Fate of Pharmaceuticals in the Environment and in Water Treatment Systems - Chapter 2 docx

of Pharmaceuticals in the Aquatic Environment Sandra Pérez and Damià Barceló 2.1 INTRODUCTION Recently, the focus of environmental analysis has shifted from the classic contami-nants, su

of Pharmaceuticals in the Aquatic Environment

Sandra Pérez and Damià Barceló

2.1 INTRODUCTION

Recently, the focus of environmental analysis has shifted from the classic contami-nants, such as the persistent organic pollutants, toward the “emerging contaminants” detected recently in many environmental compartments.1Emerging contaminants are defined as compounds that are not currently covered by existing regulations

of water quality, have not been previously studied, and are thought to be potential threats to environmental ecosystems and human health and safety In particular, the compounds that are being addressed include pharmaceuticals, drugs of abuse, and personal-care products.2The high water solubility of these organic compounds makes them mobile in the aquatic media, hence they can potentially infiltrate the soil and then reach groundwater Eventually, these compounds may find their way into the drinking water supplies

In recent years the increasing use of drugs in farming, aquaculture, and human health has become a growing public concern because of their potential to cause undesirable ecological and human health effects The main concern regarding

Contents

2.1 Introduction 53

2.2 Multiresidue Methods 56

2.3 Determination of Drugs According to Their Class 67

2.3.1 Analgesics and Antiinflammatory Drugs 67

2.3.2 Antimicrobials 68

2.3.3 Antiepileptics, Blood Lipid Regulators, and Psychiatric Drugs 70

2.3.4 Antitumoral Drugs 72

2.3.5 Cardiovascular Drugs (C-Blockers) and C2-Sympathomimetics 72

2.3.6 Estrogens 72

2.3.7 X-Ray Contrast Agents 73

2.3.8 Drugs of Abuse 74

2.3.9 Other Drugs 75

2.4 Conclusion 75

Acknowledgments 76

References 76

pharmaceuticals is that they are being introduced continuously into water bodies

as pollutants, and due to their biological activity this can lead to adverse effects inaquatic ecosystems and potentially impact drinking water supplies.3Antibiotics areone of the most problematic groups of pharmaceuticals, since their increasing use formore than four decades has led to the selection of resistant bacteria that can threatenthe effectiveness of antibiotics for the treatment of human infections.4Another groupthat has caused environmental concern is contraceptives and other endocrine disrup-tors; due to their endocrine properties they can induce the feminization or masculin-ization in aquatic organisms.5In general the short- and long-term ecotoxicologicaleffects of pharmaceuticals on wildlife have not yet been studied sufficiently.Prescription and over-the-counter drugs have probably been in the environmentfor as long as they have been used, but only recently have analytical methods beendeveloped to detect pharmaceuticals at trace levels.6Due to the dilution and possibledegradation of these substances in the environment, low levels can be expected.Therefore, an analyte preconcentration procedure is almost always necessary inorder to achieve desired levels of analytical sensitivity, often requiring high enrich-ment factors, between 100 and 10,000 Such enrichment factors for drug analysisare usually achieved using solid-phase extraction (SPE) Sensitive detection meth-ods such as gas chromatography-mass spectrometry (GC-MS), GC-tandem massspectrometry (GC-MS/MS) or liquid chromatography-mass spectrometry (LC-MS),and LC-tandem mass spectrometry (LC-MS/MS) are also crucial for the analyti-cal determination of drugs in the environment The main drawback of GC for druganalysis, however, is that this technique is limited to compounds with high vaporpressure Since most drugs are polar substances, they need to be derivatized prior toinjection in the GC For this reason, the combination of atmospheric pressure ion-ization-MS (API-MS) with separation techniques such as LC or ultra performanceliquid chromatography (UPLC) has become the method of choice in drug analysis

LC with a single quadrupole MS analyzer offers good sensitivity, but when verycomplex matrices such as raw sewage are investigated, insufficient selectivity oftenimpairs the unequivocal identification of the analytes Tandem MS affords superiorperformance in terms of sensitivity and selectivity in comparison with single quad-rupole instruments Liquid chromatographic techniques coupled to tandem MS orhybrid mass spectrometers with distinct analyzers such as triple quadrupole (QqQ),time-of-flight (ToF), quadrupole time-of-flight (QqToF), quadrupole ion trap (IT),and recently the quadrupole linear ion trap (QqLIT) are the most widely used instru-mental techniques for drug analysis.7

Most of the data on the presence on pharmaceuticals in wastewaters, rivers, anddrinking water come primarily from European studies8,9followed by those carriedout in the United States.10These substances that are used in human and veterinarymedicine can enter the environment via a number of pathways but mainly fromdischarges of wastewater treatment plants (WWTPs) or land application of sew-age sludge and animal manure, as depicted inFigure 2.1 Most active ingredients

of pharmaceuticals are transformed only partially in the body and thus are excreted

as a mixture of metabolites and bioactive forms into sewage systems Therefore, thetreatment of wastewaters in WWTPs plays a crucial role in the elimination of phar-maceutical compounds before their discharge into rivers During the application of

Advances in the Analysis of Pharmaceuticals in the Aquatic Environment 55

primary and secondary treatments, pharmaceutical compounds can be eliminated

by sorption onto the sludge or microbially degraded to form metabolites that areusually more polar than the parent drugs.11In many cases the high polarity combinedwith the low biodegradability exhibited by some pharmaceutical compounds results

in inefficient elimination in WWTPs The removal efficiencies vary from plant toplant and depend on the design and operation of the treatment systems.12,13Thus, themajor source of pharmaceutical residues detectable in surface waters are dischargesfrom WWTPs Several studies reported the occurrence of pharmaceuticals at levels

up to the μg/L range in rivers, streams, lakes, and groundwater.1 ,14

Researchers have yet to determine the occurrence, fate, and possible effects ofthe most frequently consumed drugs and their main metabolites in the aquatic envi-ronment Exceptionally high levels of drugs have been reported—for example, theoccurrence of the antiasthma drug salbutamol in water from the Po River.15 Theresearchers concluded that their data reflected the illegal use of salbutamol by localfarmers to promote growth in cattle The determination of pharmaceuticals and drugs

of abuse in the environment by applying the principle that what goes in must comeout can be a helpful tool to estimate the drug consumption in the investigated areas.For example, Italian researchers measured the levels of benzoylecgonine, the majorurinary metabolite of cocaine, in wastewater from several Italian cities.16What theyfound was surprising: cocaine use appeared to be far higher than the public healthofficials previously thought

This review provides an overview on analytical protocols used in determiningdrugs and some of their metabolites in aqueous and solid environmental samples

Technological progress in the fields of sample extraction and detection by mass trometry (MS) techniques (hybrid and tandem mass spectrometers) for analyzingantibiotics, antiinflammatory/analgesics, lipid regulating agents, psychiatric drugs,sedatives, iodated X-ray contrast media, diuretics, drugs of abuse, and some humanmetabolites in the aquatic environment are discussed.17–19The recent trends in mul-tiresidue methodologies for the determination of the drugs and their human metabo-lites will be reviewed here.

spec-2.2 MULTIRESIDUE METHODS

Many analytical methodologies for the determination of drugs in water bodies focused

on selected therapeutic classes Multiresidue methods, however, are becoming morewidespread in response to the need of monitoring a wide range of pharmaceuticalsthat belong to diverse drug classes in wastewater, surface water, and groundwater.The latter approach offers advantages in terms of providing a more comprehensivepicture of the occurrence and fate of the contaminants in the environment In addi-tion, the simultaneous determination of a large number of analytes by a single methodrepresents a less time-consuming and hence more economical approach as comparedwith applying class-specific analytical protocols The multiresidue methods found

in the literature are diverse, with target analytes being selected commonly on thebasis of their consumption in the country where the study is being conducted, therate of metabolism of drugs, the environmental occurrence, and persistence in theenvironment In this chapter, multiresidue methods for drug analysis in the aquaticenvironment are reviewed

Ternes et al.20reported the determination of neutral pharmaceuticals: azone (analgesic), phenylbutazone (antiinflammatory), diazepam (psychiatric drug),omeprazole (antiulcer), nifedipine (calcium antagonist), glibenclamide (antidiabetic),and two human metabolites: 4-aminoantipyridine (metabolite of metamizole) andoxyphenbutazone (metabolite of phenylbutazone) with a multiresidue methodologyincluding a one-step extraction method based on SPE with RP-C18material elutedwith methanol The analysis was performed by LC with detection by electrosprayionization (ESI) tandem MS in multiple reaction monitoring (MRM) mode, which

propyphen-is the acqupropyphen-isition mode providing the best sensitivity and selectivity for quantitativeanalysis Low limits of detection and reasonable recoveries for the selected drugs indifferent matrices were achieved This work20investigated the losses in the recover-ies of some drugs due to matrix impurities, which either reduced the sorption effi-ciencies on the C18material or led to signal suppression in the ESI interface Theauthors spiked influent wastewater extracts with the target analytes and found thatthe recoveries were not appreciably higher in comparison to the recoveries over thetotal method Consequently, the signal suppression in ESI played a decisive role

in the losses of 4-aminoantipyrine, omeprazole, oxyphenbutazone, phenylbutazone,and propyphenazone For most of the compounds, compensation for the losses wasachieved by addition of the surrogate standard 10,11-dihydrocarbamazepine How-ever, low corrected recoveries for oxyphenbutazone, phenylbutazone and 4-amino-

Advances in the Analysis of Pharmaceuticals in the Aquatic Environment 57

antipyridine indicated that the determination of these compounds was still rathersemiquantitative.20

Vanderford et al.21developed an analytical method for the determination of 21pharmaceuticals in water, choosing them based on their occurrence in the environ-ment and their dissimilar structural and physicochemical structures They used also

a one-step extraction method employing SPE with a hydrophilic-lipophilic balance(HLB) The separation and detection was performed with LC-MS/MS, using ESI ineither positive or negative mode or atmospheric pressure chemical ionization (APCI)

in positive mode The analytical method provided a simple and sensitive method forthe detection of a wide range of pharmaceuticals with recoveries in deionized waterabove 80% for all of the compounds The authors also studied the effect of samplepreservatives on the recovery of the pharmaceuticals.21They compared formalde-hyde and sulfuric acid, obtaining the best results for the latter, which prevented thedegradation of the target compounds and did not adversely affect their recoveries.Matrix effects were also examined in this work showing that all compounds detectedwith (+)ESI and (–)ESI, except hydrocodone, showed a considerable degree of ion-ization suppression Hydrocodone, though, showed signal enhancement In anotherwork the same group reported a methodology using an isotope dilution technique forevery analyte to compensate for matrix effects in the ESI source, SPE losses, andinstrument variability.22 The method was tested with three matrices (wastewater,surface water, and drinking water), and the results indicated that the method wasvery robust using isotope dilution for each target compound The work described amethod that analyzed 15 pharmaceuticals and 4 metabolites using SPE (HLB) cou-pled with LC-MS/MS with ESI source Matrix spike recoveries for all compoundswere between 88 and 106% for wastewater influent, 85 and 108% for wastewatereffluent, 72 and 105% for surface water impacted by wastewater, 96 and 113% forsurface water, and 91 and 116% for drinking water The method detection limitswere between 0.25 and 1 ng/L

A study23evaluated different strategies to reduce matrix effects in LC-MS/MSwith an ESI interface First, the peak area of the target compounds in solvent werecompared with the target compounds spiked in matrix extracts obtaining signal sup-pressions in the range of 40 to 90% Next, internal calibration curves with inter-nal labeled standard in solvent and in spiked matrix extracts were prepared Theoverlapping of both curves confirmed that signal losses experienced by the analyteswere corrected by the internal standards Finally, the effectiveness of diluting sampleextracts was studied For this purpose, the signals obtained after sequential dilution

of a WWTP effluent and influent extract were compared with the ones obtained forthe corresponding concentrations of the standards in the solvent The authors consid-ered that matrix effects were eliminated with dilutions 1:2 and 1:4, and this approachwas selected for this work For the extraction of the target analytes, one-step SPEtesting Oasis HLB, Isolute ENV+ and Isolute C18with and without sample acidifi-cation was optimized Oasis HLB, with sorbent based on a hydrophilic-lipophilicpolymer, provided high recoveries for all target compounds at neutral pH Recoverieswere higher than 60% for both surface and wastewaters, with the exception of sev-eral compounds: ranitidine (50%), sotalol (50%), famotidine (50%), and mevastatin(34%)

Miao et al.24reported a method using SPE (C18) and LC-(-)-ESI-MS/MS for thesimultaneous detection of nine acidic pharmaceutical drugs (bezafibrate, clofibricacid, diclofenac, fenoprofen, gemfibrozil, ibuprofen, indomethacin, ketoprofen, andnaproxen) in WWTP effluents The recoveries ranged from 59% (indomethacin) to92% (fenoprofen) in the WWTP effluent The specificity of the method was checkedspiking samples with analytes at concentration of 0.05 μg/L Two interfering peaksresulting from endogenous components in the WWTP effluent were detected inthe MRM channels for fenoprofen and indomethacin Coextractives in the WWTPyielded fragmentation patterns similar to fenoprofen and indomethacin However, theseparation efficiency provided by high performance liquid chromatography (HPLC)was sufficient to resolve these interfering compounds from the analytes showing theimportance of using LC to improve the selectivity of the analysis.

A multiresidue analytical method using SPE and LC-MS/MS for 28 ceuticals including antimicrobial drugs, two diuretics (furosemide and hydrochlo-rothiazide), cardiovascular (atenolol and enalapril), antiulcer, psychiatric drugs, anantiinflammatory, a C2-sympathomimetic (salbutamol), a lipid regulator, some estro-gens (17C-estradiol, 17B-ethinylestradiol, estrone), two antitumorals (cyclophospha-mide and methotrexate), and two metabolites (clofibric acid and demethyl diazepam)was developed.25To optimize the extraction method, several stationary phases anddifferent PH samples were tested The cartridges were Oasis MCX at pH 1.5/2.0and 3.0 for all the compounds and at pH 7.0/7.5 for omeprazole; LiChrolute EN at

pharma-pH 3.0, 5.0, 7.0, and 9.0 for all the compounds; Bakerbond C18at pH 8.0 and 9.5for the extraction of amoxicillin; andOasis HLB at pH 7.0 for omeprazole and pH8.5/9.0 for amoxycillin They selected Oasis MCX for water samples at pH 1.5/2.0and LiChrolute EN for water samples at pH 7 Recoveries of the pharmaceuticalswere mostly greater than 70% and instrumental and method limits of detection inthe order of ng/L

Vieno et al.26developed a method that allowed the quantification of the fourblockers—acebutolol, atenolol, metoprolol and sotalol, carbamazepine—and the threefluoroquinolones antibiotics—ciprofloxacin, ofloxacin, and norfloxacin—in ground-water, surface waters, and raw and treated sewages The authors26studied the effect

C-of the washing and C-of the eluting solvent and pH on the extraction step using a singlepretreatment (SPE, Oasis HLB) Prior to the elution step, the adsorbent was washedwith 2 mL of 5% of methanol in 2% aqueous NH4OH showing improvements in the

MS detection in terms of decreased ion suppression and thus improved detectability

of the compounds Methanol was the solvent of choice yielding the highest recoveries

as compared with those obtained with acetonitrile or acetone The study of the ence of the pH of the water in the extraction methodology was performed at three

influ-pH values: 4.0, 7.5, and 10.0 For most of the compounds, the influ-pH did not have a nounced effect on the recovery, with the exception of atenolol and sotalol, which werepoorly recovered at low pH (<10% at pH 4.0) The samples were analyzed with LC-MS/MS using ESI in positive mode showing ion suppression in the ESI source.26Toevaluate the matrix effects, the authors infused continuously a standard solution intothe mass spectrometer and then injected either solvent or a real sample extract ontothe LC column Moreover, SPE extracts of groundwater, surface water, and wastewa-ter influent and effluent were spiked with pharmaceuticals, and spiked samples were

pro-Advances in the Analysis of Pharmaceuticals in the Aquatic Environment 59

analyzed in LC-MS/MS with ESI interface No ion suppression was noticed for any

of the analytes in groundwater extracts; some signal suppression (<8%) was noticedfor sotalol, acebutolol, and metoprolol for the surface-water extract; and more severesignal suppression (40%) was observed in the wastewater influents and effluents Theauthors26reported relative recoveries higher than those reported previously by otherauthors24showing an improvement of the general methodology for all the target ana-lytes, except for ciprofloxacin and norfloxacin

The determination of selected drugs and their metabolites with a multiresiduemethodology was also reported by Zuehlke et al.27 Carbamazepine, dimethylami-nophenazone, phenazone, propyphenazone, 1-acetyl-1-methyl-2-dimethyloxanoyl-2-phenylhydrazide, 1-acetyl-1-methyl-2-phenylhydrazide, two human metabolites ofmetamizole (formylaminoantipyridine and aminoantipyridine), and two micobio-logical metabolites (1,5-dimethyl-1,2-dehydro-3-pyrazolone, 4-(2-methylethyl)-1,5-dimethyl-1,2-dehydro-3-pyrazole) were studied To allow for efficient SPE of the twomicrobiological metabolites from water on a conventional C18sorbent, the authors27

prepared the water samples by a simple in situ derivatization with acetic

anhy-dride in basic media in order to decrease the polarity and to increase the molecularweight of these substances by acetylation Only the two analytes 1,5-dimethyl-1,2-dehydro-3-pyrazolone and 4-(2-methylethyl)-1,5-dimethyl-1,2-dehydro-3-pyrazolewere derivatized while the other compounds were quantitatively extracted withoutchemical transformation The analytes were then separated by LC-APCI-MS/MSand quantified by comparison with the internal standard, dihydrocarbamazepine.27

Although ESI led to higher peak intensities than APCI, the latter interface was sen because it provided a matrix-independent ionization resulting in recoveries of

cho-~100%(Table 2.1)

Although the use of GC-MS generally requires the derivatization of polar drugs,Boyd et al.28 used this approach to analyze acetaminophen, fluoxetine, ibuprofen,naproxen, and clofibric acid, a human metabolite of clofibrate and etofibrate The tar-get compounds were isolated from wastewater, surface water, and untreated drink-ing water samples by SPE using a polar SDB-XC Empore disk Derivatization with

N,O-bis(trimethylsilyl)-trifluoroacetamide in the presence of trimethylchlorosilane

was used to enhance thermal stability of clofibric acid, which thermally degraded inthe GC injection port, and to reduce the polarity of specific target analytes (clofibricacid, ibuprofen, and naproxen) in order to facilitate their GC-MS analysis The limits

of detection were between 0.6 (clofibric acid) and 25.8 ng/L (fluoxetine) Althoughthe recoveries for most of the compounds were greater than 47% (Table 2.1), acet-aminophen was repeatedly not detected possibly due to the weak retention of thiscompound on the extraction disk

Next, analytical methods using multiple extraction methods, different uid chromatography eluents, or the combination of two detection techniques arereviewed.10,29,30Sacher et al.29 reported the determination of 60 pharmaceuticalsincluding analgesics, antirheumatics, C-blockers, broncholitics, lipid regulatorsincluding two metabolites, antiepileptics, vasodilators, tranquilizers, antitumoraldrugs, iodated X-ray contrast media and antimicrobials in groundwater with dif-ferent SPE procedures, and the combination of GC-MS (after derivatization of theacidic compounds) and LC-ESI-MS/MS Different stationary phases, pH (3, 5, and

Limit of Detection and

Multiresidue method for

neutral drugs and 2

[20]

Multiresidue method for

neutral and acidic drugs

SW, WW SPE: HLB, pH 2; MeOH LC-(+/–)ESI-MS/MS Deionized water: 80 IDL 6 :12–32 ng/L [21] Multiresidue method for 15

drugs and 4 human

metabolites

DW7, SW, WW SPE: HLB; MeOH/MTBE

(1:9)

LC-(+/–)ESI-MS/MS 90–110 MDL: 0.25–1 ng/L [22]

Multiresidue method for

neutral and acidic drugs

and 5 metabolites

SW, WW SPE: HLB, pH 7; MeOH

[Optimization of stationary phases and pH]

LC-(+/–)ESI-MS/MS SW: 50–116

WW: 60–102

MDL 8

SW:1–30 ng/L WW:3–160 ng/L

[23]

Multiresidue method for

neutral and basic drugs

IQL 9 : 0.46–10.6 μg/L MQL

GW:1–10 ng/L, SW: 1–24 ng/L, WW: 1.4–29 ng/L

[26]

Multiresidue method for

neutral and acidic drugs

and 5 metabolites

GW, SW, WW SPE: C18; MeOH LC-(+)APCI-MS/MS

Interface optimization (ESI and APCI)

GW, SW and WW:87–

117 except for dimethylaminophenazone

Multiresidue method for 28

drugs and 2 metabolites

WW SPE: 1 Oasis MCX, pH

1.5/2.0; MeOH, MeOH (+2% NH3) and MeOH (+0.2% NaOH)

2 LiChrolute EN, pH 7;

MeOH, EtOAc [Optimization of stationary phases and pH]

LC-(+/–)ESI-MS/MS >70 IQL: 600–39400 ng/L

MQL:0.1–5.2 ng/L

[25]

Multiresidue method for 4

drugs and 1 human

metabolite

DW, SW, WW SPE: SDB-XC, pH 2; MeOH,

CH2Cl2/MeOH

Combined method for 60

drugs and their metabolites

SW SPE: RP C18pH 3, PPL

Bond-Elut pH 7, LiChrolute

EN pH 3, Isolut ENV+ pH 5; MeOH, acetonitrile, water, triethylamine

GC-MS and LC-(+)ESI-MS/MS

Combined method for 11

drugs and 2 metabolites

SW, WW SPE: Strata X, pH 3; MeOH

[Stationary phase optimization]

LC-(+/–)ESI-IT-MS >60

Except for lofepramine and mefenaminic acid

MQL: 10–50 ng/L [30]

Combined method for 11

drugs and 2 metabolites

SW, WW SPE: Strata X, pH 3; MeOH,

MeOH (+2% HOAc), MeOH (+2% NH3) [Stationary phase optimization]

LC-(+/–)ESI-IT-MS >60

Except for chloroquine and chlosantel

MDL: 1–20 ng/L IQL: 20–105 pg

60–75 except for fenofibrate (36)

MQL: 5–25 ng/L [33]

(Continued)

Combined method for >50

drugs and their metabolites

SW SPE: 1:tandem HLB and

MCX; MeOH (+5% NH3) 2:HLB; MeOH

Combined method for >10

drugs and 3 human

metabolites

SW, Seawater SPE: Oasis HLB; hexane,

EtOAc and MeOH

LC-(+)ESI-MS/MS and GC-MS

Combined method for 5

neutral ad acidic drugs and

Acidic drugs, acetylsalicylic

acid and 4 metabolites

SW, DW, WW SPE: C18, pH 2; MeOH GC-MS and

GC-IT-MS/MS

WW: 50–250 (GC-MS) SW:5–20 (GC-MS) DW: 1–10 (GC-IT-MS/MS)

[36]

5 acidic drugs GW, SW, WW SPE: Oasis MCX, pH 2;

acetone

LC-(–)ESI-MS/MS GW: 82–103

SW: 75–112 WW: 57–100

MQL:1–25 ng/L [39]

LC-(+)-ESI-IT-MS GW: 51–120

SW: 74–127 WW: 82–126

MDL: 0.027–0.19 μg/L MQL: 0.10–0.65 μg/L

[43]

13 antimicrobials SW SPE: Oasis HLB, pH 2–3;

MeOH

LC-(+)-ESI-IT-MS and LC-DAD

[48]

4 blood lipid regulators GW, SW, WW SPE: C18, pH 7 LC-(+/–)ESI-MS/MS SW: 71–86

WW: 61–91

IDL: 0.7–15.4 pg MDL: 0.1–15.4 ng/L

[49] Carbamazepine and 5

metabolites

SW, WW SPE: Oasis HLB, pH 7;

MeOH [Optimization of stationary phases]

LC-(+)ESI-MS/MS SW: 96–103

WW: 84–104

IDL: 0.8–4.8 pg [51]

(Continued)

C 2 -symphatomimetics

SW, GW, WW SPE: C18-endcapped, pH 7.5;

MeOH

GC-MS and LC-(+)ESI-MS/MS

SW and GW: 5–10 ng/L WW: 50 ng/L

C/MS: 1–20 ng/mL LC-ESI-MS: 0.1–20 ng/L LC-ESI-MS/MS: 0.1–10 ng/L

LC-(+)ESI-MS/MS SW: 90–116

WW: 57–113 (ioxithalamic acid: 35)

MQL:10–50 ng/L [62]

4 ICM and 2 possible

human metabolites of ICM

SW, WW SPE: ENV+ and Envi-Carb,

pH 3.5; MeOH and acetonitrile/water (1:1) back flush

64]

Cocaine and its metabolite

Cocaine :0.12 ng/L Metabolite: 0.06 ng/L

[16]

6 barbiturates GW, SW, WW SPE: Oasis HLB, pH 7;

acetone and EtOAc

SW: 64–105 WW: 52–105

MDL:

SW: 1–5 ng/L WW: 10–20 ng/L

[72]

1 GW: Groundwater

2 SW: Surface water

3 WW: Wastewater

4 SPE: Solid phase extraction

5 MQL: Method quantification limits

6 IDL: Instrumental limit of detection

7 DW: Drinking water

8 MDL: Method detection limit

9 IQL: Instrumental quantification limit

10 Not reported

11 ICM: Iodinated Contrast Media for X-ray

7), and eluting solvents were used for the determination of the target compounds.Recoveries varied between 75 and 125% in both tap water and surface water, andlimits of detection were very low for some of the target compounds (Table 2.1).

A combined method was developed for the determination of 11 pharmaceuticals(dextropropoxyphene, diclofenac, erythromycin, ibuprofen, lofepramine, mefenamicacid, paracetamol, propanolol, sulfamethoxazole, tamoxifen, trimethoprim) and 2metabolites (N4-acetyl-sulfamethoxazole and clofibric acid) The method relied on aone-step-SPE, an HPLC separation using four different solvent gradients and detec-tion by IT-MS in consecutive reaction monitoring (CRM) mode.30A number of sta-tionary phases were evaluated for the extraction of the target compounds (IsoluteENV+, Oasis HLB, Oasis MCX, Isolute C8, Isolute C18, Varian Bond Elut C18, andPhenomenex Strata X) The latter two sorbents were identified as being the mosteffective, and Strata X was shown the better phase for extracting the majority of theselected compounds Recoveries typically higher than 60%, except for lofepramine(not recovered) and mefenamic acid (24%), were found.30 For some pharmaceuti-cals, ionization suppression due to solvent gradient is critical and must be optimizedaccordingly for individual analytes Areas of ion suppression by the matrices wereidentified by injecting a blank sample matrix (sewage effluent and freshwater) into astream of analyte causing an elevated baseline.31Only the suppression of N4-acetyl-sulfamethoxazole by the effluent matrix was a cause of concern Another methodusing IT-MS in CRM mode for the determination of an innovative list of 10 pharma-ceuticals (chloropromazine, chloroquine, closantel, fluphenazine, miconazole mid-azolam, niflumic acid, prochlorperazine, trifluoperazine, and trifluperidol) listed onthe Oslo and Paris Commission for the Protection of the Marine Environment of theNorth East Atlantic (OSPAR) as well as for fluoxetine in water was developed.32Thelimited occurrence of these compounds was thus not surprising, as some of themare used in fairly small quantities in the country studied Three extraction materi-als, Oasis HLB, the mixed mode Oasis HLB cation-exchange cartridges MCX, andPhenomenex Strata X, were tested showing recoveries greater than 60% for the thirdextraction material for almost all the compounds except for closantel and cloroquine.Method detection limits were in agreement with those reported by Hilton et al.30

using also IT-MS in CRM mode

Stolker et al.33 reported a combined methodology using LC-(+/-)ESI-MS/MSand quadrupole-time of flight mass spectrometry (LC-QqToF-MS) for the analysis

of 13 pharmaceuticals, including 4 analgesics (acetylsalicylic acid, diclofenac, profen, and paracetamol), 3 antimicrobials (sulfamethoxazole, erythromycin, andchloramphenicol), 5 blood-lipid regulators andC-blockers (fenofibrate, bezafibrate,clofibric acid, bisoprolol, and metoprolol), and the antiepileptic drug carbamazepine.The samples were extracted in HLB-MCX SPE column, and the recoveries of themethod were between 60 and 75% for all the compounds except fenofibrate, whoserecovery was too low—36%; probably because of its relatively nonpolar character,the selected extraction conditions were not optimum for this compound.33 Otherauthors24reported higher recoveries for fenofibrate—more than 90% using LiChro-lute 100 RP-18 as a stationary phase to extract this compound from waters samples.Acetylsalicylic acid presented a recovery of 195% This could be explained by thephenomenon of ion enhancement for this early eluting compound LC-QqToF-MSwas used only for confirmatory purposes