本研究以毛細管紫外光電泳、螢光電泳兩種技術，成功分離了 六種安非他命狡詐家濫用藥物，另外利用 paper spray 技術快速且便 利的偵測到對-氯安非他命的質譜圖。此外，在真實樣品的應用上，
也可成功的分離及偵測到質譜圖，不受背景雜訊的干擾。研究成果統 整如下:
1. 在毛細管紫外光電泳方面，以 CZE 方法成功分離六種鹵化安非他 命狡詐家濫用藥物，並利用三種材料之電動進樣、MEKC 以及 sweeping-MEKC 三種方法增加了樣品的偵測極限。
2. 以毛細管螢光電泳偵測六種鹵化安非他命，相較於毛細管紫外光 電泳可增加偵測極限，且在真實樣品的應用上，可成功測到法定 標準 0.5 ppm。
3. 利用 paper spray 的技術，針對對-氯安非他命做偵測，可快速且有 效的測得質譜圖，並在四種材料的比較下發現濾紙的偵測極限最 好。且對於唾液真實樣品，也可清楚辨認對-氯安非他命的質譜。
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論文發表
Rapid screening and determination of designer drugs in saliva by a nib-assisted paper spray-mass spectrometry and separation technique
Hsun Lee, Chih-Sheng Jhang, Ju-Tsung Liu and Cheng-Huang Lin*
投稿期刊 Journal of Separation Science
投稿日期 21-May-2012 修稿日期 31-May-2012 再投稿日期 11-June-2012 被接受日期 12-June-2012
For Review Only
Rapid screening and determination of designer drugs in saliva by a nib-assisted paper spray-mass spectrometry and
separation technique
Journal: Journal of Separation Science Manuscript ID: jssc.201200480.R1
Wiley - Manuscript type: Short Communication Date Submitted by the Author: n/a
Complete List of Authors: Lee, Hsun
Jhang, Chih-Sheng Liu, Ju-Tsung
Lin, Cheng-Huang; National Taiwan Normal University , Chemistry;
Keywords: nib-assisted paper spray-mass spectrometry, amphetamine derivatives
Journal of Separation Science
For Review Only
Rapid screening and determination of designer drugs in saliva by a nib-assisted paper spray-mass
spectrometry and separation technique
Hsun Lee, Chih-Sheng Jhang, Ju-Tsung Liu and Cheng-Huang Lin*
Department of Chemistry, National Taiwan Normal University, 88 Sec. 4, Tingchow Road, Taipei, Taiwan
* Corresponding author. E-mail: [email protected] (C.-H. Lin) Fax: +886-2-2932-4249
Tel: +886-2-7734-6170
Page 1 of 20 Journal of Separation Science
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Abstract
A method for the rapid screening and determination of amphetamine-type
designer drugs in saliva by a novel nib-assisted paper spray-mass spectrometry
procedure is described. Under optimized conditions, the limit of detections for
amphetamine derivatives (model samples: o-, m-, p-chloro- and o-, m-,
p-fluoro-amphetamines, respectively) were determined to 0.1 µg/mL by the
NAPS-MS method. This method is easier and has a higher sensitivity than similar
methodologies, including atmospheric pressure/matrix-assisted laser desorption
ionization mass spectrometry and electrospray-assisted laser desorption
ionization/mass spectrometry. Data obtained using more classical separation
methods, including liquid chromatography and capillary electrophoresis, are also
reported.
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1 Introduction
Substitutions to the amphetamine molecule give rise to a group of derivatives,
and, as a result, a number of illegal, amphetamine-like drugs are produced in
underground labs for sale on the street [1-3]. From the point of view of screening
and the confirmation of amphetamine derivatives on the illicit market, more
detailed detection and separation information would be highly desirable. Thus far,
gas chromatograph-electron impact-mass spectrometer (GC-EI-MS) [4-7] and
liquid chromatography electrospray ionization-mass spectrometry (LC-ESI-MS)
[8-10] are the most popular and powerful techniques for the analysis of illicit drugs
and analogs thereof. As complementary methodologies, the use of a capillary
electrophoresis-UV (CE-UV) method [11-15], CE-laser induced fluorescence
detection (CE-LIF) [16-20] and CE-mass spectrometry (MS) [21-25] have also
been reported. Although each of these above methods has certain unique
advantages and disadvantages with respect to sensitivity, precision, and simplicity
of use, they can be time consuming when a separation is required. Hence, a
rapid and highly accurate screening method would be highly desirable in this
area. The capabilities of ambient ionization mass spectrometry have recently
been demonstrated, including atmospheric pressure-matrix assisted laser
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desorption ionization-mass spectrometry (AP-MALDI-MS) [26-29],
electrospray-assisted laser desorption ionization mass spectrometry (ELDI-MS)
[30-34] and paper spray-mass spectrometry (PS-MS) [35-39], respectively.
These methods are useful for rapid screening, since they can be used in
conjunction with a variety of samples, either extracted from blood, urine or saliva.
In this study, we selected o-, m-, p-chloro- and o-, m-, p-fluoro-amphetamines
as model compounds. The results obtained by the AP-MALDI-MS, ELDI-MS and
NAPS-MS methods were compared and the results are discussed. As regular
analytical methods, results using the LC and CE methods were also obtained and
the findings are compared.
2 Experimental section
Reagents. o-, m-, p-chloro- and o-, m-, p-fluoro-amphetamines were
generously donated by the Military Police Command, Forensic Science Center,
Taiwan. The procedures for their synthesis have been described previously by
Ann and Alexander Shulgin in their book entitled TiHKAL. Following the
synthesis-steps, the final products were verified by NMR, IR and GC/MS.
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Chromatography paper was purchased from Advantec (Japan). All the other
chemicals were of analytical grade and were obtained from commercial sources.
Apparatus. A mass spectrometer (Finnigan LCQ Classic LC/MS/MS) was
used in the AP-MALDI-MS, ELDI-MS and NAPS-MS experiments, respectively.
A nitrogen laser (Spectra-Physics Model: 337201-00, USA) was used for the
former two cases and an in-house fabricated nib was specially prepared and used
for the NAPS-MS (as shown in Figure 1). A LC-Q-TOFMS system, which
consisted of a Waters 1525 binary HPLC pump, a reversed phase column
(Cosmosil 5C18-MS, 5 µm, 25 cm × 4.6 mm I.D; Nacalai Tesque, Kyoto, Japan)
and a mass spectrometer (Micromass Q-TOF) were also used in this study. As
complementary methods, in-house fabricated CE-UV and CE-LIF systems were
also used. The CE set-ups were identical to those used in our previous studies
[40-42] and are abbreviated herein.
3 Results and discussion
Figure 1 shows a schematic diagram of the nib-assisted paper spray-mass
spectrometry (NAPS-MS) used in this study. A piece of paper was cut into a
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solution was dropped on the triangular spray-paper, and then directly placed on
the nib. The nib was made from brass and was designed to easily connect with a
capillary (I.D. 250 µm). As a result, it was possible to continuously elute the
paper with methanol at a rate of 6 µL/min. The volume of the syringe injector
used was 50 µL. As shown in Figure 2A (test sample: p-chloro-amphetamine;
concentration level: 10 µg/mL), we found that the sharpness of the portion of the tip
of the triangular paper has a substantial effect on the ionization efficiency; the S/N
ratios are improved dramatically when the degree is sharper than 30º. This
indicates that the corona discharge also plays an important role in the process of
ionization. The optimized distance from the tip of the paper to MS inlet was
determined to be 6 mm, which is similar with the value reported in literature [36].
When a sharp (15º-tip; 5 mm in length) paper was used and a 15 µL sample
solution (concentration levels, 0.1 and 0.5 µg/mL; a and b, respectively) was
dropped on it, the ion signals can be clearly observed (applied voltage, + 3 kV).
Figure 2B shows the relationship between the paper-spray ion intensity (total ion
current; m/z: 169.05 ~ 170.05) and the period of ion occurring successively (time).
The ion intensities were decreased very slowly. It still can be observed ~1/5 ion
intensity even 10 min later and this would be useful for rapid screening and
determination of designer drugs. In this case, it can be estimated that
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p-chloro-amphetamine was ionized and continuously ejected from the tip at a rate
of ~ 1 pg/s, within the initial 5 min of the procedure. Furthermore, the mass
spectrum c was obtained by a single acquisition and this could be improved
substantially when multiple acquisitions are used, as shown in mass spectrum d
(541 acquirements). For para-chloroamphetamine, a linearity was found from 0.1
~ 25 µg/mL. The LODs (at S/N = 3) for the 6 amphetamines obtained by the
NAPS-MS as well as AP-MALDI-MS and ELDI-MS procedures are summarized in
Table I. In most conventional MALDI-MS, it is necessary to search around the
sample to find what is called a "sweet spot", which is formed by the type of matrix
used and the sample itself. This is time consuming and difficult to control; the
LODs were determined to be 7 ~ 8 µg/mL. In contrast to MALDI, the ELDI-MS
method can be more convenient because no matrix is required. Furthermore, this
method combines laser desorption and post-ionization by electrospray, and is
suitable for the rapid analysis of solid materials under ambient conditions.
However, when a pulsed nitrogen laser is used, the sample molecules are ejected
from the surface, and then ionized when they encounter the electrospray-clusters.
It can be imagined that the process could be intense, and, indeed, a certain
amount of experimental skill is needed. The LODs obtained by the ELDI-MS
method were determined to be 3 ~ 4 µg/mL. On the other hand, in the traditional
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PS-MS method, the sample should be preloaded onto the paper, and the wetting
solution then added. However, a quantitative analysis is difficult, since the
solution can evaporate during the ionization steps and, when this occurs, the
electrospray process is terminated. Sometimes additional added solution is
needed. In this study, a nib-assisted method was used and is described. The
ionization process became more stable, which resulted in the production of a
high-quality, characteristic mass spectrum. As a result, the LODs were
dramatically improved to 0.1 µg/mL. In an analysis of a saliva sample, a 495-µL
aliquot of a saliva sample obtained from a human volunteer was placed in a tube
and then spiked with p-chloro-amphetamine (5 µL). Although unknown matrix
effects were observed, the LODs could be determined to be 0.5 µg/mL (data not
shown). Hence, we conclude that NAPS-MS is, under most circumstances, the
most favorable rapid “drug-screening” method for use under ambient conditions.
Table II shows the results obtained by regular separation methods, including LC
and CE, respectively. Extraction procedures were referenced and modified from
the literature [43-44], and are abbreviated herein. In the case of LC/MS, when a
gradient elution (A, 0.1% formic acid aqueous solution/pH, 2.5; B, methanol) was
used, p-chloro-amphetamine eluted at ~3.8 min; the LODs were determined to be
0.5 and 1.0 µg/mL for the standard solution and the saliva extract, respectively.
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When the CZE/UV method was used, the six model samples can be completely
separated within ~ 20 min; buffer conditions: phosphate buffer (NaH2PO4, 50
mM/Na2HPO4, 100 mM) in acetonitrile–methanol–water (12.5:17.5:70, v/v/v)
containing 7.5 mM ß-CD; pH, 3.1. Using sweeping-MEKC (phosphate buffer
(NaH2PO4, 50 mM) in acetonitrile-methanol-water (5:30:65, v/v/v) containing 75
mM SDS; pH, 2.13), or CE-LIF, dramatic increases in sensitivity are possible.
Meanwhile, the limit of detection can be improved when the CE/LIF and CE/MS
methods, respectively, are applied. Thus, we can conclude that to a LC/MS or
CE/UV method, in general, it takes at least ~3.8 and 20 minutes for a single
measurement, respectively, whereas the use of NAPS-MS is more convenience
for rapid screening.
4 Conclusions
In this study, we describe the development of a novel NAPS-MS method. It is
suitable for use in the rapid screening of drugs, since it has a high degree of
sensitivity, the operating procedure is simple and the ion signal can be observed
immediately and continuously. The present method can save time because a
number of illegal drugs may be screened first, without the need for any separation
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techniques. We believe this method has the potential for use in practical
analyses and can also be regarded as a helpful tool for use in forensic and clinical
analysis.
This work was supported by a grant from the National Science Council of Taiwan under Contract No. 100-2113-M-003-006-MY3.
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Table I. Limit of detection (µg/mL; n=7) values for the 6 amphetamines based
on various screening methods.
o-F m-F p-F o-Cl m-Cl p-Cl
NAPS-MS 0.11 ±0.01 0.13 ± 0.01 0.12 ± 0.01 0.10 ± 0.01 0.13 ± 0.01 0.10 ± 0.01
AP-MALDI-MS 7.00 ± 1.75 7.10 ± 2.27 7.87 ± 2.05 7.99 ± 2.32 8.10 ± 2.27 8.41 ± 1.77
ELDI-MS 3.73 ± 1.12 3.73 ± 0.93 3.10 ± 0.96 3.53 ± 0.88 4.17 ± 0.92 2.99 ± 0.87
Abbreviations: NAPS-MS, nib-assisted paper spray mass spectrometry; AP-MALDI-MS, atmospheric pressure-matrix assisted laser desorption ionization-mass spectrometry; ELDI-MS,
electrospray-assisted laser desorption ionization mass spectrometry; o-F, o-fluoroamphetamine; m-F, m-fluoroamphetamine; p-F, p-fluoroamphetamine; o-Cl, o-chloroamphetamine; m-Cl,
m-chloroamphetamine; p-Cl, p-chloroamphetamine.
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Table II. Comparison of limit of detection (µg/mL) values for a p-chloroamphetamine standard solution and saliva extracts by liquid chromatography (LC) and capillary electrophoresis (CE) methods, respectively.
Methods Standard Saliva Extracts
LC-Q-TOFMS 0.5 1.0
Abbreviations: LC-Q-TOFMS, liquid chromatography/electrospray ionization quadrupole
time-of-flight mass spectrometry; CZE-UV, capillary zone electrophoresis-UV absorbance detection;
MEKC-UV, micellar electrokinetic chromatography-UV absorbance detection; LIF, laser induced fluorescence; CE-MS, capillary electrophoresis-mass spectrometry.
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Figure Captions
Figure 1 Schematic diagram of the nib-assisted paper spray-mass spectrometry
(NAPS-MS) method used in this study.
Figure 2 A, relationship between the sharpness of the portion of the tip of
triangular paper and ionization efficiency; test sample,
p-chloro-amphetamine (10 µg/mL). B, relationship between the
paper-spray ion intensity (total ion current; m/z: 169.05-170.05) and the
period of ion occurring successively (time). The mass spectrum c was
obtained by a single acquisition and this could be improved substantially
when multiple acquisitions are used, as shown in mass spectrum d (541
acquirements).
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254x190mm (96 x 96 DPI)
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254x190mm (96 x 96 DPI)
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行政院公報 第017 卷 第 086 期 20110511 外交、國防及法務篇 中華民國100 年 5 月 9 日
法務部公告 法檢字第1000802520 號
主 旨：預告修正「毒品危害防制條例」第二條第二項第三款附表三。
依 據：行政程序法第一百五十一條第二項及第一百五十四條第一項。
公告事項：
一、修正機關：法務部。
二、修正依據：毒品危害防制條例第二條第三項。
三、 「毒品危害防制條例」第二條第二項第三款附表三修正草案如附件。本案另載於全國 法規資料庫網站（網址http://law.moj.gov.tw/）之「法規草案」網頁及本部主管法規資料 庫之草案論壇網頁（網址：http://locallaw.moj/DraftForum.aspx）。
四、 對於本公告內容如有意見或修正建議者，請於本公告刊登公報之日起七日內，以書面 向本部陳述意見或洽詢：
(一) 承辦單位：法務部檢察司。
(二) 地址：臺北市重慶南路 1 段 130 號。
(三) 電話：(02)23146871 轉 2308。
(四) 傳真：(02)23811528。
(五) 電子郵件：[email protected]。
部 長 曾勇夫
毒品危害防制條例第二條第二項第三款附表三修正草案總說明