Journal of Chromatography A 1640 (2021) 461961

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Journal of Chromatography A
journal homepage: www.elsevier.com/locate/chroma

Sample preparation and instrumental methods for illicit drugs in

environmental and biological samples: A review
Xinlv Chen a, Xinyan Wu a, Tiangang Luan b, Ruifen Jiang a,∗, Gangfeng Ouyang c,d,e,∗
a
Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangzhou 511443, China
b
Guangdong Provincial Key Laboratory of Psychoactive Substances Monitoring and safety, Institute of Environmental and Ecological Engineering, Guangdong
University of Technology, 100 Waihuanxi Road, Guangzhou 510006, China
c
KLGHEI of Environment and Energy Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China
d
Guangdong Provincial Key Laboratory of Emergency Test for Dangerous Chemicals, Guangdong Institute of Analysis (China National Analytical Center
Guangzhou), Guangzhou, 510070, China
e
Chemistry College, Center of Advanced Analysis and Gene Sequencing, Zhengzhou University, Kexue Avenue 100, Zhengzhou 450001, China

a r t i c l e i n f o a b s t r a c t

Article history: Detection of illicit drugs in the environmental samples has been challenged as the consumption increases
Received 15 November 2020 globally. Current review examines the recent developments and applications of sample preparation tech-
Revised 28 January 2021
niques for illicit drugs in solid, liquid, and gas samples. For solid samples, traditional sample preparation
Accepted 28 January 2021
methods such as liquid-phase extraction, solid-phase extraction, and the ones with external energy in-
Available online 2 February 2021
cluding microwave-assisted, ultrasonic-assisted, and pressurized liquid extraction were commonly used.
Keywords: The sample preparation methods mainly applied for liquid samples were microextraction techniques in-
Illicit drugs cluding solid-phase microextraction, microextraction by packed sorbent, dispersive solid-phase extraction,
environmental samples dispersive liquid-liquid microextraction, hollow fiber-based liquid-phase microextraction, and so on. Cap-
sample preparation illary microextraction of volatiles and airborne particulate sampling were primarily utilized to extract
detection and determination techniques illicit drugs from gas samples. Besides, the paper introduced recently developed instrumental techniques
applied to detect illicit drugs. Liquid chromatograph mass spectrometry and gas chromatograph mass
spectrometry were the most widely used methods for illicit drugs samples. In addition, the development
of ambient mass spectrometry techniques, such as desorption electrospray ionization mass spectrometry
and paper spray mass spectrometry, created potential for rapid in-situ analysis.
© 2021 Published by Elsevier B.V.

1. Introduction deaths or disability in 2017 [4]. It is worth noting in the UNODC re-
port that rapidly growing numbers of new psychoactive substances
The circulation of illicit drugs around the world has become a (NPS) such as synthetic opioids have become a new problem of il-
serious problem that greatly influences public health, crime rate, licit drug suppression. These groups of substances are synthesized
and traffic safety [1–3]. According to the report from the United by modification of the insignificant molecular structures of psy-
Nations Office on Drugs and Crime (UNODC) in 2019, approxi- choactive substances, which may avoid legal restrictions because
mately 271 million people had used drugs in 2017, which is 30% the list of controlled substances does not include these synthetic
higher than the ones in 2009 [4]. However, some states in US and substances [7]. The most important features of NPS is its variabil-
Canada still allow the consumption of cannabis, which is the most ity in the market. Therefore, the procedures of sample preparation
widely used drug all around the world [4]. The abuse of illicit drug and instrumental analysis for NPS sample are varied with different
is bound to the increase of many health, social, and even envi- types of substance, which poses a challenge to develop analytical
ronmental problems [5]. Another report published by the Cana- protocols for targeted NPS [8].
dian Centre on Substance Abuse showed that about 34.2% of fa- Illicit drugs are more and more frequently detected in environ-
tal car accidents were related to the abuse of drugs in 2010 [6]. ment and these psychotropic drugs may cause harmful effects on
Illicit drug of abuse was also responsible for almost a quarter of the ecosystem and human health [9–11]. Thus, high demand of de-
veloping accurate and sensitive instrumental methods for the de-
tection of illicit drugs in different kinds of samples is assumed. Ex-
∗
Corresponding authors.
cellent sample preparation and highly sensitive analytical instru-
E-mail addresses: [email protected] (R. Jiang), [email protected] (G.
Ouyang).
ments are required. As the most tedious and essential step in the

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

analysis procedures, sample preparation plays a crucial role in ex- and demand for large volume of organic solvents, limit the ap-
traction of target analytes and removal of interferences from the plication of the technique [22]. Liquid-phase extraction technique
sample, especially in trace analysis of complex matrices. A mature was used for extracting the compounds from the solid samples di-
and advanced sample preparation protocol should meet the follow- rectly. To evaluate the degree of contamination in clandestine labo-
ing requirements: (1) high extraction efficiency for target analytes ratories, inspectors firstly used surface wipe method to collect the
with few steps; (2) low cost and fast; (3) easily coupled with an- residue of methamphetamine from the walls and other surfaces
alytical instrument; (4) green chemistry with low solvent use, low in the house [23]. Then the wipe samples were extracted by LPE
toxicity, and environmental-friendly. Conventional extraction tech- before instrument analysis. Wright et al. [24] also used a gauze
niques, such as solid-phase extraction and liquid-phase extraction swab to collect compounds from a sample area of 100 cm2 be-
were the most widely used methods for sample preparation. How- fore desorbing in 30 mL solution (0.1M sulfuric acid) which was
ever, their well-known drawbacks, such as time-consuming, labo- placed on a rotary mixer at 10 0-30 0 rpm for at least 1 h. The des-
rious, and high consumption of organic solvent, limit the appli- orption solution was then filtered through a 0.45 μm pore size
cation of these techniques. Therefore, more and more researchers syringe filter before analysis. The author succeeded in detecting
pay attention to the microextraction techniques which effectively the methamphetamine from the walls of a house with a liquid
overcome the disadvantages of conventional techniques [12]. In chromatography-tandem mass spectrometric (LC-MS-MS) and the
recent years, some reviews have focused on the microextraction LOD of the method was 0.02 μg per sample.
techniques for specific illicit drugs detection. For example, Jain
and Singh [13] introduced microextraction techniques for cannabi- 2.2. Pressurized liquid extraction (PLE)
noids by classifying them into sorbent-based and solvent-based.
Regarding sorbent-based microextraction techniques, solid-phase Pressurized liquid extraction used high temperatures (50-
microextraction (SPME), solid-phase dynamic extraction, microex- 200°C) and pressure (10 0 0-30 0 0 psi) to improve the solubility and
traction by packed sorbents (MEPS), and polymer monolithic mi- mass transfer of the organic solvents. Compared with LPE, it is
croextraction were introduced. For solvent-based methods, hollow more efficient for solid or semi-solid samples with shorter pro-
fiber-based liquid-phase microextraction (HF-LPME) and disper- cessing time and lower amount of desorption solution [25,26].
sive liquid-liquid microextraction (DLLME) were briefly presented. Similar to other solvent-based extraction techniques, PLE usually
Chalavi et al. [12] reviewed the microextraction procedures for couples with solid-phase extraction (SPE) to improve the extrac-
the detection of amphetamines in biological samples with simi- tion efficiency. Baker et al. [27] developed a multi-residue method
lar classification. Gorynski [14] presented a comprehensive review with PLE and SPE to determine the concentration of common il-
of SPME applied for testing the drugs of abuse. Because of the licit drugs adhered to suspended particulate matter in wastewa-
abuse of drug, illicit substances have been detected in air, waters, ter. The method showed high sensitivity for the majority of the
and organisms. Besides, as a result of legal restrictions, these sub- compounds after optimization of the extraction solutions, extrac-
stances have been tracked from various items such as the surface tion temperatures, and times of extraction cycle. Mastroianni et al.
wipe samples, banknotes, and e-cigarette. Thus, it is of great im- [28] used PLE method to extract 20 abused and illicit drugs in
portance to develop different sample preparation techniques and freeze-dried sewage sludge and followed by SPE to purify the ex-
instrumental analysis methods for various forms of samples. In lit- tracts. The PLE recoveries were from 61% to 113% for most analytes
erature, many research works [15–17] have studied the illicit drugs and the method’s relative recoveries were between 89% to 130%.
in liquid samples, such as water, blood, saliva, urine, and beverage, Results also showed that the illicit drugs present in sewage sludge
while few of them have considered these compounds in solid and were easily overlooked, which caused underestimate of the con-
air samples, which is prerequisite for evaluating the effects of these centration in wastewater.
substances. In this review, sample preparation methods for illicit
drugs in solid, liquid, and gas samples were comprehensively in- 2.3. Dispersive liquid-liquid microextraction
troduced based on the reports in the past ten years. Fig. 1 presents
the general samples for detection of illicit drugs summarized in Rezaee et al. [29] first presented DLLME in 2006. A ternary
this study. Apart from sample preparation, the development of an- components solvent system was formed by dispersing organic
alytical instruments is also the key to determine whether the re- droplets in liquid sample with the assistance of dispersant. Due
sults meet the needs. Therefore, the advanced analytical instru- to the large contact area between the small droplets of extrac-
ments that have been applied for detecting the illicit drugs were tant and the sample solution, the hydrophobic target can quickly
also outlined and suggestions for subsequent research in the fu- reach extraction equilibrium between two phases and achieve en-
ture were provided. Fig. 2 shows an overview of the techniques richment in extractant. After extraction, the extract can be col-
mentioned in the literature. lected through centrifugation. The technique showed dramatic ex-
traction efficiency and sensitivity for organic compounds from wa-
2. Sample preparation techniques for solid samples ter samples. Compare to SPE, DLLME requires less extraction time
and amount of organic solvent, but with better enrichment fac-
Solid samples like wipe samples, biological tissue, and hair are tors [30]. Many factors should be considered to obtain excellent
frequently used in the detection of illicit drugs. Sample preparation performance. The selections of the extraction solvent, disperser,
of solid samples usually contains sample extraction and clean-up and extraction time are essential for the outcome. Vincenti et al.
procedure [18–20]. Table 1 summarizes the application of sample [20] compared four types of extraction solvents, including chloro-
preparation techniques for solid samples. form, dichloroethane, octanol, and 1-decanol for sixty drugs and
found that chloroform was the best one for most of the drugs.
2.1. Liquid-phase extraction (LPE) The author also compared the results with the ones from NaOH di-
gestion and methanol extraction, which were two most commonly
Liquid-phase extraction is the oldest isolation technique for or- used methods in literature for hair samples. The result showed that
ganic compounds [21], which uses organic solvent to extract tar- coupling with high performance liquid chromatography-mass spec-
get compounds with hand shaking or some simple assistance. This trometry (HPLC-MS), PLE-DLLME had less matrix effect and higher
technique is widely used to extract target analytes from solid sam- sensitivity which met the cut-off values from SoHT guidelines (rec-
ples. However, disadvantages such as time-consuming, laborious, ommend 0.5 ng mg−1 for ࢞9-tetrahydrocannabinol (THC) and co-

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

Fig. 1. General samples for illicit drugs detection.

2.4. Ultrasonic-assisted extraction (UAE)

Ultrasonic-assisted extraction is a mature extraction technology

that accelerates the process of target components into the solvent
by applying ultrasound during LPE. It has been proved that the
UAE can improve the extraction efficiency compared with normal
solvent extraction because of its physicochemical effects like ul-
trasonic cavitation, disturbance, fragmentation, emulsification, and
erosion [32–34]. The extraction performance of UAE, microwave-
assisted extraction (MAE), and soxhlet extraction were assessed
for pharmaceuticals, personal care products, and other emerging
contaminants including illicit drugs in sediment [35]. The result
showed that UAE followed by SPE had the highest recovery with
median of 52.3%, while MAE and soxhlet extraction were only
14.2% and 21.7%, respectively. UAE was frequently applied to ex-
traction of biological samples because of its powerful ability of
fragmentation. For instance, Miller et al. [36] used the UAE to ex-
Fig. 2. The overview of sample preparation and instrumental methods for illicit
drugs. tract illegal drugs in Gammarus pulex sample and then applied tan-
dem SPE to reduce contaminants and preconcentrate analytes. The
method showed excellent extraction efficiency with 74% of average
absolute recovery and the median LOD of 0.6 ng g−1 (dry weight).
Yin et al. [37] developed a method by combining UAE and SPE fol-
caine, 0.2 ng mg−1 for opioids and amphetamines). Meng et al.
lowed by ultra-performance liquid chromatography-tandem mass
[31] also developed a DLLME method coupled to capillary elec-
spectrometry analysis (UPLC-MS/MS) to detect 12 illicit drugs and
trophoresis and ultra violet detection for measuring three groups
their metabolites in fish tissue. The obtained LODs and LOQs were
of chiral drugs and heroin on forensic samples like banknotes and
0.001-0.025 ng g−1 and 0.005-0.050 ng g−1 , respectively. Since all
kraft paper. The linear range of the method was 0.15 to 6500 μg
12 analytes were basic compounds, the authors found that the
L−1 and the LOD was in the range from 0.05 to 0.2 μg L−1 . Besides,
acidified mixed solvent of methanol-acetonitrile had a better re-
the enrichment factors of this method were up to 545 to 611.

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

Table 1
Sample preparation techniques for detection of illicit drugs in solid samples.

Analyte Matrix Method Analytical Recovery LOD Precision (RSD) Linear Ref.
instrument range

Intra-day Inter-day

sixty drugs of abuse hair PLE&DLLME HPLC- 8-95% 0.1-5 pg < 15% < 25% 0.1-4000 [20]
HRMS/MS mg−1 pg mg−1
amphetamines, cocaine, hair UAE&d-SPE UPLC-MS/MS. 87.1- 2-20 pg < 10.6% < 12.9% 5-2000 [38]
opioids and their metabolites tube 105.3% mg−1 pg mg−1
6-acetylmorphine, codeine, hair PLE&SPE capillary 81-96% 0.1-1 ng < 12.8% < 9.68% 0.3-25 ng [50]
methadone morphine and electrophoresis mg−1 mg−1
cocaine and its major
metabolite, benzoylecgonine
cocaine, benzoylecgonine, hair SPME GC-MS 88-94% 0.01 ng < 15% < 20.5% 0.02-40 [48]
norcocaine, cocaethylene, mg−1 ng mg−1
and tropococaine
stimulants, opioid and soil and PLE&SPE UPLC-MS/MS ≥ 60 % < 0.05 < 10% < 15% 0.5-500 [27]
morphine derivatives wastewater for most ng g−1 ng g−1
suspended analytes for soil <
particulate in both 1 ng g−1
matter (SPM) matrices for SPM
AMP, METH, MDMA, MDA sewage sludge MAE&SPE HPLC-MS/MS 67-84% 0.73-5.15 < 15.2% < 13.1% 0.025-250 [44]
ng g−1 μg L−1
cocainics, amphetamine-like sewage sludge PLE&SPE LC–ESI- 89-130% Lower < 19% - 0.1-1000 [28]
compounds, opioids, (QqLIT)MS/MS (relative than 2.5 ng g−1
cannabinoids recovery) ng g−1
(expect
cannabi-
noids)
benzoylecgonine, MDMA, SPM and UAE&SPE UHPLC -HRMS 77-89% 1.3-2.1 < 16% < 22% 0-250 μg [140]
mephedrone (4-MP), sediment ng g−1 L−1
methylephedrine (4-MMC),
Cocaine
cocaine, ketamine, MDMA, Gammarus pulex LE&SPE LC-MS 54-80% 0.5-2.9 < 15% < 24% 0.5-500 [36]
METH, methedrone ng g−1 ng g−1
stimulants, opioids, Phragmites MAE&SPE UPLC-MS/MS 80-120% 0.04-3.02 < 16.2% < 13.6% 0.05-500 [43]
ketamine, morphine and australis ng g−1 ng g−1
metabolites
AMP, METH, MDA, MDMA, fish tissues UAE&SPE UPLC-MS/MS. 60-127% 0.001- < 10.65% < 11.56% 0.1-10 ng [37]
ketamine, cocaine, heroin 0.025 ng g−1
and their metabolites g−1
heroin, D/L- METH, banknote, kraft DLLME capillary 85.9- 0.05–0.20 < 4.4%- - 0.15– [31]
D/L-MDMA, ketamine paper, plastic bag electrophoresis 95.4% μg L−1 6500 μg
and silver paper with ultra (absolute L−1
violet recovery)
detection.
THC, cannabidiol and solid matrices SPME Nanoliquid 88-128% 2-5 ng - - 8-100 ng [88]
cannabinol such as plastic Chromatogra- mL−1 mL−1
bag, office paper, phy
and cloth
Abbreviations: AMP amphetamine; METH methamphetamine; MDMA 3,4-Methylenedioxymethamphetamin; MDA 3,4-Methylenedioxyamphetamin; SPM suspended par-
ticulate matter.

covery than the pure solvent. This method has been applied to ple preparation technique and UHPLC-MS/MS as analytical instru-
measure the illicit drugs in wild fish from four urban rivers in Bei- ment for determination of multi-residues (pharmaceuticals, per-
jing, China. Compared with traditional liquid phase extraction, UAE sonal care products, and illicit drugs) in Phragmites australis. Ex-
greatly reduced the consumption of organic solvents. Shin et al. cellent recoveries with range from 80% to 120% were obtained for
[38] only used 1 mL methanol to extract 10 mg hair samples in most of the analytes. The method quantitation limits (MQLs) for
an ultrasonic bath for 60 min at temperature of 50 °C and then 65 from 81 compounds were less than 1 ng g−1 . The authors also
cleaned up by SPE tubes. The mean recoveries of 75 abuse drugs found that the factors influencing the recovery of MAE sampling
were 87.1-105.3% with LODs ranging from 2 to 20 pg mg−1 (hair) were extraction temperature, sample mass, and amounts of sol-
for most analytes when analyzed by LC-MS/MS. The method was vent. Similarly, Evans et al. [44] proposed the method of MAE-SPE
successfully applied to real hair samples of 11 drug abusers. for the extraction of illicit drugs in 1 g digested sludge. The result
showed that the relative recoveries for majority compounds were
2.5. Microwave-assisted extraction in the range of 67%-84% and the MDLs were 0.73-5.15 ng g−1 .

As early as 1975, Abu-Samra et al. [39] had already applied 2.6. Others
microwave technique to promote the extraction process of LPE.
Microwave-assisted extraction can enormously decrease the extrac- In addition to the methods mentioned above, others also re-
tion time (typically only 10 min) because microwaves directly heat ported in literature. For instance, Beasley et al. [45] reported a
up the solutions instead of containers [40,41]. The technique also method utilizing 2-fluoro-1-methylpyridinium p-toluenesulfonate
reduces the consumption of organic solvent and allows multiple for in-situ derivatization of cannabinoids in hair samples. This
samples [42]. Petrie et al. [43] employed MAE and SPE as sam- method can directly identify three isomers of cannabinoids in

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

a single hair sample by matrix-assisted laser desorption ioniza- the analytes were from 0.02 to 0.72 ng mL−1 and 1 to 2.5 ng
tion mass spectrometry (MALDI-MS) profiling and imaging. Mainly, mL−1 , respectively, with recoveries ranging from 83.2% to106%. Fi-
Mieczkowski [46] chose to enzymatically digest hair samples with nally, the proposed method was successfully applied to seven fatal
Proteinase K after removing environmental contamination by iso- forensic cases. The extraction solvent of the LLE is chosen based
propanol. The LOD of the method were as follow: 5 ng per 10 on the properties of target substances, which is the most impor-
mg hair for cocaine and amphetamines, 0.01 ng per 10 mg hair tant parameter. To find out the most suitable extraction solvent for
for cannabinoids, and 2 ng per 10 mg hair for opiates. Interest- cannabinoid and synthetic cannabinoid metabolites, Mariño et al.
ingly, Gambier et al. [47] placed positive cocaine hair samples on [52] compared the extraction performance of hexane, ethyl ac-
a 200 °C iron plates consequently 30 times with 2 s each time etate, and the mixture of them with ratio of 1:1 in volume. Re-
and compared the concentration of cocaine from heated hair with sults found that hexane had lower extraction capacity for JWH-
non-treated samples. They found that the median concentrations type metabolites than ethyl acetate which cannot extract any of
of anhydroecgonine methyl ester and benzoylecgonine increased the non-synthetic cannabinoids. Thus, hexane:ethyl acetate with
and the ratio of median benzoylecgonine to cocaine increased from ratio of 1:1 in volume was the most comprehensive solvent in this
0.6 to 1.5 after thermal treatment, which may be due to the hy- study. The LOQ of the method was in the range of 1–59 ng L−1 .
drolysis and pyrolysis of cocaine. Similarly, Molnar et al. [53] used 5 mL hexane:ethyl acetate mix-
SPME is a powerful technique for hair sample detection due to ture with ratio of 9:1 in volume as an extraction solvent to en-
its automation and high throughput capacity. Gambelunghe et al. rich the THC in oral fluid. The author mentioned that LLE cou-
[48] measured cocaine, benzoylecgonine, norcocaine, cocaethylene, pled with LC-MS/MS was a reliable method for detecting THC in
and tropococaine in hair samples by direct immersion SPME with saliva with no significant matrix effect and the recovery was up to
gas chromatography-mass spectrometry (GC-MS). The method was 65%. The LOD was 0.25 ng mL−1 and the linear range was between
successfully applied to analyze 90 hair samples. The method LOD 1-500 ng mL−1 . Interestingly, Robin et al. [54] presented a fully
and LOQ for the selected analytes were 0.01 and 0.02 ng mg−1 , automated liquid extraction procedure to determine concentration
respectively. Headspace extraction mode of solid-phase microex- of abuse drugs in plasma. They only needed to load the urine or
traction was also applied for illicit drugs detection due to its con- blood sample onto the system and the analysis result of LC-MS/MS
venience and prevention of matrix effect. For instance, Moosmann would come out in 18 min on average, which largely reduced op-
et al. [49] applied headspace solid-phase microextraction to mea- eration time and allowed parallel sample preparation.
sure cannabinoids in hair sample and achieved LOQ of 0.01 ng
mg−1 for THC, CBN, and CBD. Based on the result from 41 children, 3.2. Dispersive liquid-liquid microextraction
4 teenagers, and 34 drug-consuming parents, the author found that
9-tetrahydrocannabinolic acid A (THCA-A) cannot transfer from Traditional liquid liquid extraction used large amount of or-
blood to the hair and can be only absorb from the environment, ganic solvents, which is environmental unfriendly. Hence, Jeannot
which can be an evident for external contamination. For solid ma- and Cantwell [55] developed liquid-liquid microextraction (LLME)
trix, extraction techniques like PLE, MAE, UAE are non-selective, in 1996 to reduce the consumption of organic solvent as well
thus usually combine with a clean-up process. SPE was commonly as improve the extraction efficiency. For analysis of illicit drugs,
used purification and preconcentration procedure for determina- DLLME and hollow fiber-based liquid-phase microextraction were
tion of illicit drugs in solid sample. Baciu et al. [50] applied SPE as two common techniques of LLME [56]. Martins et al. [57] opti-
clean-up process for drug detection in hair sample and investigated mized the DLLME method for the extraction of cocaine and its
better conditions for the procedure. They found that Oasis HLB was metabolites in hospital effluent. For 5 mL effluent sample, the best
suitable as the SPE sorbent not only because of its polar group but conditions were 150 μL extraction solvent (chloroform) and 350 μL
also its hydrophilic and lipophilic retention characteristics, which disperser solvent (methanol) with NaCl concentration of 0.3 mol
facilitated its extraction of acid, neutral, and basic compounds in L−1 in pH=9. The obtained recovery for cocaine was 98.3% and
a wide pH range. Furthermore, for basic drugs, such as cocaine, 6- the LOD of the method was 0.1 μg L−1 when analyzed by HPLC.
acetylmorphine, codeine, and morphine, a high pH condition pro- Mercieca et al. [58] utilized hexyl chloroformate as a derivatiza-
moted better retention in this sorbent and methanol containing 2% tion agent added into the sample and followed by DLLME to ex-
(v/v) of formic acid performed excellent elution efficiency. tract illegal drugs in urine and blood within 6 min. The extract
was analyzed by GC-MS. The same as the study by Martins et al.,
3. Sample preparation techniques for liquid samples extractant and disperser solvents were chloroform and methanol,
respectively. The LOD of the method ranged between 1 and 10 ng
Liquid samples are most commonly used in the detection of il- mL−1 and the linear range for all stimulants was from LOD to 10 0 0
licit drugs. According to literature, liquid samples are mainly water ng mL−1 . The extraction recoveries for two concentration levels (50
samples (including environmental water, wastewater, and drinking and 500 ng mL−1 ) were 92% and 115%, respectively. DLLME is also
water), beverage, oil, and biological fluids such as urine, plasma, an efficient extraction technique for non-targets analysis. Odoardi
and saliva. The overview of the sample preparation techniques for et al. [59] used DLLME to extract 78 NPS in blood sample and ana-
liquid samples is shown in Table 2. lyzed by UHPLC-MS/MS. The method achieved recoveries from 10%
to 99% with the LOD from 0.2 to 2.0 ng mL−1 and linear range
3.1. Liquid-liquid extraction (LLE) between 5 and 100 ng mL−1 for all the NPS. Since NPS are now
controlled substances in most countries, a number of researchers
Liquid-liquid extraction is widely used for the liquid sample have paid attention to the development of the analytical methods
analysis. Because of different solubility of target compounds in two for them. Fernández et al. [60] applied ultrasound-assisted DLLME
immiscible liquids, the method can separate the compounds from coupled with UPLC-MS/MS to detect ten synthetic cathinones and
liquid sample with proper solvents. Woźniak et al. [51] reported ten drugs of abuse in saliva. By comparing six extractants and dis-
a LLE method for sampling of amphetamines and synthetic cathi- persants, the authors confirmed that chloroform and 5% ammo-
none in whole blood. After optimization, one milliliter of ethyl ac- nium hydroxide in methanol were the best extraction solvent and
etate was used to extract 200 μL blood samples. The mixture was dispersant, respectively. The linear range of the method was 0.5
then vortexed for 1 min before separation. The extract was an- to 500 ng mL−1 and the LOD was in the range from 0.1 to 2.5
alyzed by GC-MS/MS after derivatization. The LODs and LOQs of ng mL−1 (expect morphine for 25 ng mL−1 ). The recoveries of the

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

Table 2
Sample preparation techniques for detection of illicit drugs in liquid samples.

Analyte Matrix Method Analytical Recovery LOD Precision (RSD) Linear Ref.
instrument range
Intra-day Inter-day

morphine, MDMA, human plasma MEPS UPLC-photodiode 80-104% 0.005-0.025 μg < 13.8% < 13.8% 0.05-10 μg [95]
6-acetylmorphine, array detectors mL−1 mL−1
mephedrone, (PDA)
benzoylecgonine, cocaine,
MDPV, cocaethylene, EDDP,
methadone
designer benzodiazepines human plasma MEPS UHPLC-MS/MS 61-123% 0.5-5 ng mL−1 < 6.5% < 10.6% 0.5-500 ng [98]
and Z-hypnotics mL−1
11 amphetamines and 34 whole blood LLE with penta- GC–MS/MS 83.2–106% 0.02-0.72 ng < 10.2% < 8.1% 1-250 ng [51]
synthetic cathinones fuoropropionyl mL−1 mL−1
derivatization
78 NPS whole blood DLLME UPLC–MS/MS 10-99% 0.2-2 ng mL−1 - - 5-1000 ng [59]
mL−1
AMP, METH, MDMA plasma EME CE–C4 D 99.2- 1.0-2.5 ng < 19.0% - 5-500 ng [68]
100.8% mL−1 mL−1
AMP, METH urine and EM-SPME GC-MS 96.9- 1-2 ng mL−1 < 7.3% < 12.5% 10-300 ng [73]
whole blood 102.1% mL−1
cocaine, MDMA postmortem d-SPE GC-MS 87-116% 0.02-0.03 μg < 7.2% < 19.7% 0.02-4.0 [101]
blood mL−1 for LOQ μg mL−1
cathinones, blood and DLLME GC-MS 92-115% 1-10 ng mL−1 < 15% < 15% 5–1000 ng [58]
amphetamine-like stimulants urine mL−1
and NPS
AMP, METH, MDMA, MDA, blood and DLLME GC-MS 79.3- 0.5-4 ng mL−1 < 5.7% - 0.0030-10 [65]
methcathinone, ketamine, urine 103.4% μg mL−1
methadone
methadone, blood and EME CE-UV 57.5-85% 0.91-3.0 μg < 11.7% - 3-750 μg [69]
methamphetamine, and urine L−1 L−1
tramadol
AMP, METH, MDMA whole blood SFME paper spray mass 74.2- 0.01-0.05 ng < 12.9% < 13.8% 0.5-500 ng [75]
and raw urine spectrometry 103.6% mL−1 mL−1
synthetic and natural oral fluid SPME GC-MS - 1-10 ng mL−1 < 12.8% < 6.4% 10-1000 ng [87]
cannabinoids mL−1
ketamine, mephedrone and oral fluid MEPS DESI-MS 83-120% 0.05-0.5 mg < 15.9% < 19.9% 0.05-10 mg [97]
10 NPS L−1 for LOQ L−1
21 NPS and their metabolite oral fluid MEPS UPLC–MS/MS 75-125% 0.25-2.5 ng < 13.7% < 16.6% 0.5-500 ng [94]
mL–1 mL−1
dichloropane oral fluid MEPS Ion mobility 85-110% 30 μg L−1 < 8% - 100-1000 [96]
spectrometry μg L−1
10 synthetic cathinones and oral fluid DLLME UPLC-MS/MS 74-129% 0.1-2.5 ng < 14.8% < 14.8% 0.5-500 ng [60]
10 illicit drugs mL–1 mL–1
AMP, METH, ephedrine oral fluid SPME Capillary - 0.5-0.8 μg < 6% - 1-10 μg [91]
chromatography mL−1 mL−1
with fluorimetric
detection
31 NPS oral fluid MEPS UPLC-MS/MS 31-96% 0.005-0.850 ng - < 25% LLOQ to [7]
mL−1 200 ng
mL−1
THC oral fluid LLE LC-MS 65% 0.25 ng mL−1 < 8.6% < 9.4% 1-500 ng [53]
mL−1
cocaine and cocaine urine d-SPE HPLC-MS 75.1- 0.09-1.10 ng < 4.8% < 5.4% 5-200 ng [102]
metabolites 105.7% mL−1 mL−1
METH urine d-SPE HPLC-UV 99.76% 9 ng mL−1 < 5.51% < 5.98% 30-800 ng [103]
mL−1
−1
AMP, METH, urine SBSE HPLC-UV 98.62- 5-8 ng mL < 6.58% < 6.54% 20-2500 ng [106]
pseudoephedrine. 99.82% mL−1
AMP, METH, MDMA and THC urine SBSE HPLC-MS/MS 37.1-84.3% 0.17-1.08 ng - < 8.7% 12.5-2000 [105]
metabolite mL−1 ng mL−1
cocaine, ketamine, and urine HF-LPME GC-MS 65-71.5% 0.01-0.05 μg < 7.3% < 9.3% 1-500 μg [63]
lidocaine L−1 L−1
AMP, MDA urine HS-HF-LPME GC-MS 5.2-19.6% 0.25 ng mL−1 < 4.0% - 50-700 ng [64]
(absolute for AMP(LOQ); mL−1
recovery) 1.00 ng mL−1
for MDA(LOQ)
methamphetamine urine EME GC-MS 95-98.5% 2.4 ng mL−1 < 5.5% < 6.5% 8-800 ng [70]
mL−1
METH, ephedrine and urine EME CE 56-60% 1.51-3.03 ng < 4.4% - 10-1000 ng [71]
methadone mL−1 mL−1
AMP and urine SDME GC-MS 82.7-96.2% 0.27 μg L for < 8.3%
−1
< 12.8% 1-2000 μg [74]
methylamphetamine (MA) AM 0.14 μg L−1
L−1 for MA
THC and 11-nor–9-carboxy- wastewater SPME with GC-MS 92-112% 1.0 ng L−1 for < 15% - LOQ-1000 [89]
9-tetrahydrocannabinol on-fiber THC; 2.5 ng ng L−1
(THCCOOH) derivatization L−1 for
THCCOOH
(continued on next page)

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

Table 2 (continued)

Analyte Matrix Method Analytical Recovery LOD Precision (RSD) Linear Ref.
instrument range
Intra-day Inter-day

THC and its major wastewater LLE UHPSFC-MS/MS 59-138% 1-59 ng L−1 for < 17.8% - 0.5-100 ng [52]
metabolites, 4 JWH-type LOQ mL−1
synthetic cannabinoid
metabolites
20 drugs of abuse and drinking water SPE UPLC-MS 62-107% 0.01-1.09 ng < 8.32% - 0.05-1000 [83]
pharmaceuticals L−1 ng mL−1
cocaine, diazepam, beverages, TFME dielectric barrier - 3-300 pg mL−1 < 21% - 10-30K pg [16]
desipramine, imipramine, urine and discharge ionization mL−1
MDMA , MDEA , methadone, blood with MS
fentanyl
cocaine, hospital DLLME HPLC-FLD-DAD 98.3- 0.10 μg L−1 < 16.3% - 15-195 μg [57]
effluent 102.6% L−1
−1
THC, cannabinol and breast milk QuEChERS UPLC-MS/MS 85-118% 1 ng mL for < 13% < 18% 1-100 ng [107]
cannabidiol LOQ mL−1
THC, cannabidiol and human breast HS-SPME GC-MS - 10 ng mL−1 < 13.3% < 9.2% 20-200 ng [92]
cannabinol milk mL−1
cannabinoids honey QuEChERS HPLC-ESI-MS/MS >82% 0.3 ng g−1 < 7.6% < 7.6% 0.5-50 ng [108]
g−1
Abbreviations: MDVP Methylenedioxypyrovalerone; MDMA 3,4-Methylenedioxymethamphetamin; EDDP 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; AMP am-
phetamine; METH methamphetamine; MDA 3,4-Methylenedioxyamphetamin; THC ࢞9-tetrahydrocannabinol; MA methylamphetamine; THCCOOH 11-nor-9-carboxy-9-
tetrahydrocannabinol; JWH a type of synthetic cannabinoid; MDEA methyldiethanolamine.

method were between 74% and 129% with intra-day and inter-day 3.4. Electromembrane extraction (EME)
precision lower than 14.8%. Finally, this method was successfully
utilized to analyze 15 real samples from patients. Electromembrane extraction is developed to overcome the
problem of HF-LPME, which is time-consuming due to the low
mass transfer efficiency. With connection of an external elec-
tric field, the extraction time of EME decreased 6-17 times com-
3.3. Hollow fiber-based liquid-phase microextraction
pared to HF-LPME because the charged ions go through the sup-
porting liquid film quickly in the electric field [66,67]. Further-
Hollow fiber liquid-phase microextraction was first introduced
more, the technique showed excellent ability of pre-concentration
by Pedersen-Bjergaard and Rasmussen for sample preparation of
due to greatly different volumes between the sample solu-
methamphetamine in biological fluids [61]. Firstly, an organic sup-
tion and the acceptor solution. Mamat and See [68] used a
ported liquid membrane was formed on the wall of a porous
hollow polymer inclusion membrane with a high voltage DC
hollow fiber by dipping the fiber into an organic solvent. Then,
power to analyze amphetamine, methamphetamine, and 3,4-
the extraction solvent was injected into the lumen of the fiber
methylenedioxymethamphetamine (MDMA) in human plasma. The
which was immersed in the liquid sample for extraction. This tech-
result showed that EME was a powerful pretreatment tool for illicit
nique showed excellent performance such as stable, low-cost, su-
drug in biological samples with enrichment factors in the range of
perior clean-up effects, and good extraction ability compared with
97-103 folds and LOD from 1.0 to 2.5 ng mL−1 . Many new ma-
other liquid-phase microextraction [62]. Yamini et al. [63] used
terials were applied in the EME system to increase the extrac-
n-dodecane as supported liquid membrane solvent and acetoni-
tion efficiency and selectivity. For example, metal-organic frame-
trile as extraction solvent to enrich cocaine, ketamine, and lido-
work material [69] and graphene oxide [70] were added in the hol-
caine in human urine and analyzed by GC-MS. The method de-
low fiber wall to enable the conductivity of membrane [71]. EME
tection limit ranged from 0.01 to 0.05 μg L−1 with intra-assay
is also combined with other sample preparation methods such as
and inter-assay precision less than 7.3% and 9.3%, respectively. HF-
SPME for dirty samples [72]. Rezazadeh et al. [73] integrated elec-
LPME is also suitable for headspace sampling. Chiang and Huang
tromembrane with SPME to extract amphetamine and metham-
[64] presented a method using headspace hollow fiber protected
phetamine in human urine and whole blood. The method LOD was
liquid-phase microextraction for the extraction of amphetamine
less than 2.0 ng mL−1 within 15 min for extraction.
and methylenedioxyamphetamine in urine. Three microliters of 1-
nonanol (extraction reagent) containing pentafluorobenzaldehyde
(derivatizing reagent) was loaded into the hollow fiber and placed 3.5. Other forms of liquid-liquid microextraction
in the headspace of the sample during extraction. The method
achieved LOD of 0.25 and 1.00 ng mL−1 for amphetamine and Single-drop microextraction (SDME), the first extraction mode
methylenedioxyamphetamine, respectively, with RSD less than 4%. of LLME, was applied to extract amphetamine and metham-
Besides, Meng et al. [65] compared the extraction performance phetamine in human urine. In order to increase the mass transfer
of ultrasound-assisted low-density solvent DLLME (UA-LDS-DLLME) rate, Song and Yang [74] applied a potential of -4V on the SDME
with HF-LPME for illicit drugs in urine and blood sample. UA-LDS- system and compared the result with the one obtained from SPME.
DLLME utilized ultrasound energy to facilitate the emulsification The result showed that the electro-enhanced SDME system short-
process. The result showed that both of the methods were sensi- ened the extraction time (about 10 times) and extended the lin-
tive enough for the analysis of illicit drugs in biological fluids. The ear range, while SPME achieved lower LOD and RSD values. How-
recovery of HF-LPME was 79.3-98.6% with RSDs of 1.2-4.5%, while ever, when the volume of the droplets exceeded 2 μL, it became
the recovery of UA-LDS-DLLME was between 79.3% and 103.4% unstable. Another extraction mode of LLME, slug-flow microextrac-
with RSDs of 2.4-5.7%. The LODs of two techniques were also com- tion, was introduced in recent years. Yang et al. [75] applied this
parable, with 0.5-5 ng mL−1 for HF-LPME and 0.5-4 ng mL−1 for technique to extract amphetamine-type illicit drugs in whole blood
UA-LDS-DLLME. and raw urine followed by paper spray mass spectrometry analy-

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

sis. They confirmed that it was a reliable sample preparation tech- of 1-10 ng mL−1 . Martínez et al. [88] developed a method cou-
nique for illegal drug in biological fluid. The LODs were 0.01 to pling in-tube SPME with nano liquid chromatography to analyze
0.05 ng mL−1 for AM, MA, and MDMA, respectively, and the re- trace cannabis. Ten microliters cannabis plant samples were ex-
coveries were from 74.2% to 94.9% for whole blood and 80.2% to tracted with a mixture of methanol and chloroform (9:1in volume)
103.6% for raw urine. and 10 μL of the extracts were analyzed by in-tube SPME-nanoLC.
The result demonstrated good sensitivity with LOD of 2 ng mL−1 ,
3.6. Solid-phase extraction 5 ng mL−1 and 5 ng mL−1 and average recoveries of 91%, 88%, and
128% for THC, cannabinol (CBN), and cannabidiol (CBD), respec-
As an efficient and convenient extraction method, SPE is widely tively. In recent years, thin-film microextraction was developed as
used in different samples, including environment, food chemistry, a new geometry of SPME showing better extraction ability than
forensic, and pharmaceutical [76]. Solid-phase extraction usually classical fiber. Mirabelli et al. [16] developed a PDMS/DVB thin-
includes four steps: (i) The column is activated by solvent to re- film microextraction devices coupled with dielectric barrier dis-
move contamination and create a certain solvent environment. (ii) charge ionization-mass spectrometry to detect illicit drugs in bev-
liquid samples pass through the column which contains adsorbent erages and biological fluids (human urine and plasma). The LOD
and analytes are retained in adsorbent. (iii) appropriate solvents was from 10 to 30 pg mL−1 for target analytes in vodka and 3
are used to clean up the impurities. (iv) solvents are used to elute to 100 pg mL−1 in urine. Many coatings have been developed for
the analytes [77]. By transferring analytes from the mobile phase illicit drugs analysis including PDMS, PDMS/DVB [89], C18/strong
to the solid phase, it can not only preconcentrate trace target an- cation exchange fiber [90], and carbon nanotubes modified coat-
alyte but also effectively reduce the impact of the sample matrix ings [91]. For complex matrices which can lead to high matrix ef-
[78]. Compared with traditional LLE, SPE showed many advantages fect, headspace mode of SPME is a suitable method. Silveira et al.
such as less solvent consumption and shorter extraction time. Fur- [92] applied headspace SPME coupled with GC-MS to measure
thermore, due to the large number of developed sorbents and eas- cannabinoids in breast milk. A 100 μm PDMS fiber was exposed
ily automation, SPE has become one of the best sample extraction to the headspace of 50 μL sample for 40 min and then directly
techniques for liquid samples [79–81]. It is worth noting that evap- injected into the instrument for analysis. The method provided a
oration temperature of pre-concentration procedure has a great linear range from 20.0 to 200 ng mL−1 with intra-day and inter-
impact on the recovery of SPE sampling. Baker et al. [82] evalu- day precision lower than 13.3%. The LOD for all analytes was 10 ng
ated the influence of different factors including evaporation tem- mL−1 demonstrating that this technique can be an alternative for
perature, pH, elution solvent when applied SPE to sample the illicit complex matrix.
drug in aqueous environmental samples. The result indicated that
evaporation temperature of 20°C achieved the greatest recovery for 3.8. Microextraction by packed sorbent
almost all 60 analytes including stimulants, opioid and morphine
derivatives, benzodiazepines and so on. Peng et al. [83] applied SPE Microextraction by packed sorbent is the miniaturization of SPE
to extract 20 abuse drugs and pharmaceuticals in drinking water device. It is made by a syringe packing a sorbent on the bot-
and analyzed by LC-MS. The LOD and LOQ of this method were tom of the barrel. When liquid samples are drawn through the
0.01-1.09 ng L−1 and 0.02-3.64 ng L−1 , respectively. Wang et al. syringe barrel, the analytes will be trapped on the sorbent car-
[17] utilized a SPE cartridge to extract analytes from water sam- tridge. Compared with conventional SPE technique, MEPS has a in-
ples and succeeded in measuring the concentration of common il- tegrated structure and simple extraction process with advantages
licit drugs (amphetamine-like compounds, ketamine, cocaine, and like less samples and solvents consumption. MEPS usually includes
opioids) in 36 rivers in north China, which showed its excellent the following steps: condition, sample load, wash, and elution [93].
abilities of pre-concentration and clean-up for environmental sam- Therefore, extraction sorbents and elution solvents are significant
ples. parameters in the extraction process. Both Ares et al. and Fernán-
dez et al. [94,95] investigated the influential factors on the MEPS
3.7. Solid-phase microextraction process for illicit drug analysis using a symmetric screening design.
The results showed that mixed-mode C8/SCX sorbent eluted with
Solid-phase microextraction technique was first introduced by 90 μL mixture of dichloromethane/2-propanol/ammonium hydrox-
Janusz Pawliszyn in 1990 to solve the problems of traditional sam- ide (78:20:2 in volume) were suitable for determining the concen-
ple preparation methods, such as multiple steps, large organic sol- tration of NPS in oral fluid, and the extraction recoveries were be-
vent consumption, time-consuming, and loss of analytes [84]. Tra- tween 75% and 125% for most of the analytes.
ditional SPME device is based on a modified syringe whose needle In recent years, MEPS coupled with different instruments were
contains a fused silica fiber coated with a layer of polymer. The developed to measure the NPS. For example, MEPS followed by the
fiber can be directly immersed in liquid sample or placed on top ion mobility spectrometry (IMS) [96] and desorption electrospray
of the sample for headspace extraction. Solid-phase microextrac- ionization high resolution mass spectrometry [97] were applied to
tion uses a small amount of extraction phase and sample with- measure the NPS in saliva. Rocchi et al. [7] developed a sensitive
out reducing the sensitivity. [85]. Since SPME was first reported, method for the detection of four classes of NPS in oral fluids. After
this technique has become a vital pretreatment method for il- protein precipitation, a MEPS syringe with a C18 sorbent was used
licit drug analysis. In 1996, Degel et al. [86] evaluated the SPME for the analytes preconcentration and sample clean-up. Then, 100
method for sampling of illicit drugs in urine. The author com- μL methanol containing 10 mM HCOOH was used as elution sol-
pared the performance of LLE, SPE, and SPEC R
discs with SPME vent and analyzed by the UHPLC-MS/MS. The LOD and LOQ of the
and pointed out that the SPME showed obvious advantages with method ranged from 0.005 to 0.850 ng mL−1 and 0.015 to 2.600 ng
headspace extraction. Anzillotti et al. [87] applied SPME fibers to mL−1 , respectively. In addition, Ares-Fuentes et al. [98] utilized this
extract the synthetic and natural cannabinoids in oral fluid. They technique to extract designer benzodiazepines and Z-hypnotics in
compared the extraction efficiency of four types of fibers which plasma. Since plasma contains many proteins and metabolites, the
were 7 and 100 μm polydimethylsiloxane (PDMS), 65 μm poly- authors added 200 μL of methanol to 300 μL plasma sample for
dimethylsiloxane/divinylbenzene (PDMS/DVB) and 85 μm polyacry- purification. Subsequently, a 100 μL syringe packed with 4 mg of
late. Result showed that 100 μm PDMS fiber was the best for modified polystyrene DVB was used to extract 100 μL sample. The
cannabinoids sampling. The LOD of this method was in the range extraction process was carried out by sucking all the samples and

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

injecting them back into the same vial for 8 replicates to complete was applied to further clean the extract. (iv) the supernatant was
the extraction. After eluting with DCM/IPA/NH4OH (78: 20: 2, v: v: analyzed by analytical instruments. QuECHERS technique has been
v), 5 μL of extract was analyzed by UHPLC-MS/MS. The LOD and widely used for sample preparation of complex matrices such as
LOQ of this method were 0.5-5 ng mL −1 and 1-10 ng mL −1 , re- food and biological samples. Ramnarine et al. [107] applied QuECh-
spectively. The recoveries of all analytes ranged from 61% to 123% ERS method to extract cannabinoids in breast milk and analyzed by
with RSD less than 10.6%. UPLC-MS/MS. The method was found to be linear in the range of 1
to 100 ng mL−1 for THC, CBN and CBD with recoveries of 98%, 85%,
3.9. Dispersive solid-phase extraction (d-SPE) and 118%, respectively. Though QuEChERS had outstanding clean-
up ability, the method involved a longtime process. Brighenti et al.
Solid-phase extraction is a widely used method that also has [108] developed a technique that only consisted of the first two
many disadvantages such as stacking of packing material in SPE steps of QuEChERS for the detection of cannabinoids in honey. The
cartridges [99]. Therefore, Anastasslades and Lehotay [100] intro- honey was first diluted with water and extracted with 10 mL ace-
duced an efficient SPE-based technique called dispersive solid- tonitrile before adding 4.0 g of MgSO4 and 1.0 g of NaCl. The super-
phase extraction. Instead of packing the sorbent in a column, they natant of the mixture was then separated and concentrated. Then
directly added a small amount of sorbent (25 mg) into the liquid the concentrated extract was redissolved in 150 μL CH3 COONH4 -
sample and then separated from the sample before elution. Due to acetonitrile (50:50, v/v) solution with concentration of 2.0 mM. Fi-
its numerous advantages like low sorbent consuming, easy oper- nally, 25 μL of the sample was analyzed by HPLC-ESI-MS/MS. The
ation, and prevention of blockage, d-SPE has been widely applied linear range of the method was from 0.5 to 50.0 ng g−1 with LOD
for the sample preparation of a range of substances including illicit and LOQ of 0.3 and 0.5 ng g−1 , respectively. The author also com-
drugs. Júnior and Caldas [101] used 50 mg of primary secondary pared this extraction technique with UAE followed by LLE and the
amine and 150 mg of anhydrous MgSO4 as sorbent to extract result showed that the QuEChERS extraction offered better recov-
cocaine and 3,4-Methylenedioxymethamphetamine hydrochloride eries, higher reproducibility, and less time consumption
from postmortem blood. Coupling with GC-MS and large volume
injection-programmed, the method was demonstrated to be rapid 4. Sample preparation of illicit drugs in gas sample
and suitable in a forensic laboratory with extraction recoveries for
cocaine and MDMA ranging from 103.2% to 116.3% and 86.7% to Recently, more and more research has been done on the illicit
104.6%, respectively. Selection of dispersive sorbents for different drugs presented in the gas environment. Capillary microextraction
kinds of illicit drugs was also important. Yang et al. [102] used were commonly used to adsorb the illicit drugs in air, while the
modified magnetic nanoparticles to extract cocaine and cocaine drugs presented in aerosols were commonly detected by collecting
metabolites in human urine. Jabbari et al. [103] applied carbon- airborne particle followed by liquid phase extraction.
based conductive polypyrrole nanocomposite for the detection of
methamphetamine, while Zadeh et al. [104] developed a ternary 4.1. Capillary microextraction of volatiles (CMV)
nano-composite (magnetite/reduced graphene oxide/silver nano-
composite) for preconcentration of morphine and codeine. Fan and Almirall developed the capillary microextraction of
volatiles based on design of planar SPME device, which was
3.10. Stir bar sorptive extraction (SBSE) first applied to detect volatile explosives and gunshot residue
[109]. Compared with traditional SPME, capillary microextraction
As a new geometric of SPME, SBSE coated a magnetic stir bar of volatiles coated the stationary phase to the inner wall of the
instead of a fiber with a layer of sorbent. Compared with SPME, capillary and connected it with a vacuum pump, which signifi-
SBSE has larger volume of extraction phase and extraction capac- cantly reduced the extraction time. In recent years, researchers
ity. It has been widely applied to the extraction of organic com- applied the technique to detect of the illicit drugs in airborne.
pounds including illicit drugs in biological samples. Goto et al. Nair and Miskelly [110] reported the application of CMV device
[105] used commercial PDMS stir bar to preconcentrate phenethy- with PDMS coating for sampling of methamphetamine vapor and
lamines and THC metabolites from urine, and then analyzed by compared with the result from the dynamic SPME method (PDMS
LC-MS/MS after derivatization. The method LOD ranged from 0.17 fiber) under the same sampling condition. Results showed that the
to 1.08 ng mL−1 for phenethylamines and THC-COOH. In addition, sensitivity of CMV sampling was about 30 times higher than the
the author compared the clean-up effect of SBSE (PDMS coating) dynamic SPME sampling. In order to further improve the sensitiv-
with SPE (Oasis HLB sorbent) and found that the SBSE had bet- ity, a new CMV coating with pre-loaded pentafluorobenzyl chloro-
ter clean-up effect with a smoother baseline and less contaminated formate was developed for on-sorbent derivatization for metham-
compounds in chromatogram. The same as SPME, various coatings phetamine [111]. The LOD of the method was 0.36 μg m−3 for 10
can be prepared for SBSE. Taghvimi et al. [106] developed a novel min sampling according to the ICH guidelines, which was 60 times
ceramic carbon-coated magnetic nanoparticles for extracting am- higher than the dynamic SPME under the same conditions.
phetamines from urine sample. The new coating achieved extrac-
tion recovery of 99.82%, 98.62%, and 99.30% and linearity range of 4.2. Airborne particulates sampling
20-20 0 0 ng mL−1 , 20-2500 ng mL−1 and 30-1500 ng mL−1 for am-
phetamine, methamphetamine, and pseudoephedrine, respectively. For outdoor air, the concentration of illicit drugs on airborne
particulate was detected. Particulates were collected onto filters
3.11. QuEChERS using samplers and then extracted with organic solvents. Mas-
troianni et al. [112] collected the PM10 to study the temporal
QuEChERS is an extraction technique presented by Anastassi- and spatial distribution of 22 abuse drugs in the air of Barcelona.
ades et al. [100] and featured by “quick, easy, cheap, effective, The collected PM10 was pretreated by PLE with methanol and the
rugged, and safe”. The method was suitable for trace analysis of extract was analyzed by LC-MS/MS. The method obtained good
complex matrices. The whole process of QuEChERS includes four recoveries (97-134%) with RSD less than 15% and LOD between
steps: (i) organic solvent was added into the sample for extraction 0.1 pg m−3 and 26 pg m−3 . The result showed that the high-
and then separated by centrifugation. (ii) MgSO2 was added into est detection rate of 22 drugs in Barcelona was cocaine and the
the extracted solvent to remove the water. (iii) a dispersion sorbent compound with highest concentration was CBN (985 pg m−3 ).

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

Balducci et al. [113] collected PM2.5 and PM10 particulates onto UHPLC-MS/MS was a powerful technique for illicit drug in complex
quartz fiber filters with medium volume samplers (16.7 L min−1 matrices such as plant sample and whole blood [18,83].
and 38.3 L min−1 ). Then, the collected particulates were ex- Matrix effect is one of the most critical factors that has great
tracted by dichloromethane:acetone mixture (4:1 in volume) with influence on the signal response of analytes in complex samples,
assistance of sonication. The extracts were purified on a neu- especially when electrospray ionization was used as ionization
tral alumina chromatography column followed by elution with source [120]. that the matrix effect is caused by the competition of
dichloromethane:acetone (1:1). After solvent evaporation, cocaine analytes and interferences in the ionization process [121]. Common
and cannabinoids were redissolved in chloroform and analyzed by strategies used to reduce matrix effect including: (i) optimization
GC-MS. The LOQ of cocaine and cannabinoids were 0.003 ng m−3 of the sample preparation technique and chromatographic sepa-
and 0.01 ng m−3 with precision less than 6.9%. The authors com- ration condition. (ii) usage of internal-standard for caliabration.
pared the concentration of cocaine in PM2.5 and PM10 collected (iii) applying stronger analyzer such as MS/MS analyzers [122]. For
from the same site. The result showed that the concentration of whole blood, Dulaurent et al. [123] demonstrated that QuEChERS
cocaine in PM2.5 was similar to PM10 with PM2.5 /PM10 concen- sample preparation prior to LC-MS/MS was a powerful technique
tration ratio of 102%. In addition, the authors found that concen- to reduce matrix effect for detection of opiates, amphetamines, and
trations of cocaine between airborne particulates and wastewater cocaine metabolites with difference of signal intensity within 20%.
showed a good correlation with considering the temporal variabil- Odoardi et al. [59] utilized DLLME as clean-up technique for de-
ity of the consumption and the population. tection of NPS in whole blood. The result showed that the matrix
effect ranged from 10% - 39% with no carry-over effect. Compared
4.3. Other with blood, hair sample and saliva sample showed relatively low
matrix effect for illicit drugs detection [20,38,53]. It is worth noting
Recently, Collins et al. [114] developed a microfluidic gas-to- that the authors compared with the results obtained from salin-
liquid interface device to extract the amphetamine-like compounds ized and non-salinized glassware and found that salinized glass-
and their precursors from the air sample. The device consisted ware caused larger variability on the recovery of low level of THC
three layers from bottom to the top, which were extraction sol- in oral fluid with LC-MS/MS analysis [53]. For solid environmental
vent channels, gas chamber, and the seal with two wells for input sample such as Phragmites australis and sludge, low matrix effect
and output of air or solvents. The air sample went through the gas was observed for illicit drugs analysis when determined in nega-
chamber and the analytes were extracted by the extraction solvent tive ionization mode compared to positive ionization mode [43].
(100 mM α -cyclodextrin in ultra-pure water), which was then an-
alyzed by GC-MS. The method provided a linear range from 10 to 5.2. Gas chromatography
32 mg m−3 and the LOD of this method was 1.8-6.9 μg mL−1 .
Although LC-MS/MS was selective, accurate, and precise for the
5. Development of instrumental methods for illicit drugs separation of most illicit drugs, this technique required a large vol-
ume of organic solvent and was expensive. As most established
Analytical instruments for illicit drugs with various chemical technique in forensic or clinical analysis, GC-MS was more eco-
groups have been greatly developed in recent years. The most nomical than LC-MS [58,124]. Non-polar columns such as HP-5MS
commonly used ones were LC-MS/MS and GC-MS because of their or DB-5MS were commonly used for separation of illicit drugs.
excellent performance and automation. As for illicit drugs, most of Derivatization process was sometimes applied to improve the sep-
them were polar compounds, LC was more suitable than GC which aration efficiency. For example, Woźniak et al. [51] determined
sometimes needed the assistance of derivatization [115]. In recent the concentrations of 11 amphetamines and 34 synthetic cathinone
years, new analytical instruments including matrix-assisted laser in whole blood with pentafluoropropionyl derivatization process
desorption ionization, paper spray mass spectrometry, desorption and analyzed by GC-MS/MS to improve the sensitivity. Other op-
electrospray ionization, etc. have been developed to complement tion to improve the sensitivity was to utilize a large volume injec-
the traditional ones. At present, there are many studies concern- tor like programmed temperature vaporization for GC-MS analysis
ing single chemical groups such as amphetamine-type stimulants, [101]. Another advantage of GC-MS/MS was that it can be easily in-
cannabis, and opioids while relatively a few of studies about the tegrated with SPME and CMV sample preparation techniques and
detection of multiple drugs with comprehensive chemical groups achieved fully automation [104,109].
were reported. Fig. 3 summarizes the reported instrumental tech- Matrix effect is also an issue in the GC analysis for environ-
niques mentioned in this review. mental samples or biological samples. Compared with high con-
centration of analytes, higher matrix effect was found in low con-
5.1. Liquid chromatography centration samples for MDMA and cocaine in postmortem blood
[101]. Due to high lipid content of breast milk, it is necessary to
Compared with GC, LC has a broader application in the field of reduce the lipid content when detecting cannabinoids in breast
illicit drug detection. Methanol, acetonitrile, or their mixture were milk. Saponification before extraction and headspace extraction
usually used as mobile phase for LC and gradient elution mode was were confirmed to effectively solve this problem [92,125]. In addi-
performed to increase the separation efficiency [11,28,78]. As for tion, exogenous interferences and carryover were often evaluated
ion source, the most frequently used in LC was electrospray ion- in real sample analysis. Mercieca et al. [51,58] evaluated the se-
ization. Since biological samples or complex matrix were used in lectivity and carryover effects in blood. The result showed that no
the determination of illicit drugs, a high selectivity and sensitivity interferences and carryover were observed for amphetamine-like
detector was essential. Tandem mass spectrometry was frequently stimulants in blood sample and no interferences were found for
coupled with LC for analysis of illicit drugs because of its low back- cocaine. Similarly, no interferences were found for cocaine and its
ground interference, high sensitivity, and high sample throughput metabolites in blank hair sample [48].
[38]. Besides, compared with quadrupoles, ion traps, and q-trap
systems, time-of-flight mass analyzers have higher resolution and 5.3. Matrix-assisted laser desorption ionization
mass accuracy with fast scan times [116]. Other detectors such as
diode array detection [117], ultraviolet [118], and photodiode ar- Matrix-assisted laser desorption ionization is a soft ionization
ray [119] were also reported for illicit drugs detection. In addition, technique usually used in mass spectrometry imaging (MSI). This

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

Fig. 3. Instrumental methods for detection of illicit drugs (adapted from Ref. [131,134,141,142]).

technique was first applied to measure the biomolecules and il- 5.4. Paper spray mass spectrometry (PS-MS)
licit drugs in recent years. The advantages of MALDI were time-
consuming, non-destructive of the sample and identifying the iso- As an ionization technique, paper spray mass spectrometry was
forms [126]. Kernalleguen et al. [126] simply rinsed the hair sam- first reported by Cooks and Ouyang [129]. This analytical instru-
ple with dichloromethane and directly applied MALDI-Quadrupole ment significantly reduced the sample preparations steps and the
Ion Trap-Time of Flight-MSn for measuring three synthetic cannabi- raw samples could be analyzed directly by adding to the paper
noids in a single hair sample and results showed that MALDI was where an ionization event was occurred. This technique was ap-
a useful tool for identification of isoforms with LOD for JWH-122 plied to measure drugs and chemical warfare agent hydrolysis
as low as 69 pg mg−1 . Poetzsch et al. [127] utilized ethyl ac- products in soil samples without sample enrichment and clean-
etate: butyl acetate (1:1) as extraction solvent to extract MDMA in up steps [130]. Vandergrift and Gill [131] reviewed the application
saliva and analyzed by MALDI-triple quadrupole mass spectromet- of PS-MS in the detection of opioid overdose crisis and deemed
ric within 10 seconds. This result was in good agreement (P=0.89) that this method had a great prospect in drug detection, especially
with the one obtained from LC-MS/MS for real sample analysis. in the analysis of compounds with similar structures. In addition,
The linear range was from 5 to 20 0 0 ng mL−1 and the recovery they also evaluated the quantitative ability of PS-MS for fentanyl
of this method was up to 95.3% with intra-day and inter-day pre- in complex matrices such as street drug samples. Result showed
cision less than 12%. MALDI-MSI was a powerful tool for qualita- that this method can achieve requirement even with high inter-
tive analysis while it was unsuitable for compounds with molec- ference from street drugs. Yang et al. [75] combined slug-flow mi-
ular weights below 700 Da because of its high background and croextraction with PS-MS and successfully achieved on-site anal-
overlap of matrix adducts. Skriba and Havlicek [128] developed ysis of trace amphetamine-type illicit drugs in whole blood and
a matrix-free laser-desorption ionization method to overcome the raw urine. The total analysis time of the method was less than 2
issue of small molecules, which showed less background inter- min and the LOD was from 0.01 to 0.05 ng mL−1 for amphetamine,
ference from the matrix. With employment of silicon nanowires, methamphetamine, and MDMA with intra-day and inter-day pre-
the author applied nanostructure-assisted laser desorption ioniza- cision less than 13.8%. The recoveries of the method were 74.2%-
tion mass spectrometry imaging (NALDI-MSI) to detect the illicit 94.9% and 80.2%-103.6% for whole blood and raw urine, respec-
drugs in latent fingerprints. Volunteers pressed fingers (contami- tively. Many studies concerned about the modification of the pa-
nated with 1 μL of 100 μmol L−1 standard solution) on NALDI plate per to improve sensitivity and reduce the matrix effect of the
followed by deposition with a-cyano-4-hydroxycinnamic acid. Then technique. For amphetamine-type illicit drugs, results found that
the fingerprint samples were directly analyzed and successfully de- the sensitivity can be improved by adding some diluted acid into
tected by mass spectrometry imaging. The author also found that the spray solvent. Burr et al. [132] developed a gold nanoparti-
the sensitivity for contaminated fingerprints from high to low were cle (AuNP)-embedded paper which could enhance Raman scatter-
NALDI, MALDI, and desorption electrospray ionization (DESI). Al- ing and be compatible with PS-MS at the same time. One micro-
though this instrument has remarkable ability for qualitative anal- liter of five drugs sample was directly deposited on the paper for
ysis, its ionization process is usually affected by the interferences analysis. The method achieved LOD of 1-100 ng μL−1 and provided
in the sample which may cause high matrix effects. Thus, selection 99.8% accuracy for 500 samples and successfully identified several
of an appropriate MALDI matrix is the key to reduce the matrix ef- JWH-018 isomers which cannot be distinguished by MS or MS2
fect. spectra.

11
X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

5.5. Desorption electrospray ionization mass spectrometry from 0.1 to 2.5 ng mL −1 and liner range was between 0.5 and
200 ng mL−1 . The recoveries for most analytes were achieved 83.9-
Desorption electrospray ionization mass spectrometry is an am- 115.1% with RSD less than 11%.
bient ionization method which is widely applied in forensic chem-
istry since its presentation in 2004. This technique allows gener- 6. Concluding remarks
ating ions in-situ without sample preparation and the sample can
remain in its original state, which significantly reduces the analy- Suitable sample preparation procedure and excellent instru-
sis time [133]. Other advantages of DESI-MS include high through- mental methods are crucial in illicit drug analysis. This review in-
put, sensitivity, and non-destructive nature [134]. Due to its out- troduces the development and application of the sample prepara-
standing performance, this technique has received widely atten- tion technology and the analytical instruments for drug analysis in
tion in judicial determination, especially for biological studies. For recent years. Overall, most of the studies focused on the concentra-
instance, Taemeh and Ifa [135] utilized QuEChERS method to ex- tions of drugs in liquid samples such as environmental water and
tract THC in 1 g of chocolate and used DESI-MS to analyze 1.5 biological fluid. However, it was also critical to evaluate the illicit
μL extract. The method achieved quantitative analysis with LOD drugs in solid samples, including biological tissue, hair, airborne
of 20 μg mL−1 and the linearity between 30 and 80 μg mL−1 . bound compounds, etc. In addition, many reports showed that il-
In addition, the recovery of this method was 114% with intra-day licit drugs were detected in indoor and outdoor air, which is of
and inter-day precision less than 15%. There are also disadvan- great significance for subsequent toxicology study. It was also note-
tages of DESI-MS, such as matrix effect, issues of automation and worthy that rapid in-situ analysis of illicit drugs in non-invasion
reproducibility. Studies have been done to solve these problems. samples like oral fluid and hair was vital for drug testing.
For example, Bianchi et al. [97] evaluated three different sample- For solid samples, the most commonly used sample prepara-
substrates including polytetrafluorethylene, polylactide-based ma- tion method was solvent-based extraction combining with clean-
terials, and a silica-based coating for detection of NPS in saliva. The up step. Many modification methods were gradually developed
result showed that non-functionalized polylactide-based materials in illicit drug analysis to improve the performance of tradi-
achieved the best signal intensity and repeatability for most ana- tional extraction methods. Pressurized liquid extraction acceler-
lytes in positive ionization mode. On the other hand, some com- ated mass transfer through high temperature and pressure, while
pounds needed to be analyzed by silica substrate with negative DLLME achieved miniaturization with high extraction efficiency.
ionization mode. Before DESI-MS analysis, a MEPS procedure was Ultrasonic-assisted extraction and microwave-assisted extraction
carried out as extraction and clean-up process. This method pro- assisted the homogenization of sample and accelerated mass trans-
vided linear range from 0.05 to 10 mg L−1 with recovery between fer by external energy for biological tissue. Compared with the tra-
89% and 115%. Although sometimes the sensitivity of DESI-MS was ditional methods like LE and SPE, microextraction techniques min-
not as good as traditional analysis method, its short analysis time imized the volume of solvent and sample while significantly im-
and convenience showed great potential in qualitative analysis of proved the extraction efficiency. At present, more and more stud-
drugs. Cheng et al. [136] utilized thermal desorption electrospray ies focused on the microextraction techniques which could be di-
ionization mass spectrometry to qualitatively detect illicit drugs in vided into solid-phase based microextraction (SPME, SBSE, etc.)
drinks, instant powders, jelly candies and on the surface of the and liquid-phase based microextraction (DLLME, HF-LPME, EME).
stamp. The result showed that this method was rapid and sensi- Both of them have excellent extraction performance and widely
tive enough for real sample analysis without pretreatment. applied in illicit drug analysis. Solid-phase based microextraction
showed the advantages of simple operation, easy coupling with GC,
5.6. Direct analysis in real time (DART) and solvent-free. However, the wide application of this technique
usually limited by the selection of the coatings. On the other hand,
In recent years, ambient mass spectrometry techniques have re- liquid phase microextraction provided more options for different
ceived extensive attention in forensic chemistry due to its rapid target compounds, especially for polar compounds like illicit drugs.
analysis without the chromatographic step, solvent-save, and re- Not many studies concerned about the detection of illicit drugs in
ducing or no need for sample preparation. As an ambient mass gaseous or air samples, which was expected to be further devel-
spectrometry, DART achieves ionization by heating the energetic oped. The concentration levels of illicit drugs in outdoor air are re-
helium gas. Cui et al. [137] combined DART with high-resolution lated to consumption behavior of illicit drugs. Although detection
mass spectrometry to detect real heroin powder samples. Heroin of atmospheric levels of illicit drugs has so many uncertainties, it is
sample (30 mg) was dissolved in 1 mL water followed by anal- possible to introduce suitable correction factors for better assess-
ysis of DART-MS. The method was able to identify 26 impurities ment [139].
in the sample and successfully distinguished the heroin samples Analytical instruments played a critical role in the final de-
from Southeast Asian and Southwest Asian with an accuracy of tection of illicit drugs. LC (HPLC/UHPLC) and GC were the most
93.33% for 50 samples using multivariate statistical analysis. Chen widely used instruments. Recently, with the development of am-
et al. [138] evaluated the ability of DART for multiplex analysis. bient ionization techniques, in-situ analysis technology was gradu-
They spiked methamphetamine, 3,4-methylenedioxypyrovalerone, ally developed. In contrast with LC or GC, ambient ionization tech-
ketamine, nimetazepam and p-fluoromethamphetamine into three niques allowed to rapidly and directly analyze samples under am-
different drinks and found that the instrumental method could bient temperature and pressure conditions. In addition, it was easy
accurately achieve the qualitative requirement under matrix ef- to achieve automation making fast in-situ detection possible and
fects. For quantitative analysis, DART usually coupled with exter- could be an alternative to LC or GC, especially in rapid qualitative
nal sample preparation steps to enhance the sensitivity. SPME was analysis. Furthermore, with the growing popularity of NPS such as
one of the most commonly used technique that can easily com- synthetic opioids, improving the ability of non-target detection is
bine with DART due to its geometry. Vasiljevic et al. [6] devel- of great significance for analytical instruments. The review shows
oped a novel solid-phase microextraction-transmission device with that appropriate sample preparation techniques combined with ad-
polyetheretherketone mesh for detection of drugs in saliva and vanced instrumental methods are extremely important in the anal-
urine. The mesh was immersed in the sample for 1 min and the ysis of illicit drugs in environmental and biologicals matrices. This
mesh was directly analyzed by DART-MS. The method showed article can be considered as a guideline for applicants who want to
good sensitivity for both oral fluid and urine with LOD ranging do research work and routine analysis of illicit drug samples.

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X. Chen, X. Wu, T. Luan et al. Journal of Chromatography A 1640 (2021) 461961

Declaration of Competing Interest [17] D.G. Wang, Q. Da Zheng, X.P. Wang, J. Du, C.G. Tian, Z. Wang, L.K. Ge, Il-
licit drugs and their metabolites in 36 rivers that drain into the Bohai Sea
and north Yellow Sea, north China, Environ. Sci. Pollut. Res. 23 (2016) 16495–
The authors declare no competing financial interest. 16503, doi:10.1007/s11356- 016- 6824- 9.
[18] T. Rosado, M. Barroso, D.N. Vieira, E. Gallardo, Determination of Selected Opi-
CRediT authorship contribution statement ates in Hair Samples Using Microextraction by Packed Sorbent: A New Ap-
proach for Sample Clean-up, J. Anal. Toxicol. 43 (2019) 465–476, doi:10.1093/
jat/bkz029.
Xinlv Chen: Investigation, Writing - original draft. Xinyan Wu: [19] M. del M. Ramírez Fernández, S.M.R. Wille, D. Jankowski, V. Hill, N. Samyn,
Writing - review & editing. Tiangang Luan: Writing - review & Development of an UPLC–MS/MS method for the analysis of 16 synthetic
opioids in segmented hair, and evaluation of the polydrug history in fen-
editing. Ruifen Jiang: Conceptualization, Methodology, Resources,
tanyl analogue users, Forensic Sci. Int. (2020) 307, doi:10.1016/j.forsciint.2019.
Project administration, Supervision. Gangfeng Ouyang: Resources, 110137.
Writing - review & editing. [20] F. Vincenti, C. Montesano, L. Cellucci, A. Gregori, F. Fanti, D. Compagnone,
R. Curini, M. Sergi, Combination of pressurized liquid extraction with dis-
persive liquid liquid micro extraction for the determination of sixty drugs
Acknowledgments of abuse in hair, J. Chromatogr. A. 1605 (2019) 360348, doi:10.1016/j.chroma.
2019.07.002.
We acknowledge the financial support from the Natural Science [21] P.W. Looser, M. Berg, K. Fent, J. Muhlemann, R.P. Schwarzenbach, Phenyl- and
butyltin analysis in small biological samples by cold methanolic digestion and
Foundation of Guangdong Province (CN) (32220027) and National GC/MS, Anal. Chem. 72 (20 0 0) 5136–5141, doi:10.1021/ac0 0 05520.
Natural Science Foundation of China (21777058). [22] D.A. Lambropoulou, T.A. Albanis, Liquid-phase micro-extraction techniques in
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