Full text of DOI:10.1093/chromsci/40.6.359

Journal of Chromatographic Science, Vol. 40, July 2002
Fully Automated Determination of Amphetamines and
Synthetic Designer Drugs in Hair Samples Using
Headspace Solid-Phase Microextraction and
Gas Chromatography–Mass Spectrometry
Frank Musshoff*, Heike P. Junker, Dirk W. Lachenmeier, Lars Kroener, and Burkhard Madea
Institute of Legal Medicine, University of Bonn, Stiftsplatz 12, D-53111 Bonn, Germany
sonication extraction of the hair matrix, followed by further
clean-up by solid-phase extraction). Finally, the analytes are
Abstract
This study
derivatized and analyzed, usually by gas chromatography (GC)–
mass spectrometry (MS).
describes a fully automated procedure using alkaline hydrolysis and
headspace (HS) solid-phase microextraction (SPME) followed by on-
fiber derivatization and gas chromatographic (GC)–mass
spectrometric (MS) detection of amphetamine, methamphetamine,
methylendioxyamphetamine, methylendioxymethamphetamine,
methylendioxyethylamphetamine, methylendioxyphenylbutanamine,
and methylmethylendioxyphenylbutanamine in human hair
samples. Ten milligrams of hair is washed with deionized water,
petroleum ether, and dichloromethane. After the addition of
deuterated internal standards the sample is hydrolyzed with sodium
hydroxide and directly submitted to HS-SPME. After the absorption
of analytes for an on-fiber derivatization procedure the fiber is
directly placed into the HS of a second vial containing
Solid-phase microextraction (SPME), discovered and developed
by Pawliszyn et al. (13), has emerged in the past few years as a
variable solvent-free alternative to conventional liquid–liquid
extraction procedures. SPME in conjunction with analysis by
GC–MS has been employed for a variety of classes of organic com-
pounds, especially of volatile and semivolatile agents using the
headspace (HS) technique. For the analysis of amphetamines and
synthetic designer drugs, the direct extraction from an aqueous
medium, direct immersion (DI)-SPME has been used for the
analysis of urine samples (14–17) as well as serum samples (18).
Compared with DI-SPME, the HS technique (HS-SPME) showed
significant advantages because of the avoidance of organic sol-
vents, simpler execution, and a lower chromatographic back-
ground signal. The methods have been described for the analysis
of urine samples (19–24) as well as blood (25–27) and hair sam-
ples (10–12).
However, in hair analysis the SPME procedure was restricted
because of the necessity of digestion prior to extraction. Sporkert
and Pragst (11) described a procedure that combined alkaline hair
hydrolysis, HS-SPME, derivatization, and GC–MS analysis for the
determination of amphetamines. An “in-sample” derivatization
was performed by the addition of methyl- or n-butyl-chlorofor-
mate to the hydrolyzed samples. The resulting carbamates were
extracted by HS-SPME and analyzed by GC–MS. Recently, Liu et
al. (12) developed a similar extractive derivatization method for
the detection of amphetamines in hair samples using hep-
tafluoro-n-butyryl chloride, and Namera et al. (24) used
ethylchloroformate for the analysis of urine. However, for this
procedure the sample vial had to be opened for the addition of
agents for the derivatization after hydrolysis. For an “on-fiber”
derivatization procedure, Jurado et al. (23) used trifluoroacetic
anhydride (TFA), and Koster et al. (17) used pentafluorobenzoyl
chloride for the analysis of urine samples. For the analysis of
N-methyl-bis(trifluoroacetamide) before GC–MS analysis. The limits
of detection are determined between 0.01 and 0.17 ng/mg.
Absolute analyte recoveries are in the range between 0.3% and
7
.5%. Linearity is proven over a range from 0.1 to 50 ng/mg with
coefficients of correlation from 0.998 to 1. In comparison with
conventional methods of hair analysis, this fully automated
HS-SPME–GC–MS procedure is substantially faster and easier to
perform without using solvents. It uses minimal sample amounts
and has the same degree of sensitivity and reproducibility.
Introduction
Hair analysis for drug-of-abuse testing has been established as
an important instrument in clinical and forensic toxicology (1–3).
Various methods have been described for the determination of
amphetamine and designer amphetamines in hair samples
(
4–12). Conventional procedures consist of several consecutive
and time-consuming steps (e.g., digestion of the sample with
alkaline, an acid extraction, an enzymatic treatment, or methanol
*
Author to whom correspondence should be addressed: email f.musshoff@uni-bonn.de.
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher’s permission.
359

Journal of Chromatographic Science, Vol. 40, July 2002
amphetamine and methamphetamine (MA) in serum samples,
Lee et al. (18) used the vapor of an heptafluorobutyric anhy-
dride–ethyl acetate solution for on-fiber derivatization in a labo-
ratory-made HS device with an oil bath, but a comparatively high
temperature of 270°C was necessary for this procedure. In a
single case Sporkert and Pragst (11) used N-methyl-
bis(trifluoroacetylamide) (MBTFA) for on-fiber derivatization of
the analytes after hydrolysis of hair samples, and the trifluo-
roacetyl derivatives were analyzed by GC–MS. Using such an HS
on-fiber derivatization, the method could be performed automat-
ically with a multipurpose autosampler. In comparison with the
HS-SPME method of Koide et al. (10), which did not employ
derivatization of the analytes, the detection limits were markedly
enhanced.
used as the carrier gas. An SPME 0.75-mm-i.d. insert liner and a
Merlin Microseal septum (Supelco) were also used.
Electron impact mass spectra of the analytes were recorded by
total ion monitoring. Retention times and characteristic mass
fragments were recorded, and the chosen diagnostic mass frag-
ments were monitored in the selected ion monitoring (SIM)
mode. The characteristic ions used for quantitation were as fol-
lows: amphetamine–TFA (m/z 140, 91, 118), amphetamine-
d5–TFA (m/z 144, 92, 123), MA–TFA (m/z 154, 110, 118),
MA-d –TFA (m/z 160, 113, 126), MDA–TFA (m/z 135, 162, 275),
11
MDA-d –TFA (m/z 136, 167, 280), MDMA–TFA (m/z 154, 110,
5
135), MDMA-d –TFA (m/z 158, 113, 136), MDEA–TFA (m/z 168,
5
140, 303), MDEA-d –TFA (m/z 173, 141, 308), MBDB–TFA (m/z
5
168, 176, 303), MBDB-d –TFA (m/z 172, 178, 308), and BDB–TFA
5
In this study, a fully automated method combining HS-SPME
and GC–MS with prior alkaline hydrolysis of hair samples was val-
idated using HS on-fiber derivatization with MBTFA for the anal-
ysis of amphetamine, MA, and various synthetic designer drugs.
(m/z 135, 176, 289). Deuterated BDB was not available, and MDA-
d5 was used as the internal standard. For quantitation, peak area
ratios of the analytes to the internal standard were calculated as a
function of the concentration of the substances.
HS-SPME procedure
The washing of the hair samples was performed according to a
modified procedure of Kauert et al. (28); the samples were subse-
quently washed for 5 min in 5 mL of deionized water, petroleum
ether, and finally dichloromethane using a Vortex Genie 2 mixer
(Bender & Hobein AG, Zurich, Switzerland). After drying, the hair
samples were cut into small pieces approximately 1 mm long. The
washing solutions were analyzed by conventional GC–MS proce-
dures to exclude external contamination.
Ten milligrams of hair was submitted to alkaline hydrolysis into
a 10-mL HS vial in the presence of 1 mL of NaOH (10M) and an
aqueous internal standard solution (250 ng deuterated ana-
lytes/mL, 80 µL). The vial was sealed using a silicone/PTFA
septum and a magnetic cap and was shaken for 5 min at 50°C in
the agitator of the autosampler (650 rpm, agitator on-time was
0:05 min, and agitator off-time was 0:02 min). For absorption, the
needle of the SPME device containing the extraction fiber was
inserted through the septum of the vial, and the fiber was exposed
into the HS of the vial for 10 min. For analyte derivatization, the
fiber was exposed to a second vial containing 25 µL of MBTFA for
2 min at 50°C. The compounds absorbed on the fiber were des-
Experimental
Reagents and materials
The following chemicals were purchased from Promochem
(
Wesel, Germany) as methanolic standard solutions:
amphetamine, -amphetamine-d5, -MA, -MA-d11
-3,4-methylendioxyamphetamine (MDA), -3,
-methylendioxyamphetamine-d (MDA-d ), -3,4-methylen-
-3,4-methylendioxyethy-
-3,4-methylendioxymeth-
-3,4-methylendioxymethampheta-
-3,4-methylendio- xyphenyl-2-butana-
-N-methyl-1-(3,4-methylendioxyphenyl)-2-
-1,2-dideutero-N-trideuteromethyl-
-(3,4-methylendioxyphenyl)-2-butanamine (MBDB-d ). The
D
,
L
-
D
,
L
D
,
L
D,L
(
4
MA-d ),
D
,
L
D L
,
1
1
D,L
5
5
dioxyethylamphetamine (MDEA),
lamphetamine-d5 (MDEA-d5),
amphetamine (MDMA),
D L
,
D L
,
D L
,
mine-d (MDMA-d ),
D,L
5
5
mine (BDB),
D L
,
butanamine (MBDB), and
D,L
1
5
solutions were stored at 8°C and used after dilution to the
required concentrations. MBTFA was obtained from Macherey-
Nagel (Düren, Germany). An SPME device for an autosampler
with a replaceable 100-µm polydimethylsiloxane fiber was from
Supelco (Deisenhofen, Germany). The fiber was conditioned at
250°C in the injection port of the GC for 1 h, according to the sup-
plier’s instructions.
GC–MS method
An Agilent Model 6890 Series + GC in combination with a
Model 5973 Network MS and a CTC-Combi-PAL-Autosampler
(
Chromtech, Idstein, Germany) were used for analysis. Data
acquisition and analysis were performed using standard software
supplied by the manufacturer. Substances were separated on a
fused-silica capillary column (HP-5MS, 30-m × 0.25-mm i.d.,
0
.25-µm film thickness) (J&W Scientific, Cologne, Germany).
The GC temperature program was as follows: 110°C held for
1
2
min, 8°C/min up to 210°C, held for 2 min, 30°C/min up to
80°C, and held for 5 min. The temperatures for the injection
port, ion source, quadrupole, and interface were set at 240°C,
30°C, 150°C, and 280°C, respectively. The splitless injection
mode was used, and helium with a flow rate of 1.0 mL/min was
Figure 1. Influence of the incubation temperature on the extraction yield
2
(n = 3).
360

Journal of Chromatographic Science, Vol. 40, July 2002
orbed by exposing the fiber in the injection port for 4 min fol-
lowed by analysis.
For validation, spiked hair samples containing 2 ng/mg of the
analytes were analyzed using the procedure described previously.
Before validation, the following parameters were optimized suc-
cessively: conditions of hydrolysis, the addition of various salts,
incubation time and temperature, agitator speed, extraction time
and temperature, derivatization time and amount of derivatiza-
tion reagent, desorption time and temperature, and depth-of-
fiber insertion into the vial and injection port.
Results and Discussion
Parameter optimization for the HS-SPME method
Additions
The fully automated extraction of hair samples either in buffer
solutions (phosphate buffer pH 2–10) or by acidic hydrolysis gave
inadequate results. Alkaline hydrolysis in the presence of sodium
hydroxide (10M) was found to be optimal. The addition of salts
(
ammonium sulfate, sodium sulfate, sodium carbonate, sodium
bicarbonate, sodium chloride, sodium fluoride, or sodium iodide)
did not increase the extraction yield, contrary to the salting-out
effect observed with other substance classes.
Heating temperature
Figure 2. Influence of the derivatization time on the extraction yield (n = 3).
The incubation of the samples at increased temperatures before
the absorption process led to an improvement of sensitivity,
because the crossing of the analytes was thereby facilitated from
the aqueous into the gaseous phase. The analytes showed a max-
imum response at 50°C, though at higher temperatures a reduc-
tion of the extraction yield could be observed (Figure 1).
Incubation time
The duration of the incubation of the samples in the agitator
before absorption also had a substantial influence on the extrac-
tion yield. A duration of 5 min was found to be optimal.
Agitator speed
The optimum was achieved at 600 rpms.
Extraction
For the HS-SPME it is necessary that a 3-phase equilibrium
adjusts between the liquid phase of the sample, the gaseous phase,
and the solid phase of the fiber. The equilibrium of
the semivolatile analytes was reached after 10 min.
Figure 3. Influence of the desorption time on the extraction yield (n = 3).
Derivatization
The derivatization was finished after 2 min. A
longer derivatization time led to a decrease of the
extraction yield (Figure 2). It is important to note
that for each sample, a separate vial with a deriva-
tization reagent has to be used, because using only
one vial in an analysis sequence can lead to sample
carry-over. The use of 25 µL MBTFA was sufficient
for derivatization.
Desorption
The thermal desorption of the analytes took
place in the injector of the GC. A desorption time
Figure 4. Total ion chromatogram of a spiked hair sample (5 ng/mg) compared with a blank hair sample
dotted line).
of 4 min at 240°C appeared to be optimal (Figure
).
(
3
361

Journal of Chromatographic Science, Vol. 40, July 2002
Depth of fiber insertion in vial and injection port
The depth of the fiber insertion into the injector of the GC
affected the extraction yield. A depth of 52 mm was found to be
optimal.
were between 8.0% and 12.6%, which are in the typical range for
an HS-SPME procedure. The linearity of the SPME method was
investigated by varying the concentration of the analytes in spiked
hair samples over a 0.1–50-ng/mg range. The calibration curves
were constructed from peak areas using the SIM mode and
showed a linear relationship for each drug in the given concen-
tration range. Precision resulted in ranges between 0.9% and
Validation
Figure 4 presents chromatograms of spiked and blank hair
samples. During routine analyses of authentic samples, no inter-
ferences were observed. Validation data are demonstrated in
Tables I and II. For the semivolatile analytes the extraction yields
1
3.2% (intraday) and 1.7% to 17.0% (interday), the bias was
between 0.3% and 17.5% (intraday) and 2.0% to 22.4% (interday).
The presented method for the determination of amphetamine,
MA, MDMA, MDA, MDEA, BDB, and MBDB by means of fully
automated HS-SPME and GC–MS with on-fiber derivatization
showed limits of detection (e.g., 0.01 ng/mg for amphetamine and
MA) that were comparable or lower than the values indicated in
literature, which were obtained by conventional extraction (0.01
ng/mg (6), 0.1 ng/mg (7), or 0.25 ng/mg (8) requiring at least
Table I. Validation Results
Spiked
concentration
Intraday (n = 6)
Precision* Bias
Interday (n = 18)
Precision* Bias
†
†
(ng/mg hair)
(%)
(%)
(%)
(%)
5
0
0–100 mg of hair) or SPME (0.04 ng/mg for amphetamine and
.02 ng/mg for MA determined by Sporkert and Pragst (11)).
For all applications of SPME the CTC-Combi-PAL-Autosampler
Amphetamine
MA
0.5
2
2.1
1.6
0.9
6.8
5.7
2.6
13.2
6.8
6.0
2.3
3.5
1.8
3.3
1.7
1.8
8.1
6.2
4.1
9.8
4.5
2.9
9.2
3.1
0.9
2.3
0.3
0.8
1.8
0.8
6.5
1.6
2.9
6.9
7.8
2.7
7.5
17.5
6.6
3.3
3.8
11.7
7.8
3.2
2.1
1.7
8.2
8.0
3.6
15.1
9.9
5.9
8.2
7.4
4.2
8.0
4.1
2.1
12.1
9.6
4.2
17.0
7.1
4.8
9.9
4.7
2.4
3.7
3.3
2.0
7.0
2.7
7.6
5.1
3.1
7.0
9.6
1.5
4.3
22.4
8.1
6.7
11.1
14.0
8.2
4
4
4
4
4
4
4
0
0.5
2
0
0.5
2
0
0.5
2
0
0.5
2
0
0.5
2
0
0.5
2
offers extensive advantages. All steps that were necessary for the
HS-SPME (such as heating and shaking of the sample, extraction
in the HS at increased temperature, and desorption in the
injector of the GC) were programmable and automatically exe-
cuted, whereby the number of sources of error was reduced dis-
tinctly concerning the reproducibility of the individual working
steps. A large advantage of the HS technique in relation to direct
immersion is the protection of the SPME fiber and the exclusion
of matrix effects, which affects the system and chromatography.
According to our own experience, approximately 90–100 sam-
plings are possible using the HS technique compared with 20–30
samplings using DI.
Compared with the detection of underivatized analytes the
determination of TFA derivatives after an on-fiber derivatization
resulted in sharper peaks as well as an improved chromato-
graphic resolution and larger analyte sensitivity. In comparison
with this procedure, the addition of the derivatization agents
directly to the sample after hydrolysis of the hair matrix is com-
paratively time-consuming (12,16,24,27). Another alternative is
on-column derivatization, which has been described by Nagasawa
et al. (25) and Namera et al. (26); they injected heptafluorobutyric
acid or anhydride in the injection port of the GC before the fiber
was inserted. Desorption and derivatization were achieved by
exposing the fiber in the injection port. Such a procedure, how-
ever, cannot be performed automatically.
MDA
MDMA
MDEA
BDB
MBDB
0
*
Precision, standard deviation/mean value x 100 (%)
Bias, (measured concentration—spiked concentration)/spiked concentration × 100 (%)
†
Table II. Extraction Yield, Limit of Detection and
Quantitation (LOD/LOQ), Linear Range, and Correlation
Coefficient of the Calibration Curves
Linear
range
The potential contamination of the hair by external sources
Extraction
LOD†
LOQ†
Correlation
(e.g., pulverized drugs) could probably generate false-positive
yield* (%) (ng/mg) (ng/mg) (ng/mg) coefficient
results. Therefore, in those cases with positive results for one of
the analytes, we analyzed the washing solutions using conven-
tional GC–MS methods. In hair samples from drug abusers we
found low amounts only in the petroleum ether solution. The
third wash with dichloromethane was negative in all cases, which
demonstrated that no analytes were extracted from the interior of
the hair by using this washing procedure.
In order to demonstrate the applicability of the developed
method on real samples, hair samples of drug abusers were ana-
lyzed. An HS-SPME chromatogram of an authentic hair sample is
shown in Figure 5.
Amphetamine
MA
MDA
MDMA
MDEA
BDB
10.2
8.0
0.01
0.01
0.10
0.06
0.04
0.17
0.10
0.03
0.05
0.33
0.20
0.14
0.54
0.31
0.1–50
0.1–50
0.1–10
0.1–10
0.1–50
0.1–50
0.1–50
0.9991
0.9998
0.9968
0.9992
1.0000
0.9988
0.9999
11.4
12.6
11.1
10.3
9.2
MBDB
*
Percentages of SPME-extracted amount per total amount (20 ng) as determined by
injection of a methanolic solution (n = 3).
LOD and LOQ were determined by a calibration curve established from samples
containing the analytes in the range of LOQ according to German norm DIN 32645.
†
Amphetamines and synthetic designer drugs were found in
362

Journal of Chromatographic Science, Vol. 40, July 2002
1
0. I. Koide, O. Noguchi, K. Okada, A. Yokoyama,
H. Oda, S. Yamamoto, and H. Kataoka. Deter-
mination of amphetamine and methamphetamine
in human hair by headspace solid-phase microex-
traction and gas chromatography with nitrogen-
phosphorus detection. J. Chromatogr. B 707:
99–104 (1998).
11. F. Sporkert and F. Pragst. Analysis of amphetamines
and other basic drugs in hair by combined alkaline
digestion, headspace solid-phase microextraction
and derivatization. In Proceedings of TIAFT
International Meeting. Tallinna Raamatutrükikoja,
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1
2. J. Liu, K. Hara, S. Kashimura, M. Kashiwagi, and
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amphetamines in hair. J. Chromatogr. B 758:
Figure 5. Total ion chromatogram of an authentic hair sample containing 0.55 ng/mg amphetamine and
0.22 ng/mg MA.
95–101 (2001).
1
3. Z. Zhang and J. Pawliszyn. Headspace solid-phase
2
0 hair samples from drug abusers. The following concentrations
microextraction. Anal. Chem. 65: 843–52 (1993).
were determined: 0.2–21.8 ng/mg of amphetamine, 0.1–9.6
ng/mg of MA, 1.3–26.4 ng/mg of MDA, 0.5–12.4 ng/mg of MDMA,
1
4. A. Ishii, H. Seno, T. Kumazawa, M. Nishikawa, K. Watanabe,
H. Hattori, and O. Suzuki. Simple clean-up of methamphetamine
and amphetamine in human urine by direct-immersion solid phase
microextraction (DI-SPME). Jpn. J. Forensic Toxicol. 14: 228–32
0.1–9.9 ng/mg of MDEA, and 0.2–0.9 ng/mg of MBDB.
(1996).
1
5. S.W. Myung, H.K. Min, S. Kim, K. Kim, J.B. Cho, and T.J. Kim.
Determination of amphetamine, methamphetamine and dimetham-
phetamine in human urine by solid-phase microextraction (SPME)-
gas chromatography/mass spectrometry. J. Chromatogr. B 716:
Conclusion
The application of fully automated HS-SPME followed by
GC–MS analysis for the determination of amphetamine, MA,
MDMA, MDA, MDEA, BDB, and MBDB in hair was tested and suc-
cessfully applied to the analysis of hair samples from drug
abusers. The SPME turned out to be a substantially simpler and
faster procedure than the conventional sample processing. The
method meets the sensitivity and selectivity requirements of clin-
ical and forensic toxicology.
359–65 (1998).
1
1
1
1
6. H.G. Ugland, M. Krogh, and K.E. Rasmussen. Automated determina-
tion of ‘Ecstasy’ and amphetamines in urine by SPME and capillary
gas chromatography after propylchloroformate derivatization.
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7. E.H.M. Koster, C.H.P. Bruins, C. Wemes, and G.J. de Jong. On-fiber
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