the spectra and signal:noise ratio for both amphetamine and methamphetamine..18 7. Analytical curves demonstrating procedure linearity ...................................... 19 8. Total ion chromatograms of TPC derivatives......20 iv Figure Page 9. Total ion chromatogram demonstrating spectral differentiation between phentermine and meth- amphetamine........................22 V INTRODUCTION Amphetamine and methamphetamine are sympathomimetic phenethylamines. Sympathomimetic agents are so called be- cause their effects resemble stimulation of adrenergic nerves. As a result, these agents have profound effects on almost all systems. These include peripheral excitation or inhibition depending on the type of receptor present, card- iac excitation, metabolic increases and central nervous system (CNS) excitation. The differences in these drugs are seen in the degree to which each effects the above actions. In comparison to other sympathomimetic agents, ampheta- mine and methamphetamine have markedly more pronounced CNS effects. This is particularly true for methamphetamine which partitions more easily into the CNS because of its lipid solubility. These compounds have been used therapeutically in the treatment of obesity, narcolepsy, parkinsonism and behavior disorders. However, they have been largely replaced by other sympathomimetic agents for their peripheral effects with lesser CNS effects (1). With the decrease in therapeu- tic use amphetamine and methamphetamine are most often seen associated with cases of self administration and abuse. Amphetamine and methamphetamine both occur as stereo- isomers. Two molecules are isomers if they have the same 1 2 molecular formula but differ either in their structural arrangement (structural isomers) or in their spatial ar- rangement (stereoisomers). This is possible in any molecule that contains asymmetric carbons. An asymmetric carbon is one that is bound to four different atoms or groups. Molecules that contain asymmetric carbons are said to be chiral (handed) and they can be arranged spatially so that they are mirror images of each other and cannot be superimposed. These mirror images are called enantiomers. Diastereoisomers, molecules with more than one asymmet- ric carbon that are not superimposable, differ in energy content so their chemical and physical properties are dif- ferent and they can be resolved analytically. Enantiomers differ only in the direction of rotation of plane polarized light and therefore do not lend themselves to analytical resolution. The nomenclature for enantiomers consists of designation as d (dextrorotatory) or 1 (levorotatory), alternatively + or -, indicating the direction of rotation of plane polarized light. The absolute sterochemical config- uration about asymmetric carbons is designated by the sym- bols R and S. The synthesis of optically active drugs usually produc- es racemic mixtures. These are mixtures that contain both forms of the enantiomers. Enantiomers may have significantly different pharmacokinetic and pharmacodynamic properties (2). 3 Because of these differences drug stereochemistry is an area of growing importance in both clinical and forensic toxicology. Methamphetamine exemplifies stereochemical im- portance. Pharmacologically the d-isomer has much greater central activity than the 1-isomer and forensically the d- isomer is an illicit drug while the 1-isomer is an active ingredient in an over the counter nasal decongestant (3). The central psychic effects of normal dosages include alertness, elevation of mood, elation and euphoria. Metham- phetamine is also easily synthesized in clandestine labora- tories (4,5) and is therefore widely encountered in illegal trade and abuse. As the dosage of methamphetamine used increases and toxicity develops, hallucinations and paranoid delusions are common. This is particularly true in cases of chronic intox- ication rather than acute toxicity. The wide range of doses required to produce toxicity in different individuals reduc- es the predictability of onset and increases occurrence. Toxicity can occur with as little as a single 2 mg dose while some tolerant individuals may use as much as 1700 mg/day without apparent ill effects (1). The abuse potential, the type of toxic manifestations involved and the ease of synthesis by clandestine laborato- ries all contribute to making the use of amphetamines and methamphetamines a social problem. For this reason they are 4 included in the list of drugs routinely screened for during urine drug testing. Increased public awareness of the deleterious effects of drug abuse and the fact that U.S. companies spend around $33 billion dollars annually (6) on drug testing reflects acceptance of drug testing. From 1985 to 1986 employee drug testing by Fortune 500 companies rose from 18 to 40 percent (7). The impact that urine drug testing has on people's lives and careers causes a proportional concern regarding the accuracy and reliability of results. This concern is manifested in the legal system and demands that urine drug testing be legally defensible. Legally defensible testing systems must include: (a) witnessed urine collection; (b) maintenance of external and internal chain of custody docu- ments; (c) records of procedures and worksheets regarding instrument operation, maintenance and quality control, and records of personnel training and experience; (d) participa- tion in accreditation and proficiency programs; (e) report- ing procedures and recall; and (f) storage of all specimens, whether they gave negative or positive results (6). Experts indicate that single procedure methods of testing are not legally defensible and that only screening followed by confirmation methods, EMIT-GC/MS, TDX-GC/MS and RIA-GC/MS, are fully defensible (8). One ongoing problem with drug testing programs has been the lack of consistency which is obtained through common 5 methodology and defined criteria for positive results. This was first addressed by the National Institute of Drug Abuse (NIDA) in drafting guidelines for accreditation of drug testing laboratories (9) and drug testing programs (1.0). There are now two entities that offer accreditation for drug testing laboratories, NIDA and College of American Patholo- gist (CAP). Methodologies required for accreditation are now con- sistent but there is considerable evidence that the "cutoff" limits used to determine positive/negative results as out- lined by NIDA are much too high and results in false nega- tive reporting. The effects of this are seen in that while drug testing programs have decreased the incidence of drug related incidents a serious problem still remains. The high, 500ng/ml (11), "cutoff" limits enables too many abusers to beat the system. The "gold standard" for confirmations is gas chromato- graphy with mass spectrometry (GC/MS) (8); however, there is still need for improvement. Most laboratories use quadrupole mass spectrometers in the selected ion monitoring (SIM) mode. This method relies on GC retention time plus the molecular structure evidence provided by the ratios of selected ions (conventionally three ions). Increased cer- tainty can be obtained by using full scan spectra with chemical ionization mass
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