Application of aqueous two-phase systems for the extraction of pharmaceutical compounds from water samples

Journal Pre-proof Application of aqueous two-phase systems for the extraction of pharmaceutical compounds from water samples

Roberta C. Assis, Aparecida B. Mageste, Leandro R. de Lemos, Ricardo Mathias Orlando, Guilherme D. Rodrigues PII:

S0167-7322(19)36140-9

DOI:

https://doi.org/10.1016/j.molliq.2019.112411

Reference:

MOLLIQ 112411

To appear in:

Journal of Molecular Liquids

Received date:

5 November 2019

Revised date:

20 December 2019

Accepted date:

26 December 2019

Please cite this article as: R.C. Assis, A.B. Mageste, L.R. de Lemos, et al., Application of aqueous two-phase systems for the extraction of pharmaceutical compounds from water samples, Journal of Molecular Liquids(2020), https://doi.org/10.1016/ j.molliq.2019.112411

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© 2020 Published by Elsevier.

Journal Pre-proof APPLICATION OF AQUEOUS TWO-PHASE SYSTEMS FOR THE EXTRACTION OF PHARMACEUTICAL COMPOUNDS FROM WATER SAMPLES

Roberta C. Assisa, 1, Aparecida B. Magesteb, Leandro R. de Lemosc, Ricardo Mathias Orlandoa, Guilherme D. Rodriguesa, 1*

Universidade Federal de Minas Gerais, DQ/ICEX, Belo Horizonte, MG, Brasil,

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a

Universidade Federal de Ouro Preto, DQUI/ICEB, Ouro Preto, MG, Brasil, 35.450-

-p

b

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31.270-901

c

re

000

Universidade Federal dos Vales do Jequitinhonha e Mucuri, DEQUI, Diamantina, MG,

Laboratório de Soluções Analíticas Verdes

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1

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Brasil, 39.100-000

*Corresponding author:

Guilherme Dias Rodrigues Phone: +55 31 34095738 Fax: +55 31 34095700

e-mail:[email protected]

1

Journal Pre-proof Abstract In this study, the proposal was to use aqueous two-phase systems (ATPS) as a sample preparation technique for the determination of five pharmaceuticals, classified as emerging contaminants (EC): ibuprofen, paracetamol, ciprofloxacin, norfloxacin and amoxicillin. The evaluation of this study was performed through the partition coefficient (K) of each pharmaceutical by varying some parameters of the system, such as the pH value of the medium, the nature of the ATPS-forming electrolyte and

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polymer, the tie-line length (TLL), the system temperature and the mass ratio between

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the top and bottom phases of the ATPS. Values of K between 9.30 and 1150 were

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obtained for the five pharmaceuticals during the system optimization. The ATPS also

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proved to be efficient as a sample preparation technique in the partition of the studied pharmaceuticals when applied to water samples, including drinking water, surface water

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and filtered water from a water treatment plant. The values of the partition coefficients

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found in these complex samples ranged from 2.49 to 74.2.

Keywords: Aqueous two-phase systems; Extraction; Emerging contaminants; Pharmaceuticals; Water samples.

2

Journal Pre-proof 1. Introduction Emerging contaminants (EC) are defined as compounds used in industry, agriculture or personal care that, even in low concentrations in water, have effects on the ecosystem [1-3]. Some examples of these compounds classified as EC are pesticides, pharmaceuticals, illicit drugs, flame retardants, surfactants, hormones and caffeine [4-6]. These substances are released in water, generally by incorrect disposal, excretion

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or by the disposal of treated or untreated effluents into the environment. Conventional

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treatment in water treatment plants (WTP) can remove EC, through the stages of

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coagulation and disinfection of the treatment, the stages in which the largest removal of

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EC occurs. However, some studies have demonstrated that WTP is not always able to completely remove all contaminants during the operating time. Thus, EC can be found

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tap water [7-9].

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in low concentrations (pg, ng or μg L-1) in water bodies such as lakes, rivers or even in

Studies on the effects caused by EC persistence in water have demonstrated

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reproductive abnormalities, effects on sperm production, bacterial resistance, morphological damage and carcinogenic effects [10-14]. Despite the already known consequences to the environment, there is still no limit value in current legislation for most of these compounds. Only some pesticides are already at maximum values in water for human consumption (Portaria n° 5 de 28 de setembro de 2017 do Ministério da Saúde) and are on the list of priority substances of the European Commission [15,16]. The most commonly used techniques for EC removal from water are adsorption, solid-phase extraction (SPE) and advanced oxidation processes (AOPs) [17-21]. These techniques present well-established results for the extraction or removal of several

3

Journal Pre-proof analytes, including EC. However, they have disadvantages, such as high cost, high consumption of electricity, large volume of organic solvents and, consequently, large amounts of waste, the possibility of formation of by-products with a higher degree of toxicity and reagent storage risks [22]. Aqueous two-phase system (ATPS) is a liquid-liquid extraction technique that does not use organic solvents. It is composed mainly of water and is formed by two heterogeneous phases, generally composed of a polymer and an electrolyte. Therefore, it

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is considered a greener technique with low environmental impact, since the system is

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mainly formed by water and other components that are biodegradable, non-toxic and

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non-flammable [23].

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ATPS presents other advantages, such as simplicity, low cost and similarity with the cellular environment, since it is composed mainly of water [24]. ATPS also has a

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low interfacial tension [25] and the large-scale application is possible due to the short

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time required for phase separation. In addition, ATPS has the ability to extract both neutral and charged species to the top phase [26, 27] and to pre-concentrate, enabling

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the determination of substances at low levels, such as EC [28-30]. Roxithromycin, a semi-synthetic antibiotic used in human and animal medicine, was efficiently extracted by an ATPS formed by an ionic liquid (1-butyl-3methylimidazolium tetrafluoroborate, [bmim] BF4) + Na2CO3. Under the optimal conditions of the system, this compound was extracted and analyzed by molecular fluorescence spectrophotometry; the mean recovery of this compound in water samples was 90.7% [31]. A great number of studies reporting on pharmaceuticals are present in the literature due to the high degree of consumption by the population and their incorrect disposal. These include ibuprofen, paracetamol, amoxicillin, ciprofloxacin and

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Journal Pre-proof norfloxacin, which are very common pharmaceuticals found in high amounts in water bodies [32-35]. The aim of this work was to study the partition behavior of pharmaceuticals employing ATPS, a low environmental impact liquid-liquid extraction technique. The main experimental parameters of this system (pH value, nature of ATPSforming electrolyte and polymer, tie-line length, temperature and mass ratio of top and bottom phases) were optimized for the extraction and determination of anti-

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inflammatories and antibiotics (ibuprofen, paracetamol, amoxicillin, ciprofloxacin

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and norfloxacin) in water samples.

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2. Experimental 2.1. Equipments

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In all experiments, a pH meter (HI 2221, Hanna) was used to perform pH

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adjustments of the deionized water used in the preparation of ATPS stock solutions. Other equipments included an analytical balance (AUY 220, Shimadzu) with

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uncertainty ± 0.0001 g, a centrifuge (Excelsa II, FANEN) to accelerate phases separation and an ultra-thermostatic bath with uncertainty ± 0.1 ºC (MA 184, Marconi) to establish the thermodynamic equilibrium of the samples. Analytical signals were obtained through a UV-Vis spectrophotometer (Hitachi U-2010) using a 1.0 cm optical quartz cuvette at the maximum wavelengths of ibuprofen (221 nm), paracetamol (242 nm), ciprofloxacin (275 nm), norfloxacin (275 nm) and amoxicillin (230 nm), previously determined by obtaining the respective molecular absorption spectra.

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Journal Pre-proof 2.2. Reagents The polymer PEO1500 (composition: HO(C2H4O)nH and molar mass 1500 g mol−1) obtained from Vetec, and the copolymers L64 (composition: (EO)13(PO)30(EO)13 and molar mass 2900 g mol−1) and L35 (composition: (EO)11(PO)16(EO)11 and molar mass 1900 g mol−1), both manufactured by Sigma-Aldrich (being PO blocks of propylene oxide and EO blocks of ethylene oxide) were used in the composition of the ATPS. The salts anhydrous sodium sulfate (Na2SO4, 99.0%), sodium tartrate

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(Na2C4H4O6.2H2O, 99.5%), sodium citrate (Na3C6H5O2.2H2O, 99.0%), sodium

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carbonate (Na2CO3, 99.0%) and lithium sulfate (Li2SO4.H2O, 99.0%) were obtained

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from Vetec, and magnesium sulfate (MgSO4.7H2O, 98.0%) was manufactured by Synth.

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In all experiments, deionized water (resistivity = 18.2 MΩ·cm at 298.15 K) was used, obtained from a Simplicity UV ultrapure water system (Millipore). For the pH

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adjustments, sulfuric acid (H2SO4, 96.0%) obtained from Merck and sodium hydroxide

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(NaOH, 99.0%) purchased from Vetec were used. The pharmaceutical ciprofloxacin hydrochloride 500 mg was obtained from

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Geolab, norfloxacin 400 mg from Pharmascience, ibuprofen 600 mg from Teuto, paracetamol 750 mg from Medquímica and amoxicillin 500 mg from Neoquímica. Table 1 shows the chemical structures of the studied pharmaceuticals, as well as their main properties.

Table 1. Chemical structures of the studied pharmaceuticals and their properties: solubility in water (at 298.15 K), acid dissociation constant (pKa) and octanol/water partition coefficient (log Kow) [5, 36, 37].

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Journal Pre-proof

Solubility in water (mg L-1)

pKa

Log Kow

Ibuprofen

2.10 x 101

4.91

3.97

Paracetamol

1.40 x 104

9.38

0.46

Ciprofloxacin

3.00 x 104

6.27; 8.87

0.28

1.78 x 105

6.34; 8.75

0.46

3.43 x 103

2.68; 7.49; 9.63

0.87

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Structural Formula

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Pharmaceutical

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-p

Norfloxacin

2.3.

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Amoxicillin

ATPS composition and extraction procedure

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Aqueous stock solutions of polymer and electrolyte, which were used as top phase (TP) and bottom phase (BP) of ATPS assays, respectively, were prepared in deionized water after pH adjustment employing sulfuric acid or sodium hydroxide. The concentrations of these solutions were obtained through of the predetermined tie-line length (TLL) of the system (Equation 1), obtained from phase diagrams found in the literature (Table 2).

TLL = [(CPTP − CPBP )2 + (CSTP − CSBP )2]1/2

Eq. 1

7

Journal Pre-proof where CPTP and CPBP are the concentrations of the polymer and CSTP and CSBP are the concentrations of the salt in % (w/w) in the top and bottom phases, respectively.

Table 2. Composition of the polymer, salt and water of the studied systems. Global Composition (% m/m):

Systems

Temperature (K)

Polymer: 22.22 Salt: 11.59

298.15

PEO1500 + Li2SO4.H2O+ H2O

Polymer: 25.16 Salt: 11.29

298.15

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PEO1500 + Na2SO4 + H2O

298.15

Polymer: 26.55 Salt: 11.33

283.15

Polymer: 28.99 Salt: 11.26

313.15

Polymer: 19.28 Salt: 14.20

298.15

Polymer: 18.62 Salt: 13.95

298.15

Polymer: 23.98 Salt: 6.11

298.15

L35 + Na2C4H4O6.2H2O + H2O

Polymer: 25.35 Salt: 11.11

298.15

L35 + Na3C6H5O7.2H2O + H2O

Polymer: 24.68 Salt: 10.79

298.15

Polymer: 24.75 – 30.18* Salt: 8.29 – 12.84

298.15

Polymer: 24.74 Salt: 5.12

313.15

Polymer: 24.25 Salt: 8.73

298.15

Polymer: 23.39 – 32.60* Salt: 7.77 – 11.97

298.15

Polymer: 25.76 Salt: 9.25

283.15

Polymer: 23.35 Salt: 5.31

313.15

Polymer: 25.59 Salt: 7.60

298.15

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Polymer: 22.01 – 28.54* Salt: 8.91 – 11.54

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PEO1500 + Na2C4H4O6.2H2O + H2O

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PEO1500 + MgSO4.7H2O+ H2O

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L64 + Na2SO4 + H2O

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PEO1500 + Na3C6H5O7.2H2O + H2O

L35 + Na2SO4 + H2O

L35 + Li2SO4.H2O + H2O

L35 + MgSO4.7H2O + H2O

L35 + Na2CO3 + H2O

References

[38]

[39]

[40]

[41]

[42]

[43]

8

Journal Pre-proof * Range of ATPS global compositions studied in different TLL.

The two-phase systems described were obtained by mixing the polymer and electrolyte solutions in 50 mL centrifuge tubes according to the desired overall composition (Table 2). The tubes were manually stirred for 3 min, centrifuged for 20 min at 560 ×g to accelerate the phase separation and placed in a 24-hour thermostatic bath at 298.15 K to establish the thermodynamic equilibrium of the phases.

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After thermodynamic equilibrium, the phases were collected separately and the

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TP was used as the solvent in the preparation of the pharmaceutical solutions. The

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concentration of the pharmaceuticals was constant and equal to 1000 mg kg−1 in TP in

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each experiment.

Then, 2.0000 g of each phase (TP containing the pharmaceutical and the BP

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collected from the ATPS stock) were weighed and placed in a 15 mL Falcon tube,

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except in experiments where the masses of the phases were varied. Pharmaceuticals were studied separately, and all experiments were performed in duplicate, at

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atmospheric pressure and 298.15 K (except in experiments where the temperature was varied). One blank was prepared for each of the different assays. The 15 mL tubes were stirred, centrifuged and left in a thermostatic bath in the same way as the ATPS stocks assays. Posteriorly, the TP and BP of each tube were collected using syringes and diluted appropriately with deionized water for analysis in the UV-Vis spectrophotometer.

2.4.

Parameters optimized in the extraction

Several parameters that influence the partitioning of the analytes in the ATPS were evaluated to obtain the optimal partition conditions, such as the pH of the medium

9

Journal Pre-proof (2.00, 4.00, 6.00, 8.00 and 10.00), the nature of ATPS-forming electrolyte (Na2SO4, Na2CO3, Li2SO4·H2O, MgSO4·7H2O, Na2C4H4O6·2H2O and Na3C6H5O7·2H2O), the nature of the polymer (PEO1500, L64, and L35), the tie-line length of the system, the controlled temperature of the thermostatic bath (283.15 K, 298.15 K and 313.15 K) and the mass ratio between the bottom (mBP) and top (mTP) of the system (mBP/mTP: 1/1, 2/1,

2.5.

Evaluation of the partition process

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3/1, 4/1 and 5/1).

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The partition coefficient (K) of the pharmaceuticals in each assay was calculated

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from the ratio of the molecular absorption signals obtained from the pharmaceuticals in

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the two system phases. Thus, K was calculated using Equation 2:

Eq. 2

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K=

where AbsTP and AbsBP are the signals of the absorbance of the top and bottom phases

phase.

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respectively at the specified wavelength. And fTP and fBP are the dilution factors for each

In addition, through the calculated K values, thermodynamic parameters of partition were also determined. The Gibbs free energy variation according to K of the assays at different temperatures was calculated through the following thermodynamic relationship (Equation 3):

Eq. 3

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Journal Pre-proof where

is the molar Gibbs free energy variation of the pharmaceutical partitioned (J

mol-1); T is the temperature at which the experiment was performed (K); R is the real gas constant (8.314 J K-1 mol-1); and K is the partition coefficient of the pharmaceutical. Another parameter calculated was the enthalpy variation (ΔpH) in the pharmaceutical partitioning process. This was obtained by the van't Hoff approximation that relates the variation of the equilibrium constant with temperature variation

Eq. 4

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( )

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linear regression of the constructed graph (lnK x 1/T).

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(Equation 4). ΔpH was obtained through the slope value of the curve resulting from the

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where ΔpH is the molar enthalpy variation of the pharmaceutical partitioned (J mol-1); T is the temperature at which the experiment was performed (K); R is the real gas constant

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(8.314 J K-1 mol-1); ΔpS is the variation of molar entropy in the partitioning process of

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each pharmaceutical (J mol-1 K-1); and K is the partition coefficient of the pharmaceutical.

Entropy variation (ΔpS) of the partitioning process was determined from the Gibbs free energy equation (Equation 5), since the other parameters were found previously.

Eq. 5

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Journal Pre-proof 2.6.

Application of the optimized method in water samples

After finding the optimal ATPS conditions for each pharmaceutical, an experiment to obtain a condition that would provide an adequate extraction of all pharmaceuticals studied was performed. This strategy was adopted to facilitate the analysis of these pharmaceuticals in three different water samples: drinking water collected from a tap in the chemistry department of the Federal University of Minas Gerais, surface water collected at the

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edge of the Pampulha lagoon located in the city of Belo Horizonte-MG and a sample of

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water obtained in a filter before the disinfection step of the WTP of the Autonomous

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Water and Sewage Service of the city of Viçosa-MG. These samples are of different

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origins and received different treatments, so they do not have the same composition and could have different amounts of pharmaceuticals present.

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The five pharmaceuticals studied were added separately to three water samples:

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drinking water, surface water and filtered water from a WTP. Samples were first centrifuged and then fortified in a concentration equal to 1000 mg kg-1. The ATPS

3.

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assays with the water samples followed the entire procedure described in section 2.3.

Results and Discussion

Partitioning of an analyte in the ATPS, without any extracting agent, is governed by its affinity with the electrolyte present in the BP or with the polymer/copolymer in the TP of the system. The studied pharmaceuticals, being organic analytes, remain more easily in the TP of the system without the use of extracts. This is due to the higher hydrophobic character of the polymer phase and also to the micelles formed by the copolymers above the critical micelle concentration (CMC) [44].

12

Journal Pre-proof Several experimental parameters were varied to study and increase the partitioning of the analyte, such as the pH of the medium, the composition of the ATPS, the TLL of the system and the temperature. All of these factors were studied individually.

3.1.

Influence of the ATPS-forming polymer

The nature of the ATPS-forming polymer in the partition of each pharmaceutical

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was evaluated using PEO1500, L35 or L64. ATPS composed of: PEO1500, L35 or L64

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+ Na2SO4 + H2O, at pH 2.00 and TLL = 46.97; 46.77; 47.82% w/w, respectively, were

80

re

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used (Figure 1).

14 L64 L35 PEO1500

60

C)

5

10

50

K

K

40

L64 L35 PEO1500

4

8

K

6

L64 L35 PEO1500

B) 12

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A)

70

3

na

6

30

2

4

20

1

2

10 0

0

0

Paracetamol

Ciprofloxacin

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Ibuprofen

Norfloxacin

Amoxicillin

Fig. 1. Effect of the ATPS-forming polymer/copolymer (L35, L64 and PEO1500) on the pharmaceuticals partitioning process.

According

to

Figure

1,

the

pharmaceuticals

ibuprofen,

paracetamol,

ciprofloxacin and norfloxacin were preferentially concentrated in TP in the ATPS composed of copolymer L35, with K values equal to 76.0, 20.2, 12.4 and 12.3, respectively. For amoxicillin, the highest value (K = 5.49) was obtained in the presence of PEO1500.

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Journal Pre-proof Although the analytes are organic compounds and, at first, have high affinity for TP due to their higher hydrophobicity, these pharmaceuticals have polar groups. Thus, depending on the pH value of the medium, the compounds are charged or neutral. At pH 2.00, these pharmaceuticals have a positive or a neutral charge due to their pKa values, which increases their affinity for less hydrophobic polymers and for BP. Among these pharmaceuticals, ibuprofen and amoxicillin demonstrated that their partitioning processes were more susceptible to variations in the polymers/copolymers.

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Ibuprofen presented the lowest solubility in water among the studied compounds, so

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higher K values were obtained when working with copolymers instead of PEO1500,

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which is more hydrophilic. In contrast, amoxicillin also has low solubility in water, but

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has three ionizable groups in its molecular structure. The pKa1 value of 2.68 could explain why this pharmaceutical presented the highest K value in the ATPS composed

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of PEO1500.

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Ibuprofen, paracetamol, ciprofloxacin and norfloxacin had higher affinity for L35 ((EO)11(PO)16(EO)11), a polymer containing 50% EO and molar mass 1900 g mol-1,

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which corresponds to an intermediate hydrophobicity between L64 (40% EO) and PEO1500.

Thus, L35 was chosen to compose the ATPS in the partitioning studies of the pharmaceuticals ibuprofen, paracetamol, ciprofloxacin and norfloxacin, while PEO1500 was chosen for the studies on amoxicillin.

3.2.

Influence of the ATPS-forming electrolyte

When the nature of the electrolytes in the ATPS composition was varied, six different

salts

were

chosen:

Na2SO4,

Na2CO3,

Li2SO4·H2O,

MgSO4·7H2O,

Na2C4H4O6·2H2O and Na3C6H5O7·2H2O to form the BP of the systems formed by L35

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Journal Pre-proof or PEO1500 in TP, since these were chosen in the previous study. The K values obtained in this study are presented in the Figure 2.

Li2SO4.H2O

A)

450 400 350

12

Na2C4H4O6.2H2O Na3C6H5O2.2H2O

10

Li2SO4.H2O MgSO4.7H2O Na3C6H5O2.2H2O

C)

8

Na2C4H4O6.2H2O Na2SO4

Na2CO3 Na2SO4

6

8

K

250

MgSO4.7H2O Na3C6H5O2.2H2O

B)

Na2C4H4O6.2H2O

Na2CO3 Na2SO4

300

K

Li2SO4·H2O MgSO4·7H2O

K

500

6

4

200 4

150

2

100

2

50 0

0

Ciprofloxacin

Paracetamol

Norfloxacin

Amoxicillin

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Ibuprofen

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0

re

the pharmaceuticals partitioning process.

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Fig. 2. Effect of the nature of the ATPS-forming electrolyte (L35/PEO1500 + H2O) on

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According to Figure 2, in the presence of magnesium sulfate (MgSO4·7H2O) the ibuprofen, paracetamol and amoxicillin were preferentially concentrated in TP (K =

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481, 53.1 and 7.01, respectively). Amoxicillin presented a similar value in the presence

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of lithium sulfate (K = 7.07), but due to the higher cost of this reagent it was decided to continue the other experiments using magnesium sulfate as the ATPS-forming salt. On the other hand, the pharmaceuticals ciprofloxacin and norfloxacin presented higher values of K, equal to 12.4 and 12.3 respectively, in the ATPS composed of sodium sulfate (Na2SO4). In view of these results, it was concluded that the sulfate anion had a considerable influence on the partitioning process of these pharmaceuticals. For fluoroquinolones, an expressive partition for the TP was also observed in the presence of the carbonate anion. According to the Hofmeister series, which orders the relative influence of the ions on the physical properties of aqueous processes, CO32- and SO42are high-capacity ions in terms of structuring water molecules (strongly hydrated 15

Journal Pre-proof anions), causing greater salting-out in the system [45]. This effect may have caused greater differences between TP and BP (due to the degree of structuring of the water molecules) in the system. Therefore, the MgSO4·7H2O salt was chosen to compose the ATPS in the partition studies on ibuprofen, paracetamol and amoxicillin, and Na2SO4 was used to compose the BP of the systems in the studies on ciprofloxacin and norfloxacin. It is important to note that many of the studies that use ATPS in the extraction of several

Effect of pH

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3.3.

-p

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the system, as was observed in this work [46-48].

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analytes present better partitioning results in the presence of sulfate salts in the BP of

After choosing the ATPS composition, the pH value of the deionized water used

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in the preparation of the polymer and electrolyte stock solutions was varied. Although

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the systems described in the literature have not been determined in the presence of acid or base, this addition is necessary for the pH study. Importantly, due to the

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high concentration of electrolytes in the system, the phase composition when comparing the systems used with those in the literature does not change significantly.

Figure 3 shows the influence of the pH of the medium (2.00, 4.00, 6.00, 8.00 and 10.00) on the partitioning of pharmaceuticals in the ATPS formed of L35 + MgSO4 + H2O (ibuprofen and paracetamol), L35 + Na2SO4 + H2O (ciprofloxacin and norfloxacin) and PEO1500 + MgSO4 + H2O (amoxicillin).

16

Journal Pre-proof

500 pH= 2.00 pH= 4.00 pH= 6.00 pH= 8.00 pH= 10.00

A)

400 350

10

pH = 2.00 pH = 4.00 pH = 6.00 pH = 8.00 pH = 10.00

6 5

K

250

C)

7

8

300

K

8

pH= 2.00 pH= 4.00 pH= 6.00 pH= 8.00 pH= 10.00

B)

12

K

450

6

200

4 3

4

150 100

2

2

50 0

Paracetamol

Ibuprofen

1 0

0

Ciprofloxacin

Norfloxacin

Amoxicillin

Fig. 3. Effect of pH influence (2.00, 4.00, 6.00, 8.00, 10.00) of the medium on the

ro

of

pharmaceuticals partitioning process.

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Figure 3 shows that the pH value of the stock solutions can make a high influence on the partitioning of the pharmaceuticals to the TP. At pH 6.00, ibuprofen

re

had a higher partition coefficient value (K = 485). Although paracetamol obtained a

lP

higher value of K at pH 10.00 (K = 59.7), the other experiments for this pharmaceutical were conducted at pH 6.00 (K = 32.0), as in the ibuprofen studies. This is because the

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experiments for these pharmaceuticals were performed together, and as pH influenced

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more the partition of ibuprofen than paracetamol, so pH 6.00 was chosen for the experiments on both pharmaceuticals. Ciprofloxacin, norfloxacin and amoxicillin presented higher values of K (12.4, 12.3 and 7.01, respectively) when the pH value was adjusted to 2.00.

Ibuprofen and paracetamol presented higher K values at pH values of 6.00 and 10.00, higher than their pKa values, 4.91 and 9.40, respectively. The predominant anionic specie in the BP is SO42-, while the compounds at these pH values have a negative or neutral charge. This led to the conclusion that the interaction of the pharmaceuticals with the BP species under these conditions was reduced and a higher partition of the analytes to TP was observed.

17

Journal Pre-proof For the other pharmaceuticals, it was not possible to obtain a completely assertive relation between the type and amount of charges of the molecules/ions involved in the system, the pH value of the system and the partitioning of these analytes. Thus, pH = 6.00 was chosen in the partitioning studies of ibuprofen and paracetamol, while pH = 2.00 was chosen for the studies of the other

3.4.

Influence of tie-line length (TLL)

of

pharmaceuticals studied.

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In the following study, the tie-line length of the systems of each pharmaceutical

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in the following levels was evaluated: 39.64, 45.52, 52.73, 59.17 and 61.30% w/w in the

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ATPS formed by L35 + MgSO4 + H2O; 46.77, 51.74, 57.5, 60.79 and 64.06% w/w in the ATPS formed by L35 + Na2SO4 + H2O; and 33.81, 39.87, 43.76, 47.28 and 52.40%

TLL= 39.64% w/w TLL= 45.52% w/w TLL= 52.73% w/w TLL= 59.17% w/w TLL= 61.30% w/w

A)

450

350

250 200 150 100 50 0

10

Ibuprofen

10

C)

TLL = 33.81% w/w TLL = 39.87% w/w TLL = 43.76% w/w TLL = 47.28% w/w TLL = 52.40% w/w

8

8

6

6

4

4

2

2

0

0

Paracetamol

12

TLL= 46.77% w/w TLL= 51.74% w/w TLL= 57.50% w/w TLL= 60.79% w/w TLL= 64.06% w/w

K

K

300

B)

12

Jo ur

400

14

K

500

na

lP

w/w in the ATPS formed by PEO1500 + MgSO4 + H2O (Figure 4).

Ciprofloxacin Norfloxacin

Amoxicillin

Fig. 4. Effect of the five tie-line lengths on optimized ATPS compositions in the pharmaceuticals partitioning process.

According to Figure 4, the second TL (TLL = 45.52%, w/w) resulted in the highest partition coefficient of ibuprofen (K = 485). Paracetamol was preferentially concentrated in TP (K = 161) when using TLL = 61.30% w/w. However, due to the 18

Journal Pre-proof feasibility of working at lower tie-line lengths, where reagent consumption and system viscosity are lower, TLL = 45.52% (w/ w) was also used in subsequent optimization experiments for paracetamol. For ciprofloxacin and norfloxacin, the highest values of K, 12.4 and 12.3, were obtained in the first TL (TLL = 46.77% w/w). Finally, amoxicillin concentrated preferentially in TP (K = 8.76) at the TLL equal to 52.40% w/w. By increasing the length of the tie-line, the differences between the compositions of the TP and BP of the system, such as the intensive thermodynamic properties, are

of

increased. In this way, the interaction of the pharmaceuticals intensifies with the phase

ro

of greater affinity. Pharmaceutical that has a higher affinity for more viscous

-p

polymers/copolymers will have its higher partition coefficient when TLL increases.

re

Possibly due to the low solubility of amoxicillin in water, its partition was higher in the last TL of this system, the one of greatest hydrophobicity. The pharmaceuticals

lP

ciprofloxacin and norfloxacin showed a higher K value in the first TLL of the system,

na

indicating that partitioning occurred better in L35 in less viscous systems. This result may be justified due to the higher water solubility of these pharmaceuticals.

Jo ur

By determining the compositions, pH and TLL of the systems in the pharmaceuticals partition studies, these conditions were used in subsequent optimization experiments.

3.5.

Influence of system temperature

The study on the influence of temperature on the partitioning of pharmaceuticals was also carried out. The systems, which are found in phase diagrams in the literature [38, 42], have TLL at different temperature values, so this is another parameter that may influence partitioning. The ATPS formed by L35 + MgSO4 + H2O has diagrams at temperatures equal to 283.15 K, 298.15 K and 313.15 K; the system formed by L35 +

19

Journal Pre-proof Na2SO4 + H2O has diagrams reported in the literature at 298.15 K and 313.15 K; and the ATPS composed of PEO1500 + MgSO4 + H2O also have temperatures of 283.15 K, 298.15 K and 313.15 K. The results of this study are shown in Figure 5.

1200

A)

T = 283.15 K T = 298.15 K T = 313.15 K

1050

25

12

T = 298.15 K T = 313.15 K

B)

900

8

600

K

15

K

450

10

4

300 5

2

150

0

0

Ciprofloxacin

Norfloxacin

ro

Paracetamol

Amoxicillin

-p

Ibuprofen

6

of

K

T = 283.15 K T = 298.15 K T = 313.15 K

20

750

0

C)

10

lP

pharmaceuticals partitioning process.

re

Fig. 5. Influence of temperature (283.15, 298.15 and 313.15 K) of the system on the

From Figure 5, it can be seen that the highest K values for the pharmaceuticals

na

ibuprofen, ciprofloxacin and norfloxacin were obtained at 313.15 K (K = 1150, 23.8 and

Jo ur

23.6, respectively). Paracetamol and amoxicillin presented a higher partition coefficient, equal to 103 and 9.30, respectively, at 283.15 K. The higher partition coefficients obtained for ibuprofen, ciprofloxacin and norfloxacin by raising the temperature of the system suggest that the partitioning process of these pharmaceuticals, under these conditions, is endothermic. The opposite can be inferred for paracetamol and amoxicillin, since the decrease in the temperature of the system caused a greater partitioning of these pharmaceuticals. The results and discussion in section 3.7 regarding the thermodynamic parameters provide additional evidence for this result.

20

Journal Pre-proof 3.6.

Effect of the phase mass ratio

The last parameter studied was the influence of the phase mass ratio in the system on the partition of the pharmaceuticals. This was performed at 298.15 K, varying the following mass ratios between the phases: mBP/mTP = 1/1, 2/1, 3/1, 4/1 and 5/1, for the partitioning of the pharmaceuticals in the optimized systems as shown in Figure 6. An increase in the mass of the BP in relation to the TP was used in order to obtain the best compromise between extraction efficiency and pre-concentration of the

0.10

ro

0.3

0.2

C)

mBP/TP=1/1 mBP/TP=2/1 mBP/TP=3/1 mBP/TP=4/1 mBP/TP=5/1

0.6 0.5

Absorbance

0.15

-p

0.4

re

0.20

0.7

mBP/TP=1/1 mBP/TP=2/1 mBP/TP=3/1 mBP/TP=4/1 mBP/TP=5/1

B)

Absorbance

0.25

Absorbance

0.5

mBP/TP=1/1 mBP/TP=2/1 mBP/TP=3/1 mBP/TP=4/1 mBP/TP=5/1

A)

lP

0.30

of

analytes.

0.4 0.3 0.2

0.1

0.05

0.1

0.0

0.00

Ibuprofen

Ciprofloxacin

Norfloxacin

0.0

Amoxicillin

na

Paracetamol

Jo ur

Fig. 6. Influence of the mass ratio of BP and TP (mBP / mTP = 1/1, 2/1, 3/1, 4/1 and 5/1) on the pharmaceuticals partitioning process.

According to Figure 6, except for ibuprofen, all pharmaceuticals presented a higher absorption signal at the mass ratio of the phases equal to 1/1 (mBP/mTP = 1/1). Ibuprofen showed higher absorption signals for mBP/mTP = 2/1, 3/1 and 4/1. The influence of the TP and BP masses on the extraction of an analyte in ATPS is related to two facts. An increase in TP mass relative to BP implies in a larger partition, since the greater amount of polymer present in this phase is able to concentrate a larger quantity of the analyte. Additionally, an increase in the mass of BP relative to TP implies a higher pre-concentration of the analyte in TP (increase of 21

Journal Pre-proof signal), which is interesting for methodologies that aim to determine low levels of analytes. With the exception of ibuprofen, increasing the BP mass of the ATPS to the other pharmaceuticals, there was saturation in the polymer-rich phase. Therefore, the K value decreased with increasing mass ratio of the phases (mBP/mTP). For ibuprofen, on the other hand, it was possible to obtain its pre-concentration by increasing the mass of BP under TP up to 4/1. For the 2/1, 3/1 and 4/1 ratios signal stagnation was observed.

of

Subsequently, when using a mass ratio of 5/1, due to possible saturation of the TP, the

-p

ro

value of K decreased.

Thermodynamic parameters of partition

re

3.7.

The data obtained from the ATPS optimization study provided K values at

lP

different temperatures (section 3.5). From these results, it was possible to calculate the

na

Gibbs energy variation of the partition (ΔpG) through Eq. 3 for each pharmaceutical.

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The thermodynamic parameters are presented in Table 3.

Table 3. Values of the thermodynamic parameters (ΔpG, ΔpH and ΔpS) determined in the pharmaceutical partitioning process using ATPS. Temperature (K)

Ibuprofena

Paracetamolb

Partition coefficient (K)

∆pG

∆pH

(KJ mol-1) (KJ mol-1)

∆pS (KJ mol-1)

283.15

65.0

-9.83

0.285

298.15

481

-15.3

313.15

1150

-18.4

0.285

283.15

103

-10.9

-0.102

298.15

58.8

-10.1

313.15

20.2

-7.82

71.0

-39.8

0.290

-0.0996 -0.102

22

Journal Pre-proof

Amoxicillinc

Ciprofloxacind Norfloxacine a, b: c:

283.15

9.30

-5.25

298.15

8.76

-5.38

313.15

8.14

-5.46

298.15

12.4

-6.24

313.15

23.8

-8.25

298.15

12.3

-6.23

313.15

23.6

-8.24

0.0070 -3.26

0.0071 0.0070

33.7

33.5

0.134 0.134 0.133 0.133

L35 + MgSO4 + H2O, pH 6.00, TLL = 45.52% w/w.

PEO1500 + MgSO4 + H2O; pH 2.00; TLL = 52.40% w/w. L35 + Na2SO4 + H2O, pH 2.00, TLL = 46.77% w/w.

ro

of

d, e:

The ΔpG was calculated for all pharmaceuticals by varying the temperature of

-p

the systems at 283.15 K, 298.15 K and 313.15 K. This parameter always presented a

re

negative value, which confirms the spontaneity of the partitioning process for TP in the

lP

three temperatures studied (K > 1). The higher the value of K, the more negative the ΔpG value. In other words, if the pharmaceutical partitioned more into the TP, this

na

occurred due to the spontaneity of this fact (ΔpG < 0).

Jo ur

The enthalpy variation of the partition (ΔpH) of each pharmaceutical was estimated from the van't Hoff approximation (Fig. S1 of the Supporting Information). As can be seen in Table 3, the ΔpH value of the van't Hoff approximation is not temperature dependent. In addition, these estimated values of ΔpH for each pharmaceutical show that the partitioning of ibuprofen, ciprofloxacin and norfloxacin was an endothermic process (ΔpH > 0) and that paracetamol and amoxicillin partitioning was an exothermic process (ΔpH < 0). This result is consistent with the temperature studies (section 3.5). Finally, the entropy variation (ΔpS) of each pharmaceutical was calculated. These values were obtained by Eq. 5 since all other parameters had been found. The negative values for paracetamol indicated that there was a decrease in the entropy of the 23

Journal Pre-proof system during its partition into TP, while the opposite can be concluded for the other pharmaceuticals. It can be concluded from these thermodynamic values, where ΔpS < 0 and ΔpH < 0, that the partitioning process of paracetamol was enthalpically driven. For the pharmaceuticals ibuprofen, ciprofloxacin and norfloxacin, the partitioning process was entropically driven due to ΔpS > 0 and ΔpH > 0. The partitioning process of amoxicillin can be considered to be both enthalpically and entropically driven, since ΔpS > 0 and

Partition study in water samples

-p

3.8.

ro

of

ΔpH < 0.

re

From the three ATPS compositions obtained as optimal condition for the pharmaceuticals (L35 + MgSO4, pH 6.00, TLL = 45.52% w/w; PEO1500 + MgSO4, pH

lP

2.00, TLL = 52.40% w/w; and L35 + Na2SO4, pH 2.00, TLL = 46.77% w/w),

na

experiments as described in section 2.3 were carried out at 298.15 K. These results determined, using the above conditions, a common condition/composition of ATPS for

Jo ur

all pharmaceuticals.

The system formed by L35 + Na2SO4 + H2O, at pH 2.00 and TLL = 46.77% w/w was the system that allowed satisfactory partitioning of pharmaceuticals in general, with K values for ibuprofen, paracetamol, ciprofloxacin, norfloxacin and amoxicillin equal to 221, 44.8, 12.4, 12.3 and 2.68, respectively. The water samples were fortified since, in the equipment used (UV-Vis spectrophotometer), the blank samples did not show any signal of the pharmaceuticals (Fig. S2 of the Supporting Information). The values of pharmaceuticals partition coefficients in each sample are shown in Table 4 and the spectra of the pharmaceuticals in the three samples are presented in Fig. S3 of the Supporting Information.

24

Journal Pre-proof Table 4. Partition coefficient (K) values of the pharmaceuticals studied in water samples, using ATPS composed of: L35 + Na2SO4 + H2O; pH 2.00; at 298.15 K; and TLL = 46.77% w/w. Partition coefficients (K)

water Surface water

Paracetamol

Amoxicillin Ciprofloxacin Norfloxacin

63±16

32.7±3.9

2.5±0.1

3.9±0.3

3.68±0.04

29.7±8.7

35.4±2.7

2.7±0.2

3.66±0.01

3.6±0.1

42.4±15.6

39.6±6.2

2.6±0.3

3.69±0.02

3.7±0.3

221±25

44.8±0.3

12.4±0.1

12.30±0.01

-p

(WTP) Deionized

2.68±0.02

lP

water

re

water

ro

Filtered

of

Drinking

Ibuprofen

na

When comparing the K values of each pharmaceutical separately in the three water samples (of tap, lagoon and WTP water), it was observed that these were similar.

Jo ur

Pharmaceutical partitioning in ATPS can be considered independent of the composition of the sample, under the studied conditions. Only for ibuprofen partitioning there was a significant variation in the value of K when changing the analyzed sample. Its low solubility value in water compared to the other pharmaceuticals may be a possible explanation for this variation of K when using samples of water with different compositions. In addition, it is necessary compare the K values obtained of the pharmaceuticals in the water samples with the values obtained of the pharmaceuticals in deionized water. The pharmaceuticals paracetamol and amoxicillin presented very similar values to the results in deionized water. The fluoroquinolones, ciprofloxacin and norfloxacin, had

25

Journal Pre-proof their K values reduced by approximately four-fold the value obtained in deionized water. Again, the K value of ibuprofen was the one that differed most when compared to the value of its partition coefficient in deionized water. The decrease in K values when using water samples can be explained by of their greater complexity. The composition of these waters may influence the solubility of the pharmaceuticals in solution and also their partitioning process in the system. In the literature, there are few references that have studied the partition

of

coefficient of these pharmaceuticals using an ATPS composed of a polymer + a salt.

ro

However, these values of K between 2.49 and 74.2 are in accordance with examples of

-p

studies reported that evaluated the partitioning of pharmaceuticals using ATPS in

Conclusion

lP

4.

re

different samples [49-53].

na

An efficient, low environmental impact liquid-liquid extraction method, which follows the principles of green chemistry, was optimized for the partitioning study of

Jo ur

five pharmaceuticals, classified as emerging contaminants, and successfully applied to water samples.

During ATPS optimization, parameters such as the pH of the medium, the nature of the electrolyte and the forming polymer, the tie-line length, the system temperature and the mass ratio of the phases were analyzed. The results showed high values of the partition coefficient of the pharmaceuticals, with K values varying from 9.30 to 1150. The ATPS was also efficient when applied to different water samples: drinking water, surface water and filtered water from a WTP. The partition coefficient values found in the water samples for the five pharmaceuticals (ibuprofen, paracetamol, ciprofloxacin, norfloxacin and amoxicillin) ranged from 2.49 to 74.2.

26

Journal Pre-proof Thermodynamic parameters were also calculated to confirm and support the discussions about the spontaneity of the partitioning process in the ATPS. Finally, we can conclude that the extraction using ATPS is an environmentally friendly and efficient alternative for liquid-liquid extraction, appropriate under these conditions for the extraction and determination of these emerging contaminants and can be applied as an alternative sample preparation method.

Acknowledgements

of

5.

ro

The authors acknowledge Fundação de Amparo à Pesquisa do Estado de Minas

-p

Gerais (FAPEMIG, grant number APQ-03688-18), Coordenação de Aperfeiçoamento

re

de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento

References

na

6.

lP

Científico e Tecnológico (CNPq) for financial support in this Project.

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Journal Pre-proof [41] Martins, J.P., Mageste, A.B., da Silva, M.D.H., da Silva, L.H.M., Patricio, P.D., Coimbra, J.S.D., Minim, L.A., 2009. Liquid-Liquid Equilibria of an Aqueous Two-Phase System Formed by a Triblock Copolymer and Sodium Salts at Different Temperatures. J. Chem. Eng. Data 54(10), 2891-2894. [42] da Silva, M.D.H., da Silva, L.H.M., Amim, J., Guimaraes, R.O., Martins, J.P., 2006. Liquid-liquid equilibrium of aqueous mixture of triblock copolymers L35 and F68 with Na2SO4, Li2SO4, or MgSO4. J. Chem. Eng. Data 51(6), 2260-2264.

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separations in polyethylene glycol-based aqueous biphasic systems: correlation of partitioning behavior with available thermodynamic hydration data. J. Chromatogr. B Biomed. Sci. Appl. 680, 221-229. [46] Mota, M.F.B., Gama, E.M., Rodrigues, G.D., Costa, L.M., 2016. Optimization and validation of an environmentally friendly method for zinc determination in new and used lubricating oil samples. Anal. Methods 8, 8435–8442. [47] Leite, D.S., Carvalho, P.L.G., de Lemos, L.R., Mageste, A.B., Rodrigues, G.D., 2017. Hydrometallurgical separation of copper and cobalt from lithium-ion batteries using aqueous two-phase systems. Hydrometallurgy 169, 245-252.

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Journal Pre-proof [48] Valadares, A., Valadares, C.F., de Lemos, L.R., Mageste, A.B., Rodrigues, G.D., 2018. Separation of cobalt and nickel in leach solutions of spent nickel-metal hydride batteries using aqueous two-phase systems (ATPS). Hydrometallurgy 181, 180-188. [49] Domínguez-Pérez, M., Tomé, L.I.,N., Freire, M.G., Marrucho, I.M., Cabezaa, O., Coutinho, J.A.P., 2010. (Extraction of biomolecules using) aqueous biphasic systems formed by ionic liquids and aminoacids. Sep. Purif. Technol. 72, 85-91.

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[52] Han, J., Wang, Y., Yu, C., Yan, Y., Xie, X., 2011. Extraction and determination of chloramphenicol in feed water, milk, and honey samples using an ionic

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liquid/sodium citrate aqueous two-phase system coupled with high-performance liquid chromatography. Anal. Bioanal. Chem. 399, 1295-1304. [53] Liu, Q., Yu, J., Li, W., Hu, X., Xia, H., Liu, H., Yang, P., 2006. Partitioning Behavior of Penicillin G in Aqueous Two Phase System Formed by Ionic Liquids and Phosphate. Sep. Sci. Technol., 41, 2849-2858.

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Journal Pre-proof CRediT author statement

Conceptualization: Roberta C. Assis, Aparecida B. Mageste, Leandro R. de Lemos, Ricardo Mathias Orlando and Guilherme D. Rodrigues. Methodology: Roberta C. Assis, Aparecida B. Mageste, Leandro R. de Lemos, Ricardo Mathias Orlando and Guilherme D. Rodrigues.

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Formal analysis: Roberta C. Assis, Aparecida B. Mageste and Guilherme D.

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Rodrigues.

Investigation: Roberta C. Assis, Aparecida B. Mageste, Leandro R. de Lemos

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and Guilherme D. Rodrigues.

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Resources: Ricardo Mathias Orlando and Guilherme D. Rodrigues.

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Data Curation: Roberta C. Assis, Ricardo Mathias Orlando and Guilherme D. Rodrigues.

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Writing - Original Draft: Roberta C. Assis, Aparecida B. Mageste, Leandro R.

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de Lemos, Ricardo Mathias Orlando and Guilherme D. Rodrigues. Writing - Review & Editing: Roberta C. Assis, Ricardo Mathias Orlando and Guilherme D. Rodrigues.

Visualization: Aparecida B. Mageste, Leandro R. de Lemos, Ricardo Mathias Orlando and Guilherme D. Rodrigues. Supervision: Ricardo Mathias Orlando and Guilherme D. Rodrigues. Project administration: Guilherme D. Rodrigues. Funding acquisition: Guilherme D. Rodrigues.

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Journal Pre-proof Declaration of interests

X The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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Journal Pre-proof

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Highlights

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Graphical abstract

- Liquid-liquid extraction without the use of organic solvents; - Optimization of aqueous two-phase systems (ATPS) parameters for the partition of pharmaceuticals; - Greater interaction of the analytes with the polymer phase; - Application of ATPS in the partition of pharmaceutical compounds (2.49 < K < 74.2) in water samples.

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