Surface-activated chemical ionization ion trap mass spectrometry in the analysis of amphetamines in...

RAPID COMMUNICATIONS IN MASS SPECTROMETRY

Rapid Commun. Mass Spectrom. 2004; 18: 1847–1855

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/rcm.1558

Surface-activated chemical ionization ion trap mass

spectrometry in the analysis of amphetamines in

diluted urine samples

Simone Cristoni1*, Luigi Rossi Bernardi1, Piermario Gerthoux2, Elisabetta Gonella2

and Paolo Mocarelli2

1University of Milan, Centre for Bio-molecular Interdisciplinary Studies and Industrial Applications (CISI), Via Fratelli Cervi 93,

20090 Segrate Milano, Italy2University Department of Laboratory Medicine, University of Milano-Bicocca, Hospital of Desio, Via Mazzini 1, 20033 Desio, Milan, Italy

Received 9 March 2004; Revised 17 June 2004; Accepted 18 June 2004

A new ionization method, named surface-activated chemical ionization (SACI), was employed for

the analysis of five amphetamines (3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy-

methamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDE), amphetamine and

methamphetamine) by ion trap mass spectrometry. The results so obtained have been compared

with those achieved by using atmospheric pressure chemical ionization (APCI) and electrospray

ionization (ESI) using the same instrument, clearly showing that SACI is the most sensitive of

the three. The limit of detection and linearity range for SACI were compared with those obtained

using APCI and ESI, showing that the new SACI approach provides the best results for both cri-

teria. SACI was used to analyze MDA, MDMA MDE, amphetamine and methamphetamine in four

urine samples, and the quantitation results are compared with those achieved using ESI. Copyright

# 2004 John Wiley & Sons, Ltd.

Amphetamines are compounds able to produce hallucino-

genic and euphoric effects.1 They are potent sympathomi-

metic amines causing stimulation of the central nervous

system. Street use of amphetamines may lead to a syndrome

called amphetamine psychosis, which is indistinguishable

from paranoid schizophrenia.2–5 The unfortunately wide dif-

fusion of amphetamines has dramatically increased in the last

years on the European illegal market. This trend is confirmed

by the European Monitoring Centre for Drugs and Drug

Addiction (EMCDDA).2

Amphetamines can be usually detected in urine, plasma

samples, nails or hair samples.5–7 Several different analytical

techniques are routinely employed for the analysis of these

compounds, based on the immunochemical approach (radio-

immunoassay (RIA), enzyme immunoassay (EIA), and

fluorescence immunoassay polarization (FPIA)).5 Mass spec-

trometry is usually employed as a confirmative assay. The

immunochemical approaches suffer, in practice, from a

number of limitations: (1) high cut-off values permit positive

detection only for recent ingestion of high doses, resulting in

the risk of false negative analyses;8,9 (2) low cut-off values

lead to a high number of false positive results, due to presence

of substances employed for therapeutic purposes such as

ephedrine and ranitidine, as well as to interfering substances

present in the biological matrix;10,11 and (3) immunochemical

assays are cost-effective only when many samples are

analyzed.5

Mass spectrometry is a powerful technique, in terms of

sensitivity and specificity, for the detection of drugs. In

particular gas chromatography/mass spectrometry (GC/MS)

has been widely employed for the analysis of amphetamines

and other drugs, using both positive- and negative-ion modes

and using various derivatization procedures;5,12–29 in

most cases a derivatization step is essential to achieve valid

results, even if it is time-consuming and often leads to sample

loss.

Other methods employed to analyze amphetamines and

other drugs are based on the use of capillary electrophoresis/

mass spectrometry (CE/MS)30–34 and particularly on liquid

chromatography/mass spectrometry (LC/MS).35–42 The

ionization technique mainly used to analyze amphetamines

and other drugs are electrospray ionization (ESI)35–39 and

atmospheric pressure chemical ionization (APCI).40,41

Another interesting technique successfully employed for

drug analysis is sonic spray ionization (SSI).42 This method is

similar to ESI but it does not use a high potential on the

nebulizer spray needle; the ionization and vaporization of the

sample are achieved by using a high nitrogen nebulizer gas

flow. It must be emphasized that, in most cases, a solid-phase

extraction (SPE) step is usually employed before the

analysis;36,37,39 on one hand this approach strongly increases

the sensitivity of the developed methods, but on the other it is

time-consuming.

Copyright # 2004 John Wiley & Sons, Ltd.

*Correspondence to: S. Cristoni, Universita degli Studi di Milano(CISI), Via Fratelli Cervi 93, 20090 Segrate Milano, Italy.E-mail: [email protected]

Scheme 1. Structural formulas of the five amphetamines analyzed.

Figure 1. Full scan mass spectra of a mixture of MDMA, MDA, MDE, amphetamine and

methamphetamine obtained using (a) APCI, (b) ESI, and (c) SACI. The concentration was 50 ng/

mL for each compound. The direct infusion sample flow was 30 mL/min. The counts/s value and the

S/N ratio of the most abundant peak in each spectrum are also reported. The S/N ratio was

calculated using the RMS algorithm.

Copyright # 2004 John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom. 2004; 18: 1847–1855

1848 S. Cristoni et al.

As shown by Sato et al.,35 an interesting approach for drug

analysis is based on the direct injection of urine samples into

the LC/MS system. However, it must be emphasized that,

although this method is fast (due to the absence of sample

pre-treatments), the direct injection of urines into the

chromatographic column can lead to serious decrease of

chromatographic performance due to the urine matrix that

contains salts and other compounds present at high

concentration which can precipitate inside the chromato-

graphic column. Moreover, some matrix compounds can

exhibit negative effects with respect to sample ionization

efficiency in both ESI and APCI, leading to instability of the

analyte signal and thus to quantitation errors.

Surface-activated chemical ionization (SACI) has been

recently developed in our laboratory.43 This ionization

technique is an improvement of the no-discharge ionization

approach.44–46 As in the case of SSI, it does not use a high

potential in order to ionize the sample molecules. It is

composed of a heated vaporization chamber into which a

metallic surface is inserted, leading to high ionization

efficiency when no or low potential (generally lower than

150 V) is applied to it. The new device has been tested in the

analysis of some high molecular weight standard peptides

(peptide YY fragment 13-36, 3014 Da; diabetes associated

peptide fragment 8-37, 3200 Da; gastrin-releasing peptide

(human), 2859 Da; phospholipase A2 activating peptide,

2330 Da; and vasoactive intestinal peptide fragment 6-28,

2816 Da) and also of peptides obtained by tryptic digestion of

cytochrome C, introduced by direct infusion. This new

approach exhibits high performance in term of selectivity

and sensitivity, and this encouraged us to employ it also for

the analysis of amphetamines in order to verify the

performance of SACI in the analysis of these compounds.

The aim of this work is to compare the data obtained

using SACI, APCI and ESI techniques in term of sensitivity,

linearity range and limit of detection (LOD) in the analysis

of five amphetamines (3,4-methylenedioxyamphetamine

(MDA), 3,4-methylenedioxymethamphetamine (MDMA),

3,4-methylenedioxyethylamphetamine (MDE), ampheta-

mine and methamphetamine). After the optimization of

the instrumental parameters for a mixture of the pure

compounds, four urine samples were analyzed; they were

strongly diluted (1:100) in order to prevent either matrix-

sample interaction effects taking place during ionization, or

column damage due to the matrix composition. Further-

more, the diluted urine samples were directly analyzed,

without pre-treatment, using LC/MS and LC/MS/MS; the

results obtained are reported and discussed.

EXPERIMENTAL

ChemicalsStandard MDMA, MDA, MDE, amphetamine and metham-

phetamine were purchased from SALARS (Como, Italy).

Acetonitrile was purchased from J. T. Baker (Deventer, The

Netherlands). Formic acid was purchased from Sigma

Aldrich (Milan, Italy).

Sample preparationThe urine samples obtained from four drug addict subjects, in

which the amphetamine composition had been previously

qualitatively and quantitatively evaluated using GC/MS,

were diluted using two dilution ratios (1:20 and 1:100). These

samples were directly analyzed by LC/MS and LC/MS/MS

using different ionization sources.

Scheme 2. Fragmentation pathways of the [MþH]þ ions of MDMA, MDA and MDE.

SACI-LC/MS analysis of amphetamines in urine 1849


ChromatographyA Surveyor LC system (ThermoFinnigan, San Jose, CA, USA)

was used. The chromatographic column was a reverse-phase

C18 (150� 1 mm, 5mm, 300 A). The HPLC gradient used two

eluents: (A) H2Oþ 0.05% formic acid and (B) CH3CNþ0.05% formic acid: 20% of B was maintained for 2 min, then

a linear gradient was used passing from 20% of B to 80% of

B in 10 min. Then 80% of B was maintained for 3 min, and

then over the next 2 min the initial conditions were reached.

Thus, 17 min of chromatographic analysis time were used,

but the mass chromatogram acquisition cycle time was set

to 20 min in order to make it possible to re-equilibrate the chro-

matographic column. The eluent flow rate was 100mL/min.

Mass spectrometryThe APCI mass spectra were obtained using an LCQ-DecaXP

(ThermoFinnigan, San Jose, CA, USA) ion trap. The vaporizer

temperature was 3508C and the entrance capillary tempera-

ture was 1508C. The corona discharge voltage was 5 kV. The

flow rate of nebulizing sheath gas (nitrogen) was 2.00 L/min.

The He pressure inside the trap was kept constant; the pres-

sure directly read by ion gauge (in the absence of N2 stream)

was 2.8� 10�5 Torr. The maximum injection scan time was

200 ms, five microscans were used and the automatic gain

control (AGC) was turned on.

The same instrument was used to obtain the ESI mass

spectra. The needle voltage was 5 kV. The entrance capillary

temperature was 2408C. The flow of nebulizing gas (nitrogen)

was 1.5 L/min. The He pressure inside the trap (in the

absence of N2 stream), maximum injection scan and micro-

scan times were the same as those used to obtain the APCI

spectra. The AGC was turned on.

SACI spectra were obtained using a gold surface held at a

potential of 150 V. The vaporizer temperature was 4008C and

the entrance capillary temperature was 1508C. The surface

temperature, monitored using an optical pyrometer, was

808C. The flow of nebulizing gas (nitrogen) was 2.5 L/min.

The He pressure inside the trap (in the absence of N2 stream),

maximum injection scan and microscan times were the same

as those used in order to obtain the APCI spectra. The AGC

was turned on.

LC/ESI, APCI and SACI mass chromatograms were

obtained using both full scan MS, and by MS/MS with single

reaction monitoring (SRM) (only for analyzing MDA); the full

Figure 2. LC/APCI extracted mass chromatograms of (a) MDMA, (b) MDA (obtained

using SRM), (c) MDE, (d) amphetamine, and (e) methamphetamine, obtained by injecting

20 mL of a 50 ng/mL standard mixture (corresponding to 1 ng injected on column for

each drug).



scan range was m/z 110–220, and the scan time and peak

width (FWHM) were 200 ms and 0.6 Da, respectively. In these

conditions the instrumental peak width was 1 Da. In the case

of SRM experiments, the isolation width of the precursor ion

was 3 Da and the peak width for the monitored fragment ion

was 3 Da. The collision energy was 30% of its maximum value

(5 V peak to peak); five microscans were used and the

microscan time in SRM mode was 20 ms.

The mass spectra were acquired using positive-ion mode.

The direct infusion mass spectra were obtained using a

sample flow of 30mL/min.

Data analysisThe signal/noise (S/N) ratio was calculated using the

root mean square (RMS) algorithm. The chromatographic

data were elaborated using Xcalibur qualbrowser and Excel

software.

RESULTS AND DISCUSSION

Preliminary results were obtained by direct infusion of a

mixture of the five selected drugs (Scheme 1), with a concen-

tration of 50 ng/mL for each compound, using APCI, ESI and

SACI methods; the mass spectra obtained are shown in

Figs. 1(a), 1(b) and 1(c), respectively. The counts/s values

and the S/N ratios of the most abundant peaks in the spectra

are also reported. It is emphasized that an ion at m/z 163 is

present at high relative abundance in both APCI and ESI

spectra (Figs. 1(a) and 1(b)), but the intensity of this peak is

very low in the spectrum obtained using SACI. This ion

could have originated through ‘in-source’ fragmentation of

[MþH]þ ions of MDMA, MDA and MDE, leading to the

structure shown in Scheme 2. To verify this hypothesis the

MS/MS spectra of the [MþH]þ ions of these compounds,

obtained by injection of 200 ng/mL solutions of pure com-

pounds, were obtained (data not shown); they exhibit an

abundant peak at m/z 163 and this clearly shows that this

fragmentation pathway is strongly favored. These results

indicate that partial fragmentation of the [MþH]þ ions of

these amphetamines takes place using both APCI and ESI,

while in SACI conditions it does not occur, indicating that

this approach is the most suitable ionization technique for

the analysis of these compounds. Furthermore, the lowest

chemical noise and the best S/N ratio were obtained in

Figure 3. LC/ESI ion extracted mass chromatograms of (a) MDMA, (b) MDA (obtained

using SRM), (c) MDE, (d) amphetamine, and (e) methamphetamine obtained by

injecting 20mL of a 50 ng/mL standard mixture (corresponding to 1 ng injected on

column for each drug). The counts/s values and the S/N ratios are also reported. The S/

N ratio was calculated using the RMS algorithm.



SACI conditions, even though the counts/s value is lower

than those achieved using ESI and APCI (Figs. 1(a), 1(b)

and 1(c)). It must be emphasized that, at this analyte concen-

tration level, no [MþH]þ signals were detected in APCI con-

ditions (Fig. 1(a)); by using the ESI source these species

became detectable (Fig. 1(b)), but in the presence of abundant

chemical noise. The chemical noise present in the ESI spec-

trum, higher than that observed in SACI conditions, is prob-

ably due to the high potential (5 kV) at which the spray

needle of the ESI source operated; this high potential gives

rise to high production of solvent ion clusters that lead to

increases in the chemical noise.

An LC method was also developed in order to analyze the

five drugs. The compound that gave rise to the lowest signal

intensity was MDA, detected at m/z 180 (see Figs. 1(b)

and 1(c)). The collision spectra (MS/MS) of [MþH]þ of MDA,

obtained in both ESI and SACI conditions, show an abundant

peak at m/z 163 corresponding to loss of NH3 (Scheme 2,

fragmentation pathway b). Thus, this fragmentation reaction

can be used to perform SRM analysis in order to increase the

instrumental sensitivity via increased selectivity (decrease in

chemical noise); use of SRM to analyze this drug resulted in

an LOD lower by a factor 10. Thus, two acquisition methods

were alternatively used during the chromatographic analy-

sis. The first was the full scan analysis used to detect MDMA,

MDE, amphetamine and methamphetamine, while SRM was

used to detect MDA only.

The LC/APCI ion extracted mass chromatograms

obtained by injecting 20 mL of a 50 ng/mL standard mixture

solution (corresponding to 1 ng injected on-column) are

shown in Figs. 2(a)–2(e); in the case of APCI no chromato-

graphic peaks were detected at this analyte concentration

level. Better results were achieved using ESI (Figs. 3(a)–3(e))

in which all compounds except MDA (Fig. 3(b)) were clearly

detected. Each compound exhibits a characteristic retention

time (MDMA 10.60 min, MDE 11.04 min, amphetamine

9.66 min, methamphetamine 10.39 min). The S/N ratio was

between 11 and 33.

Figure 4. LC/SACI ion extracted mass chromatograms of (a) MDMA, (b) MDA (obtained

using SRM), (c) MDE, (d) amphetamine, and (e) methamphetamine obtained by injecting 20 mLof a 50 ng/mL standard mixture (corresponding to 1 ng injected on column for each drug). The

counts/s values and the S/N ratios are also reported. The S/N ratio was calculated using the RMS

algorithm.



Using the SACI source a strong improvement in terms of S/

N ratio (between 102 and 371, Figs. 4(a)–4(e)) was achieved. It

is emphasized that, by using this new ionization method,

MDA was clearly detected (retention time 10.07 min).

Calibration curves for MDMA, MDA, MDE, amphetamine

and methamphetamine were also obtained using the three

ionization sources, to obtain and compare the linearity ranges

achieved for each compound (Table 1). The R2 values of the

calibration curves were in the range 0.9545–0.9948. The lower

limit of the linearity range for SACI is about a factor 15–100

lower than that achieved using ESI and APCI, and the upper

limit is a factor of 10 lower with respect to that obtained with

ESI and APCI. In fact, in the case of SACI, if the upper

linearity range limit is exceeded, the calibration curve flattens

to reach a plateau. This is probably due to a saturation effect

of the ionizing surface that leads to a decrease in ionization

efficiency. However, the upper to lower linearity limit ratio is

definitely better for SACI (between 20–50) than for ESI

(between 13–20) and APCI (between 2–5). Thus, all these

effects lead to a good linearity range at lower concentration

levels with respect to ESI and APCI. Moreover, this fact

makes it possible to strongly dilute the urine samples before

executing the direct injection analysis (see below).

As expected the worst LOD was achieved using APCI

(200 ng/mL for MDMA, MDE, amphetamine and metham-

phetamine injecting 20mL on-column corresponding to 4 ng,

and 500 ng/mL for MDA injecting 20 mL on-column corre-

sponding to 10 ng). The LOD values obtained using ESI were

lower than those for APCI (50 ng/mL for MDMA, MDE,

amphetamine and methamphetamine injecting 20 mL on-

column corresponding to 1 ng, and 75 ng/mL for MDA

injecting 20 mL on-column corresponding to 1.5 ng). Again,

however, the best performance was obtained using SACI

(LOD 2 ng/mL for MDMA, MDE, amphetamine and

methamphetamine injecting 20mL on-column corresponding

to 0.04 ng, and 5 ng/mL for MDA injecting 20mL on-column

corresponding to 0.1 ng). The high sensitivity of SACI can be

accounted for, at least in part, by a low degree of in-source

fragmentation of the [MþH]þ ions and better ion focusing

conditions of this ionization approach. It is believed that the

ionizing surface can act as an electrostatic mirror after

formation of the ions to better direct the ions to the mass

analyzer. Some experiments are currently in progress using

molecules of different m/z ratios to study the effect of the

surface potential on both ionization and focusing efficiency.

From these data it was clear that the ESI and SACI

approaches gave the best performance, and thus they were

chosen to analyze four urine samples containing some of the

selected drugs. Two dilution ratios (1:20 and 1:100) were used

in order to perform direct analyses of the urine samples. The

quantitation values for these drugs, quoted with reference to

the undiluted urine samples, detected using both ESI (urine

dilution ratio 1:20) and SACI (urine dilution ratio 1:100), are

reported in Table 2. To reduce the quantitation errors, three

injection replicates were used for each sample. The standard

deviations reported in Table 2 were calculated considering

the standard deviation of the linearity calibration curves. The

agreement between the results obtained using the two

ionization sources is quite good; the percent variations of

the quantitation values of the detected drugs using SACI with

respect to those obtained using ESI are between 0.1–8%. This

is the range expected based on the instrumental precision.

The ion trap analyzer employed to obtain the experimental

data is affected by space charge effects47 that must be

accounted for by the AGC, and leads to lower precision in

quantitative analyses. Better results should be obtained using

other mass analyzers such as a triple quadrupole that can

provide high quantitation precision.48

It must be emphasized that ESI was able to detect drugs

when the sample dilution ratio was 1:20, but no drugs were

detected using ESI when the dilution ratio was 1:100. As an

example, Figs. 5(a)–5(c) show the extracted mass chromato-

grams for the [MþH]þ ion of MDMA at m/z 194, obtained by

injecting 20mL of urine 2 (Table 2) diluted 1:100 and using the

APCI, ESI and SACI techniques, respectively. The only

technique able to detect the analyzed drug at this concentra-

tion level was SACI. Furthermore, some drugs were detected

only using the SACI source and not with ESI even when using

Table 1. Linearity ranges obtained using APCI, ESI and

SACI for analysis of MDMA, MDA, MDE, amphetamine and

methamphetamine. The injection volume was 20 mL

Compound

Linearity ranges

APCI (ng/mL) ESI (ng/mL) SACI (ng/mL)

MDMA 200–1000 50–1000 2–100MDA 500–1000 75–1000 5–100MDA 200–1000 50–1000 2–100Amphetamine 200–1000 50–1000 2–100Methamphetamine 200–1000 50–1000 2–100

Table 2. Quantitation values, referred to the undiluted urine

samples, for MDA, MDMA, MDE, amphetamine and

methamphetamine detected in urine samples using both

ESI (urine dilution ratio 1:20) and SACI (urine dilution ratio

1:100). Three injection replicates were used for each sample.

The injection volume was 20 mL

Sample Compounds ESI (ng/mL) SACI (ng/mL)

Urine 1 MDMA — —MDA N.D.* 688� 10MDE — —Amphetamine — —Methamphetamine — —

Urine 2 MDMA 1236� 28 1138� 23MDA N.D.* 512� 10MDE — —Amphetamine — —Methamphetamine — —

Urine 3 MDMA 1803� 32 1800�30MDA — —MDE — —Amphetamine N.D.* 434� 17Methamphetamine N.D.* 797� 14

Urine 4 MDMA — —MDA — —MDE — —Amphetamine N.D.* 750� 10Methamphetamine 1825� 36 1810� 22

* The compounds classified as N.D. were detected using SACI but notusing ESI.



the dilution ratio 1:20 (Table 2). This observation corresponds

to the higher LODs of ESI, mentioned above.

Finally, an experiment was performed in order to evaluate

whether SACI is affected by the signal suppression phenom-

enon due to endogenous components in the biological matrix

that typically affects liquid ionization sources.49 A urine

sample that did not contain the previous mentioned drugs

was spiked in three aliquots of 1 mL. MDMA was added to

the three urine samples at concentrations of 500 (sample A),

1000 (sample B) and 1500 (sample C) ng/mL. These samples

were then diluted 1:100 and analyzed by LC/SACI-MS. The

MDMA external calibration curve (obtained using clean

solutions of standards) was used to measure the MDMA

quantitation values in the three samples. The measured and

real quantitation values, referred to the undiluted urine

samples, are reported in Table 3. The calculated amounts of

MDMA are about 39–47% lower with respect to those

predicted by calibration using the standard solutions. Thus,

it can be concluded that SACI is also affected by the matrix

effect. In future work a detailed study of this and other

instrumental aspects of the SACI source will be performed.

CONCLUSIONS

The new SACI method provides performance in terms of sen-

sitivity, limit of detection and linearity range in the analysis of

MDMA, MDA, MDE, amphetamine and methamphetamine,

that are superior to those achieved by the usually employed

APCI and ESI techniques. The high sensitivity available using

this technique allows direct detection of these drugs in

strongly diluted (1:100) urine samples. Using this approach

it is possible to directly inject the dilute urines on the chroma-

tographic column without any noticeable column damage

caused by the urine matrix (salts, proteins, etc.). However it

must be emphasized that SACI, like ESI and APCI, is affected

by the matrix suppression effect.49 In future work the behavior

of SACI under various experimental conditions will be better

evaluated and also the matrix effect will be investigated.

Future developments will be focused on applying this

method to the analysis of other street drugs and of

compounds of clinical interest. Also, new surface materials

will be tried in order to further improve the instrumental

performance in terms of selectivity and sensitivity.

Figure 5. Extracted mass chromatograms for the [MþH]þ ion of MDMA at m/z 194 obtained by

injecting 20 mL of urine 2 diluted 1:100 and using (a) APCI, (b) ESI, and (c) SACI techniques. The

counts/s value and the S/N ratio are reported in the chromatogram obtained using SACI. The S/N

ratio was calculated using the RMS algorithm.

Table 3. Measured and real quantitation values of MDMA

added to a urinary matrix solution. The quantitation values

were obtained using the MDMA external calibration curve

obtained using clean standard solutions. The % differences

of the measured values with respect to the real ones are also

reported. Three injection replicates were used for each

sample. The injection volume was 20 mL

Urinesample

MDMAmeasured

concentration(ng/mL)

MDMA realconcentration

(ng/mL) % Difference

A 304� 20 500 39B 552� 15 1000 45C 796� 14 1500 47



AcknowledgementsThe authors thank Dr. Pietro Traldi for useful advice. The

authors also thank Dr. Remo Cristoni, Mrs. Maria Florio

and Mrs. Karim Amaya Mendoza for their support.

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