A study of impurities found in methamphetamine synthesized from ephedrine

The synthesis of methamphetamine from ephedrine via reduction with hydriodic acid is discussed. Impurities which arise from this method are identified and rationalized. The in situ formation of iodoephedrine from ephedrine leads to trace impurities via internal substitution to 1,2-dimethyl-3-phenylaziridine, followed by retro ring-opening and hydrolysis to phenyl-2-propanone (P-2-P). This ketone or the retro ring-opened aziridine further condenses in an aldol condensation followed by dehydration to give 1-benzyl-3-methylnaphthalene and 1,3-dimethyl-2-phenyl-naphthalene. Two-dimensional nuclear magnetic resonance (2-D NMR) was utilized to elucidate the structure of these impurities.     

Abuse of "pheticol" and its interference to the analysis of methamphetamine

The study was to eliminate interference from ephedrine in the analysis of methamphetamine. The extraction procedure for methamphetamine was modified to include an oxidation step (2 ml urine specimen was treated with 0.5 ml of 1 mol/L phosphate buffer (pH 6.8) and 0.5 ml 0.3 mol/L sodium periodate). Results showed that ephedrine could be oxidized in the presence of periodate ions into smaller fragments while leaving methamphetamine intact. It is recommended that specimens be treated with sodium periodate prior to extraction in order to eliminate any interference caused by ephedrine.     

Australian Federal Police seizures of illicit crystalline methamphetamine ('ice') 1998-2002: impurity analysis

Nineteen crystalline methamphetamine ('ice') seizures captured by the Australian Federal Police (AFP) at the Australian border between 1998 and 2002 were analysed. Using a modified gas chromatograph-mass spectrometry (GC-MS) impurity profiling approach of these samples we have identified >30 compounds associated with methamphetamine and/or its synthetic route. Major impurities detected include 1,2-dimethyl-3-phenylaziridine 8, dimethylamphetamine 14, N-formylmethamphetamine 24, N-acetylmethamphetamine 25, 1,3-dimethyl-2-phenylnaphthalene 32, 1-benzyl-3-methylnaphthalene 33 and methamphetamine dimer 34. These data are suggestive of ephedrine/pseudoephedrine as the main precursor of the 'ice' samples seized during 1998-2002. Additionally the two naphthalenes 32 and 33 further identified that 15 items in 9 seizures were produced via the more specific ephedrine/hydriodic acid/red phosphorus method. One sample comprised 75% dimethylamphetamine and 9.7% methamphetamine, representing the first Australian seizure of imported dimethylamphetamine reported.     

Carbon and Nitrogen Stable Isotope Analyses of Ephedra Plant and Ephedrine Samples and Their Application For Methamphetamine Profiling

In this study, stable isotope ratio analysis was used to track the precursor information of methamphetamine. The δ¹³C and δ¹⁵N values of 30 nature ephedra plants, 12 synthetic ephedrine/pseudoephedrine (ephedrine), 14 natural ephedrine, and 987 seized methamphetamine samples were measured and compared. Due to different weather and earth conditions, the δ¹³C and δ¹⁵N values of ephedra plants grown in the east and the west of Inner Mongolia showed great difference. The δ¹⁵N values of ephedra plants were consistent with related ephedrine extracted from them. Moreover, the criteria to infer the synthetic origin of ephedrine were set up after the analysis of natural and synthetic ephedrine samples. Finally, the precursor origins of 949 seized methamphetamine samples synthesized by Emde and Nagai method were tentatively inferred. Influenced by different preprecursors, the δ¹³C values of seized methamphetamine samples that synthesized from P2P also showed great difference, and this result is consistent with the reported data.     

Capillary gas-liquid chromatography separation of phenethylamines in amphetamine-positive urine samples

Good gas chromatography (GC) separation of molecules is essential for clean gas chromatography/mass spectrometry (GC/MS) confirmation of compounds. The trifluoro derivatives of ephedrine (E) and methamphetamine (MA) coelute on dimethyl silicone capillary columns, such as DB-1, which are most commonly used by chromatographers. Methods are described to separate E and MA to aid GC/MS confirmations of methamphetamine, ephedrine, or both E and MA together, whichever may be present in Enzyme Immunoassay (EIA)-analyzed amphetamine-positive urine samples. The use of the heptafluoro derivatives of E and MA on a DB-1 column, or the trifluoro derivatives of E and MA on a DB-17 column, is suggested for good gas chromatographic separation.     

超高效液相色谱法（UPLC）同时筛选检测吗啡等7种常见毒品

目的建立快速筛选检测中毒者血液、尿液中吗啡、甲基苯丙胺、苯丙胺、麻黄碱、3，4-亚甲基双氧甲基苯丙胺（MDMA）、3，4-亚甲基双氧苯丙胺（MDA）、氯胺酮并定量分析的方法；方法采用超高效液相色谱（UP—LC）-二极管阵列检测器（PAD）；结果峰面积和质量浓度的线性关系良好，分离效果好、速度快、灵敏度提高；结论该方法与传统的HPLC相比能够更好满足实际办案中吗啡、甲基苯丙胺、苯丙胺、麻黄碱、MDMA、MDA、氯胺酮等中毒者血液、尿液的筛选检测并定量分析。     

A screening method for urinary methamphetamine--latex agglutination inhibition reaction test

Methamphetamine in urine samples from abusers was detected by the latex agglutination inhibition reaction test with latex-antibody (Latex-Ab) and latex-methamphetamine (Latex-MA) reagents. Anti-methamphetamine antibody was produced in rabbits by immunization with bovine serum albumin (BSA)-methamphetamine conjugate. Latex particles were coated with antibodies or with rabbit serum albumin (RSA)-methamphetamine conjugate to obtain Latex-Ab and Latex-MA reagents, respectively. The results are read at 4-5 min after mixing the latex reagents. The sensitivity of this method for methamphetamine was 0.4 micrograms/ml urine. Methamphetamine analogs (methylephedrine, amphetamine, phentermine, methoxyphenamine, ephedrine, beta-phenylethylamine, OH-methamphetamine, OH-amphetamine, and OH-ephedrine) all cross-react in varying degrees, while glucosiurea and albuminurea give false positive results in the tests. Though attention must be paid to these effects this simple and rapid test is suitable for the mass screening of urine samples.     

Methamphetamine in hair and interpretation of forensic findings in a fatal case

Hair analysis for drugs has been developing and is considered a significant tool for distinguishing between recent and long-term drug abuse in forensic and clinical toxicology. Chronic consumption of drugs can gradually induce certain harmful effects on the human organism and can exacerbate some pre-existing diseases. Analysis for drugs in blood or urine in isolation does not provide sufficient information about the history of drug-use by a person and their results cannot be correlated directly with the toxic effects displayed. The chronic abuse of methamphetamine is known to be associated with cardiovascular diseases. During or after autopsy certain types of morphologic alterations are found in the hearts of stimulant addicts. The rapid increase in blood pressure after an intravenous methamphetamine dose can be risky for addicts with arteriosclerosis. However, the anamnestic data about a deceased person may not always be available to explain the pathological findings and to classify the cause of death correctly. The aim of this study was to demonstrate the value of hair analysis for drugs in the context of explaining pathological cardiovascular alterations observed during the autopsy in a case where methamphetamine consumption was involved. In this case, only methamphetamine and metabolites were detected with traces of ephedrine. Ephedrine is the precursor chemical in the illicit synthesis of methamphetamine (known in the Czech Republic as "Pervitin"). The femoral blood level of methamphetamine was 1500 ng/ml. It was documented by a witness that the 31-year-old man died within 1h after an intravenous injection of the drug. The cause of death was established as cerebral edema due to cerebellar bleeding shortly after an intravenous dose of methamphetamine. Findings of methamphetamine in the first three 2-cm hair segments (numbered from the roots) were nearly equal (132+/-9 ng/mg). In the fourth 2-cm segment, it was approximately one-half of previous values. In the remaining, distal 7-cm hair segment sample, the value of methamphetamine was higher and comparable to the third segment. These results provide clear evidence that the man had been a chronic methamphetamine abuser for more than 8 months. This information can help to explain the pathology, the consequence of which could be the bleeding into the cerebellum after the last single methamphetamine dose.     

甲基苯丙胺对映异构体两种衍生化方法的比较分析

目的建立甲基苯丙胺毒品的对映异构体分析的优化方法。方法按文献方法用（S）-（＋）-a-甲氧基-a-（三氟甲基）苯基乙酰氯（MTPACl）对甲基苯丙胺直接衍生化和在碱性条件下用有机溶剂萃取后再用MTPACl衍生化（对文献方法优化）,分别对其衍生物采用全扫描形式进行GC-MS分析,比较其结果。结果优化方法的检测限低,峰型好,副反应少。文献方法的检测限是0.1ng,优化方法的检测限是0.001 6ng。结论优化方法用于甲基苯丙胺的对映体特征分析,结果更准确,实用性更强。     

Population data on the 11 STR loci in the Upper Silesia (Poland)

Smuggling of methamphetamine is affected by enforced regulation and international situation, resulting in changes of precursors and synthetic methods used. Enantiomer ratio of methamphetamine can provide information concerning its precursor and synthetic method. This information is useful for the prevention of smuggling methamphetamine and its precursor, and resultant reduction of methamphetamine abuse. In the present study, we investigated on the enantiomer ratios of 433 crystalline methamphetamine samples seized in Korea from 1994 to 2005. Excluding 17 samples of low purity, 416 samples were used for enantiomer profiling. The methamphetamine samples were derivatized with (S)-(+)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride ((S)-(+)-MTPACl), and the derivatives were analyzed by GCMS in selected ion monitoring (SIM) mode. The enantiomer ratios of the samples were calculated from the standard calibration curves of each enantiomer, both of which showed good linearity in the range of 0-1.2 microg. Most of the seizures were pure S(+)-enantiomer, but 21% (95 of 416 samples) contained R(-)-enantiomer above 1%. They began to appear from 1997, and increased continuously up to 50% in the year 2005 (55 of 111 samples). From this study, we could find out that alternative precursors have been used recently for the illicit manufacture of methamphetamine seized in Korea.     

Chiral identification and determination of ephedrine,pseudoephedrine, methamphetamine and metecathinone by gas chromatography and nuclear magnetic resonance

The enantiomers of the related substances methamphetamine, ephedrine, pseudoephedrine and methcathinone were determined by both gas chromatography after derivatization and by nuclear magnetic resonance using a chiral solvating agent. For GC the substances were derivatized with (R)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) to give diasteromeric derivatives. Resolution (baseline) of at least 1.6 was obtained between all derivatives. NMR determination of the enantiomers was conducted in a chiral environment by the addition of the chiral solvating agent, (R)-(+)-1,1′-bi-2-naphthol, to NMR solutions of the substances. Racemization of methcathinone was demonstrated to be facile by exposure to alkaline solutions for varying periods of time. Enantiomeric ratios of some products derived from the oxidation of ephedrine were determined.     

Optimum methamphetamine profiling with sample preparation by solid-phase microextraction

Solid-phase microextraction (SPME) is a relatively new technique in which a small, polymer-coated fiber is employed to extract volatile and semivolatile organic compounds from the sealed headspace above a questioned sample. SPME, coupled with gas chromatography/mass spectrometry (GC/MS), was used to characterize impurities in illicit methamphetamine samples. Trace impurities present in a specimen were tentatively identified using mass-spectral databases and included 1,2-dimethyl-3-phenyl-aziridine (indicating synthesis via a halogenated ephedrine intermediate), ethyl vanillin (a flavoring compound), and caffeine (a stimulant used as cutting agent). The types and numbers of organic compounds sampled by SPME were compared with those collected by various solvent extraction protocols. In addition to unambiguously confirming the presence of methamphetamine, SPME-GC/MS analyses detected approximately 30 more organic analytes than were found by GC/MS following the ethyl acetate extraction method adopted by the United Nations International Drug Control Programme. SPME-GC/MS is a superior method for generating material "fingerprint" profiles in methamphetamine samples. The detection and characterization of increased points of comparison in drug samples provide more detailed chemical signatures for both intelligence and operational information.     

Identification of impurities and statistical classification of methamphetamine tablets (Ya-Ba) seized in Thailand

Impurity profiles of methamphetamine tablets seized in Thailand have been investigated. The samples are extracted with small amounts of ethyl acetate under alkaline condition and the extracts are analyzed by capillary gas chromatography. Nine compounds (1,2-dimethyl-3-phenylaziridine, ephedrine, methylephedrine, N-formylmethamphetamine, N-acetylmethamphetamine, N-formylephedrine, N-acetylephedrine, N,O-diacetylephedrie, methamphetamine dimer) are identified as impurities in methamphetamine tablet. Caffeine and ethyl vanillin are also detected as diluents and/or adulterants, and acetylcodeine monoacetylmorphine and diacetylmorphine are contained in many samples. In addition, trans-3,4-dimethyl-5-phenyl-2-oxazolidone is newly found as an impurity. For characterization and comparison of methamphetamine tablet exhibits, intensely and commonly detectable nine peaks are selected as the factor for multivariate analysis. The procedures reported here permit classification of 250 analyzed exhibits into five groups and characterization of classified groups.     

Implementation of the Comprehensive Methamphetamine Control Act of 1996; regulation of pseudoephedrine, phenylpropanolamine, and combination ephedrine drug products and reports of certain transactions to nonregulated persons. Final rule

DEA is amending its regulations to implement the requirements of the Comprehensive Methamphetamine Control Act of 1996 (MCA) with respect to the regulation of pseudoephedrine, phenylpropanolamine, and combination ephedrine drug products as List I chemicals, and the reporting of certain transactions involving pseudoephedrine, phenylpropanolamine, and combination ephedrine drug products. The MCA removed the previous exemption from regulation as List I chemicals which had applied to pseudoephedrine, phenylpropanolamine, and combination ephedrine drug products. This action makes persons who distribute the products subject to the registration requirement. Also, distributions, importations, and exportations of the products became subject to the existing chemical controls relating to regulated transactions, except in certain circumstances specified in the MCA. The MCA also requires that reports be submitted for certain distributions involving pseudoephedrine, phenylpropanolamine, and ephedrine (including drug products containing those chemicals) by Postal Service or private or commercial carrier to nonregulated persons. This final rule amends the regulations to make them consistent with the language of the MCA and to establish specific procedures to be followed to satisfy the new reporting requirement. DEA has, where possible, taken action to limit the public impact of these new requirements while remaining consistent with the intent of the MCA to attack the diversion of regulated drug products to the clandestine manufacture of methamphetamine.     

Enantiomeric separation of methamphetamine and related analogs by capillary zone electrophoresis: intelligence study in routine methamphetamine seizures

A method for simultaneous enantiomeric separation of ephedrine, pseudoephedrine, and methamphetamine (MA) in a single run by simple capillary zone electrophoresis (CZE) with beta-cyclodextrin as a chiral selector is described. The effects of the buffer pH, phosphate concentration, beta-cyclodextrin concentration, voltage and temperature on the peak resolution were examined. Good enantiomeric resolution was attained for each analyte under our optimized conditions: 15 mM beta-cyclodextrin, 300 mM NaH2PO4 at pH 2.5 with an uncoated capillary (64.5 cm x 50 microm), applied potential at 20 kV and temperature at 30 degrees C. Ultraviolet (UV) detection at a fixed wavelength (200 nm) was employed using a diode array detector. Using phentermine as an internal standard, migration times for all analytes are reproducible within 0.16% for intra-day and 0.6% for inter-day runs. Application of this method to the analysis of confiscated drugs is discussed.     

Immunoassay for methamphetamine with a new antibody

p- and o-Aminomethamphetamine were synthesized as haptens to be coupled with carrier protein at the benzene ring of methamphetamine. Immunogens were prepared by the glutaraldehyde method or the MBS (N-(m-maleimidobenzoyloxy)succinimide) type cross-linking reagent method. In particular, immunization with p-aminomethamphetamine-bovine serum albumin (BSA) conjugate prepared by the glutaraldehyde method gave an anti-methamphetamine antiserum having a low cross-reactivity with methylephedrine. With the antiserum, three kinds of immunoassays for methamphetamine were established. An enzyme immunoassay (EIA) and an enzyme-linked immunosorbent assay (ELISA) were developed with alkaline phosphatase (ALP) as a label enzyme. The amount of antibody bound ALP conjugate was determined by its activity in dephosphorylating p-nitrophenyl phosphate in EIA and nicotinamide adenine dinucleotide phosphate (NADP+) in ELISA. The range of methamphetamine measurable by ELISA was 0.025-0.5 ng/well and its sensitivity was superior to that of EIA (0.3-300 ng/tube). A latex agglutination inhibition reaction test (LAIRT) was also developed for the mass screening method of urine samples. The sensitivity of this method for methamphetamine was 0.1 micrograms/ml urine.     

Resolution of some enantiomeric amines of forensic interest by high-performance liquid chromatography

The high-performance liquid chromatographic resolution of the enantiomers of amphetamine, methamphetamine, ephedrine, and pseudoephedrine is described. The sugar isothiocyanate, 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC), is used as a chiral derivatizing agent, with chromatographic separations of the diastereomers formed with each amine made using a standard achiral C18 stationary phase.     

A study of the use of Ephedra in the manufacture of methamphetamine

The Ephedra plant has been identified as an excellent source of ephedrine and pseudoephedrine, both of which can be chemically reduced to form the widely abused illicit drug methamphetamine. Ephedra contains several additional alkaloids that undergo analogous reductions to form amphetamine and N,N-dimethylamphetamine (also drugs of abuse). The main alkaloids obtained from the Ephedra plant have been reduced using four common methods used by the clandestine operator. The intermediates and byproducts of these reductions have been identified and/or tentatively assigned and the mechanism of formation discussed.     

Analysis of the impurities in the methamphetamine synthesized by three different methods from ephedrine and pseudoephedrine

Organic impurities of methamphetamine may show different patterns by synthesis. In the present study, we tried to find the impurities reflecting the conditions of synthesis by comparing impurity patterns of the methamphetamine samples synthesized by different methods. Sixteen methamphetamine samples were synthesized from ephedrine and pseudoephedrine by the three different manufacturing methods of Emde, Nagai and Moscow. The synthesized samples were extracted with ethyl acetate containing four internal standards, and the patterns of the organic impurities were investigated by GC-MS and GC-FID . Through the investigation, we found 10 peaks appearing in the latter part of GC chromatograms are characteristic to synthesis. The areas of the selected peaks were converted to the variables suitable for the statistical calculation, and the synthesized samples could be classified into four groups through the resultant cluster analysis.