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. 2016 Apr 13;3:307–314. doi: 10.1016/j.mex.2016.04.004

Universal method to determine acidic licit and illicit drugs and personal care products in water by liquid chromatography quadrupole time-of-flight

María Jesús Andrés-Costa 1,⁎, Eric Carmona 1, Yolanda Picó 1
PMCID: PMC4840423  PMID: 27144129

Graphical abstract

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Method name: Non-target screening by SPE and UHPLC quadrupole time-of-flight

Keywords: High resolution mass spectrometry, UHPLC, emerging contaminants, water, identification, quantification

Abstract

Pharmaceuticals, illicit drugs and personal care products are emerging contaminants widely distributed in water. Currently, a number of solid-phase extraction (SPE) procedures followed by liquid chromatography tandem mass spectrometry (LC–MS/MS) have been reported. However, target analysis of selected compounds is commonly used whereas other related contaminants present in the sample remain invisible. Carmona et al. [1] described a method for determining 21 emerging contaminants by LC–MS/MS with improved mobile phases. We tested this protocol in combination with high resolution mass spectrometry using a quadrupole time-of-flight (QqTOF) instrument to get a wide non-target screening approach in order to have a broader scope and more practical method for detecting licit and illicit drugs and personal care products than traditional target methods. The essential points in the method are:

  • •

    The screening capabilities of QqTOF (ABSciex Triple TOF™) are used for detecting and identifying non-target pharmaceuticals and a large number of other emerging contaminants in water.

  • •

    The quantitative features of the instrument, the Achilles heel of the QqTOF mass spectrometers, are established for few selected compounds.

  • •

    The method may be applied to identify a large number of emerging contaminants in water. However, pre-validation will be needed to quantify them.

Method details

Many different types of pollutants have been found in environmental compartments as water. Licit and illicit drugs or personal care products are some of the so-called emerging contaminants extensively used by humans [1], [2]. A number of analytical methods are already available [3], [4], [5], [6], [7], [8], [9] to determine emerging contaminants in environmental matrices at low concentrations. However, these methods are only reported for one type of instrument. In this study, we proposed a procedure to analyse pharmaceuticals, illicit drugs, personal care products and others contaminants on different water matrices through a common method for a triple quadrupole (QqQ) and a quadrupole time-of-flight (QqTOF) mass spectrometers.

Reagents and materials

Acetaminophen, bezafibrate, bisphenol A, butylparaben, chloramphenicol, clofibric acid, diclofenac, ethylparaben, flufenamic acid, gemfibrozil, ibuprofen, indomethacin, methylparaben, naproxen, propylparaben, salicylic acid, thiamphenicol, triclocarban, triclosan and warfarin from Sigma-Aldrich (The Woodlands,Texas, USA) and tetrahydrocannabinol (THC) and 11-nor-9-carboxy-<DELTA>9-tetrahydrocannabinol (THC-COOH) from LoGiCal (Luckenwalde, Germany) were used as target analytes for QqQ analysis. Calibration standards were prepared by serial dilution of the mixed working solution. Stock and working solutions were stored at −20 °C in the dark [10].

Water used for preparation of calibration standards and LC–MS mobile phase was purified by an Elix Milli-Q system (Millipore, Billerica, MA, USA). Methanol was purchased from Panreac (Castellar del Vallès, Barcelona, Spain) and formic acid was purchased from Amresco (Solon, OH, USA). Ammonium fluoride was acquired from Alfa Aesar GmbH & Co KG (Karlsruhe, Germany).

Extraction procedure

  • (1)

    Vacuum filter the samples (250 mL) through 0.45 μm retention capacity glass fiber filter of 90 mm diameter by Advantec (Toyo Roshi Kaisha, Ltd., Japan) using a Bücher funnel (with the filter) over a 250 mL Kitasato flask with 400 mbar h−1 Pa−1 of vacuum, to remove solid particles before the solid phase extraction (SPE).

  • (2)

    Put the Phenomenex Strata-X 33u Polymeric Reversed Phase (200 mg/6 mL) cartridges (Phenomenex, Torrance, Ca, USA) into a 12 port vacuum manifold Supelco Visiprep 57030-U of Sigma-Aldrich (St. Louis, MO, EEUU).

  • (3)

    Condition the cartridge with 6 mL methanol and 6 mL of Milli-Q water both with 400 mba h−1 Pa−1 vacuum.

  • (4)

    Pass the samples through the cartridges under previous vacuum at a flow rate of 10 mL min−1.

  • (5)

    Wash the cartridges with 6 mL of Milli-Q water.

  • (6)

    Dry the cartridges under vacuum for 15 min.

  • (7)

    Elute the analytes on a 15 mL Falcon tube VWR (Radnor, PA, USA) with 6 mL of methanol and then 3 mL of a methanol–dichloromethane solution (1:1, v/v) at gravity flow.

  • (8)

    Evaporate the extracts to dryness at 40 °C using a combined sample concentrator model SBHCONC/1 and a heating plate model SBH130D/3 both manufactured by Stuart® (Stafford, UK).

  • (9)

    Redissolve the residue in 1 mL of water-methanol (70:30, v/v) by agitation and ultrasonication for 1 min and pass the extract to 2 mL amber vials with stoppers 99 mm + Septum Sil/PTFE, both manufactured by Análisis Vínicos S.L. (Tomelloso, Spain).

UHPLC-QqTOF-MS/MS conditions

The chromatography was performed with an Agilent 1260 Infinity (Agilent, Waldbronn, Germany) using an Agilent Poroshell EC-C18 maintained at temperature of 30 °C. A constant flow rate of 0.2 mL min−1 was used. The mobile phase consists of two solvents, 2.5 mM ammonium fluoride in methanol (as organic solvent) and 2.5 mM ammonium fluoride in water (as aqueous solvent). The UHPLC system was coupled to a hybrid QqTOF ABSciex Triple TOF™ 5600 (Framingham, MA, USA). The MS acquisition was performed using negative ionization (NI) and scan mass spectra between m/z 100–700 with the Turbo Ionspray source. The MS parameters were: ion spray voltage, 5000 V; declustering potential (DP), 120 V; collision energy (CE), 10; temperature 400 °C with curtain gas (CUR) 25 (arbitrary units); ion source gas 1 (GS1) 50 and ion source gas 2 (GS2) 50. The QqTOF-MS/MS instrument was calibrated after every three samples using external reference compounds. The MS/MS acquisition was also performed using information-dependent acquisition (IDA) following operating parameters: declustering potential two (DP2), 110 V; ion release delay (IRD), 67 V; ion release width (IRW), 25 V; IDA MS/MS was performed at a fixed CE of 40 V, ions that exceeded 100 cps and ion tolerance of 50 mDa (isotopes higher than 4 Da were excluded). Data acquisition and processing was carried out using software Analyst (Framingham, MA, USA), Peak View 1.0 with the application XIC manager and MultiQuant 2.0.

Sampling

The developed method was applied to 21 influent and 21 effluent samples collected from three wastewater treatment plants (WWTPs) of metropolitan area of Valencia and 25 surface waters from Túria River. Wastewater samples were 24-h composite samples and river samples were grab ones. All samples were stored in polyethylene terephthalate (PET) bottles and once arrived at the laboratory, immediately frozen at −20 °C until analysis to prevent degradation of contaminants.

Validation of the analytical method

Validation of the analytical method was performed partly according to the Commission Decision 2002/657/EC [11] and partly to the Eurachem guide [12] on that subject since none of them has a binding nature for water contaminants.

Table 1 shows limit of quantification (LOQ), matrix effect (ME), recovery and relative standard deviation (RSD) obtained by UHPLC-QqTOF determination. The method provides LOQ between 1 and 150 ng L−1, recoveries from 39% to 115%, matrix effects ranged from 6 to −52% and relative standard deviations (RSD) lower than 21%. The linearity was determined by calibration curves from LOQ- 5000 ng L−1 in water-methanol (70:30) or as a matrix matched standards, with linear coefficients of determination (R2) ≥ 0.99, except for salicylic acid (R2) ≥ 0.98. Table S1 in Supplementary information depicts these parameters for UHPLC-QqQ.

Table 1.

Method performance parameters: limit of quantification (LOQ, ng L−1), absolute recoveries (%), method repeatability (RSD, %) and matrix effect (ME, %) using QqTOF for effluent, influent and river water samples.

Analyte WWTP Influent
 WWTP Effluent
 River water
LOQ (ng L−1) Recovery (%) RSD (%) ME (%) LOQ (ng L−1) Recovery (%) RSD (%) ME (%) LOQ (ng L−1) Recovery (%) RSD (%) ME (%)
Acetaminophen 30 84 15 −33 15 86 14 −26 15 95 10 −12
Bezafibrate 30 75 15 −32 20 78 13 −28 10 85 11 −16
Bisphenol A 20 80 19 −12 10 80 12 −10 5 89 17 −18
Butylparaben 10 79 17 −19 5 101 18 −19 5 115 12 −10
Chloramphenicol 50 62 11 −36 20 75 17 −32 20 92 10 −23
Clofibric acid 100 61 12 −41 30 70 21 −31 20 76 20 −31
Diclofenac 150 82 10 −47 40 91 15 −45 30 98 12 −15
Ethylparaben 50 81 13 −31 25 95 11 −35 20 96 18 −28
Flufenamic acid 40 71 14 −29 30 69 15 −18 5 89 15 −16
Gemfibrozil 10 61 9 −29 10 67 12 −20 10 78 17 −9
Ibuprofen 100 80 11 −32 80 92 18 −15 50 90 12 −11
Indomethacin 50 78 15 −15 50 98 10 −11 30 79 13 −2
Methylparaben 30 80 9 −33 10 90 12 −35 5 89 20 −19
Naproxen 50 71 17 −30 20 85 18 −32 30 89 17 −21
Propylparaben 50 71 21 −31 5 81 13 −24 10 102 13 −5
Salicylic Acid 100 39 10 −52 50 62 18 −39 20 61 25 −13
THC 50 48 18 −9 20 52 17 −10 10 54 19 −6
THC-COOH 10 50 9 −19 10 63 14 −19 5 62 15 6
Thiamphenicol 120 74 11 −21 100 92 19 −20 80 89 18 −7
Triclocarban 50 85 13 −19 5 79 15 −21 5 91 14 5
Triclosan 20 82 19 −10 20 91 15 2 10 76 15 −12
Warfarin 30 73 8 −11 20 84 12 −22 1 86 13 −13
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Linearity: linear coefficients (R2) were ≥ 0.99 in all cases, except for salicylic acid (R2 ≥ 0.98); LOQ was established as the concentration that, after extraction, gives a UHPLC peak height value 1.0 × 104; Recoveries and relative standard deviations (RSDs) of selected compounds were calculated in samples spiked at 100 ng L−1 subtracting the peak areas corresponding to native analytes in the sample and tested in quintuplicate; Matrix effect was evaluated by comparing the slope of the calibration curves obtained for spiked influent, effluent or surface water extracts with the slope of that obtained for standard prepared in water-methanol (70:30, v/v) spiked at the same level.

Table 2 shows the quantification of the selected analytes in the different water samples, as mean value ± RSD using QqQ and QqTOF instruments. The quantification of the detected compounds in the three matrices with QqQ was carried out according to the instrumental conditions previously reported [1] (see Table S2 in Supplementary information). The quantification of detected compounds with QqTOF was performed using MultiQuant 2.0 software. The results of QqQ and QqTOF were very similar, which confirms that the method is valid for both.

Table 2.

Comparison of the quantitative results obtained using the ABSciex TripleTOF™ 5600 (QqTOF) and a more traditional triple quadrupole (QqQ) for influent, effluent and river water samples.

Compoundsa Sample 1 Influent (ng L−1)b
 Sample 2 Effluent (ng L−1)b
 Sample 3 River Water (ng L−1)b
QqTOF QQQ QqTOF QQQ QqTOF QQQ
Acetaminophen 2114 2497 31 21 139 177
Bezafibrate 35 47 11 15 12 7
Bisphenol A 495 571 96 72 36 41
Butylparaben 35 22 n.d. n.d. 7 5
Chloroamphenicol n.d. n.d. n.d. n.d. 62 68
Clofibric acid 12 7 n.d. n.d. n.d. n.d.
Diclofenac 296 331 109 173 39 33
Ethylparaben 99 113 49 71 n.d. 6
Flufenamic acid 75 90 39 48 29 22
Gemfibrozil 105 155 n.d. 5 31 34
Ibuprofen 1796 1978 n.d. n.d. 159 153
Indomethacin n.d. 7 n.d. 18 n.d. n.d.
Methylparaben 259 331 121 99 19 24
Naproxen 2963 3327 21 10 38 36
Propylparaben 494 519 36 45 11 12
Salicylic acid 596 778 n.d. n.d. 29 22
THC n.d. n.d n.d. n.d. n.d. n.d.
THC-COOH 409 592 n.d. n.d. 21 23
Thiamphenicol n.d. n.d. n.d. n.d. n.d. 10
Triclocarban n.d. 7 n.d. n.d. n.d. n.d.
Triclosan 752 926 n.d n.d. n.d. n.d.
Warfarin n.d. 11 29 31 33 54
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n.d.: non-detected.

a

Only analytes that occur in any of the samples.

b

Average (SD) n = 3.

Table 3 presents, mass (Da), adduct, extraction mass (Da), mass error (ppm), retention time (RT) and intensity of the selected compounds (spiked Milli-Q water with 100 ng L−1). The identification of target and non-target was carried out against the XIC manager Table with data of 1212 pharmaceuticals, 546 pesticides, 378 polyphenols and 233 mycotoxins. Furthermore, a total of 86 ± 9 pharmaceuticals, 2 ± 1 pesticides and 14 ± 3 other compounds were detected in influent samples; 45 ± 14 pharmaceuticals, 1 ± 1 pesticides and 7 ± 3 other compounds were detected in effluent samples, and 20 ± 6 pharmaceuticals, 1 ± 1 pesticides and 5 ± 3 other compounds in river water samples. Fig. 1 illustrates the identification of acetaminophen (paracetamol) and Fig. 2 of the non-selected hydrochlorothiazide to show the identification system capabilities. Fig. S1 in Supplementary information shows the extracted ion chromatogram of all substances present in water and the non-target compound identification of theophylline in influent wastewater sample.

Table 3.

Experimental parameters used for the identification of the target analytes (n = 5).

Name Mass (Da) Adduct Extraction Mass (Da) Found at mass (Da) Error ppm Error (mDa) Found at RT (min) Intensity
Acetaminophen 151.06333 −H 150.05605 150.05612 0.4 0.3 1.12 35326
Bezafibrate 361.10809 −H 360.10427 360.10409 −0.8 −0.2 14.36 40634
Bisphenol A 228.11504 −H 227.11496 227.11431 −2 −0.7 14.86 73687
Butylparaben 194.09430 −H 193.09421 193.09438 0.8 0.2 13.31 70035
Chloramphenicol 322.01233 −H 321.01129 321.01174 1.2 0.4 10.38 63257
Clofibric acid 214.03967 −H 213.03037 213.02899 −4.2 −1.4 9.89 55963
Diclofenac 295.01669 −H 294.01596 294.01617 0.6 0.2 15.87 75981
Ethylparaben 166.06299 −H 165.06196 165.06323 3.3 1.3 12.36 62257
Flufenamic acid 281.06636 −H 280.05909 280.05942 1.2 0.3 14.63 45704
Gemfibrozil 250.15689 −H 249.14962 249.1498 0.7 0.2 14.59 64434
Ibuprofen 206.13068 −H 205.1234 205.12357 0.8 0.2 14.52 70035
Indomethacin 357.07678 −H 356.07536 356.07640 2.9 2.9 16.25 59363
Methylparaben 152.04735 −H 151.04631 151.04657 0.9 0.9 9.64 61259
Naproxen 230.09430 −H 229.09411 229.09489 2.6 2.6 13.91 79632
Propylparaben 180.07864 −H 179.07796 179.07803 0.4 0.4 14.47 42963
Salicylic acid 138.03169 −H 137.03165 137.03172 0.4 0.4 2.56 49332
THC 314.22458 −H 313.2173 313.21728 −0.1 0 16.11 44379
THC-COOH 344.19876 −H 343.19148 343.19193 1.3 0.4 14.63 73637
Thiamphenicol 355.00479 −H 354.00432 354.00499 1.5 1.5 2.67 75336
Triclocarban 313.97806 −H 312.97124 312.97111 −0.4 −0.4 15.63 48525
Triclosan 287.95117 −H 286.90985 286.91012 1 1 16.57 71225
Warfarin 308.10486 −H 307.10362 307.10348 −0.4 −0.4 10.78 79325
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RT: retention time.

Fig. 1.

Fig. 1

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MS and MS/MS Spectra of target analyte acetaminophen (paracetamol).

Fig. 2.

Fig. 2

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MS and MS/MS Spectra of non-target analyte hydrochlorothiazide.

Additional information

Background

There are hundreds, even thousands of emerging contaminants that can occur in water. Traditionally, the scheme used for their determination involves generic sample preparation procedures able to extract almost any of them, and target determination for the unique and highly specific detection of the selected contaminant(s) [3], [4], [5]. This scheme is time-consuming (ca. 30 min each chromatographic run for a specific group of contaminants) and do not have versatility to detect unexpected emerging contaminants not selected for the target analysis. Currently, there are some reports of non-target detection through high resolution mass spectrometry that provide full scan information as well as compound fragmentation (any m/z signal from the sample extract) [2], [8]. However, high resolution mass spectrometer can provide inaccurate quantification [8] or enough sensitivity [2]. Latest generation instruments have improved their quantification possibilities as well as the identification capabilities of any unexpected substance by the application information dependent acquisition (IDA) modes that automatically provide MS/MS spectra of the most intense precursor ions (without previous selection) as an additional confirmation of the detected compounds [2].

The few examples of these broad screening systems are mostly focus on the positive ionization mode because there are more contaminants that ionized in positive mode and their MS sensitivity is higher. When mass spectrometry is combined with liquid chromatography (recommended for polar compounds as the emerging contaminants) the commonly used additives of the mobile phases (volatile salts and acids) enhanced the ionization in the positive ionization mode and inhibited it in the negative ionization one. Acidic contaminants, commonly better ionized by negative ionization are more difficult to detect and frequently the sensitivity does not reach the low levels emerging contaminants are present in water. Recently, Petrie et al. [9] demonstrated a substantial improvement of ionization efficiency in negative ionization mode by using NH4F enriched mobile phase to metabolomics studies. Our previously reported method using NH4F as mobile phase additive instead of more conventional substances also improved the ionization efficiency of the 21 selected compounds in a reproducible way using a triple quad instrument [1]. These results were recently confirmed for wide range of compounds [10]. Our current study proves that the addition of NH4F to the mobile phase instead of more conventional ammonium formate is also successful for the simultaneous determination of acidic contaminants in water by UHPLC-QqTOF [13], [14] increasing sensitivity and quantification capabilities. The strong basicity of the fluoride anion (F−) in the gas phase increases deprotonation of basic analytes.

The results showed good agreement between both systems for the analysed samples. For QqQ, naproxen was the pharmaceutical at highest concentration (3327 ng L−1) at the influent of the WWTPs which was in a lower concentration at the effluent (10 ng L−1). Indomethacin, clofibric acid and triclocarban were the lowest detected with 7 ng L−1 in influent samples. Regarding effluent samples, the highest detected concentration was diclofenac with 173 ng L−1, being the gemfibrozil the compound with the lowest (5 ng L−1). Finally, for river waters, the concentration of target analytes was, in general, lower than WWTPs samples being the compound in major concentration the acetaminophen with 177 ng L−1 and ibuprofen with 153 ng L−1. Concerning the concentration calculated with QqTOF, the mean concentration levels detected in influent samples ranged from 12 ng L−1 (clofibric acid) to 2963 ng L−1 (naproxen) being naproxen the most detected compound as in the case of QqQ. In the effluent the highest concentrations were methylparaben (121 ng L−1) followed by diclofenac (109 ng L−1). In river waters the concentration levels ranged from 7 ng L−1 (butylparaben) to 159 ng L−1 (ibuprofen). These results show a good correlation between both techniques as in our previous paper [3].

Acknowledgements

This work has been supported by the Spanish Ministry of Economy and Competitiveness through the project GCL2015-64454-C2-1-R and the University of Valencia through the project (UV-INV-AE15-348995). We thank to the mass spectrometry section of the Central Services of Support to the Experimental Research (SCSIE) of the Universitat de València for providing us access to the Linear QTOF (Applied Biosciences) and especially to Dr. Sales Galletero to help us in this study. M. Jesús Andrés-Costa also thanks the Spanish Ministry of Economy and Competitiveness for her FPI grant. We also thank to the Public Entity of Wastewater Treatment (EPSAR) and especially to Fernando Llavador. Enrique Albors, Gloria Fayos and all the personal of the WWTPs (Aguas de Valencia, Spain) are acknowledged for their help with the sampling.

MethodsX thanks the reviewers (anonymous) of this article for taking the time to provide valuable feedback.

Footnotes

Appendix A

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mex.2016.04.004.

Appendix A. Supplementary data

The following are Supplementary data to this article:

mmc1.docx (1.9MB, docx)

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