Next Article in Journal
Metal-Incorporated Mesoporous Silicates: Tunable Catalytic Properties and Applications
Next Article in Special Issue
Marine Natural Peptides: Determination of Absolute Configuration Using Liquid Chromatography Methods and Evaluation of Bioactivities
Previous Article in Journal
Food-Grade Synthesis of Maillard-Type Taste Enhancers Using Natural Deep Eutectic Solvents (NADES)
Previous Article in Special Issue
Enantiomeric Resolution and Docking Studies of Chiral Xanthonic Derivatives on Chirobiotic Columns
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 23
Issue 2
10.3390/molecules23020262
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Chiral Drug Analysis in Forensic Chemistry: An Overview

by
Cláudia Ribeiro
1,2,
Cristiana Santos
1,
Valter Gonçalves
3,
Ana Ramos
4,
Carlos Afonso
2,3 and
Maria Elizabeth Tiritan
1,2,3,*
1
Institute of Research and Advanced Training in Health Sciences and Technologies, Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal
2
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
3
Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto , Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
4
Institute of Science and Innovation in Mechanical and Industrial Engineering (INEGI), Faculty of Engineering of the University of Porto, Rua Dr. Roberto Frias, 400, 4200-465 Porto, Portugal
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(2), 262; https://doi.org/10.3390/molecules23020262
Submission received: 30 December 2017 / Revised: 19 January 2018 / Accepted: 25 January 2018 / Published: 28 January 2018
(This article belongs to the Special Issue Chirality in Health and Environment: Recent developments)
Browse Figures
Versions Notes

Abstract

:
Many substances of forensic interest are chiral and available either as racemates or pure enantiomers. Application of chiral analysis in biological samples can be useful for the determination of legal or illicit drugs consumption or interpretation of unexpected toxicological effects. Chiral substances can also be found in environmental samples and revealed to be useful for determination of community drug usage (sewage epidemiology), identification of illicit drug manufacturing locations, illegal discharge of sewage and in environmental risk assessment. Thus, the purpose of this paper is to provide an overview of the application of chiral analysis in biological and environmental samples and their relevance in the forensic field. Most frequently analytical methods used to quantify the enantiomers are liquid and gas chromatography using both indirect, with enantiomerically pure derivatizing reagents, and direct methods recurring to chiral stationary phases.

1. Introduction

Chiral compounds are asymmetric three dimensional molecules with one or more stereogenic centers or asymmetry originated by planes or axis that gives two non-superimposable mirror images molecules, called enantiomers [1]. In an achiral environment, a pair of enantiomers shares similar physical and chemical properties, however, in a chiral environment such as living organisms, enantiomers may exhibit different biological activities and/or toxicity due to enantioselective interactions [2,3,4]. Separation of enantiomers has gained relevance in forensic chemistry and has been applied in the analysis of biological fluids, environmental samples and in the control of illicit drug preparations [5,6,7,8,9]. Figure 1 summarizes the applications of chiral analysis in forensic chemistry.
Substances of forensic interest include pharmaceuticals and various classes of illicit drugs misused to improve sports performance or due to their psychotropic effects. The consumption of these substances can cause toxicological effects and/or increased risk of death [10,11,12,13]. These substances can be consumed by medical prescription or illicit practice and are available either as a racemates, or as a single enantiomer. Data from chiral analysis in both biological samples and illicit drugs preparations can be important in the control of manufacturing, consumption of illicit drugs or linking between illicit drug preparations, consumers and traffickers [5,6,14]. Besides, both impurity and chiral profile may provide a link between starting materials and the illicit drugs synthesized by a clandestine laboratory [5,15]. Chiral analysis in biological fluids can give information regarding consumption and differentiation between illegal drugs or legal pharmaceuticals containing only a single enantiomer [7,16]. For example, the ingestion of dexedrine (S-(+)-amphetamine (AM)) used in the treatment of narcolepsy, attention deficit disorders and hyperactivity in children results only in serum concentrations of S-(+)-AM in contrast to the ingestion of the illegal AM that leads to both enantiomers [7,8,16].
Furthermore, the presence of these compounds in wastewater has been shown to be a tool for the monitoring drug consumption at a community level (sewage epidemiology) [17,18,19]. In fact, once excreted, residues of chiral drugs reach the aquatic environment mainly through the sewage system as parent compounds and metabolites [20,21]. Concentration of target pharmaceuticals or illicit drug residues in wastewater influent may be used to backcalculate drug consumption for local communities (sewage forensics) [17,22,23,24]; an approach to provide direct quantitative estimates, in a non-invasive manner and in almost real-time [17,24,25]. Since most of these compounds are chiral, the determination of the enantiomeric fraction (EF) can give further information about the use of legal and illegal substances. Furthermore, once in the sewage system these compounds are subject to biotic processes that causes changes in the enantiomeric composition. This information may be used to evaluate the efficiency of the wastewater treatment plant (WWTP) or illegal discharges of sewage since it may be expected that their EF in untreated sewage would differ from the one observed in treated effluents [9,18,26]. Also, information about environmental occurrence and distribution of chiral pharmaceuticals in the environment is important for evaluation of enantio-(eco)toxicity in particular for aquatic organisms [27,28,29]. In this sense, chiral analysis applied to drugs preparations, biological fluids and environmental samples may give information about: distinction between legal and illicit drugs; linking between samples, illegal laboratories, consumers and trafickers; estimation of consumption patterns at community level (sewage epidemiology); identification of manufacturing locations of illicit drugs; illegal discharge of sewage and information about ecotoxicity (Figure 1). Concerning the importance of chiral drug analyses in various forensic contexts, the present work aims to critical discuss the applicability of chiral drug analyses concerning pharmaceuticals and illicit drugs in forensic chemistry regarding biological and environmental matrices. The references search were based in ScienceDirect and ISI Web of Knowledge databases considering articles up to 2017 that comprise biological matrices such as urine, plasma, serum, blood and hair and environmental samples as surface waters, influents and effluents from WWTPs as aquatic environmental matrices.

2. Chromatography in Chiral Analyses

The separation of enantiomers is currently carried out using liquid chromatography (LC), gas chromatography (GC), capillary electrophoresis (CE) and supercritical fluids chromatography [15,20,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]. Chromatographic methods for resolution of enantiomers include indirect and direct methods. The indirect method is based on the reaction of the enantiomers with chiral derivatization reagents (CDRs) and the formation of diastereoisomers with different physico–chemical properties that can be separated by conventional means such as chromatography. The direct method can be achieved by chiral stationary phases (CSPs), mostly applied in LC, or using chiral mobile phase additives. Both GC and LC methods are available in indirect and direct [35,45,46,47,48,49]. However, for GC only few chiral columns are available. Thus, most works with GC used indirect approaches with CDRs, which are then separated by achiral columns. Examples of most used CDRs are S-(−)-N-(trifluoroacetyl)propyl chloride (S-TPC), R-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl (R-MTPCl) and S-(−)-N-(heptafluorobutyryl)propyl chloride (S-HFBPrCl) [46,50]. Regarding direct methods, many types of CSP are available, however the cyclodextrin (CD), Pirkle-type, polysaccharide derivatives, antibiotics-based and polymeric-based are most used [20,51,52,53].
GC and LC methods have been widely used for the enantioselective analysis of various classes of illicit drugs in biological fluids though LC methods are most used concerning environmental samples [20,54]. This is probably due to the high number of commercial columns available for LC and the limit of quantification that LC with mass spectrometer (MS) can be achieved. For GC methods most work uses MS while LC use different detectors as MS, ultraviolet-visible (UV/Vis), diode array (DAD) and fluorescence detectors (FD) (Table 1 and Table 2).
LC/MS and LC/MS/MS are the most applied techniques to quantify chiral compounds in the environment. Nevertheless, MS detection presents some limitations in the type of elution mode and the additives that can be used. Capillary electrophoresis (CE) has also been used for the separation of enantiomers of toxicological, doping and forensic interest due to its simplicity and inexpensive methodology [55]. In this work methods to quantify a variety of chiral illicit drugs and pharmaceuticals (listed in Table 1) in biological and environmental matrices are reunited.

3. Chiral Analyses in Biological Samples

This study reviewed 58 articles that have been published between 1996 and 2017 based on ScienceDirect and ISI Web of Knowledge databases. The investigated compounds included synthetic psychoactive drugs (stimulants), synthetic opioids, β-blockers, antidepressants, anticoagulants, bronchodilators and dissociative anesthetics (Table 1 and Table 2). Figure 2 shows the relative number of studies of each class of chiral drug investigated and the analytical methods used for analysis of these compounds in different biological matrices.
The use of racemates typically results in stereoselective pharmacological activity and pharmacokinetic affecting bioavailability, metabolism and excretion that may contribute to the toxicity, increase risk of death or serious adverse effects [11,56,57]. Though there is a tendency for manufacturing pharmaceuticals as single enantiomers, many pharmaceuticals are still supplied as racemates [57]. Concerning illicit drugs, these compounds are also available as racemates or single enantiomers depending on the manufacturing procedure [5,6,57]. Regarding illicit administrations, consumption of pure enantiomer (eutomers), in some cases, may cause overdose or even might lead to lethal cases [10,12]. Thus, significance of chiral analysis has increased since it is possible to determine whether the drug of concern is derived from a controlled or illicit substance [58,59,60]. In fact, some controlled substances are commercialized in the enantiomeric pure form due to their advantages in therapeutic activities [5,6,57]. On the other hand, illicit production of these drugs leads to either racemic or single enantiomers depending on the manufacturing procedure, i.e, racemic or enantiomer pure precursors. Thus, in forensic chemistry, evaluation of the EF may aid in the discrimination of the consumption of legal and illegal substances, give information about method of synthesis used or profile among different seizures linking among them, consumers and traffickers. Chiral analysis can also be applied in doping control, as an example, the use of preparations containing dextromethorphan by athletes is allowed, whereas the use of levorphanol is expressly banned by the International Olympic Committee [61].
Though various works have been published concerning chiral separation of the different classes of pharmaceuticals and illicit drugs of forensic interest in biological matrices most works do not determine the enantiomeric composition. Data about the enantiomeric composition of parent compounds and metabolites is of high importance for accurate data interpretation and for further analysis of results [62]. Also, metabolites of achiral compounds can also be chiral and should be considered in biological samples.

3.1. Synthetic Psychoactive Drugs

This class of chiral drugs was the most studied (Table 1, Table 2 and Figure 2). Among synthetic psychoactive drugs are the amphetamine-like drugs, a group of structurally related compounds with vast potential for abuse, addiction and toxicity [63]. Among most studied compounds are AM, methamphetamine (MA), 3,4-methylenedioxymethylamphetamine (MDMA), 3,4-methylenedioxy-ethylamphetamine (MDEA) and methylphenidate (MPH) (Table 1 and Table 2). Enantiomers of these drugs have been discriminated in plasma, urine, blood and hair. Analytical methods used for the separation of enantiomers of these drugs included LC-MS, GC-FID and GC-MS and CE. Amphetamine-like drugs can be used for the treatment of some disorders such as selegiline (L-deprenyl, SG) used for treatment of Parkinson’s disease, Adderall or Elvanse for treatment of attention-deficit hyperactivity disorder or famprofazone, a nonsteroidal anti-inflammatory agent, used for pain control [8,59]. Consumption of SG produces S-MA and its metabolite S-AM while famprofazone produces both R-MA and S-MA and their metabolites in human body [7]. Adderall contains both R-AM and S-AM. On the other hand, these substances are often misused for recreation purposes and even by healthy individuals to enhance work or school performance (e.g., MPH) or doping in sport practice [64,65]. Thus, illicit preparations have been an alternative route of access these substances by consumers and abusers. Illicit production of AM may use 1-phenyl-2-propanone and other reagents such as formic acid, ammonium formate or formamide are used, which is designated as the Leuckart method, yielding a racemic product [17].
Manufacture of MDMA and related drugs can use safrole, isosafrole, piperonal or 3,4-methylenedioxyphenyl-2-propanone (PMK). Many illicit drug syntheses start with PMK and use either the Leuckart route or various reductive aminations, producing a racemic MDMA [17].
Therefore, studies based on determining the ratios of R- and S-isomers of the parent compounds and metabolites are important for distinctive medical drug administration or illegal abuse of amphetamine like drugs [8]. Also, chiral information is useful and essential to identify the precursor, the synthetic pathway, and intrinsic characteristics of the seized samples [5,6]. In this context, analysis of the enantiomers of AM and metabolites have revealed to be very useful, since it can provide information about the origins of the drug consumed (legal or illicit) [58,60].
In the majority of chiral amphetamine-like drugs, the S-enantiomers exhibit greater potency than the R-enantiomers [60,66,67,68,69,70].
Nishida et al. described a LC-MS method for the determination of the enantiomers of MA, AM, SG and its metabolite, desmethylselegiline (DMSG), in hair samples [59]. In this study, authors showed differences in the enantiomer ratio of MA and AM and between MA abuse consumers and SG consumers [59]. Besides, it was also shown that the existence of DMSG in SG users that is not normally found in urine demonstrating that the method can be useful for distinguish therapeutic users of SG and MA abusers. Fujii et al. described a GC-MS method based on the formation of diastereoisomers using CDR TPC for the separation of the enantiomers of MA, AM, MDMA and MDA in urine samples [8]. This method can be used for discrimination between legal and illegal consumption of these drugs [8]. Rasmussen et al. developed for the first time a GC-MS enantioselective method for the separation of AM, MA, MDA, MDMA and MDEA in whole blood based in the formation of diastereomers [67] (Figure 3).
The method was validated and applied to four whole blood samples from forensic cases including a suspected case of driving under the influence of drugs. In all cases amphetamines were ingested as racemates with stereoselective metabolism since the R/S ratio for most enantiomers were >1 showing that the R-enantiomer is metabolised faster than the S-enantiomer. Hädener et al. described a two dimensional LC-MS/MS method for quantification of AM enantiomers in human urine [16]. The study was applied to 67 urine samples from suspected AM abusers, subjects treated with S-AM prodrug and suspected MA abusers. In each 40 samples obtained from suspected AM abusers both enantiomers were present and mean R/S ration was 1.25 indicating a predominance of the R-enantiomer. The excepted value R/S would be 1 but due to stereoselective metabolism of AM in which S-AM is metabolized faster than R-AM resulting in higher concentrations of R-AM. In the consumers of the prodrug it was found only S-AM and R-AM in one sample at <LOQ probably due to imputities of the drug manufacture itself [16]. Considering individuals suspected of MA consumer, in 80% of the samples, both enantiomers were found although with a predominance of S-AM. R/S ration ranged from 0.01 to 0.47. Five samples from MA abusers contained only S-AM. This result was explained by the faster metabolization of S-enantiomer of MA. Thus, more S-MA is converted to S-AM than R-MA to R-AM.
Binz et al. developed an analytical method for chiral analysis of AM in hair [7]. In this study, analysis of hair samples from nine Elvanse patients revealed only S-AM in eight cases. One subject showed both enantiomers indicating a (side-) consumption of street AM. The analysis of the 16 AM abusers samples showed only racemic AM. Furthermore, it could be shown in a controlled study that S-AM can be detected after administration of even very low doses of lisdexamfetamine and dexamphetamine, which can be of interest in forensic toxicology and especially in drug-facilitated crime [7].
MPH, another CNS stimulant, is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Abuse of this substance has been reported [71]. This drug is commercialized in the racemic mixture though only the D-threo-form is responsible for the desired therapheutic effect. MPH is enantioselectively metabolized, preferring S-MPH over R-MPH to ritanilic acid (RA) that is pharmacologically inactive. Individual variations on MPH metabolization classified some individuals as poor metabolizers. Thomsen et al. developed an LC-MS/MS enantioselective method for determination of MPH and RA in femoral blood applied to forensic cases [65] in order to evaluate poor metabolizers by estimating R/S ratio of MPH. Postmortem blood samples from autopsy cases and antemortem blood samples from mixture of traffic, violence and sexual assault cases were analyzed. Apart from one case, R-MPH showed the highest concentration in the postmortem cases, a similar pattern to the found in living organisms. Concentration of RA was higher in all cases than MPH with equal distribution of R and S enantiomers. In antemortem individuals the same pattern was observed with higher levels of R-MPH and equal quantities of R and S forms of RA.
These reports demonstrate that knowledge about the enantioselective behavior and measure of the enantiomeric ratio of these types of drugs can provide useful and valuable data in the forensic field giving information about consumption of licit and illicit amphetamine like drugs and other psychoactive drugs and essential to aid in the correct interpretation of the use of these substances.

3.2. Synthetic Opioids

The second most studied classe of chiral compounds are the synthetic opioids (Table 1 and Table 2). Among reported compounds are tramadol, methadone and methorphan [72,73]. Opioid abuse, addiction, and overdose are considered of a serious public health [54]. In the European Monitoring Centre of Drug and Drug Addiction report of 2017, opioids were the third most consumed class of drugs of abuse in Europe and the first with more fatal cases [74]. Concerning tramadol, it is a synthetic opioid that acts as agonist by selective activity at the µ-opioid receptors commercialized as a racemate of the more active 1R,2R-enantiomer ((+)-tramadol) and the less active 1S,2S-tramadol ((−)-tramadol), with both enantiomers acting through different mechanisms, but in a synergistic manner [75]. However, there are differences in their binding properties leading to considerable differences in pharmacological activities [75]. Tramadol is metabolized to O-desmethyltramadol (ODT) and N-desmethyltramadol (NDT). O-Demethylation of tramadol is carried out by CYP2D6; enzyme expressed polymorphically [76]. Polymorphisms play an important role in inter-individual drug response [77]. The metabolite ODT is pharmacologically active, has longer half-life and is more potent than parent compounds. Tramadol has been used for nonmedical purposes due to it euphoric and mood enhancing effects [78,79]. Tramadol abusers develop physiological dependence which can cause negative effects such as convulsion and seizures [80]. Besides, genetic polymorphisms can influence biological properties including toxicity. A LC-MS/MS method for separation of tramadol, and its principal metabolites, ODT and NDT for pharmacokinetic applications in plasma samples was reported [81]. Authors showed that plasma binding was not enantioselective, nevertheless kinetic disposition of tramadol and its NDT metabolite was enantioselective, with plasma accumulation of (+)-tramadol and (+)-NDT, whereas the pharmacokinetics of ODT was not enantioselective in patients with neuropathic pain phenotyped as extensive metabolizers of CYP2D6. Thus, enantioselective methods for both tramadol and its metabolites are essential for an accurate evaluation of their biological properties and toxicity.
Methadone is a synthetic opioid frequently used for treatment of opiate dependent persons, pharmacologically similar to morphine, but lacks the euphoric effects [82,83]. Methadone can be fatal by itself or by interaction with other drugs such as depressors of the CNS. Methadone is a substrate for CYP2B6 and CYP2C19, which are all stereoselective [83]. Plus, CYP P450 isoenzymes are known to have individual variability (polymorphisms) that leads to poor metabolizers, rapid metabolizers and ultra-rapid metabolizers [83]. This chiral drug, when administred as racemate gives rise to enantiomeric metabolites S-(−)-2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and the R-(+)-enantiomer. The R-(−)-enantiomer of methadone, is the one with higher affinity for the μ-opioid receptor having a higher analgesic potency (over fifty times more) [82,83]. On the other hand, the S-enantiomer is responsible for the poor cardiac tolerance [84]. In order to investigate the enantiomeric ratios of methadone and EDDP in postmortem samples, Jantos et al. applied a LC-MS/MS method in femoral blood, urine, bile, brain, lungs, kidneys and muscle tissue samples [82]. The study was based in sixteen samples, from eleven man and five women with ages ranging between 23 to 43 years old. Concentrations of R-methadone and R-EDDP were found in all body fluids and tissues, while S-enantiomers were only found in thirteen of the cases. The R/S ratios ranged from 0.58 to 4.19 for methadone, and from 0.38 to 1.38 for EDDP [82]. Because methadone does not suffer racemization in the human body, the enantiomeric ratios found in postmortem samples, can reflect if the substance consumed was either racemic or not; also can identify if the cause of death is related to toxic exposure [82]. Moody et al. developed an enantioselective method by LC-MS/MS for methadone and EDDP in human plasma, urine and liver microsomes [85]. This study demonstrated differences in the pharmacokinetic between enantiomers of methadone and its main metabolite EDDP and suggest greater production of and lesser clearance of S-EDDP.
The antitussive dextromethorphan (allowed drug) and the narcotic analgesic levomethorphan (banned drug, not commercially available) are the R- and R- isomers of 3-methoxy-N-methylmorphinan. Aumatell and Wells developed a CE chiral method for separation of methorphan (racemate of dextromethorphan and levomethorphan) [86]. Distinction of these compounds is not only of interest in forensic science (such as the elucidation of the cause of death after intake of levomethorphan), but also for the treatment of intoxicated patients. Also, the use of preparations containing dextromethorphan by athletes is allowed, whereas the use of levorphanol is expressly banned by the International Olympic Committee [61].

3.3. Antidepressants

Although antidepressants are considered non-addictive, many people abuse of these drugs [87,88]. Users can become physically dependent and non-compliance may arise as a result, with fatal consequences in some cases [89]. Among studied antidepressants are fluoxetine (FLX), citalopram, reboxetine, venlafaxine (VNF) and its metabolites (Table 1 and Table 2). FLX is an example of antidepressants administrated as racemate, that both enantiomers have the same biological active. It acts by selective inhibition of the serotonin reuptake pump, increasing the extracellular catecholamines, such as serotonine, dopamine and norepinephrine. In the human body, it is metabolized to norfluoxetine (NFLX). FLX enantiomers are approximately equipotent in blocking the 5-HT reuptake, while the enantiomers of NFLX show marked differences in pharmacological activity. The enantiomer S-NFLX shows approximately 20 times more potency than the R-enantiomer as 5-HT reuptake inhibitor, both in vitro and in vivo [90,91,92]. Shen et al. considered the enantioseparation of FLX in human plasma but its metabolite was not considered [93]. Nevertheless, Unceta et al. developed an LC-FD method for simultaneous separation of FLX and NFLX enantiomers, in order to investigate potential sources of variability, in rats receiving chronic treatments, on concentrations of FLX and NFLX and their enantiomers [91]. The plasma levels of R-NFLX were considerably increased in comparison to the S-enantiomer. In plasma FLX R/S ratios were of 1.02 compared to 1.05 in cerebral cortex, which was in contrast with NFLX R/S ratios, that were 1.81 in plasma and 1.5 in cerebral cortex [91].
Citalopram, used in the treatment of depression, commercialized as racemate and its enantiomer S-(+)-citalopram (escitalopram, marketed in the enantiomerically pure form) is 100 times more potent as a serotonin reuptake inhibitor as compared to R-(−)-citalopram.
VNF is a phenylethylamine derivative that affects brain neurotransmission by blocking presynaptic reuptake of serotonin and noradrenaline [94], and administrated in the treatment of psychiatric disorders [95]. VNF undergoes extensive first-pass metabolism by CYP P450 enzymes into its major active metabolite O-desmethylvenlafaxine (OD-VNF), and two minor metabolites, N-desmethylvenlafaxine (ND-VNF) and N,O-didesmethylvenlafaxine (N,O-DD-VNF). OD-VNF inhibits the reuptake of serotonin and noradrenaline in similar potency to that of VNF [96]. Stereoselective metabolism has been observed both in vitro and in vivo, where CYPD2D6 displays and appreciable stereoselectivity towards the R-enantiomer [96].
Reboxetine is used as a selective noradrenaline reuptake inhibitor for the treatment of major depressive disorders, commercialized as racemate (S,S- and R,R-reboxetine). Ohman et al. developed an enantioseletive method for analysis of reboxetine in serum in patients with chronic medication [97]. Authors found that the median S,S/R,R ratio in steady state was 0.5 and ranged from 0.22 to 0.88. It was also shown that women have an approximately 30% higher S,S/R,R ratio than men. The S,S/R,R ratios of reboxetine were not found to correlate with reboxetine concentrations. Authors also found a correlation between selective noradrenaline reuptake inhibitor activity that is higher in women than in men and that may alter the enantiomeric ratio.

3.4. β-Blockers

β-Blockers, also known as β-adrenergic blocking agents, are a class of chiral drugs that are used for the management of cardiac arrhythmias. Usually one enantiomer presents higher potency than the other. For instances, S-(−)-propranolol (PHO) is 100 times more than R-(+)-PHO. Most of β-blockers (except timolol: S-isomer) are marketed as racemates, such as acebutolol, atenolol (ATE), alprenolol, betaxolol, carvediol, metoprolol (MET), labetalol, pindolol and sotalol [4]. In addition to therapeutic properties, these compounds exhibit calming neurological effects decreasing anxiety, nervousness and stabilizing motor performance. Thus, these compounds are included in prohibited list according to the World Anti Doping Agency (WADA) regulation because of the improved psychomotor performance that may be beneficial in sports requiring precision and accuracy such as shooting archery among others [61]. Among β-blockers only PHO, MET, carvediol, verapamil and its metabolite enantiomers were discriminated in plasma and urine (Table 1 and Table 2) [98,99,100,101]. Analytical methods used for the separation of enantiomers of these drugs included LC-MS and GC-MS. PHO is administered as racemate to treat hypertension and normalize tachycardia response; however, the S-enantiomer shows greater cardiosympatholytic activity [102]. Siluk et al. developed an analytical method for separation of R,S-PHO in human plasma for determination of pharmacokinetic difference among the two enantiomers and even drugs interaction [98]. In this study, authors suggest that R-PHO is eliminated faster than S-PHO. Concerning MET, Kim et al. developed an analytical method for enantioseparation of its enantiomers in urine. This method can be applied in pharmacological and pharmacokinetic studies of both enantiomers in biological samples [100]. Beyond carvediol and verapamil, there are not studies concerning the enantioseparation of other used β-blockers in biological samples. Methods of enantioseparation for these substances are important to evaluate pharmacological and pharmacokinetic differences among enantiomers and possible toxicity due to interaction with other administered drugs.

3.5. Anticoagulants

Warfarin (WFN) is one of the most commonly prescribed cardiovascular medication anticoagulant drugs used to manage thromboembolic disease. WFN is administered as an oral medication consisting of a racemate though the S-enantiomer has higher activity than the R-enantiomer. Several factors increase the risk of over-anticoagulation such as genetic polymorphisms as well as others factors, including age, sex, and histories of smoking and alcohol consumption and diets rich in vitamin K [103]. Genetic factors and drug interactions mostly account for the risk of over-anticoagulation [103]. Knowledge about enantioselective pharmacodynamic and pharmacokinetic is not only important to assure efficiency and safety but also because genetic polymorphisms may have an important impact in biological properties including toxicity. Separation of WFN enantiomers was achieved using different analytical methods: SFC-MS/MS, LC-MS/MS and Micellar electrokinetic chromatography MEKC-MS in plasma (Table 1 and Table 2) [104,105,106]. Knowledge about pharmacokinetic of enantiomers of WFN and its metabolites may add in the development of enantiopure commercialized forms of WFN that may be safer and for studies of possible toxicological and interaction of WFN with other pharmaceuticals concomitant administered. Beyond the use of WFN as anticoagulant, this compound was used as a poison, and is still marketed as a pesticide against rats and mices.

3.6. Dissociative Anaesthetics

Ketamine (K) began to be a widespread drug of abuse in many countries and primarily available through illicit means. At sub anaesthetic doses this drug provides hallucinogenic effects [107,108]. Because of these desire effects K is often used in recreational purposes and particularly dangerous with regards to traffic and workplace safety. In fact, K can be bought in the internet from suspected veterinary distributers and clinics [109]. Chiral discrimination of K and its main metabolite norketamine (NK) was done in in plasma and hair [110,111]. S-(+)-K is an anesthetic and analgesic but R-(−)-ketamine is associated to hallucinations and agitation. K is a dissociative anaesthetic that induces loss of consciousness, amnesia, immobility, and in a lesser extent analgesia [110]. It is used in paediatric emergency retrieval and in veterinary surgery, because of its reduced tendency to give respiratory depression [110]. Its main advantage is to induce profound analgesia and amnesia, while maintaining the cardiopulmonary functions and the protective airway reflexes stable [110]. K undergoes extensive first-pass metabolism to produce various free and glucurinated hydroxylated derivatives [110]. However, its main metabolic pathway occurs through N-demethylation to NK which appears to have 20–30% activity of its parent drug [110]. Although is used as a racemate, the S-enantiomer showed to have four times higher affinity for the phencyclidine site of the NMDA receptor, as well as a greater potency when compare to the R-form and the racemate [110].

3.7. Bronchodilators

Among bronchodilators are β-adrenoreceptor agonists (or β2-agonists) that are drugs commonly used for the treatment of asthma and other pulmonary disorders. They have bronchodilator and anabolic activities. Because of these properties, these compounds may be used by athletes to enhance performance and as a safer alternative to anabolic steroids though the use by asthmatic athletes is not forbidden. In this sense, like β-blockers, the β-adrenergic compounds are scheduled in the Prohibit List of the WADA [61]. Only one report was found that describes the enantioseparation of a bronchodilator, the salbutamol (SBT). This compound is commercialized as racemate, however the R-enantiomer of SBT binds to β2-adrenergic receptors with greater affinity than the S-enantiomer, which does not act through β-adrenergic receptor activation. S-SBT has adverse effects associated, such like augmentation of bronchospasm and pro-inflammatory activities. Studies have reported that the S-enantiomer can potentiate the effects of spasmogens in airway of smooth muscle from both guinea pigs and humans, with a number of clinical studies also reporting worsening of airways hyper-responsiveness in animals and in subjects with asthma [112]. The initial step in metabolism of both enantiomers is sulfate conjugation, a stereoselective process that occurs in human airway epithelial cells, as also in other cells and tissues [113]. The greater rate of sulfate conjugation of R-SBT might lead to lower plasma levels of R- than S-enantiomer in human subjects, which can be responsible for increasing the adverse effects related with the latter [112,113]. Since bronchodilator pharmacodynamic is enantioselective the development of enantioselective methods for bronchodilators is essential for stereo-pharmacokinetics and enantioselective safety studies. Data from pharmacokinetic studies can contribute to the development of enantiopure broncodilators therapeutic drugs that can be safer and used in the control of broncodilators abuse.

3.8. Anti-Helmintic

Levamisole and dexamisol [(phenyltetrahydroimidazothiazole (PTHIT)] were widely used as an anti-worm medication for both humans and animals, but they are no longer approved for use in the United States or Canada due to their toxicity. In South America, illicit cocaine laboratories have been known to add PTHIT to cocaine preparations to extend their effects [10]. Casale et al. developed an analytical method by GC-FID for the determination of PTHIT enantiomers. i.e., levamisole and dexamisole in illicit cocaine seizures and in urine cocaine abusers [10]. Beyond the possibility of linking origin of cocaine seizures, the addiction of PTHIT have been shown to cause agranulocytosis/neutropenia in cocaine abusers expanding the adverse effects of the consumption of this drug. Approximately 78% of cocaine samples contained PTHIT in an average concentration of 23%. Enantiomeric compositions of dexamisole/levamisole were different among samples. 66% of the samples contained levamisole, 19% the racemate and 15% the higher levels of levamisole. Samples containing only dexamisole were not detected. The higher content in levamisole may be due to traffickers adding tetramisole and levamisole to the cocaine or illegitimate preparation of levamisole. Considering urine samples the majority of urine extracts contained levamisole (46%), and levamisole enhanced enrichment (20%) and dexamisole-enhanced enrichment (26%). Levamisole has high toxicity affecting all organ systems, with agranulocytosis, manifested primarily as acute, profound neutropenia and have been found in concaine consumers leading to serious clinical complications. Thus, this methodology allowed clinical toxicologists and forensic chemists to establish specific enantiomer composition of PTHIT in cocaine samples and in the urine specimens of cocaine abusers [10]

4. Chiral Analyses in the Aquatic Environment

This study reviewed 33 articles that have been published between 2005 and 2017 based in ScienceDirect and ISI web of Knowledge databases (Table 3 and Figure 4). The target compounds included antidepressants, β-blockers, nonsteroidal anti-inflamatory drugs (NSAIDs), synthetic psychoactive drugs, antibiotics, synthetic opioids, antiepileptics, antihistaminic; bronchodilators, antineoplastic agents and proton pump inhibitors (Table 1). Figure 4 shows the relative number of studies of each class of chiral drug investigated and the analytical methods used for analysis of these compounds in different environmental matrices.
The entrance of pharmaceuticals and illicit drugs into the aquatic environment may occur through effluents from WWTPs which are unable to totally remove these micro-pollutants or direct discharged of sewage. WWTPs biological treatments, can alter the EF of the enantiomers present in the influent, as microbiota action generally is stereoselective [136,137]. Disposed drugs will usually be found in their parent form, either as racemate or single enantiomers. On the other hand, excreted drugs will be normally found as metabolites, frequently chiral, of the parent compound [138].
The possible adverse effects of the enantiomers on aquatic and human life lead to the studies of occurrence of chiral drugs in environmental matrices [20,136,137,139,140]. Illicit drugs can also be found in environmental samples, and environmental data are important resources for a forensic approach. This includes the usage of environmental data in order to: (1) verify patterns of illicit and prescribed drugs usage in local communities (2) application of drugs as chemical markers of faecal water contamination with (human) sewage and (3) verify the source of drugs (legal or illicit) [20,136,137,139,140].
The estimation of the consumption of substances of abuse and illicit drugs can be measured by the concentrations of these compounds in wastewater. Drugs are consumed and metabolised in human body and excreted as parent compounds or as metabolites, and finally reach WWTPs through the sewage [139]. Since the metabolic patterns of most available drugs are understood, it is assumed that the amount of drug or its metabolite quantified in raw sewage will correspond with the consumed dose—sewage epidemiology [139]. The application of the chiral discrimination has also been used for distinction between legal and illicit use of drugs, verification of the method of synthesis of illicit drugs, identification that drug residue results either from consumption of illicit drugs or metabolism of other drugs, verification of route of administration, verification of potency of abused drugs, monitoring of changing patterns of drugs abused, and differentiation between consumption and disposal of unused drugs [17,141].
Concerning biodegradation, ecotoxicity and environmental fate, the recognition of enantioselectivity is essential to provide a more realistic risk assessment of chiral compounds. The fate of chiral drugs in the environment can be studied by monitoring their EF during biological processes [20,38,136]. Degradation of these compounds relies on both abiotic and biotic processes [142]. Biodegradation in WWTP is expected to be stereoselective, which changes the EF of a given molecule in the sample, consequently bringing different removals/degradation rates [142]. Over the past five years, the amount of research published in chiral environmental analysis has been increasing on a high rate. Knowledge on how chiral micropollutant, such as pharmaceuticals and illicit drugs, behave in the environment, especially in water samples, either wastewater or superficial water, has been providing valuable information, both for risk assessment and WWTPs efficiency [139,142]. The EF of certain pharmaceuticals, such as PHO, alprenolol, VNF and climbazole [136,143,144] in surface waters, can reveal the efficiency of different WWTPs [136,139,140,143,144,145,146]. Additional these compounds have been pointed as indicators to differentiate between treated and untreated water. Analysis of wastewater samples are mostly done by comparing the EF of the influent and effluent of the target analytes, which gives an overview of the efficiency and of the WWTPs [9,147,148].
According to Kasprzyk-Hordern et al., since WWTPs are fed by fresh sewage, a long-term monitoring programme of drugs might reveal their usage patterns in local communities and their changes over longer periods of time [139]. This is the main route that chiral drugs enter the environment, and these can be found either in a modified form (metabolites) and/or with alterations in their enantiomeric EF due to human metabolism [138]. In the first attempt to apply chirality to sewage epidemiology, Kasprzyk-Hordern et al., collected wastewater samples over a period of 8 months, from seven WWTPs in London, during five sampling campaigns and, quantified the levels of AM, MA, MDMA, MDA, ephedrine and pseudoephedrine enantiomers [149]. The samples were enriched with R-AM, S-MA, S-MDA, 1R,2S-(−)-ephedrine and 1S,2S-(+)-pseudoephedrine. However, the authors could not reach any conclusion according to the use of illicit drugs, since AM and MA enantiomers can also result from the metabolism of chiral pharmaceuticals. On the other hand, when comes to MDMA and MDA, the enantiomeric profiling proved to be invaluable in making distinction between MDA abuse and its formation due to metabolism of MDMA, suggesting that this profiling could also help with making a distinction between actual consumption and direct disposal [17].
Vasquez-Roig et al., in a two week study of three WWTPs located in the city of Valencia (Spain) and surroundings, described the enantiomeric profile of some chiral drugs [148]. Although for some of the target analytes it was not possible to study their enantiomeric fate, since these were present in very low concentrations, which was the case of MDMA and AM, they were able to observe enantiomeric enrichment ofATE, where the S-enantiomer was in higher abundance in raw wastewater, meanwhile during the wastewater treatment, enrichment of both R- or S-enantiomer were observed [148]. This difference in enantiomeric enrichment seemed to be related with the technology used by the treatment plant. Although all of three used activated sludge, one of the plants had also biological nitrogen removal, which the authors believe that different bacteria were involved in this process (in aerobic conditions), that could favour the degradation of R-ATE, leading to an enrichment of S-ATE [148]. They also found enrichment at similar levels of 1R,2S-(−)-ephedrine and 1S,2S-(+)-pseudoephedrine in raw wastewater. In terms of elimination rates these ranged from 29 to 100% and showed to be compound and enantiomer dependent. AM and MA were not detected in effluents, however stereoselective degradation was observed for MDMA, where the S-enantiomer was more readily degraded than the R-MDMA. Atenolol was found to be poorly removed, thus S-atenolol removal efficiency was higher than R-atenolol [148]. VNF concentrations increased in two of the WWTPs after sewage treatment, which in according to the authors, was due to biotic effects, such like, elimination of glucuronide metabolites, back-reversion of the demethylated metabolite, or desorption from particulate matter [148]. The application of wastewater enantiomeric profiling revealed usage patterns of chiral drugs in the region, where the consumption of AM showed an irregular pattern throughout the two-week sampling campaign, while MA showed a slight increase in daily loads, throughout the weekend in one of the WWTPs. MDMA showed a clear weekly pattern of increased daily loads, during weekends [148].
Hashim, N. H. & Khan, S. J. studied the EFof ibuprofen, naproxen and ketoprofen in wastewater samples, taken from a WWTPs in Sydney (Australia) with tertiary treatment over seven separate sampling events, during June and August 2010 [147]. For ibuprofen, EF ranged from 0.49 and 0.62; 0.66 and 0.86 for naproxen and 0.54 and 0.66 for ketoprofen [147]. Also Barreiro et al in 2010, found for the first time the occurrence of (+)-omeprazole and (−)-omeprazole, while simultaneously developing a column switching, liquid chromatography method for the chiral separation of these drugs, in wastewater and estuarine samples [150]. Ribeiro et al studied, the EF of FLX, NFLX, VNF, SBT, alprenolol, MET, PHO and bisoprolol (BSP = from the final effluent of the secondary clarifier of three WWTPs located in the North of Portugal, Figure 5 [39]. Regarding antidepressants, only R-FLX was detected in two of the WWTPs, indicating a faster degradation of the S-enantiomer during the biological degradation [39]. VNF enantiomers were found between 40.4 and 129 ng/L in the three WWTPs studied, with similar EF, which varied between 0.54 and 0.55, proving that VNF found was not racemic [39]. Concerning the β-blockers enantiomers, BSP and PHO were found in all three WWTPs, while MET was only found in two, however all of them under the medium quantification level (MQL) [39].

5. General Conclusions and Further Perspectives

The LC-MS/MS is the first choice for environmental and biological matrices analyses due to the low quantification limits, the selectivity and unequivocal identification. Regarding environmental analysis the direct method by LC using CSP are mostly described. However methods for a complex mixture of chiral drugs are still scarce. Chiral analyses in biological matrices describe many indirect methods by GC, but the trend is the direct method by LC.
Despite the importance of the chiral analysis in forensic chemistry, this type of data are not yet currently in used in certificated laboratories for doping control, criminal offense, environmental monitoring and chiral drug control in general. In this sense more research is needed regarding new enantioselectivity methods with different CSP and demonstrations with practical applications to establish the importance of the chiral analysis in forensic chemistry.

Acknowledgments

This work was partially supported through national funds provided by FCT/MCTES-Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE-Programa Operacional Factores de Competitividade (POFC) programme, under the Strategic Funding UID/Multi/04423/2013, the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599-Promover a Producao Cientifica e Desenvolvimento Tecnologico e a Constituicao de Redes Tematicas (3599-PPCDT)) in the framework of the programme PT2020 as well as by the project INNOVMAR-Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and Chiral_Drugs_CESPU_2017.

Author Contributions

Maria Elizabeth Tiritan, Cláudia Ribeiro and Carlos Afonso conceived and designed the work; Cláudia Ribeiro, Cristiana Santos, Valter Gonçalves and Ana Ramos analyzed and reunited the data; Maria Elizabeth Tiritan, Cláudia Ribeiro and Cristiana Santos contributed in writing up the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. IUPAC. Basic Terminology of Stereochemistry. Available online: https://goldbook.iupac.org/src/src_PAC1996682193.html (accessed on 13 November 2017).
  2. Calcaterra, A.; D’Acquarica, I. The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds. J. Pharm. Biomed. Anal. 2018, 147, 323–340. [Google Scholar] [CrossRef] [PubMed]
  3. Tiritan, M.E.; Ribeiro, A.R.; Fernandes, C.; Pinto, M.M. Chiral Pharmaceuticals. In Kirk-Othmer Encyclopedia of Chemical Technology; Sons, J.W., Ed.; Wiley: Hoboken, NJ, USA, 2016. [Google Scholar]
  4. Nguyen, L.A.; He, H.; Pham-Huy, C. Chiral drugs: An overview. Int. J. Biomed. Sci. 2006, 2, 85–100. [Google Scholar] [PubMed]
  5. Tsujikawa, K.; Mikuma, T.; Kuwayama, K.; Miyaguchi, H.; Kanamori, T.; Iwata, Y.T.; Inoue, H. Profiling of seized methamphetamine putatively synthesized by reductive amination of 1-phenyl-2-propanone. Forensic Toxicol. 2012, 30, 70–75. [Google Scholar] [CrossRef]
  6. Tsujikawa, K.; Kuwayama, K.; Miyaguchi, H.; Kanamori, T.; Iwata, Y.T.; Inoue, H. Chemical profiling of seized methamphetamine putatively synthesized from phenylacetic acid derivatives. Forensic Sci. Int. 2013, 227, 42–44. [Google Scholar] [CrossRef] [PubMed]
  7. Binz, T.M.; Williner, E.; Strajhar, P.; Dolder, P.C.; Liechti, M.E.; Baumgartner, M.R.; Kraemer, T.; Steuer, A.E. Chiral analysis of amphetamines in hair by liquid chromatography-tandem mass spectrometry: Compliance-monitoring of attention deficit hyperactivity disorder (ADHD) patients under Elvanse® therapy and identification after controlled low-dose application. Drug Test. Anal. 2017, 1–8. [Google Scholar] [CrossRef] [PubMed]
  8. Fujii, H.; Hara, K.; Kageura, M.; Kashiwagi, M.; Matsusue, A.; Kubo, S.-I. High throughput chiral analysis of urinary amphetamines by GC-MS using a short narrow-bore capillary column. Forensic Toxicol. 2009, 27, 75–80. [Google Scholar] [CrossRef]
  9. Kasprzyk-Hordern, B.; Baker, D.R. Enantiomeric profiling of chiral drugs in wastewater and receiving waters. Environ. Sci. Technol. 2012, 46, 1681–1691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Casale, J.F.; Colley, V.L.; Legatt, D.F. Determination of phenyltetrahydroimidazothiazole enantiomers (Levamisole/Dexamisole) in illicit cocaine seizures and in the urine of cocaine abusers via chiral capillary gas chromatography-flame-ionization detection: Clinical and forensic perspectives. J. Anal. Toxicol. 2012, 36, 130–135. [Google Scholar] [CrossRef] [PubMed]
  11. Smith, S.W. Chiral toxicology: It’s the same thing...only different. Toxicol. Sci. 2009, 110, 4–30. [Google Scholar] [CrossRef] [PubMed]
  12. Buchard, A.; Linnet, K.; Johansen, S.S.; Munkholm, J.; Fregerslev, M.; Morling, N. Postmortem blood concentrations of R- and S-enantiomers of methadone and EDDP in drug users: Influence of co-medication and p-glycoprotein genotype. J. Forensic Sci. 2010, 55, 457–463. [Google Scholar] [CrossRef] [PubMed]
  13. Kikura-Hanajiri, R.; Kawamura, M.; Miyajima, A.; Sunouchi, M.; Goda, Y. Chiral analyses of dextromethorphan/levomethorphan and their metabolites in rat and human samples using LC-MS/MS. Anal. Bioanal. Chem. 2011, 400, 165–174. [Google Scholar] [CrossRef] [PubMed]
  14. Segawa, H.; Iwata, Y.T.; Yamamuro, T.; Kuwayama, K.; Tsujikawa, K.; Kanamori, T.; Inoue, H. Enantioseparation of methamphetamine by supercritical fluid chromatography with cellulose-based packed column. Forensic Sci. Int. 2017, 273, 39–44. [Google Scholar] [CrossRef] [PubMed]
  15. Płotka, J.M.; Biziuk, M.; Morrison, C.; Namieśnik, J. Pharmaceutical and forensic drug applications of chiral supercritical fluid chromatography. TrAC Trends Anal. Chem. 2014, 56, 74–89. [Google Scholar] [CrossRef]
  16. Hädener, M.; Bruni, P.S.; Weinmann, W.; Frubis, M.; Konig, S. Accelerated quantification of amphetamine enantiomers in human urine using chiral liquid chromatography and on-line column-switching coupled with tandem mass spectrometry. Anal. Bioanal. Chem. 2017, 409, 1291–1300. [Google Scholar] [CrossRef] [PubMed]
  17. Kasprzyk-Hordern, B.; Baker, D.R. Estimation of community-wide drugs use via stereoselective profiling of sewage. Sci. Total Environ. 2012, 423, 142–150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Kasprzyk-Hordern, B.; Dinsdale, R.M.; Guwy, A.J. The occurrence of pharmaceuticals, personal care products, endocrine disruptors and illicit drugs in surface water in South Wales, UK. Water Res. 2008, 42, 3498–3518. [Google Scholar] [CrossRef] [PubMed]
  19. Archer, E.; Petrie, B.; Kasprzyk-Hordern, B.; Wolfaardt, G.M. The fate of pharmaceuticals and personal care products (PPCPs), endocrine disrupting contaminants (EDCs), metabolites and illicit drugs in a WWTW and environmental waters. Chemosphere 2017, 174, 437–446. [Google Scholar] [CrossRef] [PubMed]
  20. Ribeiro, A.R.; Maia, A.S.; Cass, Q.B.; Tiritan, M.E. Enantioseparation of chiral pharmaceuticals in biomedical and environmental analyses by liquid chromatography: An overview. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2014, 968, 8–21. [Google Scholar] [CrossRef] [PubMed]
  21. Kasprzyk-Hordern, B.; Dinsdale, R.M.; Guwy, A.J. The removal of pharmaceuticals, personal care products, endocrine disruptors and illicit drugs during wastewater treatment and its impact on the quality of receiving waters. Water Res. 2009, 43, 363–380. [Google Scholar] [CrossRef] [PubMed]
  22. Baker, D.R.; Barron, L.; Kasprzyk-Hordern, B. Illicit and pharmaceutical drug consumption estimated via wastewater analysis. Part A: Chemical analysis and drug use estimates. Sci. Total Environ. 2014, 487, 629–641. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Castiglioni, S.; Thomas, K.V.; Kasprzyk-Hordern, B.; Vandam, L.; Griffiths, P. Testing wastewater to detect illicit drugs: State of the art, potential and research needs. Sci. Total Environ. 2014, 487, 613–620. [Google Scholar] [CrossRef] [PubMed]
  24. EMCDDA/Europol. Annual Report on the Implementation of Council Decision 2005/387/JHA; Europol: Lisbon, Portugal, 2011. [Google Scholar]
  25. Thomas, K.V.; Bijlsma, L.; Castiglioni, S.; Covaci, A.; Emke, E.; Grabic, R.; Hernández, F.; Karolak, S.; Kasprzyk-Hordern, B.; Lindberg, R.H.; et al. Comparing illicit drug use in 19 European cities through sewage analysis. Sci. Total Environ. 2012, 432, 432–439. [Google Scholar] [CrossRef] [PubMed]
  26. Petrie, B.; Youdan, J.; Barden, R.; Kasprzyk-Hordern, B. New Framework to Diagnose the Direct Disposal of Prescribed Drugs in Wastewater—A Case Study of the Antidepressant Fluoxetine. Environ. Sci. Technol. 2016, 50, 3781–3789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Vasquez, M.I.; Lambrianides, A.; Schneider, M.; Kümmerer, K.; Fatta-Kassinos, D. Environmental side effects of pharmaceutical cocktails: What we know and what we should know. J. Hazard. Mater. 2014, 279, 169–189. [Google Scholar] [CrossRef] [PubMed]
  28. Diao, J.; Xu, P.; Wang, P.; Lu, D.; Lu, Y.; Zhou, Z. Enantioselective degradation in sediment and aquatic toxicity to Daphnia magna of the herbicide lactofen enantiomers. J. Agric. Food Chem. 2010, 58, 2439–2445. [Google Scholar] [CrossRef] [PubMed]
  29. De Andrés, F.; Castañeda, G.; Ríos, Á. Use of toxicity assays for enantiomeric discrimination of pharmaceutical substances. Chirality 2009, 21, 751–759. [Google Scholar] [CrossRef] [PubMed]
  30. Leis, H.J.; Rechberger, G.N.; Fauler, G.; Windischhofer, W. Enantioselective trace analysis of amphetamine in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry. Rapid Commun. Mass Spectrom. 2003, 17, 569–575. [Google Scholar] [CrossRef] [PubMed]
  31. Nyström, I.; Trygg, T.; Woxler, P.; Ahlner, J.; Kronstrand, R. Quantitation of R-(−)- and S-(+)-amphetamine in hair and blood by gas chromatography-mass spectrometry: An application to compliance monitoring in adult-attention deficit hyperactivity disorder treatment. J. Anal. Toxicol. 2005, 29, 682–688. [Google Scholar] [CrossRef] [PubMed]
  32. Camacho-Munoz, D.; Kasprzyk-Hordern, B. Multi-residue enantiomeric analysis of human and veterinary pharmaceuticals and their metabolites in environmental samples by chiral liquid chromatography coupled with tandem mass spectrometry detection. Anal. Bioanal. Chem. 2015, 407, 9085–9104. [Google Scholar] [CrossRef] [PubMed]
  33. Iio, R.; Chinaka, S.; Takayama, N.; Hayakawa, K. Simultaneous Chiral Analysis of Methamphetamine and its Metabolites by Capillary Electrophoresis/Mass Spectrometry with Direct Injection of Urine. J. Health Sci. 2005, 51, 693–701. [Google Scholar] [CrossRef]
  34. Musshoff, F.; Madea, B.; Stuber, F.; Stamer, U.M. Enantiomeric determination of tramadol and O-desmethyltramadol by liquid chromatography-mass spectrometry and application to postoperative patients receiving tramadol. J. Anal. Toxicol. 2006, 30, 463–467. [Google Scholar] [CrossRef] [PubMed]
  35. Ribeiro, C.; Ribeiro, A.; Maia, A.; Tiritan, M. Occurrence of Chiral Bioactive Compounds in the Aquatic Environment: A Review. Symmetry 2017, 9, 215. [Google Scholar] [CrossRef]
  36. Iwamuro, Y.; Iio-Ishimaru, R.; Chinaka, S.; Takayama, N.; Kodama, S.; Hayakawa, K. Reproducible chiral capillary electrophoresis of methamphetamine and its related compounds using a chemically modified capillary having diol groups. Forensic Toxicol. 2010, 28, 19–24. [Google Scholar] [CrossRef]
  37. Ma, R.; Wang, B.; Lu, S.; Zhang, Y.; Yin, L.; Huang, J.; Deng, S.; Wang, Y.; Yu, G. Characterization of pharmaceutically active compounds in Dongting Lake, China: Occurrence, chiral profiling and environmental risk. Sci. Total Environ. 2016, 557–558, 268–275. [Google Scholar] [CrossRef] [PubMed]
  38. Ribeiro, A.R.; Afonso, C.M.; Castro, P.M.; Tiritan, M.E. Enantioselective HPLC analysis and biodegradation of atenolol, metoprolol and fluoxetine. Environ. Chem. Lett. 2013, 11, 83–90. [Google Scholar] [CrossRef]
  39. Ribeiro, A.R.; Santos, L.H.; Maia, A.S.; Delerue-Matos, C.; Castro, P.M.; Tiritan, M.E. Enantiomeric fraction evaluation of pharmaceuticals in environmental matrices by liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2014, 1363, 226–235. [Google Scholar] [CrossRef] [PubMed]
  40. Souchier, M.; Benali-Raclot, D.; Casellas, C.; Ingrand, V.; Chiron, S. Enantiomeric fractionation as a tool for quantitative assessment of biodegradation: The case of metoprolol. Water Res. 2016, 95, 19–26. [Google Scholar] [CrossRef] [PubMed]
  41. Suzuki, T.; Kosugi, Y.; Hosaka, M.; Nishimura, T.; Nakae, D. Occurrence and behavior of the chiral anti-inflammatory drug naproxen in an aquatic environment. Environ. Toxicol. Chem. 2014, 33, 2671–2678. [Google Scholar] [CrossRef] [PubMed]
  42. Wan Raihana, W.A.; Gan, S.H.; Tan, S.C. Stereoselective method development and validation for determination of concentrations of amphetamine-type stimulants and metabolites in human urine using a simultaneous extraction–chiral derivatization approach. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2011, 879, 8–16. [Google Scholar] [CrossRef] [PubMed]
  43. Zhao, P.; Deng, M.; Huang, P.; Yu, J.; Guo, X.; Zhao, L. Solid-phase extraction combined with dispersive liquid-liquid microextraction and chiral liquid chromatography-tandem mass spectrometry for the simultaneous enantioselective determination of representative proton-pump inhibitors in water samples. Anal. Bioanal. Chem. 2016, 408, 6381–6392. [Google Scholar] [CrossRef] [PubMed]
  44. Matamoros, V.; Hijosa, M.; Bayona, J.M. Assessment of the pharmaceutical active compounds removal in wastewater treatment systems at enantiomeric level. Ibuprofen and naproxen. Chemosphere 2009, 75, 200–205. [Google Scholar] [CrossRef] [PubMed]
  45. Morrison, C.; Smith, F.J.; Tomaszewski, T.; Stawiarska, K.; Biziuk, M. Chiral Gas Chromatography as a Tool for Investigations into Illicitly Manufactured Methylamphetamine. Chirality 2011, 23, 519–522. [Google Scholar] [CrossRef] [PubMed]
  46. Płotka, J.M.; Biziuk, M.; Morrison, C. Common methods for the chiral determination of amphetamine and related compounds I. Gas, liquid and thin-layer chromatography. TrAC Trends Anal. Chem. 2011, 30, 1139–1158. [Google Scholar] [CrossRef]
  47. Peng, L.; Jayapalan, S.; Chankvetadze, B.; Farkas, T. Reversed-phase chiral HPLC and LC/MS analysis with tris(chloromethylphenylcarbamate) derivatives of cellulose and amylose as chiral stationary phases. J. Chromatogr. A 2010, 1217, 6942–6955. [Google Scholar] [CrossRef] [PubMed]
  48. Meng, L.; Wang, B.; Luo, F.; Shen, G.J.; Wang, Z.Q.; Guo, M. Application of dispersive liquid-liquid microextraction and CE with UV detection for the chiral separation and determination of the multiple illicit drugs on forensic samples. Forensic Sci. Int. 2011, 209, 42–47. [Google Scholar] [CrossRef] [PubMed]
  49. Martins, L.F.; Yegles, M.; Chung, H.; Wennig, R. Sensitive, rapid and validated gas chromatography/negative ion chemical ionization-mass spectrometry assay including derivatisation with a novel chiral agent for the enantioselective quantification of amphetamine-type stimulants in hair. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2006, 842, 98–105. [Google Scholar] [CrossRef] [PubMed]
  50. Schwaninger, A.E.; Meyer, M.R.; Maurer, H.H. Chiral drug analysis using mass spectrometric detection relevant to research and practice in clinical and forensic toxicology. J. Chromatogr. A 2012, 1269, 122–135. [Google Scholar] [CrossRef] [PubMed]
  51. Lämmerhofer, M. Chiral recognition by enantioselective liquid chromatography: Mechanisms and modern chiral stationary phases. J. Chromatogr. A 2010, 1217, 814–856. [Google Scholar] [CrossRef] [PubMed]
  52. Fernandes, C.; Tiritan, M.E.; Pinto, M. Small Molecules as Chromatographic Tools for HPLC Enantiomeric Resolution: Pirkle-Type Chiral Stationary Phases Evolution. Chromatographia 2013, 76, 871–897. [Google Scholar] [CrossRef]
  53. Haginaka, J. Recent progresses in protein-based chiral stationary phases for enantioseparations in liquid chromatography. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2008, 875, 12–19. [Google Scholar] [CrossRef] [PubMed]
  54. Ribeiro, A.; Castro, P.; Tiritan, M. Environmental Fate of Chiral Pharmaceuticals: Determination, Degradation and Toxicity. In Environmental Chemistry for a Sustainable World; Springer: Berlin/Heidelberg, Germany, 2012; Volume 2, pp. 3–45. [Google Scholar]
  55. Zaugg, S.; Thormann, W. Enantioselective determination of drugs in body fluids by capillary electrophoresis. J. Chromatogr. A 2000, 875, 27–41. [Google Scholar] [CrossRef]
  56. Patel, B.K.; Hutt, A.J. Stereoselectivity in Drug Action and Disposition: An Overview. In Chirality in Drug Design and Development; Reddy, I.K., Mehvar, R., Eds.; Marcel Dekker, Inc.: New York, NY, USA, 2004. [Google Scholar]
  57. Hutt, A.J.; Valentova, J. The chiral switch: The development of single enantiomer drugs from racemates. Univ. Comen. Acta Fac. Pharm. 2003, 50, 7–23. [Google Scholar]
  58. Iwata, Y.T.; Inoue, H.; Kuwayama, K.; Kanamori, T.; Tsujikawa, K.; Miyaguchi, H.; Kishi, T. Forensic application of chiral separation of amphetamine-type stimulants to impurity analysis of seized methamphetamine by capillary electrophoresis. Forensic Sci. Int. 2006, 161, 92–96. [Google Scholar] [CrossRef] [PubMed]
  59. Nishida, K.; Itoh, S.; Inoue, N.; Kudo, K.; Ikeda, N. High-performance liquid chromatographic-mass spectrometric determination of methamphetamine and amphetamine enantiomers, desmethylselegiline and selegiline, in hair samples of long-term methamphetamine abusers or selegiline users. J. Anal. Toxicol. 2006, 30, 232–237. [Google Scholar] [CrossRef] [PubMed]
  60. Wang, T.; Shen, B.; Shi, Y.; Xiang, P.; Yu, Z. Chiral separation and determination of R/S-methamphetamine and its metabolite R/S-amphetamine in urine using LC-MS/MS. Forensic Sci. Int. 2015, 246, 72–78. [Google Scholar] [CrossRef] [PubMed]
  61. World Anti-Doping Agency (WADA). Prohibited List—The World Anti-Doping Code: International Standard; WADA: Montreal, QC, Canada, 2018. [Google Scholar]
  62. Evans, S.E.; Davies, P.; Lubben, A.; Kasprzyk-Hordern, B. Determination of chiral pharmaceuticals and illicit drugs in wastewater and sludge using microwave assisted extraction, solid-phase extraction and chiral liquid chromatography coupled with tandem mass spectrometry. Anal. Chim. Acta 2015, 882, 112–126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Newmeyer, M.N.; Concheiro, M.; Huestis, M.A. Rapid quantitative chiral amphetamines liquid chromatography-tandem mass spectrometry: Method in plasma and oral fluid with a cost-effective chiral derivatizing reagent. J. Chromatogr. A 2014, 1358, 68–74. [Google Scholar] [CrossRef] [PubMed]
  64. Ilieva, I.P.; Farah, M.J. Enhancement stimulants: Perceived motivational and cognitive advantages. Front. Neurosci. 2013, 7, 198. [Google Scholar] [CrossRef] [PubMed]
  65. Thomsen, R.; Rasmussen, H.B.; Linnet, K.; Consortium, I. Enantioselective determination of methylphenidate and ritalinic acid in whole blood from forensic cases using automated solid-phase extraction and liquid chromatography-tandem mass spectrometry. J. Anal. Toxicol. 2012, 36, 560–568. [Google Scholar] [CrossRef] [PubMed]
  66. Meyer, A.; Mayerhofer, A.; Kovar, K.A.; Schmidt, W.J. Enantioselective metabolism of the designer drugs 3,4-methylenedioxymethamphetamine (‘ecstasy’) and 3,4-methylenedioxyethylamphetamine (‘eve’) isomers in rat brain and blood. Neurosci. Lett. 2002, 330, 193–197. [Google Scholar] [CrossRef]
  67. Rasmussen, L.B.; Olsen, K.H.; Johansen, S.S. Chiral separation and quantification of R/S-amphetamine, R/S-methamphetamine, R/S-MDA, R/S-MDMA, and R/S-MDEA in whole blood by GC-EI-MS. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2006, 842, 136–141. [Google Scholar] [CrossRef] [PubMed]
  68. Schwaninger, A.E.; Meyer, M.R.; Barnes, A.J.; Kolbrich-Spargo, E.A.; Gorelick, D.A.; Goodwin, R.S.; Huestis, M.A.; Maurer, H.H. Stereoselective urinary MDMA (ecstasy) and metabolites excretion kinetics following controlled MDMA administration to humans. Biochem. Pharmacol. 2012, 83, 131–138. [Google Scholar] [CrossRef] [PubMed]
  69. Strano-Rossi, S.; Botre, F.; Bermejo, A.M.; Tabernero, M.J. A rapid method for the extraction, enantiomeric separation and quantification of amphetamines in hair. Forensic Sci. Int. 2009, 193, 95–100. [Google Scholar] [CrossRef] [PubMed]
  70. Wang, S.M.; Wang, T.C.; Giang, Y.S. Simultaneous determination of amphetamine and methamphetamine enantiomers in urine by simultaneous liquid-liquid extraction and diastereomeric derivatization followed by gas chromatographic-isotope dilution mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2005, 816, 131–143. [Google Scholar] [CrossRef] [PubMed]
  71. Wu, L.T.; Pilowsky, D.J.; Schlenger, W.E.; Galvin, D.M. Misuse of methamphetamine and prescription stimulants among youths and young adults in the community. Drug Alcohol. Depend. 2007, 89, 195–205. [Google Scholar] [CrossRef] [PubMed]
  72. Musshoff, F.; Madea, B. Fatality due to ingestion of tramadol alone. Forensic Sci. Int. 2001, 116, 197–199. [Google Scholar] [CrossRef]
  73. Grond, S.; Sablotzki, A. Clinical pharmacology of tramadol. Clin. Pharmacokinet. 2004, 43, 879–923. [Google Scholar] [CrossRef] [PubMed]
  74. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). European Drug Report 2017: Trends and Developments; Publications Office of the European Union: Luxembourg, Portugal, 2017. [Google Scholar]
  75. Chytil, L.; Matouskova, O.; Cerna, O.; Pokorna, P.; Vobruba, V.; Perlik, F.; Slanar, O. Enantiomeric determination of tramadol and O-desmethyltramadol in human plasma by fast liquid chromatographic technique coupled with mass spectrometric detection. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2010, 878, 481–486. [Google Scholar] [CrossRef] [PubMed]
  76. Paar, W.D.; Poche, S.; Gerloff, J.; Dengler, H.J. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur. J. Clin. Pharmacol. 1997, 53, 235–239. [Google Scholar] [CrossRef] [PubMed]
  77. Preissner, S.C.; Hoffmann, M.F.; Preissner, R.; Dunkel, M.; Gewiess, A.; Preissner, S. Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy. PLoS ONE 2013, 8, e82562. [Google Scholar] [CrossRef] [PubMed]
  78. Roussin, A.; Doazan-d’Ouince, O.; Geniaux, H.; Halberer, C. Evaluation of Abuse and Dependence in Addiction Monitoring Systems: Tramadol as an example. Therapie 2015, 70, 213–221. [Google Scholar] [CrossRef] [PubMed]
  79. Verri, P.; Rustichelli, C.; Palazzoli, F.; Vandelli, D.; Marchesi, F.; Ferrari, A.; Licata, M. Tramadol chronic abuse: An evidence from hair analysis by LC tandem MS. J. Pharm. Biomed. Anal. 2015, 102, 450–458. [Google Scholar] [CrossRef] [PubMed]
  80. Fawzi, M.M. Medicolegal aspects concerning tramadol abuse. The new Middle East youth plague: An Egyptian overview 2010. J. Forensic Res. 2011, 2, e130. [Google Scholar] [CrossRef]
  81. De Moraes, N.V.; Lauretti, G.R.; Napolitano, M.N.; Santos, N.R.; Godoy, A.L.; Lanchote, V.L. Enantioselective analysis of unbound tramadol, O-desmethyltramadol and N-desmethyltramadol in plasma by ultrafiltration and LC-MS/MS: Application to clinical pharmacokinetics. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2012, 880, 140–147. [Google Scholar] [CrossRef] [PubMed]
  82. Jantos, R.; Skopp, G. Postmortem blood and tissue concentrations of R- and S-enantiomers of methadone and its metabolite EDDP. Forensic Sci. Int. 2013, 226, 254–260. [Google Scholar] [CrossRef] [PubMed]
  83. Rodriguez-Rosas, M.E.; Medrano, J.G.; Epstein, D.H.; Moolchan, E.T.; Preston, K.L.; Wainer, I.W. Determination of total and free concentrations of the enantiomers of methadone and its metabolite (2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine) in human plasma by enantioselective liquid chromatography with mass spectrometric detection. J. Chromatogr. A 2005, 1073, 237–248. [Google Scholar] [CrossRef] [PubMed]
  84. Bouquie, R.; Hernando, H.; Deslandes, G.; Ben Mostefa Daho, A.; Renaud, C.; Grall-Bronnec, M.; Dailly, E.; Jolliet, P. Chiral on-line solid phase extraction coupled to liquid chromatography-tandem mass spectrometry assay for quantification of (R) and (S) enantiomers of methadone and its main metabolite in plasma. Talanta 2015, 134, 373–378. [Google Scholar] [CrossRef] [PubMed]
  85. Moody, D.E.; Lin, S.N.; Chang, Y.; Lamm, L.; Greenwald, M.K.; Ahmed, M.S. An enantiomer-selective liquid chromatography-tandem mass spectrometry method for methadone and EDDP validated for use in human plasma, urine, and liver microsomes. J. Anal. Toxicol. 2008, 32, 208–219. [Google Scholar] [CrossRef] [PubMed]
  86. Aumatell, A.; Wells, R.J. Chiral differentiation of the optical isomers of racemethorphan and racemorphan in urine by capillary zone electrophoresis. J. Chromatogr. Sci. 1993, 31, 502–508. [Google Scholar] [CrossRef] [PubMed]
  87. Evans, E.A.; Sullivan, M.A. Abuse and misuse of antidepressants. Subst. Abuse Rehabil. 2014, 5, 107–120. [Google Scholar] [PubMed]
  88. Center, A. Antidepressant Addiction and Abuse. Available online: https://www.addictioncenter.com/stimulants/antidepressants/ (accessed on 5 December 2017).
  89. Peles, E.; Schreiber, S.; Adelson, M. Tricyclic antidepressants abuse, with or without benzodiazepines abuse, in former heroin addicts currently in methadone maintenance treatment (MMT). Eur. Neuropsychopharmacol. 2008, 18, 188–193. [Google Scholar] [CrossRef] [PubMed]
  90. Gatti, G.; Bonomi, I.; Marchiselli, R.; Fattore, C.; Spina, E.; Scordo, G.; Pacifici, R.; Perucca, E. Improved enantioselective assay for the determination of fluoxetine and norfluoxetine enantiomers in human plasma by liquid chromatography. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2003, 784, 375–383. [Google Scholar] [CrossRef]
  91. Unceta, N.; Barrondo, S.; de Azúa, I.R.; Gómez-Caballero, A.; Goicolea, M.A.; Sallés, J.; Barrio, R.J. Determination of fluoxetine, norfluoxetine and their enantiomers in rat plasma and brain samples by liquid chromatography with fluorescence detection. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2007, 852, 519–528. [Google Scholar] [CrossRef] [PubMed]
  92. Kelly, T.; Doble, P.; Dawson, M. Chiral analysis of methadone and its major metabolites (EDDP and EMDP) by liquid chromatography–mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2005, 814, 315–323. [Google Scholar] [CrossRef] [PubMed]
  93. Shen, Z.; Wang, S.; Bakhtiar, R. Enantiomeric separation and quantification of fluoxetine (Prozac) in human plasma by liquid chromatography/tandem mass spectrometry using liquid-liquid extraction in 96-well plate format. Rapid Commun. Mass Spectrom. 2002, 16, 332–338. [Google Scholar] [CrossRef] [PubMed]
  94. Gasser, G.; Pankratov, I.; Elhanany, S.; Werner, P.; Gun, J.; Gelman, F.; Lev, O. Field and laboratory studies of the fate and enantiomeric enrichment of venlafaxine and O-desmethylvenlafaxine under aerobic and anaerobic conditions. Chemosphere 2012, 88, 98–105. [Google Scholar] [CrossRef] [PubMed]
  95. Kingbäck, M.; Josefsson, M.; Karlsson, L.; Ahlner, J.; Bengtsson, F.; Kugelberg, F.C.; Carlsson, B. Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction. J. Pharm. Biomed. Anal. 2010, 53, 583–590. [Google Scholar] [CrossRef] [PubMed]
  96. Karlsson, L.; Schmitt, U.; Josefsson, M.; Carlsson, B.; Ahlner, J.; Bengtsson, F.; Kugelberg, F.C.; Hiemke, C. Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein. Eur. Neuropsychopharmacol. 2010, 20, 632–640. [Google Scholar] [CrossRef] [PubMed]
  97. Öhman, D.; Cherma, M.D.; Norlander, B.; Bengtsson, F. Determination of serum reboxetine enantiomers in patients on chronic medication with racemic reboxetine. Ther. Drug Monit. 2003, 25, 174–182. [Google Scholar] [CrossRef] [PubMed]
  98. Siluk, D.; Mager, D.E.; Gronich, N.; Abernethy, D.; Wainer, I.W. HPLC-atmospheric pressure chemical ionization mass spectrometric method for enantioselective determination of R,S-propranolol and R,S-hyoscyamine in human plasma. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2007, 859, 213–221. [Google Scholar] [CrossRef] [PubMed]
  99. Poggi, J.C.; Da Silva, F.G.; Coelho, E.B.; Marques, M.P.; Bertucci, C.; Lanchote, V.L. Analysis of carvedilol enantiomers in human plasma using chiral stationary phase column and liquid chromatography with tandem mass spectrometry. Chirality 2012, 24, 209–214. [Google Scholar] [CrossRef] [PubMed]
  100. Kim, K.H.; Lee, J.H.; Ko, M.Y.; Shin, K.S.; Kang, J.S.; Mar, W.C.; Youm, J.R. Determination of metoprolol enantiomers in human urine by GC-MS using (−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride as a chiral derivatizing agent. Chromatographia 2002, 55, 81–85. [Google Scholar] [CrossRef]
  101. Dethy, J.M.; De Broux, S.; Lesne, M.; Longstreth, J.; Gilbert, P. Stereoselective determination of verapamil and norverapamil by capillary electrophoresis. J. Chromatogr. B Biomed. Appl. 1994, 654, 121–127. [Google Scholar] [CrossRef]
  102. Martin, L.J.; Piltonen, M.H.; Gauthier, J.; Convertino, M.; Acland, E.L.; Dokholyan, N.V.; Mogil, J.S.; Diatchenko, L.; Maixner, W. Differences in the Antinociceptive Effects and Binding Properties of Propranolol and Bupranolol Enantiomers. J. Pain 2015, 16, 1321–1333. [Google Scholar] [CrossRef] [PubMed]
  103. Piatkov, I.; Rochester, C.; Jones, T.; Boyages, S. Warfarin toxicity and individual variability-clinical case. Toxins 2010, 2, 2584–2592. [Google Scholar] [CrossRef] [PubMed]
  104. Coe, R.A.; Rathe, J.O.; Lee, J.W. Supercritical fluid chromatography-tandem mass spectrometry for fast bioanalysis of R/S-warfarin in human plasma. J. Pharm. Biomed. Anal. 2006, 42, 573–580. [Google Scholar] [CrossRef] [PubMed]
  105. Zuo, Z.; Wo, S.K.; Lo, C.M.; Zhou, L.; Cheng, G.; You, J.H. Simultaneous measurement of S-warfarin, R-warfarin, S-7-hydroxywarfarin and R-7-hydroxywarfarin in human plasma by liquid chromatography-tandem mass spectrometry. J. Pharm. Biomed. Anal. 2010, 52, 305–310. [Google Scholar] [CrossRef] [PubMed]
  106. Hou, J.; Zheng, J.; Shamsi, S.A. Separation and determination of warfarin enantiomers in human plasma using a novel polymeric surfactant for micellar electrokinetic chromatography-mass spectrometry. J. Chromatogr. A 2007, 1159, 208–216. [Google Scholar] [CrossRef] [PubMed]
  107. NIH. Hallucinogens. Available online: https://www.drugabuse.gov/publications/drugfacts/hallucinogens (accessed on 16 January 2018).
  108. Powers, A.R.; Gancsos, M.G.; Finn, E.S.; Morgan, P.T.; Corlett, P.R. Ketamine-Induced Hallucinations. Psychopathology 2015, 48, 376–385. [Google Scholar] [CrossRef] [PubMed]
  109. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Report on the Risk Assessment of Ketamine in the Framework of the Joint Action on New Synthetic Drugs; Office for Official Publications of the European Communities: Luxembourg, Portugal, 2002. [Google Scholar]
  110. Porpiglia, N.; Musile, G.; Bortolotti, F.; De Palo, E.F.; Tagliaro, F. Chiral separation and determination of ketamine and norketamine in hair by capillary electrophoresis. Forensic Sci. Int. 2016, 266, 304–310. [Google Scholar] [CrossRef] [PubMed]
  111. Rodriguez Rosas, M.E.; Patel, S.; Wainer, I.W. Determination of the enantiomers of ketamine and norketamine in human plasma by enantioselective liquid chromatography–mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2003, 794, 99–108. [Google Scholar] [CrossRef]
  112. Matera, M.G.; Calzetta, L.; Rogliani, P.; Bardaro, F.; Page, C.P.; Cazzola, M. Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi. Pulm. Pharmacol. Ther. 2011, 24, 221–226. [Google Scholar] [CrossRef] [PubMed]
  113. Henderson, W.R., Jr.; Banerjee, E.R.; Chi, E.Y. Differential effects of (S)- and (R)-enantiomers of albuterol in a mouse asthma model. J. Allergy Clin. Immunol. 2005, 116, 332–340. [Google Scholar] [CrossRef] [PubMed]
  114. Peters, F.T.; Kraemer, T.; Maurer, H.H. Drug testing in blood: Validated negative-ion chemical ionization gas chromatographic-mass spectrometric assay for determination of amphetamine and methamphetamine enantiomers and its application to toxicology cases. Clin. Chem. 2002, 48, 1472–1485. [Google Scholar] [PubMed]
  115. Holler, J.M.; Vorce, S.P.; Bosy, T.Z.; Jacobs, A. Quantitative and isomeric determination of amphetamine and methamphetamine from urine using a nonprotic elution solvent and R(−)-α-methoxy-α-trifluoromethylphenylacetic acid chloride derivatization. J. Anal. Toxicol. 2005, 29, 652–657. [Google Scholar] [CrossRef] [PubMed]
  116. Paul, B.D.; Jemionek, J.; Lesser, D.; Jacobs, A.; Searles, D.A. Enantiomeric separation and quantitation of (+/−)-amphetamine, (+/−)-methamphetamine, (+/−)-MDA, (+/−)-MDMA, and (+/−)-MDEA in urine specimens by GC-EI-MS after derivatization with (R)-(−)- or (S)-(+)-alpha-methoxy-alpha-(trifluoromethy)phenylacetyl chloride (MTPA). J. Anal. Toxicol. 2004, 28, 449–455. [Google Scholar] [PubMed]
  117. Aasim, W.R.; Gan, S.H.; Tan, S.C. Development of a simultaneous liquid-liquid extraction and chiral derivatization method for stereospecific GC-MS analysis of amphetamine-type stimulants in human urine using fractional factorial design. Biomed. Chromatogr. 2008, 22, 1035–1042. [Google Scholar] [CrossRef] [PubMed]
  118. Iio, R.; Chinaka, S.; Tanaka, S.; Takayama, N.; Hayakawa, K. Simultaneous chiral determination of methamphetamine and its metabolites in urine by capillary electrophoresis-mass spectrometry. Analyst 2003, 128, 646–650. [Google Scholar] [CrossRef] [PubMed]
  119. Foster, B.S.; Gilbert, D.D.; Hutchaleelaha, A.; Mayersohn, M. Enantiomeric determination of amphetamine and methamphetamine in urine by precolumn derivatization with Marfey’s reagent and HPLC. J. Anal. Toxicol. 1998, 22, 265–269. [Google Scholar] [CrossRef] [PubMed]
  120. Tao, Q.F.; Zeng, S. Analysis of enantiomers of chiral phenethylamine drugs by capillary gas chromatography/mass spectrometry/flame-ionization detection and pre-column chiral derivatization. J. Biochem. Biophys. Methods 2002, 54, 103–113. [Google Scholar] [CrossRef]
  121. Helmlin, H.J.; Bracher, K.; Bourquin, D.; Vonlanthen, D.; Brenneisen, R. Analysis of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in plasma and urine by HPLC-DAD and GC-MS. J. Anal. Toxicol. 1996, 20, 432–440. [Google Scholar] [CrossRef] [PubMed]
  122. Steuer, A.E.; Schmidhauser, C.; Liechti, M.E.; Kraemer, T. Development and validation of an LC-MS/MS method after chiral derivatization for the simultaneous stereoselective determination of methylenedioxy-methamphetamine (MDMA) and its phase I and II metabolites in human blood plasma. Drug Test. Anal. 2015, 7, 592–602. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Christoffersen, D.J.; Brasch-Andersen, C.; Thomsen, J.L.; Worm-Leonhard, M.; Damkier, P.; Brosen, K. Quantification of morphine, morphine 6-glucuronide, buprenorphine, and the enantiomers of methadone by enantioselective mass spectrometric chromatography in whole blood. Forensic Sci. Med. Pathol. 2015, 11, 193–201. [Google Scholar] [CrossRef] [PubMed]
  124. Campanero, M.A.; Garcia-Quetglas, E.; Sadaba, B.; Azanza, J.R. Simultaneous stereoselective analysis of tramadol and its primary phase I metabolites in plasma by liquid chromatography. Application to a pharmacokinetic study in humans. J. Chromatogr. A 2004, 1031, 219–228. [Google Scholar] [CrossRef] [PubMed]
  125. Pedersen, R.S.; Brøsen, K.; Nielsen, F. Enantioselective HPLC method for quantitative determination of tramadol and O-desmethyltramadol in plasma and urine: Application to clinical studies. Chromatographia 2003, 57, 279–285. [Google Scholar] [CrossRef]
  126. Mehvar, R.; Elliott, K.; Parasrampuria, R.; Eradiri, O. Stereospecific high-performance liquid chromatographic analysis of tramadol and its O-demethylated (M1) and N,O-demethylated (M5) metabolites in human plasma. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2007, 852, 152–159. [Google Scholar] [CrossRef] [PubMed]
  127. Ardakani, Y.H.; Mehvar, R.; Foroumadi, A.; Rouini, M.R. Enantioselective determination of tramadol and its main phase I metabolites in human plasma by high-performance liquid chromatography. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2008, 864, 109–115. [Google Scholar]
  128. Chytil, L.; Sticha, M.; Matouskova, O.; Perlik, F.; Slanar, O. Enatiomeric determination of tramadol and O-desmethyltramadol in human urine by gas chromatography-mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2009, 877, 1937–1942. [Google Scholar] [CrossRef] [PubMed]
  129. Rocha, A.; Marques, M.P.; Coelho, E.B.; Lanchote, V.L. Enantioselective analysis of citalopram and demethylcitalopram in human and rat plasma by chiral LC-MS/MS: Application to pharmacokinetics. Chirality 2007, 19, 793–801. [Google Scholar] [CrossRef] [PubMed]
  130. Leis, H.J.; Windischhofer, W. Gas chromatography-negative ion chemical ionisation mass spectrometry using O-(pentafluorobenzyloxycarbonyl)-2,3,4,5-tetrafluorobenzoyl derivatives for the quantitative determination of methylphenidate in human plasma. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2011, 879, 2299–2303. [Google Scholar] [CrossRef] [PubMed]
  131. Leis, H.J.; Schutz, H.; Windischhofer, W. Quantitative determination of methylphenidate in plasma by gas chromatography negative ion chemical ionisation mass spectrometry using O-(pentafluorobenzyloxycarbonyl)-benzoyl derivatives. Anal. Bioanal. Chem. 2011, 400, 2663–2670. [Google Scholar] [CrossRef] [PubMed]
  132. LeVasseur, N.L.; Zhu, H.J.; Markowitz, J.S.; DeVane, C.L.; Patrick, K.S. Enantiospecific gas chromatographic-mass spectrometric analysis of urinary methylphenidate: Implications for phenotyping. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2008, 862, 140–149. [Google Scholar] [CrossRef] [PubMed]
  133. Liu, W.; Wang, F.; Li, H.D. Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in human plasma by HPLC-ESI/MS using a vancomycin chiral column. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2007, 850, 183–189. [Google Scholar] [CrossRef] [PubMed]
  134. Yang, E.; Wang, S.; Kratz, J.; Cyronak, M.J. Stereoselective analysis of carvedilol in human plasma using HPLC/MS/MS after chiral derivatization. J. Pharm. Biomed. Anal. 2004, 36, 609–615. [Google Scholar] [CrossRef] [PubMed]
  135. Servais, A.C.; Fillet, M.; Mol, R.; Somsen, G.W.; Chiap, P.; de Jong, G.J.; Crommen, J. On-line coupling of cyclodextrin mediated nonaqueous capillary electrophoresis to mass spectrometry for the determination of salbutamol enantiomers in urine. J. Pharm. Biomed. Anal. 2006, 40, 752–757. [Google Scholar] [CrossRef] [PubMed]
  136. Ribeiro, A.R.; Afonso, C.M.; Castro, P.M.; Tiritan, M.E. Enantioselective biodegradation of pharmaceuticals, alprenolol and propranolol, by an activated sludge inoculum. Ecotoxicol. Environ. Saf. 2013, 87, 108–114. [Google Scholar] [CrossRef] [PubMed]
  137. Ribeiro, A.R.; Maia, A.S.; Moreira, I.S.; Afonso, C.M.; Castro, P.M.; Tiritan, M.E. Enantioselective quantification of fluoxetine and norfluoxetine by HPLC in wastewater effluents. Chemosphere 2014, 95, 589–596. [Google Scholar] [CrossRef] [PubMed]
  138. Evans, S.E.; Kasprzyk-Hordern, B. Applications of chiral chromatography coupled with mass spectrometry in the analysis of chiral pharmaceuticals in the environment. TrEAC Trends Environ. Anal. Chem. 2014, 1, e34–e51. [Google Scholar] [CrossRef]
  139. Kasprzyk-Hordern, B.; Dinsdale, R.M.; Guwy, A.J. Illicit drugs and pharmaceuticals in the environment—Forensic applications of environmental data. Part 1: Estimation of the usage of drugs in local communities. Environ. Pollut. 2009, 157, 1773–1777. [Google Scholar] [CrossRef] [PubMed]
  140. Kasprzyk-Hordern, B.; Dinsdale, R.M.; Guwy, A.J. Illicit drugs and pharmaceuticals in the environment—Forensic applications of environmental data, Part 2: Pharmaceuticals as chemical markers of faecal water contamination. Environ. Pollut. 2009, 157, 1778–1786. [Google Scholar] [CrossRef] [PubMed]
  141. Castrignano, E.; Lubben, A.; Kasprzyk-Hordern, B. Enantiomeric profiling of chiral drug biomarkers in wastewater with the usage of chiral liquid chromatography coupled with tandem mass spectrometry. J. Chromatogr. A 2016, 1438, 84–99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. MacLeod, S.L.; Wong, C.S. Loadings, trends, comparisons, and fate of achiral and chiral pharmaceuticals in wastewaters from urban tertiary and rural aerated lagoon treatments. Water Res. 2010, 44, 533–544. [Google Scholar] [CrossRef] [PubMed]
  143. Brienza, M.; Chiron, S. Enantioselective reductive transformation of climbazole: A concept towards quantitative biodegradation assessment in anaerobic biological treatment processes. Water Res. 2017, 116, 203–210. [Google Scholar] [CrossRef] [PubMed]
  144. Li, Z.; Gomez, E.; Fenet, H.; Chiron, S. Chiral signature of venlafaxine as a marker of biological attenuation processes. Chemosphere 2013, 90, 1933–1938. [Google Scholar] [CrossRef] [PubMed]
  145. Hühnerfuss, H.; Shah, M.R. Enantioselective chromatography-a powerful tool for the discrimination of biotic and abiotic transformation processes of chiral environmental pollutants. J. Chromatogr. A 2009, 1216, 481–502. [Google Scholar] [CrossRef] [PubMed]
  146. Niemi, L.M.; Stencel, K.A.; Murphy, M.J.; Schultz, M.M. Quantitative determination of antidepressants and their select degradates by liquid chromatography/electrospray ionization tandem mass spectrometry in biosolids destined for land application. Anal. Chem. 2013, 85, 7279–7286. [Google Scholar] [CrossRef] [PubMed]
  147. Hashim, N.H.; Khan, S.J. Enantioselective analysis of ibuprofen, ketoprofen and naproxen in wastewater and environmental water samples. J. Chromatogr. A 2011, 1218, 4746–4754. [Google Scholar] [CrossRef] [PubMed]
  148. Vazquez-Roig, P.; Kasprzyk-Hordern, B.; Blasco, C.; Pico, Y. Stereoisomeric profiling of drugs of abuse and pharmaceuticals in wastewaters of Valencia (Spain). Sci. Total Environ. 2014, 494–495, 49–57. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Kasprzyk-Hordern, B.; Kondakal, V.V.; Baker, D.R. Enantiomeric analysis of drugs of abuse in wastewater by chiral liquid chromatography coupled with tandem mass spectrometry. J. Chromatogr. A 2010, 1217, 4575–4586. [Google Scholar] [CrossRef] [PubMed]
  150. Barreiro, J.C.; Vanzolini, K.L.; Madureira, T.V.; Tiritan, M.E.; Cass, Q.B. A column-switching method for quantification of the enantiomers of omeprazole in native matrices of waste and estuarine water samples. Talanta 2010, 82, 384–391. [Google Scholar] [CrossRef] [PubMed]
  151. Bagnall, J.P.; Evans, S.E.; Wort, M.T.; Lubben, A.T.; Kasprzyk-Hordern, B. Using chiral liquid chromatography quadrupole time-of-flight mass spectrometry for the analysis of pharmaceuticals and illicit drugs in surface and wastewater at the enantiomeric level. J. Chromatogr. A 2012, 1249, 115–129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. MacLeod, S.L.; Sudhir, P.; Wong, C.S. Stereoisomer analysis of wastewater-derived beta-blockers, selective serotonin re-uptake inhibitors, and salbutamol by high-performance liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2007, 1170, 23–33. [Google Scholar] [CrossRef] [PubMed]
  153. Nikolai, L.N.; McClure, E.L.; Macleod, S.L.; Wong, C.S. Stereoisomer quantification of the beta-blocker drugs atenolol, metoprolol, and propranolol in wastewaters by chiral high-performance liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2006, 1131, 103–109. [Google Scholar] [CrossRef] [PubMed]
  154. Morante-Zarcero, S.; Sierra, I. Simultaneous enantiomeric determination of propranolol, metoprolol, pindolol, and atenolol in natural waters by HPLC on new polysaccharide-based stationary phase using a highly selective molecularly imprinted polymer extraction. Chirality 2012, 24, 860–866. [Google Scholar] [CrossRef] [PubMed]
  155. Fono, L.J.; Sedlak, D.L. Use of the chiral pharmaceutical propranolol to identify sewage discharges into surface waters. Environ. Sci. Technol. 2005, 39, 9244–9252. [Google Scholar] [CrossRef] [PubMed]
  156. Morante-Zarcero, S.; Sierra, I. Comparative HPLC methods for beta-blockers separation using different types of chiral stationary phases in normal phase and polar organic phase elution modes. Analysis of propranolol enantiomers in natural waters. J. Pharm. Biomed. Anal. 2012, 62, 33–41. [Google Scholar] [CrossRef] [PubMed]
  157. Barclay, V.K.; Tyrefors, N.L.; Johansson, I.M.; Pettersson, C.E. Chiral analysis of metoprolol and two of its metabolites, alpha-hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2012, 1269, 208–217. [Google Scholar] [CrossRef] [PubMed]
  158. Fono, L.J.; Kolodziej, E.P.; Sedlak, D.L. Attenuation of wastewater-derived contaminants in an effluent-dominated river. Environ. Sci. Technol. 2006, 40, 7257–7262. [Google Scholar] [CrossRef] [PubMed]
  159. Barclay, V.K.; Tyrefors, N.L.; Johansson, I.M.; Pettersson, C.E. Trace analysis of fluoxetine and its metabolite norfluoxetine. Part I: Development of a chiral liquid chromatography-tandem mass spectrometry method for wastewater samples. J. Chromatogr. A 2011, 1218, 5587–5596. [Google Scholar] [CrossRef] [PubMed]
  160. Barclay, V.K.; Tyrefors, N.L.; Johansson, I.M.; Pettersson, C.E. Trace analysis of fluoxetine and its metabolite norfluoxetine. Part II: Enantioselective quantification and studies of matrix effects in raw and treated wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2012, 1227, 105–114. [Google Scholar] [CrossRef] [PubMed]
  161. Camacho-Munoz, D.; Kasprzyk-Hordern, B. Simultaneous enantiomeric analysis of pharmacologically active compounds in environmental samples by chiral LC-MS/MS with a macrocyclic antibiotic stationary phase. J. Mass Spectrom. 2017, 52, 94–108. [Google Scholar] [CrossRef] [PubMed]
  162. Hashim, N.H.; Stuetz, R.M.; Khan, S.J. Enantiomeric fraction determination of 2-arylpropionic acids in a package plant membrane bioreactor. Chirality 2013, 25, 301–307. [Google Scholar] [CrossRef] [PubMed]
  163. Camacho-Munoz, D.; Kasprzyk-Hordern, B.; Thomas, K.V. Enantioselective simultaneous analysis of selected pharmaceuticals in environmental samples by ultrahigh performance supercritical fluid based chromatography tandem mass spectrometry. Anal. Chim. Acta 2016, 934, 239–251. [Google Scholar] [CrossRef] [PubMed]
  164. Khan, S.J.; Wang, L.; Hashim, N.H.; McDonald, J.A. Distinct enantiomeric signals of ibuprofen and naproxen in treated wastewater and sewer overflow. Chirality 2014, 26, 739–746. [Google Scholar] [CrossRef] [PubMed]
  165. Caballo, C.; Sicilia, M.D.; Rubio, S. Enantioselective determination of representative profens in wastewater by a single-step sample treatment and chiral liquid chromatography-tandem mass spectrometry. Talanta 2015, 134, 325–332. [Google Scholar] [CrossRef] [PubMed]
  166. Huang, Q.; Zhang, K.; Wang, Z.; Wang, C.; Peng, X. Enantiomeric determination of azole antifungals in wastewater and sludge by liquid chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 2012, 403, 1751–1760. [Google Scholar] [CrossRef] [PubMed]
  167. Huang, Q.; Wang, Z.; Wang, C.; Peng, X. Chiral profiling of azole antifungals in municipal wastewater and recipient rivers of the Pearl River Delta, China. Environ. Sci. Pollut. Res. Int. 2013, 20, 8890–8899. [Google Scholar] [CrossRef] [PubMed]
  168. Luo, M.; Liu, D.; Zhou, Z.; Wang, P. A new chiral residue analysis method for triazole fungicides in water using dispersive liquid-liquid microextraction (DLLME). Chirality 2013, 25, 567–574. [Google Scholar] [CrossRef] [PubMed]
Molecules 23 00262 g001 550
Figure 1. Application of chiral drug analysis in forensic chemistry.
Figure 1. Application of chiral drug analysis in forensic chemistry.
Molecules 23 00262 g001
Molecules 23 00262 g002 550
Figure 2. Relative number of each class of chiral drug referred in the reviewed enantioselective published studies and the analytical methods used for separation of the chiral drugs in biological fluids.
Figure 2. Relative number of each class of chiral drug referred in the reviewed enantioselective published studies and the analytical methods used for separation of the chiral drugs in biological fluids.
Molecules 23 00262 g002
Molecules 23 00262 g003 550
Figure 3. Chromatogram representing the enantioseparation of R/S-AM, R/S-MA, R/S-MDA, R/S-MDMA and R/S-MDEA as R-MTPCl derivatives in whole blood concentrations at (A) 2 µg/g and (B) at 0.002 µg/g, respectively. Reproduction with permission of Elsevier (Figure 1 from Rasmussen et al. [67]).
Figure 3. Chromatogram representing the enantioseparation of R/S-AM, R/S-MA, R/S-MDA, R/S-MDMA and R/S-MDEA as R-MTPCl derivatives in whole blood concentrations at (A) 2 µg/g and (B) at 0.002 µg/g, respectively. Reproduction with permission of Elsevier (Figure 1 from Rasmussen et al. [67]).
Molecules 23 00262 g003
Molecules 23 00262 g004 550
Figure 4. Relative number of each class of chiral drug referred in the reviewed enantioselective published studies and the analytical methods for separation of the chiral drugs in environmental samples.
Figure 4. Relative number of each class of chiral drug referred in the reviewed enantioselective published studies and the analytical methods for separation of the chiral drugs in environmental samples.
Molecules 23 00262 g004
Molecules 23 00262 g005 550
Figure 5. Chromatogram and mass spectra of WWTP effluent sample showing the enantiomers of FLX, VNF, BSP, MET and PHO. Reproduction with permission of Elsevier (Figure 2 from Ribeiro et al. [39]).
Figure 5. Chromatogram and mass spectra of WWTP effluent sample showing the enantiomers of FLX, VNF, BSP, MET and PHO. Reproduction with permission of Elsevier (Figure 2 from Ribeiro et al. [39]).
Molecules 23 00262 g005
Table
Table 1. Structures of the chiral illicit drugs and pharmaceuticals.
Table 1. Structures of the chiral illicit drugs and pharmaceuticals.
Chiral Compounds
Stimulants and their metabolites
Molecules 23 00262 i001 Molecules 23 00262 i002 Molecules 23 00262 i003
Amphetamine (AM)Metamphetamine (MA)3,4-Methylenedioxy-methamphetamine (MDMA)
Molecules 23 00262 i004 Molecules 23 00262 i005 Molecules 23 00262 i006
3,4-Methylenedioxy amphetamine (MDA)Methylenedioxy-N-ethylamphetamine (MDEA)p-Hydroxymethamphetamine (pOHMA)
Molecules 23 00262 i007 Molecules 23 00262 i008 Molecules 23 00262 i009
4-Hydroxy-3-methoxy methamphetamine (HMMA)Methylphenidate (MPH)Aminorex
Drug precursors
Molecules 23 00262 i010 Molecules 23 00262 i011
PseudoephedrineEphedrine
Opioids, morphine derivatives and their metabolites
Molecules 23 00262 i012 Molecules 23 00262 i013 Molecules 23 00262 i014
Methadone2-Ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)Tramadol (T)
Molecules 23 00262 i015 Molecules 23 00262 i016 Molecules 23 00262 i017
O-Desmethyltramadol (ODT)N-Desmethyltramadol (NDT)N,O-Ddidesmethyltramadol (N,O-DDM-T)
Antidepressants and their metabolites/Benzodiazepine
Molecules 23 00262 i018 Molecules 23 00262 i019 Molecules 23 00262 i020
Fluoxetine (FLX)Norfluoxetine (NFLX)Venlafaxine (VNF)
Molecules 23 00262 i021 Molecules 23 00262 i022 Molecules 23 00262 i023
O-Desmethylvenlafaxine (O-DES-VNF)N-Desmethylvenlafaxine (N-DES-VNF)N,O-Didesmethylvenlafaxine (N,O-DES-VNF)
Molecules 23 00262 i024 Molecules 23 00262 i025 Molecules 23 00262 i026
CitalopramReboxetineD-citalopram
Molecules 23 00262 i027 Molecules 23 00262 i028
MirtazapineTemazepam
Dissociative anaesthetic and its metabolite
Molecules 23 00262 i029 Molecules 23 00262 i030
KetamineNorketamine
β-Blockers and anti-arrhythmic
Molecules 23 00262 i031 Molecules 23 00262 i032 Molecules 23 00262 i033
Metoprolol (MET)Propranolol (PHO)Bisoprolol (BSP)
Molecules 23 00262 i034 Molecules 23 00262 i035 Molecules 23 00262 i036
CarvedilolNadololPindolol
Molecules 23 00262 i037 Molecules 23 00262 i038 Molecules 23 00262 i039
VerapamilNorverapamilAtenolol
Molecules 23 00262 i040 Molecules 23 00262 i041
AlprenololSotalol
Anticoagulants
Molecules 23 00262 i042
Warfarin (WFN)
Non-steroidal anti-inflamatory drugs
Molecules 23 00262 i043 Molecules 23 00262 i044 Molecules 23 00262 i045
IbuprofenCarboxyibuprofen2-Hydroxyibuprofen
Molecules 23 00262 i046 Molecules 23 00262 i047 Molecules 23 00262 i048
NaproxenKetoprofenIndoprofen
Molecules 23 00262 i049 Molecules 23 00262 i050 Molecules 23 00262 i051
CarprofenFenoprofenFlurbiprofen
Bronchodilators
Molecules 23 00262 i052
Salbutamol (SBT)
Antibiotics
Molecules 23 00262 i053 Molecules 23 00262 i054
ChloranfenicolOfloxacin
Antiepileptic and their metabolites
Molecules 23 00262 i055
10,11-Dihydro-10-hydroxycarbamazepine
Proton pump inhibitors
Molecules 23 00262 i056 Molecules 23 00262 i057 Molecules 23 00262 i058
OmeprazolLanzoprazolRabeprazole
Molecules 23 00262 i059
Pantoprazole
Antineoplastic agents and their metabolite
Molecules 23 00262 i060 Molecules 23 00262 i061
Ifosfamide3-N-Dechloroethylifosfamide
Antifungals
Molecules 23 00262 i062 Molecules 23 00262 i063 Molecules 23 00262 i064
EconazoleMiconazoleTebuconazole
Molecules 23 00262 i065 Molecules 23 00262 i066 Molecules 23 00262 i067
KetoconazoleHexaconazolePenconazole
Molecules 23 00262 i068 Molecules 23 00262 i069
TriadimefonImazalil
Anti-helminthic
Molecules 23 00262 i070 Molecules 23 00262 i071 Molecules 23 00262 i072
PraziquantelTetramisolePhenyltetrahydroimidazo thiazole (PTHIT, levamisole/dexamisole)
Antihistaminic
Molecules 23 00262 i073
Fexofenadine
Table
Table 2. Chromatographic analytical methods described for the analysis of chiral illicit drugs and pharmaceuticals in biological matrices.
Table 2. Chromatographic analytical methods described for the analysis of chiral illicit drugs and pharmaceuticals in biological matrices.
DrugMatrix ApplicationMethodStationary PhaseLODLOQConcentration Range/ER
(When Mencioned)		Reference
AMPlasmaGC/NICI-MSSGE-BPX5 (15 m × 0.25 mm, 0.25 µm film thickness)50 fg0.049 ng/mL (R)
0.195 ng/mL (S)		0.006–50 ng/mL [30]
HP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.5 µg/L5–250 µg/L;
ER (R/S): 0.97–1.66, with a mean value of 1.15		[114]
GC/EI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.5 ng/g plasma5–400 ng/g plasma[31]
BloodGC/EI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.0.004 µg/g0.004–3 µg/g[67]
GC/NICI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)0.8 pg/mg (R)
0.7 pg/mg (S)		2.7 pg/mg (R)
2.4 pg/mg (S)		0.003–60 ng/mg (R)
0.002–60 ng/mg (S)
ER (R/S): 0.03–0.95		[49]
HairGC/EI-MSHP5-MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.2.5 ng/sample2.5–100 ng/sample[31]
5% phenyl-methylsilicone capillary column (17 m × 0.2 mm, 0.33 µm film thickness)0.1 ng/mg0.2 ng/mg0.2–20 ng/mg[69]
LC/MS/MSn.r.20 pg/mg50 pg/mg50–20000 pg/mg[7]
HPLC/ESI-MSChiral DRUG (150 mm × 2 mm)0.05 ng/mgn.r.0.2–40 ng/mg [59]
UrineGC/EI-MSDB-5MS (20 m × 0.18 mm × 0.18 mm)10 ng/mLn.r.25–10000 ng/mL[115]
HP-5MS (20 m × 0.25 mm, 0.25 µm film thickness)n.r.10 µg/L10–500 µg/L[42]
HP-5MS (30 m × 0.2 mm, 0.33 µm film thickness)40 ng/mL45 ng/mL45–1000 (l; d)
45–2000 (d,l)		[70]
5% phenyl polysiloxane (15 m × 0.2 mm, 0.2 µm df)n.r.n.r.25–10000 ng/mL[116]
GC/MSHP-5MS (20 m × 0.25 mm, 0.25 µm film thickness)1.1 ng/mL (R)
1.3 ng/mL (S)		3.7 ng/mL (R)
4.3 ng/mL (S)		5–500 µg/L[117]
DB-5 (10 m × 0.1 mm, 0.4 µm film thickness)0.5 ng/mLn.r.20–1000 ng/mL[8]
CE/ESI-MSUncoated fused silica capillary (50 µm, 100 cm)0.02 µg/mLn.r.0.05–10 µg/mL[33]
0.03 µg/mLn.r.0.2–10 µg/mL (S)[118]
CEPVA chemically modified diol capillary column (40 cm × 50 µm)n.r.n.r.n.r.[36]
LC/MS-MSLux AMP (150 × 3 mm, 5 µm)n.r.0.05 mg/L0.05–25 mg/L[16]
Chirobiotic V2 (250 × 2.1 mm, 5 µm)0.02 mg/L0.05 mg/L0.05–50.00 mg/L[60]
HPLC-UVAdsorbosphere HS, C18 (150 × 4.6 mm, 5µm); C18 precolumn (7.5 × 4.6 mm)n.r.n.r.0.1–100 mg/L[119]
MAPlasmaGC/NICI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.5 µg/L5–250 µg/L
ER (R/S): 1.02–1.63, with a mean value of 1.33		[114]
BloodGC/EI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.0.004 µg/g0.004–3 µg/g [67]
HairGC/NICI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)2.1 pg/mg (R)
1.5 pg/mg (S)		6.9 pg/mg (R)
5.0 pg/mg (S)		0.007–60 ng/mg (R)
0.005–60 ng/mg (S)
ER (R/S): 0.01–0.82		[49]
GC/MS5% phenyl-methylsilicone capillary column (17 m × 0.2 mm i.d., 0.33 µm film thickness)0.1 ng/mg0.2 ng/mg0.2–20 ng/mg[69]
HPLC/ESI-MSChiral DRUG (150 mm × 2 mm)0.01 ng/mgn.r.0.04–40 ng/mg [59]
UrineGC/EI-MSDB-5MS (20 m × 0.18 mm i.d. × 0.18 mm)10 ng/mLn.r.25–10000 ng/mL[115]
HP-5MS (30 m × 0.2 mm, 0.33 µm film thickness)40 ng/mL45 ng/mL45–1000 (l; d)
45–2000 (d,l)		[70]
HP-5MS (20 m × 0.25 mm, 0.25 µm film thickness)n.r.10 µg/L10–500 µg/L[42]
5% phenyl polysiloxane (15 m × 0.25 mm, 0.2 µm df)n.r.n.r.25–10000 ng/mL[116]
GC/MSHP-1 (12 m × 0.25 mm, 0.25 µm film thickness)n.r.10 ng/mL10–2000 ng/ mL[120]
HP-5MS (20 m × 0.25 mm, 0.25 µm film thickness)2.0 ng/mL (R)
1.6 ng/mL (S)		6.8 ng/mL (R)
5.2 ng/mL (S)		5–500 µg/L[117]
DB-5 (10 m × 0.1 mm, 0.4 µm film thickness)3 ng/mLn.r.20–1000 ng/mL [8]
CE/ESI-MSUncoated fused silica capillary (50 µm, 100 cm)0.02 µg/mLn.r.0.05–10 µg/mL [33]
0.03 µg/mLn.r.0.2–10 µg/mL (S) [118]
CEPVA chemically modified diol capillary column (40 cm × 50 µm)n.r.n.r.n.r.[36]
LC/MS/MSChirobiotic V2 (250 × 2.1 mm, 5 µm)0.02 mg/L0.05 mg/L0.05–50.00 mg/L[60]
HPLC-UVAdsorbosphere HS, C18 (150 × 4.6 mm, 5µm); C18 precolumn (7.5 × 4.6 mm)n.r.n.r.0.1–100 mg/L[119]
MDMAPlasmaHPLC-DADODS-1 (150 mm × 4.6 mm) with precolumn (20 × 4.0 mm)n.r.7 ng/mLn.r.[121]
BloodGC/EI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.0.004 µg/g0.004–3 µg/g[67]
LC/MS/MSKinetex C18 column (100 × 2.1 mm, 2.6 μm film thickness)n.r.0.0025 µg/L0.0025–1.25 µg/L (R, S)[122]
HairGC/NICI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)1.7 pg/mg (R)
1.5 pg/mg (S)		5.6 pg/mg (R)
5.1 pg/mg (S)		0.006–60 ng/mg (R)
0.005–60 ng/mg (S)		[49]
GC/MS5% phenyl-methylsilicone capillary column (17 m × 0.2 mm, 0.33 µm film thickness)0.2 ng/mg0.5 ng/mg0.5–20 ng/mg[69]
UrineGC/NICI-MS
LC/HRMS		n.r. (chiral derivatization S-HFBPrCl)
Chirex3012 (250 × 4.6 mm, 5 µm film thickness)		 n.r.n.r.n.r.[68]
GC/EI-MSHP-5MS (20 m × 0.25 mm, 0.25 µm film thickness)n.r.10 µg/L10–500 µg/L [42]
5% phenyl polysiloxane (15 m × 0.25 mm, 0.2 µm df)n.r.n.r.25–10000 ng/mL [116]
GC/MSHP-5MS (20 m × 0.25 mm, 0.25 µm film thickness)1.7 ng/mL5.7–5.8 ng/mL5–500 µg/L [117]
HPLC-DADODS-1 (150 × 4.6 mm) with precolumn (20 × 4.0 mm)n.r.7 ng/mLn.r.[121]
MDAPlasmaHPLC-DADODS-1 (150 × 4.6 mm) with precolumn (20 × 4.0 mm)n.r.5 ng/mLn.r.[121]
BloodLC/MS/MSKinetex C18 column (100 × 2.1 mm, 2.6 μm film thickness)n.r.0.0025 µg/L0.0025–0.25 µg/L (R, S)[122]
HairGC/NICI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)1.6 pg/mg (R)
1.3 pg/mg (S)		5.3 pg/mg (R)
4.3 pg/mg (S)		0.005–60 ng/mg (R)
0.004–60 ng/mg (S)		[49]
GC/MS5% phenyl-methylsilicone capillary column (17 m × 0.2 mm, 0.33 µm film thickness)0.1 ng/mg0.2 ng/mg0.2–20 ng/mg[69]
UrineGC/NICI-MS
LC/HRMS		n.r. (chiral derivatization S-HFBPrCl)
Chirex3012 (250 × 4.6 mm, 5 µm film thickness)		n.r.n.r.n.r.[68]
GC/EI-MSHP-5MS (20 m × 0.25 mm, 0.25 µm film thickness)n.r.2 µg/L2–100 µg/L [42]
5% phenyl polysiloxane (15 m × 0.25 mm, 0.2 µm df)n.r.n.r.25–10000 ng/mL [116]
HPLC-DADODS-1 (150 × 4.6 mm) with precolumn (20 × 4.0 mm)n.r.5 ng/mLn.r.[121]
MDEAWhole bloodGC/EI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.0.004 µg/g0.004–3 µg/g [67]
HairGC/NICI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)2.7 pg/mg (R)
2.3 pg/mg (S)		8.9 pg/mg (R)
7.7 pg/mg (S)		0.009–60 ng/mg (R)
0.008–60 ng/mg (S)		[49]
GC/MS5% phenyl-methylsilicone capillary column (17 m × 0.2 mm i.d., 0.33 µm film thickness)0.2 ng/mg0.5 ng/mg0.5–20 ng/mg[69]
UrineGC/EI-MS5% phenyl polysiloxane (15 m × 0.25 mm, 0.2 µm df)n.r.n.r.25–5000 ng/mL [116]
pOHMABloodLC/MS/MSKinetex C18 column (100 × 2.1 mm, 2.6 μm film thickness)n.r.0.0025 µg/L0.0025–0.25 µg/L (R, S)[122]
UrineGC/NICI-MS
LC/HRMS		n.r. (chiral derivatization S-HFBPrCl)
Chirex3012 (250 × 4.6 mm, 5 µm film thickness)		n.r.n.r.n.r.[68]
CE/ESI-MSUncoated fused silica capillary (50 µm, 100 cm)0.02 µg/mLn.r.0.05–10 µg/mL [33]
0.05 µg/mLn.r.0.2–10 µg/mL (S) [118]
CEPVA chemically modified diol capillary column (40 cm × 50 µm)n.r.n.r.n.r.[36]
HMMABloodLC/MS/MSKinetex C18 column (100 × 2.1 mm, 2.6 μm film thickness)n.r.0.0025 µg/L0.0025–0.25 µg/L (R, S)[122]
MethadonePlasmaLC/EI-MS/MSChiral-AGP (50 × 2.0 mm, 5 µm)n.r.2.5 ng/mL0–500 ng/mL[85]
LC/MSChiral-AGP (100 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 2.0 mm, 5 µm)0.02 ng/mL1 ng/mL1–300 ng/mL[83]
BloodLC/ESI-MS/MSChiral-AGP (100 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 2.0 mm, 5 µm)n.r.n.r.n.r.[12]
LC/MSα-1-acid glycoprotein (100 × 4.0 mm, 5 µm) and a α-1-acid glycoprotein guard column (10 × 2.0 mm, 5 µm)n.r.0.02 mg/L0.05–2.1 mg/L[123]
Blood
Tissues		LC/MS/MSChiral-AGP column (150 × 3 mm, 5 µm)0.65 ng/L (R)
0.49 ng/L (S)		2.40 ng/L (R)
1.82 ng/L (S)		50–1000 ng/L[82]
UrineLC/EI-MS/MSChiral-AGP (50 × 2.0 mm, 5 µm)n.r.2.5 ng/mL0–500 ng/mL
ER (R/S): 1.42–2.96		[85]
LiverLC/EI-MS/MSChiral-AGP (50 × 2.0 mm, 5 µm)n.r.2.5 ng/mL0–500 ng/mL[85]
EDDPPlasmaLC/MSChiral-AGP (100 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 2.0 mm, 5 µm)0.01 ng/mL0.1 ng/mL1–25 ng/mL[83]
LC/EI-MS/MSChiral-AGP (50 × 2.0 mm, 5 µm)n.r.2.5 ng/mL0–500 ng/mL[85]
BloodLC/ESI-MS/MSChiral-AGP (100 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 2.0 mm, 5 µm)n.r.n.r.n.r.[12]
Blood
Tissues		LC/MS/MSChiral-AGP column (150 × 3 mm, 5 µm)0.77 ng/L (R)
0.76 ng/L (S)		2.82 ng/L (R)
2.79 ng/L (S)		50–1000 ng/L[82]
UrineLC/EI-MS/MSChiral-AGP (50 × 2.0 mm, 5 µm)n.r.2.5 ng/mL0–500 ng/mL
ER (R/S): 0.76–0.89		[85]
LiverLC/EI-MS/MSChiral-AGP (50 × 2.0 mm, 5 µm)n.r.2.5 ng/mL0–500 ng/mL[85]
TPlasmaLC/ESI-MS/MSChiralpak AD (250 × 4.6 mm, 10 µm)n.r.0.2 ng/mL (total)
0.5 ng/mL (unbound)		0.2–600 ng/mL (total)
0.5–250 ng/mL (unbound)		[81]
LC/APCI-MS/MSLux Cellulose-2 (150 × 4.6 mm, 3 µm); Lux Cellulose-2 guard column (4 × 3 mm)0.15 ng/mL1 ng/mL1–800 ng/mL [75]
Chiralpak AD (250 × 4.6 mm, 10 µm)1 ng/mL3 ng/mL25–1000 ng/mL[34]
HPLC-DADChiralcel OD-R (250 × 4.6 mm, 10 µm); LiChrospher 60-RP-selected B (250 × 4 mm, 5 µm)0.18 ng/mL (+)
0.16 ng/mL (‒)		1 ng/mL1–500 ng/mL [124]
HPLC-FDChiralpak AD (250 × 4.6 mm, 10 µm)1 nM5 nM0.01–1.55 µM [125]
Chiralpak AD (250 × 4.6 mm); LichroCART 4-4 LiChrospher 100 Diol (5 µm) precolumnn.r.2.5 ng/mL2.5–250 ng/mL [126]
Chiral-AGP (150 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 4.0 mm, 5 µm)n.r.2 ng/mL2–200 ng/mL [127]
UrineGC/EI-MSRt-βDEXcst (30m × 0.25 mm, 0.25 µm film thickness)0.01 µg/mL0.1 µg/mL0.1–20 µg/mL[128]
HPLC-FDChiralpak AD (250 × 4.6 mm, 10 µm)2 nM25 nM0.1–3.0 µM[125]
ODTPlasmaLC/ESI-MS/MSChiralpak AD (250 × 4.6 mm, 10 µm)n.r.0.1 ng/mL (total)
0.25 ng/mL (unbound)		0.1–300 ng/mL (total)
0.25–125 ng/mL (unbound)		[81]
LC/APCI-MS/MSLux Cellulose-2 (150 × 4.6 mm, 3 µm); Lux Cellulose-2 guard column (4 × 3 mm)0.20 ng/mL (+)
0.30 ng/mL (‒)		1 ng/mL1–400 ng/mL [75]
Chiralpak AD (250 × 4.6 mm, 10 µm)1.3 ng/mL4 ng/mL25–1000 ng/mL[34]
HPLC-DADChiralcel OD-R (250 × 4.6 mm, 10 µm); LiChrospher 60-RP-selected B (250 × 4 mm, 5 µm)0.08 ng/mL (+)
0.06 ng/mL (‒)		0.5 ng/mL0.5–100 ng/mL[124]
HPLC-FDChiralpak AD (250 × 4.6 mm, 10 µm)1 nM5 nM0.01–1.55 µM[125]
Chiralpak AD (250 × 4.6 mm); LichroCART 4-4 LiChrospher 100 Diol (5 µm) precolumnn.r.2.5 ng/mL2.5–250 ng/mL[126]
Chiral-AGP (150 × 4.0 mm × 5 µm); Chiral-AGP guard column (10 × 4.0 mm × 5 µm)n.r.2.5 ng/mL2.5–100 ng/mL[127]
UrineGC/EI-MSRt-βDEXcst (30 m × 0.25 mm, 0.25 µm film thickness)0.03 µg/mL0.1 µg/mL0.1–20 µg/mL[128]
HPLC-FDChiralpak AD (250 × 4.6 mm, 10 µm)2 nM25 nM0.1–3.0 µM[125]
NDTPlasmaLC/ESI-MS/MSChiralpak AD (250 × 4.6 mm, 10 µm)n.r.0.1 ng/mL (total)
0.25 ng/mL (unbound)		0.1–300 ng/mL (total)
0.25–125 ng/mL (unbound)		[81]
HPLC-DADChiralcel OD-R (250 × 4.6 mm, 10 µm); LiChrospher 60-RP-selected B (250 × 4 mm, 5 µm)0.15 ng/mL (+)
0.16 ng/mL (‒)		0.5 ng/mL0.5–250 ng/mL[124]
HPLC-FDChiral-AGP (150 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 4.0 mm, 5 µm)n.r.2.5 ng/mL2.5–75 ng/mL[127]
N,O-DDM-TPlasmaHPLC-FDChiralpak AD (250 × 4.6 mm); LichroCART 4-4 LiChrospher 100 Diol (5 µm) precolumnn.r.2.5 ng/mL2.5–250 ng/mL[126]
CitalopramPlasmaLC/ESI-MS/MSChiralcel OD-R (250 × 4.6 mm × 10 µm); LiChrospher 100 RP-8 precolumn (4 × 4.0 mm × 5 µm)n.r.0.1 ng/mL0.1–20 ng/mL[129]
FLXPlasmaLC/APCI-MS/MSChirobiotic V (250 × 4.6 mm, 5 µm)n.r.2 ng/mL2–1000 ng/mL[93]
KPlasmaLC/MSChiral-AGP (100 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 2.0 mm, 5 µm)0.25 ng/mL1 ng/mL1–125 ng/mL[111]
HairCE-UV-DADUncoated fused-silica capillary (450 × 50 mm)0.08 ng/mg0.25 ng/mg0.5–8.0 ng/mg[110]
NKPlasmaLC/MSChiral-AGP (100 × 4.0 mm, 5 µm); Chiral-AGP guard column (10 × 2.0 mm, 5 µm)0.25 ng/mL1 ng/mL1–125 ng/mL[111]
HairCE-UV-DADUncoated fused-silica capillary (450 × 50 mm)0.08 ng/mg0.25 ng/mg0.5–8.0 ng/mg[110]
MPHPlasmaGC/NICI-MSBPX5 fused silica (15 m × 0.25 mm)n.r.0.006 ng/mL0.006–12.5 ng/mL[130]
n.r.0.072 ng/mL0.072–18.25 ng/mL[131]
BloodLC/MS/MSChiral AGP (100 × 4.0 mm, 5 µm); guard column (10 × 2.0 mm, 5 µm)n.r.n.r.0.2–500 ng/g[65]
UrineGC/EI-MSDB-5 (30 m × 0.32 mm, 0.25 µm film thickness)n.r.10 ng/mL0–10000 ng/mL [132]
ReboxetineSerumLC/MSChiral-AGP (2 × 100 mm, 5 µm)<1 nmol/Ln.r.50–500 nmol/L
ER (S/R): 0.22–0.88, with a mean value of 0.5		[97]
VNFPlasmaLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.5 nM1–1000 nM
ER (S/R): 1.01–4.33		[95]
HPLC/ESI-MSChirobiotic V (250 × 4.6 mm, 5 µm)1 ng/mL5.2 ng/mL (R)
5 ng/mL (S)		5–400 ng/mL [133]
Whole bloodLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.5 nM10–4000 nM
ER (S/R): 0.59–1.11		[95]
OD-VNFPlasmaLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.5 nM1–1000 nM
ER (S/R): 0.70–12.3		[95]
HPLC/ESI-MSChirobiotic V (250 × 4.6 mm, 5 µm)1.5 ng/mL3.5 ng/mL (R)
4.3 ng/mL (S)		4–280 ng/mL [133]
Whole bloodLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.5 nM10–4000 nM
ER (S/R): 0.59–1.11		[95]
ND-VNFPlasmaLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.25 nM0.5–500 nM
ER (S/R): 1.24–2.91		[95]
Whole bloodLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.25 nM5–2000 nM
ER (S/R): 0.46–1.53		[95]
N,O-DD-VNFPlasmaLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.25 nM0.5–500 nM
ER (S/R): 0.42–1.18		[95]
Whole bloodLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm)n.r.0.25 nM5–2000 nM
ER (S/R): 0.90–1.99		[95]
METUrineGC/EI-MSHP-5MS (30 m × 0.25 mm, 0.25 µm film thickness)0.5 ng/mLn.r.0.1–4 ng/mL
ER (R/S): 0.83		[100]
PHOPlasmaLC/APCI-MSChirobiotic V (250 × 4.6 mm, 5 µm); Chirobiotic V guard column (20 × 4.0 mm, 5 µm) 0.03 ng/mL0.25 ng/mL0.25–200 ng/mL [98]
WFNPlasmaSFC/APCI-MS/MSChiralpak AD (250 × 4.6 mm); Chiralpak AD-H guard column (10 × 4.0 mm)n.r.13.6 ng/mL13.6–2500 ng/mL [104]
LC/ESI-MS/MSChirobiotic V (250 × 4.6 mm, 5 µm); Cyclobond I guard column (20 × 4.0 mm, 5 µm) 1.5 ng/mL5 ng/mL5–1500 ng/mL
ER (S/R): 0.47±0.14		[105]
MEKC/ESI-MSFused silica capillaries (120 cm, 375 µm o.d., 50 µm)0.1 µg/mL (instr. limit)n.r.0.25–5 µg/mL
ER (R/S): 2.24–6.20		[106]
CarvedilolPlasmaLC/ESI-MS/MSChirobiotic T (250 × 4.6 mm, 10 µm)n.r.0.2 ng/mL0.2–500 ng/mL [99]
Ace 3 C18 (50 × 2.0 mm, 3 µm)n.r.0.2 ng/mL0.2–200 ng/mL [134]
VerapamilPlasmaCE-UVFused-silica capillariesn.r.n.r.2.5–250 ng/mL[101]
NorverapamilPlasmaCE-UVFused-silica capillariesn.r.n.r.2.5–250 ng/mL[101]
SBTUrineNACE/ESI-MSFused silica capillaries (48.5 cm, 375 µm o.d., 50 µm)8–14 ng/mL18–20 ng/mL15–150 ng/mL[135]
PTHITUrineGC-FIDRt-β-DEXsm (30 m × 0.25 mm, 0.25 µm film thicknessn.r.n.r.n.r.[10]
AM: amphetamine; CE: capillary electrophoresis; CI: chemical ionization; DAD: diode array detection; EDDP: 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine; EI: electron impact; ER: enantiomeric ratio; ESI: electrospray ionization; FD: fluorescence detector; FID: flame ionization detector; FLX: fluoxetin; GC: gas chromatography; HMMA: 4-hydroxy-3-methoxymethamphetamine; HPLC: high performance liquid chromatography; K: ketamine; LC: liquid chromatography; LOD: limit of detection; LOQ: limit of quantification; MA: methamphetamine; MDA: 3,4-Methylenedioxyamphetamine; MDMA: 3,4 Methylenedioxymethamphetamine; MDEA: N-methyl-diethanolamine; MEKC: micellar electrokinetic chromatography; MET: metoprolol; MPH: methylphenidate; MS: mass spectrometry; MS/MS: tandem mass spectrometry; NACE: nonaqueous capillary electrophoresis; NDT: N-desmetil-tramadol; ND-VNF: N-desmethylvenlafaxine; NICI: negative ion chemical ionization; N,O-DD-VNF: N,O-didesmethylvenlafaxine; NFLX: norfluoxetin; NK: norketamine; ODT: O-desmetil-tramadol; OD-VNF: O-desmetil-venlafaxine; PHO: propranolol; PTHIT: phenyltetrahydroimidazothiazole; SBT: salbutamol; T: tramadol; UV: ultraviolet detector; VNF: venlafaxine; WFN: warfarin. n.r.: not referred.
Table
Table 3. Analytical methods of separation of several chiral illicit drugs and pharmaceuticals in different environmental matrices.
Table 3. Analytical methods of separation of several chiral illicit drugs and pharmaceuticals in different environmental matrices.
DrugsMatrix ApplicationMethodStationary PhaseLOD/MDLLOQ/MQLConcentration Range/EFReference
AM
MA
MDMA
MDA
Ephedrine		WastewaterUPLC/ESI-MS/MSChiral-CBH (100 × 2 mm, 5 µm); Chiral-CBH guard column (10 × 2 mm)n.r.AM: 5.1 ng/L0.5–1000 ng/L; EF: 0.52–0.84 (mean 0.64)[17]
MA: 0.6 ng/L0.05–1000 ng/L; EF ≥ 0.5
MDMA: 0.7 ng/L0.1–1000 ng/L; EF = 0.68
MDA: 4.2 ng/L0.1–1000 ng/L; EF > 0.5
Ephedrine: 5.6 ng/L0.5–1000 ng/L; EF: 0.81–0.96 (mean 0.91)
AM, MA, MDMA, MDA, Ephedrine, Pseudoephedrine, Norephedrine, Atenolol, Alprenolol, PHO, MET, T, SBT, Sotalol, FLX, Mirtazapine, VNF, OD-VNF, Citalopram, D-citalopramInfluent wastewater (IW); effluent wastewater (EW); digested sludge (DS)LC/ESI-MS/MSChiral-CBH (100 × 2 mm, 5 µm); Chiral-CBH guard column (10 × 2 mm)AM (R/S): 0.38/0.39 ng/L (IW); 0.28/0.41 ng/L (EW); 4.92/5.15 ng/L (DS)AM (R/S): 1.28/ 1.32 ng/L (IW); 0.94/1.36 ng/L (EW); 16.56/17.28 ng/L (DS)0.025–250 µg/L;
EF: 0.5 (IW); 0.6 (EW); 0.3 (DS)		[62]
MA (R/S): 0.12/0.13 ng/L (IW); 0.09/0.08 ng/L (EW); 0.73/0.77 ng/L (DS)MA (R/S): 0.38/0.41 ng/L (IW); 0.28/0.27 ng/L (EW); 3.24/2.45 ng/L (DS)0.025–250 µg/L
EF: 0.6 (IW); 0.5 (EW); 0.5 (DS)
MDMA: 0.05 ng/L (IW); 0.04 ng/L (EW); 1.43/1.79 ng/L (R/S) (DS)MDMA (R/S): 0.17/0.18 ng/L (IW); 0.13/0.14 ng/L (EW); 4.75/5.96 ng/L (DS)0.025–250 µg/L
EF: 0.7 (IW); 0.9 (EW); 0.4 (DS)
MDA (R/S): 0.33/0.36 ng/L (IW); 0.21/0.25 ng/L (EW); 2.21/4.14 ng/L (DS)MDA (R/S): 1.13/1.19 ng/L (IW); 0.72/0.83 ng/L (EW); 7.46/13.74 ng/L (DS)0.025–250 µg/L
EF: 0.6 (IW); 0.5 (EW); 0.3 (DS)
Ephedrine (1R,2S/ 1S,2R): 0.23/0.16 ng/L (IW); 0.14/0.07 ng/L (EW)Ephedrine (1R,2S/1S,2R): 0.01/0.02 ng/L (IW); 0.48/0.25 ng/L (EW)0.025–250 µg/L
EF: 0 (IW, EW)
Pseudoephedrine (1R,2R/1S,2S): 0.26/0.1 ng/L (IW); 0.15/0.11 ng/L (EW); 15.54/44.53 ng/L (DS)Pseudoephedrine (1R,2R/1S,2S): 0.01/0.03 ng/L (IW); 0.52/0.36 ng/L (EW); 51.62/148.5 ng/L (DS)0.025–250 µg/L
EF: 1 (IW); 0.2 (EW)
Norephedrine (E1/E2): 0.33/0.15 ng/L (IW); 0.19/0.21 ng/L (EW); 9.54/13.05 ng/L (DS)Norephedrine (E1/E2): 0.01/0.02 ng/L (IW); 0.63/0.71 ng/L (EW); 31.52/43.38 ng/L (DS)0.025–250 µg/L
EF: 0 (IW); 0.3 (EW); 0.1 (DS)
Chirobiotic V (250 × 2.1 mm, 5 µm)Atenolol (R/S): 28.74/17.40 ng/L (IW); 30.80/32.73 ng/L (EW); 7.55/7.12 ng/L (DS)Atenolol (R/S): 95.81/58 ng/L (IW); 102.68/109.08 ng/L (EW); 25.15/23.70 ng/L (DS)0.025–250 µg/L
EF: 0.5 (IW, EW); 0.4 (DS)
Alprenolol (R/S): 0.14/0.07 ng/L (IW); 0.06/0.03 ng/L (EW); 0.14 ng/L (DS)Alprenolol (R/S): 0.47/0.24 ng/L (IW); 0.21/0.09 ng/L (EW); 0.48/0.46 ng/L (DS)0.025–250 µg/L
EF: 0.5 (IW, EW); 0.7 (DS)
PHO (R/S): 0.08/0.09 ng/L (IW); 0.06/0.05 ng/L (EW); 0.07/0.06 ng/L (DS)PHO (R/S): 0.26/0.3 ng/L (IW); 0.20/0.17 ng/L (EW); 0.23/0.20 ng/L (DS)0.025–250 µg/L
EF: 0.4 (IW, EW); 0.5 (DS)
MET (R/S): 0.08/0.06 ng/L (IW); 0.05/0.04 ng/L (EW); 0.05/0.07 ng/L (DS)MET (R/S): 0.27/0.18 ng/L (IW); 0.15/0.12 ng/L (EW); 0.15/0.22 ng/L (DS)0.025–250 µg/L
EF: 0.3 (IW, DS)
T (E1/E2): 0.09/0.43 ng/L (IW); 0.05/0.24 ng/L (EW); 0.05/0.34 ng/L (DS)T (E1/E2): 0.29/1.43 ng/L (IW); 0.16/0.79 ng/L (EW); 0.18/1.13 ng/L (DS)0.025–250 µg/L
EF: 0.7 (IW, EW, DS)
SBT (R/S): 2.22/2.20 ng/L (IW); 1.31/0.98 ng/L (EW); 80.03/65.03 ng/L (DS)SBT (R/S): 7.41/7.32 ng/L (IW); 4.36/3.26 ng/L (EW); 265.10/225.10 ng/L (DS)0.025–250 µg/L
EF: 0.5 (IW, EW)
Sotalol (E1/E2): 0.66/0.61 ng/L (IW); 0.53/0.46 ng/L (EW); 1.64/0.76 ng/L (DS)Sotalol (E1/E2): 2.20/2.05 ng/L (IW); 1.76/1.53 ng/L (EW); 5.47/5.87 ng/L (DS)0.025–250 µg/L
EF: 0.5 (IW, EW, DS)
FLX (R/S): 0.08/0.07 ng/L (IW); 0.05/0.04 ng/L (EW); 0.09/0.07 ng/L (DS)FLX (R/S): 0.26/0.22 ng/L (IW); 0.17/0.14 ng/L (EW); 0.30/0.23 ng/L (DS)0.025–250 µg/L
EF: 0.7 (IW, EW, DS)
Mirtazapine (R/S): 0.40/1.17 ng/L (IW); 0.40/0.86 ng/L (EW); 0.31/0.73 ng/L (DS)Mirtazapine (R/S): 1.32/3.89 ng/L (IW); 1.32/2.86 ng/L (EW); 1.02/2.44 ng/L (DS)0.025–250 µg/L
EF: 0.3 (IW); 0.2 (EW); 0.5 (DS)
VNF (R/S): 0.03/0.04 ng/L (IW); 0.02/0.03 ng/L (EW); 0.03 ng/L (DS)VNF (R/S): 0.11/0.12 ng/L (IW); 0.07/0.11 ng/L (EW); 0.08 ng/L (DS)0.025–250 µg/L
EF: 0.5 (IW, EW, DS)
OD-VNF (R/S): 0.32/0.16 ng/L (IW); 0.38/0.08 ng/L (EW); 0.75/1.02 ng/L (DS)OD-VNF (R/S): 1.05/3.85 ng/L (IW); 1.28/2.30 ng/L (EW); 2.51/3.41 ng/L (DS)0.025–250 µg/L
EF: 0.5 (IW, EW, DS)
Citalopram (R/S): 0.31/0.24 ng/L (IW); 0.27/0.21 ng/L (EW); 0.21/0.09 ng/L (DS)Citalopram (R/S): 13.69/13.07 ng/L (IW); 11.78/11.15 ng/L (EW); 9.09/4.69 ng/L (DS)0.025–250 µg/L
EF: 0.6 (IW, DS); 0.7 (EW)
D-Citalopram (R/S): 0.50/0.36 ng/L (IW); 0.40/0.29 ng/L (EW); 0.42/0.36 ng/L (DS)D-Citalopram (R/S): 1.68/1.21 ng/L (IW); 1.34/0.96 ng/L (EW); 1.99/1.22 ng/L (DS)0.025–250 µg/L
EF: 1 (IW); 0.6 (DS)
AM, MA, MDMA, MDA, MDEA, Norephedrine, VNFWWTP influent (IW); WWTP effluent (EW)UPLC/ESI-MS/MSChiral-CBH (100 × 2 mm, 5 µm); Chiral-CBH guard column (10 × 2 mm)AM (R/S): 0.85/0. 9 ng/L (IW); 0.9/0.85 ng/L (EW)AM (R/S): 4.35/4.4 ng/L (IW); 4.4/4.35 ng/L (EW)0.25–1900 ng/L
EF n.r.		[149]
MA: 0.85/0. 9 ng/L (R/S) (IW); 1 ng/L (EW)MA: 2.8/2.95 ng/L (R/S) (IW); 3.35 ng/L (EW)0.25–1900 ng/L
EF n.r.
MDMA: 0.9 ng/L (IW); 0.95/1 ng/L (E1/E2) (EW)MDMA: 2.4 ng/L (IW); 2.55–2.65 ng/L (E1/E2) (EW)0.25–1900 ng/L
EF: 0.53–0.72 (mean 0.63) (IW); 0.71 (EW)
MDA: 1.95/2 ng/L (E1/E2) (IW); 2 ng/L (EW)MDA: 9.7 ng/L (IW); 10.1 ng/L (EW)0.25–1900 ng/L
EF n.r.
MDEA: 0.55 ng/L (IW); 0.6 ng/L (EW)MDEA: 2.25/2.2 ng/L (E1/E2) (IW); 2.4 ng/L (EW)0.25–1900 ng/L
EF n.r.
Norephedrine (E1/E2): 3.5/3.3 ng/L (IW); 1.4/1.35 ng/L (EW)Norephedrine (E1/E2): 11.75/10.9 ng/L (IW); 4.6/4.5 ng/L (EW)0.25–1900 ng/L
EF n.r.
VNF: 1.6 ng/L (IW); 1.65 ng/L (EW)VNF: 4.95/5.05 ng/L (E1/E2) (IW); 5.1 ng/L (EW)0.25–1900 ng/L
EF: 0.45–0.50 (mean 0.48) (IW); 0.37–0.48 (mean 0.43) (EW)
AM, MA, MDMA, MDA, Ephedrine, Atenolol, VNFWWTP influent (IW); WWTP effluent (EW); river water (RW)LC/ESI-MS/MSChiral-CBH (100 × 2 mm, 5 µm); Chiral-CBH guard column (10 × 2 mm)n.r.n.r.AM: 1–500 ng/L
EF: 0.52–0.84 (mean 0.64) (IW); 0.57–1 (mean 0.78) (EW); 0.86 (RW before WWTP); 0.81 (RW after WWTP)		[9]
MA: 1–500 ng/L
EF: 0.22–0.53 (mean 0.34) (IW); 0.7–1 (mean 0.86) (EW)
MDMA: 1–500 ng/L
EF: 0.5–0.8 (mean 0.66) (IW); 0.64–0.91 (mean 0.75) (EW); 0.56–0.81 (mean 0.68) (RW before WWTP); 0.61–0.80 (mean 0.69) (RW after WWTP)
MDA: 1–500 ng/L
EF: 0.26–0.47 (mean 0.34) (IW); 0.38–0.58 (mean 0.45) (EW); 0.58 (RW before WWTP); 0.56–0.57 (RW after WWTP)
Ephedrine: 1–500 ng/L
EF: 0.81–1 (mean 0.99) (IW); 0.22–1 (mean 0.92) (EW); 0.79–1 (mean 0.97) (RW before WWTP); 0.80–1 (mean 0.99) (RW after WWTP)
DF: 0.02–0.66 (mean 0.26) (IW); 0.04–0.82 (mean 0.36) (EW); 0–1 (mean 0.6) (RW before WWTP); 0–1 (mean 0.46) (RW after WWTP)
VNF: 1–500 ng/L
EF: 0.35–0.65 (mean 0.48) (IW); 0.46–0.69 (mean 0.52) (EW); 0.40–0.65 (mean 0.52) (RW before WWTP); 0.47–0.62 (mean 0.51) (RW after WWTP)
Atenolol: 1.7 ng/L (IW, EW); 0.3 ng/L (RW)1–500 ng/L
EF: 0.30–0.47 (mean 0.40) (IW); 0.40–0.61 (mean 0.46) (EW); 0.38–0.56 (mean 0.46) (RW before WWTP); 0.39–0.50 (mean 0.45) (RW after WWTP)
AM, MA, MDMA, MDA, Atenolol, PHO, MET, FLX, VNFSewage effluent (SE); River water (RW)LC/QTOF-MSChirobiotic V (250 × 4.6 mm, 5 µm); Chirobiotic V guard column (20 × 40 mm, 5 µm)AM: 4.6/4.4 ng/L (R/S) (SE); 1.8 ng/L (RW)AM (R/S): 12.4/11.5 ng/L (SE); 5.0/4.8 ng/L (RW)0.5–500 ng/L
EF n.r.		[151]
MA (R/S): 11.9/14.2 ng/L (SE); 4.6/5.5 ng/L (RW)MA (R/S): 47.6/47.3 ng/L (SE); 18.5/18.3 ng/L (RW)0.25–500 ng/L
EF n.r.
MDMA (E1/E2): 22.8/21.8 ng/L (SE); 9.6/10.4 ng/L (RW)MDMA (E1/E2): 85.7/81.9 ng/L (SE); 35.8/39 ng/L (RW)5–500 ng/L
EF n.r.
Atenolol (R/S): 5/5.3 ng/L (SE); 2.1/2.2 ng/L (RW)Atenolol (R/S): 11.4/11 ng/L (SE); 4.8/4.7 ng/L (RW)0.25–100/5–500 ng/L (R); 0.5–100/5–500 ng/L (S)
EF: 0.55 (SE); 0.47 (RW)
PHO (R/S): 1.4/1 ng/L (SE); 0.6/0.4 ng/L (RW)PHO (R/S): 3.4/2.6 ng/L (SE); 1.4/1.2 ng/L (RW)0.25–100/5–500 ng/L
EF: 0.43 (SE); 0.45 (RW)
MET: 0.6/0.7 ng/L (E1/E2) (SE); 0.2 ng/L (RW)MET: 1.3 ng/L (SE); 0.3/0.4 ng/L (E1/E2) (RW)0.25–100/5–500 ng/L
EF: 0.54 (SE)
FLX: 2.4/2.6 ng/L (R/S) (SE); 0.8 ng/L (RW)FLX (R/S): 7.6/6.5 ng/L (SE); 2.5/2 ng/L (RW)0.25–100/5–500 ng/L
EF n.r.
VNF (R/S): 4.8/3.9 ng/L (SE); 2.5/2.2 ng/L (RW)VNF (R/S): 15.1/14.4 ng/L (SE); 7.9/8.1 ng/L (RW)0.5–100/5–500 ng/L
EF: 0.43 (SE); 0.58 (RW)
Chiral-CBH (100 × 2 mm, 5 µm); Chiral-CBH guard column (10 × 2 mm, 5 µm)AM (R/S): 4.8/5 ng/L (RW)AM (R/S): 9.7/10 ng/L (RW)0.5–500 ng/L
EF n.r.
MA (R/S): 4.1/3.6 ng/L (RW)AM (R/S): 20.6/18.1 ng/L (RW)2.5–500 ng/L
EF n.r.
MDMA (R/S): 10.7/10.2 ng/L (RW)MDMA (R/S): 26.8/25.6 ng/L (RW)12.5–500 ng/L
EF n.r.
MDA (R/S): 2.4/2.3 ng/L (RW)MDA (R/S): 9.6/9.1 ng/L (RW)1.75–500 ng/L
EF n.r.
Atenolol (R/S): 2.3/2.1 ng/L (RW)Atenolol (R/S): 22.9/20.7 ng/L (RW)0.5–500 ng/L
EF n.r.
VNF (E1/E2): 10.3/9.6 ng/L (RW)VNF (E1/E2): 51.7/47.9 ng/L (RW)5–500 ng/L
EF n.r.
Atenolol, PHO, MET, SBT, Sotalol, Nadolol, Pindolol, FLX, CitalopramInfluent wastewater (IW); Effluent wastewater (EW)LC/ESI-MS/MSChirobiotic V (250 × 4.6 mm, 5 µm) with a nitrile guard cartridge (10 × 3 mm)Atenolol: 1.8 ng/L (IW); 1.4 ng/L (EW)6 ng/L (IW); 5 ng/L (EW)1–500 ng/mL
EF n.r.		[152]
PHO: 0.5 ng/L (IW, EW)2 ng/L (IW, EW)
MET: 2.3 ng/L (IW); 0.6 ng/L (EW)8 ng/L (IW); 2 ng/L (EW)
SBT: 0.7 ng/L (IW); 0.6 ng/L (EW)2 ng/L (IW, EW)
Sotalol: 7.5 ng/L (IW); 7.2 ng/L (EW)25 ng/L (IW); 24 ng/L (EW)
Nadolol: 1.8 ng/L (IW); 1.7 ng/L (EW)12 ng/L (IW); 3 ng/L (EW)
Pindolol: 0.4 ng/L (IW); 0.2 ng/L (EW)1 ng/L (IW, EW)
FLX: 2.2 ng/L (IW); 0.6 ng/L (EW)7 ng/L (IW); 2 ng/L (EW)
Citalopram: 2.4 ng/L (IW); 0.5 ng/L (EW)8 ng/L (IW); 2 ng/L (EW)
Atenolol, PHO, METWWTP influent (IW); WWTP effluent (EW)HPLC/ESI-MS/MSChirobiotic V (250 × 4.6 mm, 5 µm) with a nitrile guard cartridge (10 × 3 mm) and an in-line filterAtenolol: 110 ng/L IW); 12 ng/L (EW)n.r.25–1000 ng/mL
EF ≈ 0.5 (IW; EW)		[153]
PHO: 17 ng/L (IW); 4.4 ng/L (EW)n.r.25–1000 ng/mL
EF ≈ 0.5 (IW; EW)
MET: 42 ng/L (IW); 17 ng/L (EW)n.r.25–1000 ng/mL
EF: 0.5 (IW); ≠0.5 (EW)
Atenolol, MET, Sotalol, Citalopram, TemazepamEffluent wastewaterLC/ESI-MS/MSChirobiotic V (250 × 4.6 mm, 5 µm)n.r.n.r.Atenolol EF: 0.40–0.52 (mean 0.46)[142]
MET EF: 0.39–0.52 (mean 0.46)
Sotalol EF: 0.34–0.41 (mean 0.36)
Citalopram EF: 0.44–0.62 (mean 0.58)
Chiralpak AD-RH (150 × 4.6 mm, 5 µm)n.r.n.r.Temazepam EF: 0.39–0.49 (mean 0.47)
Atenolol, PHO, MET, BisoprololRiver waterLC-UVLux Cellulose-1 (250 × 4.6 mm, 5 µm)Atenolol: 22 µg/L70 µg/L12.5–100 µg/mL
EF n.r.		[154]
PHO: 3 µg/L10 µg/L
MET: 20 µg/L40 µg/L
Bisoprolol: 3 µg/L10 µg/L
Alprenolol, PHO, MET, SBT, Bisoprolol, FLX, NFLX, VNFWWTP effluentLC/ESI-MS/MSChirobiotic V (150 × 2.1 mm, 5 µm)Alprenolol (R/S): 8.08/4.52 ng/LAlprenolol (R/S): 18.5/13.7 ng/L20–400 ng/L
EF n.r.		[39]
PHO (R/S): 1.97/0.65 ng/LPHO (R/S): 5.96/1.98 ng/L
MET (R/S): 11.5/3.37 ng/LMET (R/S): 14.8/10.2 ng/L
SBT (R/S): 5.07/6.29 ng/LSBT (R/S): 15.4/19.1 ng/L
Bisoprolol (E1/E2): 2.78/4.54 ng/LBisoprolol (E1/E2): 8.44/13.8 ng/L
FLX (R/S): 8.41/3.74 ng/LFLX (R/S):19.5/11.3 ng/L
NFLX (R/S): 0.97/5.27 ng/LNFLX (R/S): 2.95/16 ng/L30–400 ng/L
EF n.r.
VNF (R/S): 9.82/1.71 ng/LVNF (R/S): 19.7/5.18 ng/L20–400 ng/L
EF: 0.54–0.55 (mean 0.55)
Alprenolol, PHO, MET, FLX, VNF, Ibuprofen, Naproxen, FlurbiprofenSurface waterLC/ESI-MS/MSChirobiotic V (250 × 4.6 mm, 5 µm); Chirobiotic V guard column (20 × 4 mm, 5 µm)Alprenolol (R/S): 0.2/0.1 ng/LAlprenolol (R/S): 0.5/0.4 ng/L5–1000 µg/L
EF n.r.		[37]
PHO (R/S): 0.6/0.5 ng/LPHO (R/S): 2.1/1.7 ng/L5–1000 µg/L
EF: 0.44–0.56 (mean 0.49)
MET: 0.2 ng/LMET (R/S): 0.6/0.5 ng/L5–1000 µg/L
EF: 0.48–0.64 (mean 0.55)
FLX: 0.1 ng/L0.5 ng/L5–1000 µg/L; EF: 0.5–0.63
VNF: 0.1 ng/L0.5 ng/L5–1000 µg/L; EF: 0.46–0.51 (mean 0.49)
Chiralpak AD-RH (150 × 4.6 mm, 5 µm)Ibuprofen (R/S): 11/9.6 ng/LIbuprofen (R/S): 37/32 ng/L5–1000 µg/L
EF n.r.
Naproxen: 0.4 ng/LNaproxen (R/S): 1.4/1.2 ng/L
Flurbiprofen (R/S): 3.3/2.4 ng/LFlurbiprofen (R/S): 11/7.9 ng/L
PHOInfluent wastewater (IW); Effluent wastewater (EW); Surface water (SW)GC/ESI-MS/MSMDN-5S (30 m × 0.25 mm, 0.25 µm film thickness)n.r.n.r.EF: 0.5 (IW); ≤0.42 (EW); 0.42–0.53 (SW)[155]
PHORiver waterLC-UVLux-Cellulose 1 (250 × 4.6 mm, 5 µm)0.4 µg/L1.3 µg/L0.125–50 µg/mL; EF n.r.[156]
METInfluent wastewater (IW); Effluent wastewater (EW)LC/ESI-MS/MSChirobiotic V (250 × 4.6 mm, 5 µm)3.7/3.5 ng/L (IW); 1.9/1.5 ng/L (EW) (R/S) 12.4/11.5 ng/L (IW); 6.5/5.1 ng/L (EW) (R/S)EF: 0.48–0.52 (IW); 0.5–0.7 (EW)[40]
METTreated wastewaterLC/MS/MSChiral-CBH (100 × 2 mm, 5 µm); Chiral-CBH guard column and in-line high-pressure filter (4 mm, 0.5 µm)0.96/2.9 pM (E1/E2)5.8/11.6 pM (E1/E2)EF: 0.51–0.55[157]
METEffluent wastewater (EW); River water (RW)GC/ESI-MS/MSMDN-5S (30 m × 0.25 mm, 0.25 µm film thickness)n.r.n.r.EF: 0.5 (EW); 0.31–0.44 (RW)[158]
FLX, NFLXRaw wastewater (RaW); Treated wastewater (TW)LC/ESI-MS/MSChiral-AGP (100 × 2 mm, 5 µm); in-line high-pressure filter with a replaceable cap frit (4 mm, 5 µm); Chiral-AGP guard column (10 × 2 mm)FLX: 3 pM (RaW); 2/1 pM (R/S) (TW)FLX: 12.4 pM (RaW); 3 pM (TW)0–500 pM
EF: 0.71 (RaW, TW)		[159,160]
NFLX: 2.4 pM (RaW); 2 pM (TW)NFLX: 12.1/14.3 pM (E1/E2) (RaW); 4 pM (TW)0–500 pM
EF: 0.69 (RaW); 0.68 (TW)
FLX, NFLXWWTP effluentHPLC-FDChirobiotic V (150 × 4.6 mm, 5 µm)FLX: 0.8–2 ng/mL4 ng/mL4–60 ng/mL; EF n.r.[137]
NFLX: 0.8–2 ng/mL2 ng/mL2–30 ng/mL; EF n.r.
VNFRiver waterLC/ESI-MS/MSChirobiotic V (250 × 2.1 mm, 5 µm); Chirobiotic guard column (10 × 2 mm)6/4 ng/L (R/S)n.r.EF: 0.46–0.74[144]
Ibuprofen, Carboxyibuprofen, 2-Hydroxyibuprofen, Naproxen, Ketoprofen, Indoprofen, Chloramphenicol, Ifosfamide, PraziquantelInfluent wastewater (IW); Effluent wastewater (EW); Surface water (SW)LC/ESI-MS/MSChirobiotic T (250 × 2.1 mm, 5 µm)Ibuprofen (R/S): 1319/1111 ng/L (IW); 498/383 ng/L (EW); 263/114 ng/L (SW)Ibuprofen (R/S): 5403/4551 ng/L (IW); 2039/1570 ng/L (EW); 1076/466 ng/L (SW)250–400 µg/L
EF: 1 (IW)		[161]
Carboxyibuprofen (E1/E2): 71/63.6 ng/L (IW); 71.4/58.6 ng/L (EW); 21.5/22.3 ng/L (SW)Carboxyibuprofen (E1/E2): 232/208 ng/L (IW); 233/191 ng/L (EW); 70.2/72.7 ng/L (SW)32.7–300 µg/L (IW); 250–400 µg/L (EW, SW)
EF: 0.83 (IW)
2-Hydroxyibuprofen (E1/E2): 31.7/20.4 ng/L (IW); 28/30.4 ng/L (EW); 10.9/10.4 ng/L (SW)2-Hydroxyibuprofen (E1/E2): 104/66.4 ng/L (IW); 91.3/99.3 ng/L (EW); 35.4/33.9 ng/L (SW)16.3–400 µg/L (E1); 16.3–300 µg/L (E2)
EF: 0.76 (IW)
Naproxen (R/S): 11/7.53 ng/L (IW); 14.4/13.4 ng/L (EW); 7.5/6.83 ng/L (SW)Naproxen (R/S): 38.1/26.1 ng/L (IW); 49.9/46.5 ng/L (EW); 25.9/23.7 ng/L (SW)8.66–50 µg/L
EF: 1 (IW)
Ketoprofen (R/S): 2.08/2.61 ng/L (IW); 2.28/2.56 ng/L (EW); 1.60/1.32 ng/L (SW)Ketoprofen (R/S): 6.85/8.59 ng/L (IW); 7.51/8.44 ng/L (EW); 5.29/4.37 ng/L (SW)1.65–400 µg/L
EF n.r.
Indoprofen (E1/E2): 2.23/3.44 ng/L (IW); 2.20/2.59 ng/L (EW); 1.54/1.46 ng/L (SW)Indoprofen (E1/E2): 7.59/11.7 ng/L (IW); 7.47/8.81 ng/L (EW); 5.24/4.95 ng/L (SW)1.70–100 µg/L
EF n.r.
Chloramphenicol (1R,2R/1S,2S): 29.1/5.66 ng/L (IW); 26.1/4.84 ng/L (EW); 13.5/2.59 ng/L (SW)Chloramphenicol (1R,2R/1S,2S): 98.9/18.8 ng/L (IW); 88.6/16.1 ng/L (EW); 45.8/8.61 ng/L (SW)17–400 µg/L (1R,2R); 3.33–800 µg/L (1S,2S)
EF n.r.
Ifosfamide (E1/E2): 0.24/0.28 ng/L (IW); 0.23/0.22 ng/L (EW); 0.12/0.13 ng/L (SW)Ifosfamide (E1/E2): 0.82/0.96 ng/L (IW); 0.78/0.74 ng/L (EW); 0.41/0.44 ng/L (SW)0.17–50 µg/L
EF n.r.
Praziquantel (E1/E2): 3.02/3.11 ng/L (IW); 2.78/2.82 ng/L (EW); 1.34/1.39 ng/L (SW)Praziquantel (E1/E2): 10.1/10.4 ng/L (IW); 9.26/9.40 ng/L (EW); 4.47/4.63 ng/L (SW)1.67–400 µg/L
EF n.r.
Ibuprofen, NaproxenInfluent wastewater (IW); Effluent wastewater (EW)GC/MSAstec Chiraldex (20 m × 0.25 mm, 0.12 µm film thickness)0.1 µg/Ln.r.Ibuprofen EF: 0.73–0.90 (IW); 0.60–0.76 (EW)[44]
Naproxen EF: 0.88–0.90 (IW); 0.71–0.86 (EW)
Ibuprofen, Naproxen, KetoprofenInfluent wastewater (IW); Effluent wastewater (EW)GC/EI-MS/MSHP5-MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.n.r.Ibuprofen EF: 0.88–0.94 (IW); 0.38–0.40 (EW)[162]
Naproxen EF: 0.99 (IW); 0.86–0.94 (EW)
Ketoprofen EF: 0.56–0.60 (IW); 0.54–0.68 (EW)
Ibuprofen, 2-Hydroxyibuprofen, Naproxen, Indoprofen, Carprofen, Fenoprofen, Flurbiprofen, Chloramphenicol, Aminorex, Tetramisole, Omeprazole, Ifosfamide, 3-N-Dechloroethylifosfamide, Praziquantel, Imazalil, OfloxacinInfluent wastewater (IW); Effluent wastewater (EW)UHPSFC/ESI-MS/MSPolysaccharide amylose tris-(3,5-dimethylphenylcarbamate) columnIbuprofen (R/S): 1410/1525 ng/L (IW); 1458/1452 ng/L (EW)Ibuprofen (R/S): 4695/5080 ng/L (IW); 4854/4837 ng/L (EW)415–2000 µg/L
EF: 1 (IW)		[163]
2-Hydroxyibuprofen (E1/E2): 409/415 ng/L (IW)2-Hydroxyibuprofen (E1/E2): 1360/1382 ng/L (IW)163.5–2000 µg/L
EF: 0.2 (IW)
Naproxen: 233/267 ng/L (R/S) (IW); 539 ng/L (R) (EW)Naproxen: 777/891 ng/L (R/S) (IW); 1796 ng/L (R) (EW)84.3–2000 µg/L
EF: 1 (IW, EW)
Indoprofen (E1/E2): 2.38/2.68 ng/L (IW); 2.88/2.65 ng/L (EW)Indoprofen (E1/E2): 7.91/8.91 ng/L (IW); 9.60/8.84 ng/L (EW)0.85–250 µg/L (E1); 0.85–500 µg/L (E2)
EF n.r.
Carprofen (E1/E2): 378/287 ng/L (IW); 584/705 ng/L (EW)Carprofen (E1/E2): 1259/956 ng/L (IW); 1945/2347 ng/L (EW)168–500 µg/L
EF n.r.
Fenoprofen (E1/E2): 571/538 ng/L (IW); 499/489 ng/L (EW)Fenoprofen (E1/E2): 1900/1793 ng/L (IW); 1660/1632 ng/L (EW)171–4000 µg/L
EF n.r.
Flurbiprofen: 331 ng/L (IW); 252/378 ng/L (E1/E2) (EW)Flurbiprofen (E1/E2): 838/1101 ng/L (IW); 838/1259 ng/L (EW)83.8–2000 µg/L
EF n.r.
Chloramphenicol (1R,2R/1S,2S): 45.6/43.5 ng/L (IW); 53.4/50.1 ng/L (EW)Chloramphenicol (1R,2R/1S,2S): 152/145 ng/L (IW); 178/167 ng/L (EW)16.9–500 µg/L (1R,2R); 16.7–500 µg/L (1S,2S)
EF n.r.
Aminorex (E1/E2): 1.82/2.57 ng/L (IW); 2.16/3.02 ng/L (EW)Aminorex (E1/E2): 6.05/8.56 ng/L (IW); 7.20/10 ng/L (EW)0.83–500 µg/L
EF n.r.
Tetramisole (R/S): 2.54/2.94 ng/L (IW); 2.83/2.87 ng/L (EW)Tetramisole (R/S): 8.46/9.79 ng/L (IW); 9.43/9.54 ng/L (EW)0.83–500 µg/L
EF n.r.
Omeprazole: 24.5 ng/L (IW, EW)81.6 ng/L (IW, EW)0.82–125 µg/L (E1); 0.82–250 µg/L (E2)
EF n.r.
Ifosfamide (E1/E2): 0.51/0.58 ng/L (IW); 0.51/0.54 ng/L (EW)Ifosfamide (E1/E2): 1.70/1.93 ng/L (IW); 1.69/1.78 ng/L (EW)0.17–125 µg/L
EF n.r.
3-N-Dechloroethyl-ifosfamide (E1/E2): 0.46/3.22 ng/L (IW); 1.35/8.62 ng/L (EW)3-N-Dechloroethyl-ifosfamide (E1/E2): 1.54/10.70 ng/L (IW); 4.50/28.70 ng/L (EW)0.17–50 µg/L (E1); 0.83–125 µg/L (E2)
EF n.r.
Praziquantel (E1/E2): 2.66/2.47 ng/L (IW); 2.64/2.77 ng/L (EW)Praziquantel (E1/E2): 8.86/8.23 ng/L (IW); 8.78/9.23 ng/L (EW)0.83–50 µg/L
EF n.r.
Cellulose tris-(3-chloro-4-methylphenylcarbamate) columnIndoprofen (E1/E2): 5.53/3.94 ng/L (IW); 6.82/5.52 ng/L (EW)Indoprofen (E1/E2): 18.4/13.1 ng/L (IW); 22.7/18.4 ng/L (EW)1.69–500 µg/L (E1); 1.69–250 µg/L (E2)
EF n.r.
Aminorex (E1/E2): 2.32/2.54 ng/L (IW); 2.23/3.44 ng/L (EW)Aminorex (E1/E2): 7.74/8.44 ng/L (IW); 7.59/11.70 ng/L (EW)0.83–500 µg/L
EF: 0.4 (IW)
Tetramisole (R/S): 2.72/3.08 ng/L (IW); 3.16/2.60 ng/L (EW)Tetramisole (R/S): 9.06/10.30 ng/L (IW); 10.50/8.65 ng/L (EW)0.83–250 µg/L (R); 0.83–500 µg/L (S)
EF: 0.6 (IW, EW)
Omeprazole: 49 ng/L (IW, EW)163 ng/L (IW, EW)1.63–500 µg/L
EF n.r.
3-N-Dechloroethyl-ifosfamide (E1/E2): 2.81/2.99 ng/L (IW); 7.69/8.68 ng/L (EW)3-N-Dechloroethyl-ifosfamide (E1/E2): 9.35/9.97 ng/L (IW); 25.60/28.90 ng/L (EW)0.83–125 µg/L
EF: 0.4 (IW)
Praziquantel (E1/E2): 6.62/5.59 ng/L (IW); 6.80/5.30 ng/L (EW)Praziquantel (E1/E2): 22/18.60 ng/L (IW); 22.60/17.60 ng/L (EW)1.67–500 µg/L (E1); 1.67–250 µg/L (E2)
EF n.r.
Imazalil (E1/E2): 5.12/5.16 ng/L (IW); 7.09/6.45 ng/L (EW)Imazalil (E1/E2): 17/17.20 ng/L (IW); 23.60/21.50 ng/L (EW)1.74–500 µg/L (E1); 1.74–250 µg/L (E2)
EF: 0 (IW)
Ofloxacin (E1/E2): 98.20/63.10 ng/L (IW); 65.20/79 ng/L (EW)Ofloxacin (E1/E2): 327/210 ng/L (IW); 218/263 ng/L (EW)16.4–500 µg/L (E1); 16.4–250 µg/L (E2)
EF: 0 (IW)
Ibuprofen, Naproxen, KetoprofenEffluent wastewaterGC/EI-MS/MSHP5-MS (30 m × 0.25 mm, 0.25 µm film thickness)Ibuprofen: 0.7 ng/L (S)n.r.0.08–300 ng/L; EF: 0.49–0.62 (mean 0.53)[147]
Naproxen: 0.7 ng/L (S)n.r.0.08–300 ng/L; EF: 0.66–0.86 (mean 0.79)
Ketoprofen: 2.2 ng/L (S)n.r.3–300 ng/L; EF: 0.54–0.66 (mean 0.60)
Ibuprofen, NaproxenInfluent wastewater (IW); Effluent wastewater (EW)GC/EI-MS/MSHP5-MS (30 m × 0.25 mm, 0.25 µm film thickness)n.r.n.r.Ibuprofen EF: 0.6–0.8 (IW); 0.5 (EW)[164]
Naproxen EF: 1 (IW); 0.7–0.9 (EW)
Ibuprofen, Naproxen, KetoprofenInfluent wastewater (IW); Effluent wastewater (EW)LC/MS/MSSumichiral OA-2500 (250 × 4.6 mm, 5 µm); Chirex 3005 guard column (30 × 4.6 mm, 5 µm)Ibuprofen: 0.7 ng/L (IW); 0.5 ng/L (EW)n.r.0.4–4000 µg/L
EF: 0.79–0.86 (IW); 0.63–0.68 (EW)		[165]
Naproxen: 1.2/1.1 ng/L (R/S) (IW); 1.1 ng/L (EW)n.r.1.2–4000 µg/L
EF: 0.98–0.99 (IW); 0.93–0.96 (EW)
Ketoprofen (R/S): 0.9/0.8 ng/L (IW); 0.8/0.7 ng/L (EW)n.r.1–4000 µg/L
EF: 0.54–0.68 (IW); 0.61–0.68 (EW)
Ibuprofen, Naproxen, Ketoprofen, Chloramphenicol, Aminorex, Tetramisole, Ifosfamide, 3-N-Dechloroethylifosfamide, Fexofenadine, 10,11-Dihydro-10-hydroxy-carbamazepine, PraziquantelEffluent wastewater (EW); Surface water (SW)LC/ESI-MS/MSChiral-AGP (100 × 2 mm, 5 µm); Chiral-AGP guard column (10 × 2 mm, 5 µm)Ibuprofen (R/S): 16.45/23.15 ng/L (EW); 9.15/9.39 ng/L (SW)Ibuprofen (R/S): 67.37/94.81 ng/L (EW); 37.47/38.46 ng/L (SW)41–492 µg/L
EF: 0.65 (EW)		[32]
Naproxen (R/S): 3.45/4.16 ng/L (EW); 2.45/3.39 ng/L (SW)Naproxen (R/S): 11.96/14.39 ng/L (EW); 8.49/11.73 ng/L (SW)8.66–416 µg/L (R); 8.66–312 µg/L (S)
EF: 0.92 (EW)
Ketoprofen: 0.52 ng/L (EW); 0.26/0.27 ng/L (R/S) (SW)Ketoprofen (R/S): 1.73/1.70 ng/L (EW); 0.86/0.88 ng/L (SW)0.83–297 µg/L (R); 0.83–396 µg/L (S)
EF n.r.
Chloramphenicol (1R,2R/1S,2S): 2.18/2.43 ng/L (EW); 1.02/1.19 ng/L (SW)Chloramphenicol (1R,2R/1S,2S): 7.39/8.09 ng/L (EW); 3.46/3.96 ng/L (SW)3.40–612 µg/L (1R,2R); 3.33–400 µg/L (1S,2S)
EF n.r.
Aminorex: 0.12 ng/L (EW); 0.06 ng/L (SW)0.39 ng/L (EW); 0.20 ng/L (SW)0.17–100 µg/L
EF n.r.
Tetramisole (R/S): 1.04/0.93 ng/L (EW); 0.48/0.47 ng/L (SW)Tetramisole (R/S): 3.42/3.08 ng/L (EW); 1.58/1.56 ng/L (SW)1.65–396 µg/L (R); 1.65–297 µg/L (S)
EF: 0.50 (EW)
Ifosfamide: 0.09/0.08 ng/L (E1/E2) (EW); 0.04 ng/L (SW)Ifosfamide (E1/E2): 0.31/0.29 ng/L (EW);
0.14/0.15 ng/L (SW)		0.17–51 µg/L
EF n.r.
3-N-Dechloroethy-lifosfamide (E1/E2): 3.33/2.94 ng/L (EW); 1.09 /1.14 ng/L (SW)3-N-Dechloroethy-lifosfamide (E1/E2): 11.10/9.79 ng/L (EW); 3.62/3.78 ng/L (SW)0.08–40 µg/L
EF n.r.
Fexofenadine (E1/E2): 56.02/58.10 ng/L (EW); 33/34.66 ng/L (SW)Fexofenadine (E1/E2): 190.29/197.33 ng/L (EW); 112.10/117.73 ng/L (SW)136–306 µg/L (E1); 136–408 µg/L (E2)
EF: 0.55 (EW)
10,11-Dihydro-10-hydroxy-carbama-zepine (E1/E2): 1.08/1.06 ng/L (EW); 0.53/0.54 ng/L (SW)10,11-Dihydro-10-hydroxy-carbama-zepine (E1/E2): 3.58/3.53 ng/L (EW); 1.75/1.79 ng/L (SW)1.67–100 µg/L (E1); 1.67–300 µg/L (E2)
EF n.r.
Praziquantel (E1/E2): 4.54/4.83 ng/L (EW); 2.52/2.21 ng/L (SW)Praziquantel (E1/E2): 15.12/16.07 ng/L (EW); 8.38/7.37 ng/L (SW)8.33–400 µg/L (E1); 8.33–200 µg/L (E2)
EF n.r.
NaproxenInfluent wastewater (IW); Effluent wastewater (EW); River water (RW)LC/ESI-MS/MSChiralpak AD-RH (150 × 4.6 mm)n.r.n.r.EF: 1 (IW); 0.88–0.91 (EW); 0.84–0.98 (RW)[41]
Omeprazole, Lansoprazole, Rabeprazole, PantoprazoleInfluent wastewater (IW); Effluent wastewater (EW); River water (RW)LC/ESI-MS/MSChiralpak IC (250 × 4.6 mm, 5 µm)Omeprazole: 2.03/2.29 ng/L (R/S) (IW); 0.74 ng/L (EW); 0.67/0.68 ng/L (R/S) (RW)Omeprazole: 2.03/2.29 ng/L (R/S) (IW); 2.81 ng/L (EW); 2.55/2.59 ng/L (R/S) (RW)2–500 µg/L
EF: 0.70 (IW); 0.53 (EW); 0.54 (RW)		[43]
Lansoprazole: 0.96/1.02 ng/L (R/S) (IW); 0.69/0.70 ng/L (R/S) (EW); 0.67 ng/L (RW)Lansoprazole (R/S): 4.34/4.63 ng/L (IW); 3.13/3.20 ng/L (EW); 3.05/3.06 ng/L (RW)2–500 µg/L
EF: 0.51 (IW); 0.52 (EW, RW)
Rabeprazole: 0.94/0.95 ng/L (R/S) (IW); 0.71/0.73 ng/L (R/S) (EW); 0.78 ng/L (RW)Rabeprazole (R/S): 3.37/3.40 ng/L (IW); 2.54/2.62 ng/L (EW); 2.81/2.78 ng/L (RW)2–500 µg/L
EF: 0.52 (IW); 0.51 (RW)
Pantoprazole (E1/E2): 0.96/0.94 ng/L (IW); 0.93/1 ng/L (EW); 0.96/0.91 ng/L (RW)Pantoprazole (E1/E2): 2.99/2.94 ng/L (IW); 2.90/3.12 ng/L (EW); 2.99/2.83 ng/L (RW)2–500 µg/L
EF: 0.54 (IW); 0.51 (EW); 0.53 (RW)
Econazole, Miconazole, Tebuconazole, KetoconazoleRaw wastewater (RaW); Treated wastewater (TW); Sludge (Sd)LC/ESI-MS/MSAGP column (100 × 4 mm, 5 µm); AGP guard column (10 × 4 mm)n.r.Econazole: 0.5 ng/L (RaW); 0.3 ng/L (TW); 3 ng/g (Sd)0.5–250 ng/mL
EF: 0.50 (Sd)		[166]
Miconazole: 0.5 ng/L (RaW); 0.3 ng/L (TW); 3 ng/g (Sd)0.5–250 ng/mL
EF: 0.5 (RaW); 0.47 (TW); 0.5 (Sd)
Tebuconazole: 0.8 ng/L/0.9 ng/L (E1/E2) (RaW); 0.3 ng/L (TW); 4/5 ng/g (E1/E2) (Sd)0.5–250 ng/mL
EF n.r.
HSA column (100 × 2 mm, 5 µm); HSA guard column (10 × 2 mm)n.r.Ketoconazole: 10 ng/L (RaW); 5 ng/L (TW); 29 ng/g (Sd)5–250 ng/mL
EF: 0.48 (RaW, TW, Sd)
Econazole, Miconazole, Tebuconazole, KetoconazoleRiver water (RW); Sludge (Sd)LC/ESI-MS/MSAGP column (100 × 4 mm, 5 µm); AGP guard column (10 × 4 mm)n.r.Econazole: 0.5 ng/L (RW); 3 ng/g (Sd)0.5–250 ng/mL (Sd)
EF: 0.52 (RW); 0.50 (Sd)		[167]
Miconazole: 0.6 ng/L (RW); 3ng/g (Sd)0.5–250 ng/mL (Sd)
EF: 0.49–0.54 (RW); 0.50–0.52 (Sd)
Tebuconazole: 0.6 ng/L (RW)EF: 0.47–0.61 (RW)
HSA column (100 × 2 mm, 5 µm); HSA guard column (10 × 2 mm)n.r.Ketoconazole: 7 ng/L (RW); 29 ng/g (Sd)5–250 ng/mL (Sd)
EF: 0.48–0.49 (Sd)
Tebuconazole, Hexaconazole, Penconazole, TriadimefonRiver waterLC/ESI-MS/MSChiralpak IC (250 × 4.6 mm, 5 µm)Tebuconazole: 19.8 µg/L (‒); 25.4 µg/L (+)60 µg/L (‒); 76.2 µg/L (+)30–1500 µg/L
EF n.r.		[168]
Hexaconazole: 9.1 µg/L (‒); 8.6 µg/L (+)27.7 µg/L (‒); 25.8 µg/L (+)
Penconazole: 29 µg/L (‒); 27.6 µg/L (+)88.1 µg/L (‒); 83.8 µg/L (+)
Triadimefon: 8.5 µg/L25.5 µg/L
AM: amphetamine; D-citalopram: desmethyl-citalopram; EF: enantiomeric fraction; ESI: electrospray ionization; FD: fluorescence detector; FLX: fluoxetin; GC: gas chromatography; HPLC: high performance liquid chromatography; LC: liquid chromatography; LOD: limit of detection; LOQ: limit of quantification; MA: methamphetamine; MDA: 3,4-methylenedioxyamphetamine; MDL: method detection limit; MDMA: 3,4 methylenedioxymethamphetamine; MDEA: N-methyl-diethanolamine; MET: metoprolol; MS: mass spectrometry; MS/MS: tandem mass spectrometry; MQL: method quantification limit; NFLX: norfluoxetin; PHO: propranolol; QTOF: quadrupole time of flight mass spectrometer; OD-VNF: O-desmethylvenlafaxine; SBT: salbutamol; T: tramadol; UHPSFC: ultra high performance supercritical fluid chromatography; UPLC: ultra performance liquid chromatography; UV: ultraviolet detector; VNF: venlafaxine. n.r.: not referred.

Share and Cite

MDPI and ACS Style

Ribeiro, C.; Santos, C.; Gonçalves, V.; Ramos, A.; Afonso, C.; Tiritan, M.E. Chiral Drug Analysis in Forensic Chemistry: An Overview. Molecules 2018, 23, 262. https://doi.org/10.3390/molecules23020262

AMA Style

Ribeiro C, Santos C, Gonçalves V, Ramos A, Afonso C, Tiritan ME. Chiral Drug Analysis in Forensic Chemistry: An Overview. Molecules. 2018; 23(2):262. https://doi.org/10.3390/molecules23020262

Chicago/Turabian Style

Ribeiro, Cláudia, Cristiana Santos, Valter Gonçalves, Ana Ramos, Carlos Afonso, and Maria Elizabeth Tiritan. 2018. "Chiral Drug Analysis in Forensic Chemistry: An Overview" Molecules 23, no. 2: 262. https://doi.org/10.3390/molecules23020262

Article Metrics

Back to TopTop