Study of electrooxidation and enhanced voltammetric determination of β-blocker pindolol using a boron-doped diamond electrode

Diamond & Related Materials 82 (2018) 109–114

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Study of electrooxidation and enhanced voltammetric determination of βblocker pindolol using a boron-doped diamond electrode

T

Gabriel F. Pereiraa,b, Patrícia B. Derococ, Tiago A. Silvac, Hadla S. Ferreiraa, ⁎ Orlando Fatibello-Filhoc, Katlin I.B. Eguiluza,b, Giancarlo R. Salazar-Bandaa,b, a

Laboratory of Electrochemistry and Nanotechnology, Institute of Technology and Research, 49.032-490 Aracaju, Sergipe, Brazil Process Engineering Graduate Program, Tiradentes University, 49.032-490 Aracaju, Sergipe, Brazil c Department of Chemistry, Federal University of São Carlos, Rod. Washington Luís km 235, 676, São Carlos 13560-970, SP, Brazil b

A R T I C L E I N F O

A B S T R A C T

Keywords: Beta blockers Diamond-based electrodes Electroanalysis Electron transfer Pharmaceutical analysis Biological samples

Pindolol (PND), an antihypertensive agent indicated for patients in the treatment of angina, hypertension, cardiac arrhythmias and recently consumed as doping agent by athletes, is electrochemically determined in this research by using a cathodically pretreated boron-doped diamond (CPT-BDD) electrode. The electrochemical response of PND studied via cyclic voltammetry on the BDD surface, shows an irreversible oxidation process. From cyclic voltammetric assays carried out at different potential scan rates, the electrochemical parameters number of electrons transferred and the apparent heterogeneous electron transfer rate constant (k0app) were determined. Additionally, chronoamperometric measurements performed at different PND concentration levels yielded the apparent diffusion coefficient of this molecule (Dapp) in 0.2 mol L−1 phosphate buffer solution (pH = 6.0). After a number of optimization steps, a differential pulse voltammetric (DPV) procedure for the sensitive determination of PND using the CPT-BDD electrode was developed. Under the optimum experimental conditions, the obtained analytical curve was linear in the wide concentration range from 0.04 to 10.0 μmol L−1 and a limit of detection of 26 nmol L−1 was also determined. The viability of the proposed voltammetric procedure was checked out towards the quantification of PND in pharmaceutical formulation samples and biological fluids. The successfully application of the proposed voltammetric procedure suggest the potentiality of this approach for field applications, such as control of pharmaceutics and monitoring of PND in biological samples from athletes subjected to anti-doping exams.

1. Introduction Pindolol (PND) is an antihypertensive agent indicated for patients in the treatment of angina, hypertension and cardiac arrhythmias; including pregnant women, because it is not teratogenic [1, 2]. Furthermore, this drug recently have been used as doping agent by athletes, particularly in sports in which good psychomotor coordination is required; due to this, PND is in the list of prohibited substances in particular sports, published by the World Anti-Doping Agency [3, 4]. PND belongs to the group of non-selective beta-adrenergic antagonists (beta-blockers), which acts to affect the response to certain nerve impulses, in certain parts of the body, for example: the heart, blood vessels and bronchi, and reduces blood pressure [5, 6]. When ingested, PND is rapidly absorbed; its metabolism occurs in the kidney and liver, being excreted in the urine in an amount of 35–40% of the dose consumed in its unchanged form, as well as in the form of inactive metabolites (60–75%) [6, 7]. ⁎

Drug analysis in biological systems provides valuable information for pharmacokinetic studies, clinical diagnosis, in cases of intoxication and also in the doping control in world sport. Thus, the sensitive determination of PND in biological fluids and pharmaceutical samples (for quality control) is required. In this sense, electroanalytical methods appear as promising alternatives to more classical approaches, because requires a short-time of analysis and low consumption of reagents, besides generally do not require steps of pre-treatment and extraction of the sample. The PND is an electroactive substance and, thus, it can be oxidized electrochemically, as reported in the literature [8–10]. Smarzewska and Ciesielski, studied the electrochemical oxidation of PND at a glassy carbon electrode (GCE) modified with reduced graphene oxide (RGO). They observed that in BR buffer (pH 5.0) medium the oxidation process involves the transfer of two electrons and two protons, generating the oxidized specie oxipindolol [8]. So far, studies found in the literature regarding the PND eletrooxidation are based on modified electrodes

Corresponding author at: Process Engineering Graduate Program, Tiradentes University, 49.032-490 Aracaju, Sergipe, Brazil. E-mail address: [email protected] (G.R. Salazar-Banda).

https://doi.org/10.1016/j.diamond.2018.01.010 Received 30 November 2017; Received in revised form 9 January 2018; Accepted 12 January 2018 0925-9635/ © 2018 Elsevier B.V. All rights reserved.

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parameters of PND redox process, as apparent diffusion coefficient and heterogenous electron transfer rate constant. From an analytical pointof-view, the experimental parameters were subjected to optimization searching a high intensity of analytical signal (peak current). Therefore, it was investigated the influence of pH and composition of supporting electrolyte and technical parameters of differential pulse voltammetry (DPV) and square-wave voltammetry (SWV). Under the optimized conditions, the analytical curves of PND were constructed using DPV and SWV. For construction of the respective analytical curves, aliquots from stock solutions of PND (obtained from dilution of the 1.0 × 10−2 mol L−1 PND stock solution) were injected in the electrochemical cell containing previously 10.0 mL of supporting electrolyte. After stirring, the DP or SW voltammograms were registered for each concentration, and the linear analytical curves were constructed. Then, the analytical parameters such as analytical sensitivity, linear concentration range and limit of detection were specified for each voltammetric technique. The voltammetric technique that presented the best analytical responses was further used to PND determination on real samples. For the analysis of the pharmaceutical tablet samples, these were subjected to a simple preliminary sample preparation protocol: ten tablets of sample were rigorously weighted and pulverized to a powder in a mortar and pestle. The correspondent mass of one tablet was weight and transferred to a 10.0 mL volumetric flask, and the flask volume completed with 0.1 mol L−1 HCl for solubilization of the PND active principle. Non-dissolved solids were removed by simple vacuum filtration. Adequate volume of sample was added in the electrochemical cell containing 10 mL of buffer solution, and the PND concentration was determined using the standard addition method. The synthetic biological fluid samples of urine and human serum were spiked with a known PND concentration and directly analyzed in triplicate in terms of recovery percentage. All measurements were made in triplicate.

whose preparation demands > 1 h, in addition to special care to ensure reproduction in the preparation [8–10]. In this aspect, the boron-doped diamond (BDD) electrode is an excellent alternative to modified electrodes, because it requires only a simple electrochemical pretreatment at the beginning of every work day, a procedure that takes < 5 min. Furthermore the BDD electrode presents attractive electrochemical properties, such as low and stable background current, wide potential window, low adsorption, and longterm stability of the response [11]. These properties of BDD electrode are extremely affected by their surface termination (oxygen or hydrogen), which can be modified by a proper electrochemical pretreatment (cathodic or anodic pretreatment, leading to hydrogen-termination or oxygen-termination enrichment of the electrode surface, respectively) [12, 13]. Thus, in this paper we describe the electrochemistry study of PND and the development of a method for its voltammetric determination in pharmaceutic and biological fluid samples using a cathodically pretreated BDD electrode. 2. Experimental 2.1. Reagents, solutions and samples Standard of PND (purity ≥ 98%) was purchased from SigmaAldrich. All reagents at least of analytical grade were used and ultrapure water with resistivity > 18 MΩ cm from a Gehaka MS 2000 system was employed for preparation of aqueous solutions. Stock standard solution of PND (1.0 × 10−2 mol L−1) was daily prepared in 0.1 mol L−1 HCl. The supporting electrolyte was a 0.2 mol L−1 phosphate buffer solution (pH 6.0). Pharmaceutical tablet samples were acquired in a local drugstore. The synthetic biological fluid samples of urine and human serum were prepared as previously reported by Laube [14] and Parham and Zargar [15] and used immediately after preparation. For the synthetic urine sample, 0.73 g of NaCl, 0.40 g of KCl, 0.28 g of CaCl2·2H2O, 0.56 g of Na2SO4, 0.35 g of KH2PO4, 0.25 g of NH4Cl and 6.25 g of urea were dissolved in water in a 250 mL volumetric flask. For the preparation of the synthetic human serum sample, 3.0 g of NaCl, 0.16 g of NaHCO3, 3.5 mg of tryptophan, 2.3 mg of glycine, 3.2 mg of serine, 3.7 mg of tyrosine, 6.6 mg of phenylalanine, 9.1 mg of lysine, 6.3 mg of histidine, 29 mg of aspartic acid, 9.1 mg of alanine and 10 mg of arginine were dissolved in water in a 250 mL volumetric flask.

3. Results and discussions 3.1. Electrochemical response of PND Using cyclic voltammetry, the electroactivity of PND compound on BDD electrode was investigated. In the initial studies a 0.2 mol L−1 phosphate buffer solution (pH = 6.0) was used as supporting electrolyte and an analyte concentration of 5.0 × 10−4 mol L−1. Fig. 1 reports the cyclic voltammograms recorded on these conditions in the potential window from +0.4 V to +1.0 V using as working electrode a CPT-BDD

2.2. Electrochemical apparatus and BBD electrode pretreatment procedures Electrochemical assays were performed at room temperature using a potentiostat/galvanostat Autolab Model PGSTAT 302N and a 20 mL three-electrode electrochemical cell. The electrodes used were a BDD (8000 ppm of boron made in the Centre Suisse d'Electronique et de Microtechnique SA (CSEM), Neuchâtel, Switzerland) as working electrode, a Pt spiral wire as a counter electrode and the reference electrode was an Ag/AgCl (3.0 mol L−1 KCl). Previously to the electrochemical experiments, the BDD electrode surface was subjected to a pretreatment step. Two types of electrochemical pretreatments were explored: anodic pretreatment (APT-BDD) by positive electrode polarization (+3.0 V for 10 s) and cathodic pretreatment (CTP-BDD) by negative polarization (−3.0 V for 30 s) in 0.5 mol L−1 H2SO4 solution [16]. 2.3. Analytical procedure Initially the cyclic voltammetric behavior of PND was explored on BDD electrode subjected to anodic and cathodic pretreatments. From this, it was accessed the electroactivity of PND and how the chemical termination of BDD surface affected the observed PND response. Subsequently, additional cyclic voltammetry and chronoamperometry assays were carried out in order to extract additional electrochemical

Fig. 1. Cyclic voltammograms obtained for 5.0 × 10−4 mol L−1 PND in 0.2 mol L−1 phosphate buffer solution (pH = 6.0) using APT-BDD or CPT-BDD electrode. Potential scan rate = 50 mV s−1.

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(0.24 cm2), C is the electroactive specie concentration (5.0 × 10−7 mol cm−3), α is the charge-transfer coefficient, R is the universal gas constant (8.314 J K−1 mol−1) and T is the thermodynamic temperature (298.15 K). Appling the natural logarithm and rearranging the Eq. (2), a linear relationship between lnIp and (Ep − E0′) is easily deducted, Eq. (2):

or an APT-BDD. For both electrodes, an oxidation peak was observed during the anodic potential scanning. After inversion of the potential scanning direction, no equivalent reduction peaks were verified, suggesting that PND suffered an irreversible oxidation reaction. This voltammetric profile agrees with previous works reporting on the PND irreversible oxidation using modified carbon electrodes [8–10]. BDD surface termination influences the oxidation and reduction reactions. Note that the pretreatment of the BDD has minimum influence on the irreversible oxidation reaction of PND. This result is in contrast with previous reports declaring significant changes of voltammetric profile of the studied molecules using hydrogenated (CPT-BDD) or oxygenated (APT-BDD) diamond electrode surfaces. In some cases, the use of cathodic pretreatment provided better response [17–21], while the opposite was observed from the use of anodic pretreatment [22–26]. However, it is consensus that CPT-BDD have been more widely applied as sensor for electroanalytical applications, providing voltammetric procedures featured by wide linear ranges, excellent repeatability and weak adsorption effects [27, 28]. Based on this previous background, we choose the cathodic pretreatment to conduct the further assays.

ln Ip = ln(0.227nFACk 0 app) + (αnF / RT )(Ep − E 0′)

constant can be Analyzing the final Eq. (2), it is evident that determined in a practical way from the linear intercept of the lnIp vs. (Ep − E0′) curve and, the number of electrons involved in the PND oxidation obtained from the slope. In Fig. 2(b) is provided the lnIp vs. (Ep − E0′) graphic constructed from the data of Fig. 2(a). For construction of this graphic, it was applied the average E0′ value (0.80 ± 0.01 V) obtained from the respective partial E0′ values calculated as I = 0.82Ip [31] at each potential scan rate. A linear plot was obtained in according to the following equation (Eq. (3)):

ln Ip = –10.78 + 31.57 (Ep − E o′), r = 0.991

(3)

Comparing the experimental slope of Eq. (3) with the theoretical slope of Eq. (2), an αn value of 0.81 was calculated. Considering α = 0.5, the number of electrons determined was 1.62. This experimental number of electrons is compatible with a number of electrons equal to 2.0, in agreement with the previously reported for other authors [8]. Then, from the comparison of intercepts of Eqs. (2) and (3) the k0app was finally determined. The k0app constant was equal to 5.2 × 10−3 cm s−1. Smarzewska and Ciesielski [8] have determined a k0app constant equal to 3.69 × 10−3 cm s−1 using a glassy GCE modified with RGO. Thus, the use of a bare CPT-BDD provide an electron transfer kinetic similar or better than using a modified sensor.

3.1.1. Effect of potential scan rate: determination of kinetic parameters Varying the potential scan rate of the cyclic voltammetry, it was determined additional electrochemical features of the irreversible oxidation reaction of PND. In Fig. 2(a) are provided the cyclic voltammograms obtained for PND in the potential scan rate range from 10 to 500 mV s−1. The increase of potential scan rate resulted in successive increments of peak current. To explore the relation between peak current and potential scan rate, the graphics of logarithm of peak current versus logarithm of potential scan rate (log Ip vs. log v) and peak current versus square root of potential scan rate (Ip vs. v1/2) were constructed and showed in the insets (i) and (ii) of Fig. 2(a), respectively. The verified slope (0.43) from the log Ip vs. log v plot is close to the value of 0.50 theoretically established for diffusion-controlled redox processes. In addition to this first finding that PND electrooxidation was controlled by diffusion, a linear plot was obtained between peak current and v1/2 (Please, see inset (ii) of Fig. 2(a)), as suggested by the Randles-Sevcik equation for irreversible oxidation reactions governed only by the diffusion mass transport [29]. Once PND electrooxidation reaction on CPT-BDD electrode was governed by the diffusion mass transport, the apparent heterogeneous electron transfer rate constant (k0app) could be predicted exploring the Nicholson and Shain's theory [30] and the results of cyclic voltammetry collected at different potential scan rates. In accordance to the Nicholson and Shain's equation, the peak current is exponentially dependent of the difference between the peak potential (Ep) and the formal potential (E0′) for different potential scan rates (Eq. (1)):

Ip = 0.227nFACk 0 app exp[(αnF / RT )(Ep − E 0′)]

(2) k0app

3.1.2. Apparent diffusion coefficient Chronoamperometry measurements, applying +0.85 V, were recorded at different analyte concentrations (from 6.62 × 10−7 mol L−1 to 3.27 × 10−5 mol L−1) to determine the apparent diffusion coefficient (Dapp) of PND in 0.2 mol L−1 phosphate buffer solution (pH = 6.0), Fig. 3. Measuring the chronoamperometric curve for background (only supporting electrolyte), the capacitive current quickly tended to zero. Then, by increasing the PND concentration a clear increment of current comparatively to the background could be discriminated. The increment of current is attributed to the contribution of faradaic current from the PND oxidation taking place at +0.85 V. The dependency of faradaic current chronoamperometrically measured and time is governed by the Cottrell's equation, Eq. (4):

I = nFAD1/2C /π1/2t 1/2

(4)

where D is the diffusion coefficient (or apparent diffusion coefficient), t is the time and other terms already were defined (please, see Eq. (1)). The background-corrected currents versus t−1/2 plot (I vs. t−1/2) obtained for each PND concentration are organized in the inset (i) of Fig. 3. Recording the slopes of each curve of inset (i), another graphic of

(1)

In this equation, the term n is the number of electrons transferred, F is the Faraday's constant (96,485 C mol−1), A is the electrode area

Fig. 2. (a) Cyclic voltammograms obtained at different potential scan rates (a: 10–o: 500 mV s−1) for 5.0 × 10−4 mol L−1 PND in 0.2 mol L−1 phosphate buffer solution (pH = 6.0) using CPT-BDD electrode. Insets: (i) Graphic of log Ip vs. log v and (ii) Ip vs. v1/2. (b) Graphic of ln Ip vs. (Ep − E0′) explored for prediction of k0app constant.

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Table 1 Optimization of technical parameters of DPV and SWV for pindolol oxidation on CPT-BDD electrode. Technique

Parameter

Range

Optimum value

DPV

Potential scan rate, mV s−1 Amplitude, mV Modulation time, ms Frequency, Hz Amplitude, mV Increment of potential, mV

10 to 20 10 to 100 5 to 15 10 to 90 10 to 50 1 to 10

20 90 5 60 30 6

SWV

oxidation profile verified previously at pH 6.0 kept in all the evaluated pHs. However, the peak current intensity changes significantly. By working with acid solutions (pH range from 2.0 to 6.0), peak currents around 60 μA were diagnosed, with a maximum signal intensity at pH 6.0. The pH 6.0 was chosen as the optimal pH condition for the further assays because the highest peak current was obtained using this pH and, because a very sharp and well defined anodic peak was also reached for the PND molecule at pH 6.0. Thus, different chemical compositions of supporting electrolyte were evaluated at pH 6.0. The cyclic voltammograms in Fig. 4(b) are those recorded for PND using as supporting electrolytes: 0.2 mol L−1 phosphate buffer solution (pH 6.0), 0.2 mol L−1 BR buffer solution (pH 6.0) and 0.2 mol L−1 Na2SO4 solution with pH adjusted to 6.0. The peak current intensity varies minimally by changing the type of supporting electrolyte, being slightly higher at phosphate buffer solution. Consequently, it was used for the further steps. Next, it was studied the influence of technical parameters of DPV and SWV. Table 1 organizes the studied parameters, their respective ranges and the selected values for each voltammetric tool.

Fig. 3. Chronoamperometric i–t profiles recorded in 0.2 mol L−1 phosphate buffer solution (pH = 6.0) containing different PND concentrations using a CTP-BDD electrode: (a) 0.00 (red dashed line); (b) 0.662; (c) 7.25; (d) 13.7; (e) 20.1; (f) 26.5 and (g) 32.7 μmol L−1. The applied potential was +0.85 V vs. Ag/AgCl (3.0 mol L−1 KCl). Inset (i): Plots of the background-corrected oxidation current (I) vs. t−1/2 for each PND concentration. Inset (ii): Plot of slopes vs. the PND concentration. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

the slope of the I vs. t−1/2 curves versus PND concentration in mol cm−3 (slope [I vs. t−1/2] vs. [PND]) was constructed and showed in inset (ii) of Fig. 3. From this graphic and having into account the Cottrell's equation (Eq. (4)), the pindolol Dapp was predicted as being 1.67 × 10−5 cm2 s−1. Interesting, this diffusion coefficient is between the reported values by Smarzewska and Ciesielski [8] and Tadi and Motghare [10]: 1.18 × 10−6 cm2 s−1 and 1.15 × 10−3 cm2 s−1. In these cases, the Dapp of PND was predicted at Britton-Robinson (BR) buffer solution with different ionic strengths. Chemical composition and ionic strength affect directly the analyte mass transport, and the observed differences can be related to these factors.

3.3. Analytical parameters After optimization of experimental conditions, the next step consisted in the construction of analytical curves for PND using DPV and SWV. The DP and SW voltammograms recorded at different PND concentrations and the respective analytical curves are displayed in Fig. 5(a) and (b). From these, the different analytical features towards PND sensing using a CPT-BDD are shown in Table 2 for both DPV and SWV. Thus, DPV provided better analytical features than SWV, including wider linear range, two times higher analytical sensitivity, and lower limit of detection. From this, DPV was applied for the further analytical assays. Furthermore, Table 3 displays the main analytical features of electroanalytical procedures dedicated to the PND determination reported to date. Comparatively, the use of a CPT-BDD provided a limit of detection value ~3.7 times lower than that attained by Cumba et al. [9] by SWV using a screen-printed graphite electrode; ~2.0 times lower that the attained by Tadi and Motghare [10] by adsorptive stripping differential pulse voltammetry using a molecularly

3.2. Optimizations Subsequently, the main experimental parameters affecting the voltammetric response of PND on the CPT-BDD were optimized using a PND concentration of 5.0 × 10−4 mol L−1. The studied parameters are pH and composition of supporting electrolyte solution as well as the technical parameters of DPV and SWV. In Fig. 4(a) are showed the cyclic voltammograms obtained in the presence of PND using as supporting electrolyte 0.2 mol L−1 phosphate buffer solutions with pH ranging from 2.0 to 9.0. The irreversible

Fig. 4. (a) Cyclic voltammograms obtained for 5.0 × 10−4 mol L−1 PND in 0.2 mol L−1 phosphate buffer solutions at different pHs (2.0–9.0) using CPTBDD electrode. Potential scan rate = 50 mV s−1. Inset: Graphic of Ip vs. pH. (b) Cyclic voltammograms obtained for 5.0 × 10−4 mol L−1 PND in different supporting electrolyte solutions using a CPT-BDD electrode. Potential scan rate = 50 mV s−1.

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Fig. 5. (a) Square-wave voltammograms and (b) differential pulse voltammograms obtained for various concentrations of PND in 0.2 mol L−1 phosphate buffer pH 6.0 using CPT-BDD electrode. Insets: corresponding analytical curves (SWV conditions a = 60 mV, f = 30 Hz, and ΔEs = 6 mV); (DPV conditions v = 20 mV s−1, a = 90 mV, t = 5 ms).

9.7 ± 0.3 mg tablet−1 was obtained. Thus, the found amount of PND by tablet using the voltammetric procedure was very close to the value declared by the manufacturer. Then, the proposed voltammetric procedure was evaluated towards the determination of PND in synthetic biological samples. Table 4 contains the recovery percentages recorded in the analyses of the respective spiked samples of urine and human serum. Recovery percentages close to 100% was obtained in all cases (from 90.9 to 97%). The synthetic urine and human serum samples were prepared containing some of the main chemical components of real samples, therefore, the excellent obtained recovery percentages suggested that the BDD electrode response did not suffer interference from possible electrooxidations or adsorption of the concomitants in the samples.

Table 2 Analytical parameters obtained for PND determination using the SWV or DPV technique coupled with CPT-BDD electrode. Parameter −1

Linearity range (μmol L ) Sensitivity (μA mol−1 L) Intercept (A) Correlation coefficient (r) Detection limit (μmol L−1)

SWV

DPV

0.08–10 0.48 9.8 × 10−8 0.998 0.043

0.04–10 1.1 2.4 × 10−7 0.997 0.026

Table 3 Comparison of analytical parameters of electroanalytical procedures reported for pindolol detection. Electrode

Technique

Linear range (μmol L−1)

Limit of detection (μmol L−1)

Reference

RGO-GC SPE MIP-CPE CPT-BDD

SWSV SWV AdSDPV DPV

0.1 to 10 0.1 to 10 0.1 to 50 0.04 to 10.0

0.026 0.097 0.05 0.026

[8] [9] [10] This work

4. Conclusions The electrochemical response of PND was investigated on the surface of a cathodically pretreated BDD electrode and a differential pulse voltammetric electroanalytical procedure optimized in this work. Different electrochemical features of the irreversible PND oxidation were determined, including number of electrons transferred, apparent heterogeneous electron transfer rate constant and apparent diffusion coefficient. Then, a wide linear concentration range from 0.04 to 10.0 μmol L−1 and a limit of detection of 26 nmol L−1 were obtained by using DPV. Finally, the proposed voltammetric procedure was successfully applied in the PND determination in different matrix samples, namely pharmaceutical formulation samples and biological samples (synthetic urine and human serum).

AdSDPV: adsorptive stripping differential pulse voltammetry; MIP: molecularly imprinted polymer carbon paste electrode; RGO–GC: glassy carbon electrode modified with reduced graphene oxide; SPE: screen-printed graphite electrode; SWSV: square wave stripping voltammetry. Table 4 Results obtained for pindolol determination in synthetic biological fluid samples of urine and human serum (n = 3). Sample

Added (μmol L−1)

Founda (μmol L−1)

Recoveryb (%)

Urine

0.27 3.3 0.27 3.3

0.26 ± 0.06 3.0 ± 0.2 0.25 ± 0.02 3.2 ± 0.3

96.3 90.9 92.6 97.0

Human serum

a b

Acknowledgments We gratefully acknowledge the Brazilian agencies FAPITEC, CAPES (grant: 2328/2012), CNPq (grants: 310282/2013-6 and 444150/20145) and PROBIC/UNIT for their financial support. P. B. Deroco is particularly grateful to the São Paulo Research Foundation (FAPESP) for the award of a doctorate scholarship (grant no. 2014/07919-2).

All results expressed as mean and confidence interval at 95% level. Recovery = (Amount measured) / (known amount added) × 100%.

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