Thermal desorption counter-flow introduction atmospheric pressure chemical ionization for direct mass spectrometry of ecstasy tablets

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Research ArticleReceived: 27 February 2009 Accepted: 28 May 2009 Published online in Wiley Interscience: 29 June 2009

(www.interscience.com) DOI 10.1002/jms.1611

Thermal desorption counter-flow introductionatmospheric pressure chemical ionization fordirect mass spectrometryof ecstasy tabletsHiroyuki Inoue,a∗ Hiroaki Hashimoto,b Susumu Watanabe,b Yuko T. Iwata,a

Tatsuyuki Kanamori,a Hajime Miyaguchi,a Kenji Tsujikawa,a

Kenji Kuwayama,a Noriyuki Tachic and Naohito Uetakec

A novel approach to the analysis of ecstasy tablets by direct mass spectrometry coupled with thermal desorption (TD) andcounter-flow introduction atmospheric pressure chemical ionization (CFI-APCI) is described. Analytes were thermally desorbedwith a metal block heater and introduced to a CFI-APCI source with ambient air by a diaphragm pump. Water in the air wassufficient to act as the reactive reagent responsible for the generation of ions in the positive corona discharge. TD-CFI-APCIrequired neither a nebulizing gas nor solvent flow and the accompanying laborious optimizations. Ions generated were sentin the direction opposite to the air flow by an electric field and introduced into an ion trap mass spectrometer. The major ionscorresponding to the protonated molecules ([M + H]+) were observed with several fragment ions in full scan mass spectrometry(MS) mode. Collision-induced dissociation of protonated molecules gave characteristic product-ion mass spectra and providedidentification of the analytes within 5 s. The method required neither sample pretreatment nor a chromatographic separationstep. The effectiveness of the combination of TD and CFI-APCI was demonstrated by application to the direct mass spectrometricanalysis of ecstasy tablets and legal pharmaceutical products. Copyright c© 2009 John Wiley & Sons, Ltd.

Keywords: thermal desorption; atmospheric pressure chemical ionization; counter-flow introduction; ecstasy tablets; ion trap massspectrometry

Introduction

In the face of today’s situation of drug abuse, it is necessary that asimple, rapid and reliable means of analysis is available. Traditionalcolor tests with specific reagents are still predominately usedfor the first step of screening of illegal drugs.[1] Although thetest is very simple, inexpensive and no requirement of scientificknowledge, recent diversity of drugs of abuse makes it complicateto evaluate the results leading to false positive and false negative.Alternative spectroscopic methods such as Raman[2] and Fouriertransform infrared spectrometry[3] have been reported for thispurpose, while these are applicable to ecstasy tablets with relativehigh percentages of the target substances.

Ambient ionization techniques, which enable the direct analysisof a variety of samples, have made a noticeable impact onmass spectrometry (MS).[4] These techniques include desorptionelectrospray ionization (DESI),[5] direct analysis in real time,[6]

desorption atmospheric pressure chemical ionization (DAPCI),[7]

electrospray-assisted laser desorption ionization,[8,9] desorptionatmospheric pressure photoionization[10,11] and easy ambientsonic spray ionization.[12,13] Since these techniques require littleor no sample preparation, their usefulness has been provedin numerous in situ analyses such as active ingredients inpharmaceutical and illegal tablets,[5,8,10,11,14 – 16] explosives presenton a variety of ambient surfaces[5,6,16,17] and alkaloids in planttissues,[5,18] by their combination with various types of MS. DESItechnique had allowed two-dimensional chemical mapping of

samples, i.e. imaging DESI.[19 – 21] These methods, however, requirea relatively high pressure of nebulizing gas (helium or nitrogen) anda high-speed charged liquid spray such as methanol and toluenein the ionization source to produce a stable signal. Recently, Chenet al. developed a surface DAPCI MS without using any toxic solventspray.[22 – 25] The method could be desirable for food regulationanalysis, pharmaceutical industry monitoring, clothes analysis andin vivo skin analysis.

Direct sampling MS, which involves minimal sample preparationand no chromatographic separation step prior to analysis by MS,has been used for real-time gas analysis such as volatile organiccompounds in air,[26] dioxin precursors[27,28] and polychlorinatedbiphenyls[29] in incinerator flue gas. In these MS, a large volume ofambient air or flue gas was introduced into various inlet systemsthat served to extract and transfer analytes from ambient pressure

∗ Correspondence to: Hiroyuki Inoue, First Chemistry Section, National ResearchInstitute of Police Science, 6-3-1 Kashiwanoha, Kashiwa, Chiba 277-0882, Japan.E-mail: [email protected]

a National Research Institute of Police Science, 6–3–1 Kashiwanoha, Kashiwa,Chiba 277-0882, Japan

b Hitachi High-Tech Control Systems Corporation, 500 Miyu, Mito, Ibaraki 319-0316, Japan

c Hitachi Limited, 1–18–13 Soto-Kanda, Chiyoda, Tokyo 101-8608, Japan

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Direct mass spectrometry of ecstasy tablets

to vacuum inside the mass spectrometer. Inlet systems includemembranes, microtrap interfaces and atmospheric pressureionization.[26]

A counter-flow introduction (CFI) atmospheric pressure chem-ical ionization (APCI) source[30,31] has been developed as one ofthe inlet systems of direct gas sampling MS for the detection ofthe explosives 2,4,6-trinitrotoluene (TNT) and 1,3,5-trinitro-1,3,5-triazacyclohexane (RDX). Vapor samples with a large volume of airwere introduced to the APCI source by a diaphragm pump andionized under negative corona discharge. TNT was ionized by anelectron-transfer reaction from an oxygen radical anion to pro-duce M− while RDX formed a cluster anion with NO−

2 to produce[M+NO2]−. The ions were sent in the direction opposite to the airflow by an electric field and were introduced into the mass spec-trometer. The ion source had a superior structure for online gassampling that enabled large volume sampling while suppressingcontamination of the APCI source by using the CFI mechanism.That is, the direction in which the vapor sample is introduced tothe corona discharge region and the direction in which ions aredrawn out of the corona discharge region are opposed to eachother, and this improves the efficiency of ionization and maintainsa stable discharge for a long time period.

In the present study, the sample introduction system wasimproved for solid samples. A metal block heater was connectedbefore the ion source for the thermal desorption (TD) of analytesthat were wiped onto it with a glass microfiber filter. Desorbedsamples were introduced into the ion source with ambient air bya diaphragm pump. The effectiveness of coupling CFI-APCI MSwith TD was evaluated by the direct and rapid analysis of ecstasytablets and other pharmaceutical products without a samplepretreatment or chromatographic separation step.

Experimental

Chemicals and reagents

d-Methamphetamine (MA) hydrochloride (HCl) and dl-3,4-methylenedioxydimethylamphetamine (MDDMA) HCl wereobtained from Dainippon Pharmaceutical (Osaka, Japan)and Lipomed AG (Arlesheim, Switzerland), respectively.dl-3,4-Methylenedioxymethamphetamine (MDMA) HCl, dl-3,4-methylenedioxyamphetamine (MDA) HCl, dl-3,4-methylenedi-oxyethylamphetamine (MDEA) HCl, dl-N-methyl-1-(1,3-ben-zodioxol-5-yl)-2-butanamine (MBDB) HCl and dl-amphetamine(AP) hemisulfate were synthesized in our laboratory. Theirpurities (>95%) were confirmed by melting point determination,thin-layer chromatography and gas chromatography/massspectrometry (GC/MS).

Acetaminophen was purchased from Sigma Chemical Co.(St. Louis, MO). Caffeine, diphenhydramine HCl and diazepamwere purchased from Wako Pure Chemical Industries, Ltd. (Osaka,Japan). All other chemicals used were of analytical grade.

Pharmaceutical tablets of HealthA2Z Extra Strength Pain ReliefPM, Tylenol and Cercine were purchased from A&Z PharmaceuticalInc. (Hauppauge, NY), McNeil-PPC Inc. (Fort Washington, PA)and Takeda Pharmaceutical Co. Ltd. (Osaka, Japan), respectively.Ecstasy tablets containing MDMA or MDA were supplied byNarcotics Control Department, Kanto-Shin’etsu Regional Bureauof Health and Welfare, Ministry of Health, Labour and Welfare,Japan. The ingredients of the ecstasy tablets were independentlyidentified by GC/MS and quantified by high-performance liquidchromatography (HPLC) or GC.[32]

Figure 1. Schematic of thermal desorption counter-flow introductionatmospheric pressure chemical ionization.

TD-CFI-APCI MS

A Hitachi model DS-1000 ion trap mass spectrometer equippedwith a CFI-APCI source[30,31] was used in the positive ionizationmode. A metal block heater was connected to the CFI-APCI source(Fig. 1).

The surface of an ecstasy tablet was gently wiped with a glassmicrofiber filter (Whatman GF/A, 90 mmφ) that was mountedin a plain-metal sample holder. Films or other coatings on thepharmaceutical tablets were scraped off before wiping. For ba-sic experiments, 10–50 µl of a standard methanolic solution wasdropped on the glass microfiber filter. The sample holder was intro-duced to the instrument, and substances adhered to the glass filterwere thermally desorbed at the metal block heater set at 250 ◦Cand sent to the CFI-APCI source through a transfer line (heated at230 ◦C) by a constant air flow at 0.8 l/min using a diaphragm pump.Ions generated by positive corona discharge were introduced intoa vacuum region through three apertures. The ions were focusedby an Einzel lens and an electrostatic ion-guide and were massanalyzed by the ion trap mass spectrometer. The mass analysisregion was evacuated with a turbo-molecular pump.

The ion source temperature was set to 210 ◦C. The needleelectrode current was set to 10.0 µA (4.0 kV). The voltages of thecounter electrode and the lens were set to 1.0 kV and −23 V,respectively. The mass spectrometer was operated under singleMS (mass range, m/z 50–400) and tandem mass specterometry(MS2) (m/z 40–320) modes. Helium was used as the collisiongas (1–2 ml/min, 7 × 10−3 Pa at the vaccum chamber). Collisionenergies were optimized to obtain the best intensity of the mostabundant product ions.

Ionization mechanism

In the present system, analytes are vaporized at the TD device.Vapor samples with a large volume of air are introduced to the

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Figure 2. MS (left side) and MS2 (right side) spectra of phenethylamines.

APCI source and ionized under positive corona discharge. Waterin the air acts as a reactive reagent responsible for the generationof ions in the positive discharge in the following reactions.[33 – 35]

N2 + e −−−→ N+2 + 2e (1)

N+2 + 2N2 −−−→ N+

4 + N2 (2)

N+4 + H2O −−−→ H2O+ + 2N2 (3)

H2O+ + (H2O)n −−−→ H+(H2O)n + OH (4)

M + H+(H2O)n −−−→ [M + H]+ + (H2O)n (5)

The ions generated are sent in the direction opposite to the airflow by an electric field and are introduced into the ion trap massspectrometer operated under MS and MS2 modes (Fig. 1).

Results and Discussion

Analysis of authentic standard solutions

About 10–50 µl of standard methanolic solutions (10 µg/ml) weredropped onto a glass microfiber filter. After evaporation of thesolvent, the sample filters were loaded into the instrument.Figure 2 illustrates MS and MS2 spectra obtained from the sevenphenethylamines. In single MS mode (Fig. 2, left side), the majorions corresponding to the protonated molecules ([M+H]+) wereobserved along with several fragment ions. One common fragmentwas derived from the cleavage of the amine moieties, i.e. m/z 163for MDMA, MDA, MDEA and MDDMA, m/z 177 for MBDB and m/z119 for MA and AP. Protonated molecules of MDA and AP were

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Figure 3. Five consecutive analyses of an authentic standard solution of dl-3,4-methylenedioxymethamphetamine hydrochloride (50 µl of 10 µg/mlmethanol). Up and down arrows indicate time points of sample load andejection, respectively.

not the base peaks of their mass spectra under applied conditions.Two regioisomers, MDEA and MBDB, could be differentiated bycomparison of their mass spectra. However, MS and MS2 spectraobtained from MDDMA, another isomer of MDEA, were verysimilar with those from MDEA. Ecstasy tablets containing MDDMAhave been reported recently.[36] Attention should be paid to theinterpretation of the results, especially for isomer differentiation.

APCI is known as a soft ionization technique for MS.[37,38] Thecorona discharge voltage and the temperature of the metal blockheater had little influence on the spectra. The APCI mass spectraof phenethylamines in the present study were similar to those ofthe previous reports that were taken by HPLC/APCI-MS.[39]

In the MS2 mode (Fig. 2, right side), the base peaks in the spectrawere formed from loss of the amine moieties from the protonatedmolecules, which were also seen in single MS mode. In actualsamples, the identification of drugs using MS2 determinationis preferable to avoid a more complex spectrum from otherconstituents, since the instrument has no separation apparatussuch as GC or HPLC.

Figure 3 shows real time traces for five consecutive analysesof an authentic standard solution of MDMA HCl, followed by ablank filter. Immediately after introduction of the samples to theinstrument, characteristic ions were observed under single MS (m/z194) and MS2 modes (m/z 194 > 163). Stable peak intensities wereobtained from five consecutive determinations. The heater unittemperature changed the peak shape, with lower temperaturesbroadening the peaks.

Figure 4. Dose–response curves for phenethylamines. Peak areas on theMS2 traces (m/z 194 > 163 for dl-3,4-methylenedioxymethamphetamine,m/z 180 > 163 for dl-3,4-methylenedioxyamphetamine, m/z 150 > 119for d-methamphetamine and m/z 136 > 119 for dl-amphetamine) wereplotted against sample amounts. Each data point represents the meanof three determinations. Sample amounts are expressed as those of theirsalts. Correlation coefficients (r) of the linear regression were all better than0.993.

Peak areas on the MS2 traces were plotted against sampleamounts (Fig. 4). Acceptable linearity (r > 0.993) was obtainedin the range of 5–500 ng of analytes. The fraction of the originalphenethylamines to that which was desorbed at the heater unitcould not be examined, as they are present as a salt on the samplefilters.

The ionization efficiency of normal DESI would be stronglyinfluenced by several additional parameters such as the nebulizinggas flow rates and the angle between the gas flow and a surfaceof samples.[40] The present ionization technique is free from theseoptimizations for each sample.

Analysis of ecstasy tablets

The surface of an ecstasy tablet was gently wiped with a glassmicrofiber filter, which was then introduced into the instrument.Consecutive analyses of ecstasy tablets could be achieved with a2-min interval. MS2 spectra at the highest intensity (Fig. 5(a and c)for MDMA and Fig. 5(d and f) for MDA) as well as lower intensity(Fig. 5(b) for MDMA and 5(e) for MDA) on total ion current traceswere coincident with those from an authentic standard (Fig. 2)with good reproducibility. Blank filters gave some ion intensityon total ion current traces but no signal at the specific MS2 ionmasses. The results show that TD-CFI-APCI MS can identify thecontents of illicit tablets within 5 s. The signals of the MS2 traceswere under background levels within 1 min.

Figure 6 shows consecutive analyses of ecstasy tablets fromdifferent seizures. The MS2 traces showed the presences of MDMAin tablets #1 and #3, MDA in #4, AP in #2 and MA in #3. All peakshad characteristic MS2 spectra corresponding to the ingredients(data not shown). Tablet #2 also showed the presence of caf-feine (Fig. 6(b) for the MS2 spectrum of the peak on the trace at


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Figure 5. Five consecutive analyses of ecstasy tablets. The contents of the active ingredients were 48% for the dl-3,4-methylenedioxymethamphetaminetablet and 45% for the dl-3,4-methylenedioxyamphetamine tablet. Up and down arrows indicate time points of sample load and ejection, respectively.

m/z 195 > 138). All the ingredients were confirmed by GC/MSanalysis. It must be emphasized that the method has no chromato-graphic separation step such as GC or HPLC, but nevertheless, MS2

analysis provides identification of both compounds within 5 s afterthe introduction of the sample. A very small amount of MA (0.3%by quantitative analysis) could be detected in the MDMA-richtablet (#3, 44% MDMA). No sample carry-over was observed onMS2 traces.

Application to pharmaceutical products

TD-CFI-APCI MS was applied to pharmaceutical products. AHealthA2Z Extra Strength Pain Relief PM tablet (ca. 650 mg) con-tains 500 mg of acetaminophen and 25 mg of diphenhydramineHCl as active ingredients. The MS2 traces showed peaks withcharacteristic MS2 spectra (Fig. 7(a and b)). This enabled the iden-tification of both of the two active ingredients by comparisonwith those obtained from authentic standards. The ion of m/z110 in the MS2 spectra of acetaminophen could be derived fromthe loss of ketene (–COCH2) during collision-induced dissociationof the protonated molecule. The spectrum was similar to that

obtained by tandem MS with surface DAPCI[22] and also withDESI.[41] The ion of m/z 167 in MS2 spectrum of diphenhydraminecould be derived from the loss of a dimethylaminoethylethermoiety (–OCH2CH2N(CH3)2), which was observed in previousreports.[42,43] Acetaminophen could be detected from a Tylenol(500 mg acetaminophen) tablet without any contamination fromthe former analysis (i.e. no peak on the MS2 traces at m/z 256 >

167).The method was also applicable to the psychotropic tablet that

contained 2% diazepam as the active ingredient (Cercine, 2 mgdiazepam/ca. 100 mg tablet, Fig. 7(c)). The spectrum of diazepamwas consistent with that of an authentic sample, and the samecharacteristic ions were observed as in previous reports fromHPLC tandem MS analyses.[44,45] Trace-level signals correspondingto acetaminophen were observed on the MS2 trace (m/z 152> 110) when the diazepam tablet was analyzed. This is mostlikely a carry-over from the former analyses of large amounts ofacetaminophen, probably present on a surface of the heater unitor the transfer line to the APCI source, due to the short analysisintervals. This would be easily avoided by increasing the time


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Figure 6. Consecutive analysis of ecstasy tablets. Active ingredients weredl-3,4-methylenedioxymethamphetamine (MDMA) (26%) in tablet #1,dl-amphetamine (13%) and caffeine (12%) in #2, MDMA (44%) and d-methamphetamine (0.3%) in #3 and dl-3,4-methylenedioxyamphetamine(45%) in #4. Up and down arrows indicate time points of sample load andejection, respectively.

between sample analyses or by confirmation of background levelswith a blank sample.

However, TD-CFI-APCI MS is not in situ analysis such as DESI anddirect analysis in real time MS, and has limited application for theanalysis of nonvolatile and large molecules such as proteins andpolymers because the analytes must be thermally desorbed (up to280 ◦C) before chemical ionization. The limited mass range of themass spectrometer (m/z ≤ 500) means that the single-chargedions of large molecules by APCI cannot be determined by thismass spectrometer. The method also would be unfavorable tothermolabile compounds.

The present technique will provide a simple and rapid screeningmethod for ecstasy tablets and other drugs of abuse, thougha subsequent confirmatory test using GC/MS or HPLC/MS isinevitable for the unequivocal identification of the compounds.

Conclusions

The unique CFI-APCI source coupled with a TD unit enabledeffective and reproducible ionization of analytes. It requiresneither a nebulizing gas nor a solvent flow accompanied with thelaborious optimizations of geometry, spray, chemical and surface

Figure 7. Consecutive analysis of pharmaceutical products. Up and downarrows indicate time points of sample load and ejection, respectively.

parameters typically required for DESI measurements.[40] TD-CFI-APCI combined with ion trap tandem MS provided identification ofthe target compounds in the tablets. This method requires neitherpretreatment nor chromatographic separation step, and rapidconsecutive analysis could be achieved. Development of miniaturemass spectrometers and pumps, which improve the portability ofthese devices, will facilitate the use of a mass spectrometer withthe TD-CFI-APCI source for rapid and easy on-site screening ofecstasy tablets and other drugs of abuse.

This method would be applicable to liquid samples as wellas biological materials such as urine, blood and saliva, althoughinterference from endogenous substances and ion suppression


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effects must be carefully evaluated. Application to drug urinalysisis under investigation.

Acknowledgements

The authors thank Dr. Y. Makino, Narcotics Control Department,Kanto-Shin’etsu Regional Bureau of Health and Welfare, Ministryof Health, Labour and Welfare for supplying the ecstasy tablets.This research was supported in part by a Grant-in-Aid for ScientificResearch (C) from the Japan Society for the Promotion of Science(No. 19590687, 2007–2008).

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