MWCNTs modified glassy carbon electrode for simultaneous determination of tramadol and acetaminophen

Sensors & Actuators: B. Chemical 285 (2019) 562–570

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Sensors and Actuators B: Chemical journal homepage: www.elsevier.com/locate/snb

Lanthanum doped fern-like CuO nanoleaves/MWCNTs modified glassy carbon electrode for simultaneous determination of tramadol and acetaminophen

T

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Mohammad Mehdi Foroughia, , Shohreh Jahanib,c, Hadi Hassani Nadikia a

Department of Chemistry, Kerman Branch, Islamic Azad University, Kerman, Iran NanoBioElectrochemistry Research Center, Bam University of Medical Sciences, Bam, Iran c Student Research Committee, School of Public Health, Bam University of Medical Sciences, Bam, Iran b

A R T I C LE I N FO

A B S T R A C T

Keywords: Lanthanum doped fern-like CuO nanoleaves Tramadol Acetaminophen Modified electrode

An innovative and adept single-stage approach was created to synthesis lanthanum doped fern like CuO nanoleaves (La3+-CuO fern-like nanoleaves). The morphology and structure of fern like La3+-CuO nanoleaves are characterized by using the FT-IR, EDX, SEM, XPS and TEM techniques. Drop casting fern-like La3+-CuO nanoleaves suspension on MWCNTs/GC was used to fabricate the La3+-CuO/MWCNTs nanocomposites modified glassy carbon (GC) electrode. For electrochemical behavioral assessment of tramadol, differential pulse voltammetric analysis (DPV) and cyclic voltammetry (CV) was implemented and the oxidation performance on MWCNTs/GC, La3+-CuO/MWCNTs/GC and bare GC was compared. The obtained results indicate that amalgamation of fern-like La3+-CuO nanoleaves and multiwall carbon nanotubes will entail a significant improvement of sensor sensitivity. A limit detection of 0.014 μM within a linear range of 0.5–900.0 μM was determined for obtaining the quantitative tramadol detection. Moreover, this sensor proved favorable to simultaneously determine tramadol and acetaminophen. Additionally, great sensitivity and stability was shown by the fabricated sensor which will be beneficial for tramadol and acetaminophen clinical assay.

1. Introduction Since 1977, Tramadol (TRA) (( ± )-cis-2-(dimethylaminomethyl)-1(3-methoxyphenyl) cyclohexanol hydrochloride) applied for treatment of mild surgical pain, obstetric pain, chronic pain, cancer pain control and surgical pain in children [1]. It is also synthetic codeine analog and is not defined as one of the controlled substances [2–4]. This opioid cannot be abused as with other narcotics. The therapeutic plasma concentration for this opioid has a range of 100–300 mg L−1 [5]. Tramadol is promptly and almost wholly absorbed upon oral intake but because of first pass metabolism, its absolute bioavailability is approximately 65%–70% [6]. Approximately 10%–30% of this drug is excreted in the urine [7]. Acetaminophen (ACP) (N-acetyl-p-aminophenol) also referred to as paracetamol is an extensively used antipyretic and analgesic drug. In the cases of more severe pain, lower dosages of additional non-steroidal anti-inflammatory drugs i.e. NSAIDs are used, thus reducing overall side effects [8–10]. This drug is typically regarded safe medicine taken in therapeutic doses but overdoses may originate numerous problems

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since toxic metabolites may accumulate resulting in acute and often fatal nephrotoxicity and hepetoxicity [11]. Other types of intoxication related issues may cause an abundance of unfavorable effects such as pancreas inflammation, liver problems and skin rashes. The mentioned issues are relevant to the misuse of large doses, chronic usage or accompanying use with other drugs or alcohol [12]. By taking into account the complementary action mechanism of acetaminophen and tramadol, the amalgamation of the mentioned drugs in tablets typically improves analgesic efficacy and minimizes side effects [13,14]. Therefore, it is vital to create a fast-acting, selective, simple and sensitive approach to concurrently determine such drugs. Numerous approaches have been implemented to simultaneously determine acetaminophen and tramadol. Some of these methods include second derivative spectroscopy, LC–MS and high performance liquid chromatography [15–17]. Although, the mentioned methods are expensive, require pretreatment processes and take considerable time. In addition, such methods are complex since they require derivative processes or the amalgamation of various other detection mechanisms

Corresponding author. E-mail address: [email protected] (M.M. Foroughi).

https://doi.org/10.1016/j.snb.2019.01.069 Received 6 August 2018; Received in revised form 11 January 2019; Accepted 14 January 2019 Available online 15 January 2019 0925-4005/ © 2019 Elsevier B.V. All rights reserved.

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Fig. 1. SEM images of fern-like La3+-CuO nanoleaves prepared using different molar ratios of lanthanum nitrate to copper acetate (represented by La3+/Cu ratio) of (a) 0, (b) 0.01, (c) 0.02, (d) 0.04 and (e) 0.08. (f) Digital photograph of fern leaves.

nanostructures have been examined extensively to establish various growth morphologies and sensing usages. Doping plays a key role in the synthesis of unique nanostructures such as nanoflowers, nanowires, vertical or aligned nanorods for particular applications [37–41]. Lanthanum has numerous benefits among elements as a dopant. La ionic radius is greater than the Cu element which effects numerous structural attributes and is easily implemented in CuO crystal frameworks. The prominent purpose of La doping in CuO nanostructures is to acquire differing nanostructure morphology and improved catalytic characteristics [42]. According to our knowledge, research on copper oxide nanostructure fabrication modified electrode for the electrochemically induced tramadol and acetaminophen simultaneous determination are not referred to in the literature. Hence, this paper presents the significant efforts for fern-like La3+CuO nanoleaves fabrication used in MWCNTs/GC nanocomposite film modified electrode for tramadol electrochemical oxidation. Methods for differential pulse voltammetry and cyclic voltammetry of the La3+CuO/MWCNTs/GC modified electrode for tramadol electrochemical determination are explained. The results of the La3+-CuO/MWCNTs/ GC modified electrode provide desirable electrochemical movement to simultaneously determine acetaminophen and tramadol.

[18–20]. Moreover, some of these methods are not ideal in terms of selectivity and sensitivity when it comes to corresponding determination. Thus, a new method should be created that is sensitive, simple and efficient enough to detect these molecules. In order to overcome these barriers, electrochemical methods are utilized due to their sensitive and elegant characteristics. However, utilizing bare unadjusted electrodes to detect such compounds entail restrictions namely poor reproducibility and sensitivity, lack of stability concerning a range of solution compositions and stagnant electron transfer kinetics. In order to compensate these deficiencies, electrodes that are configured using nanomaterials have been examined [21–24]. From the most encouraging schemes, the ones that include carbon nanotubes fabrication with metal oxide nanoparticles typically possess favorable electrocatalytic attributes by improving electrode conductivity, expediting electron transfer while the anti-fouling ability hinders modified electrode over-potential [25]. Lately, significant attempts have been made on synthesizing nanoparticles to improve their current usages in magnetic storage media, solar cells, batteries, gas sensors, antimicrobial and biosensors [26–36]. Recently CuO nanostructures synthesis using suitably defined shapes and sizes (nanoleaves, nanoneedles, nanoshuttles, nanowhiskers, nonosheets, nanotubes, nanowires and nanorods) via a straightforward low-cost route is still challenging. Transition metal doped CuO 563

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Fig. 2. (a) TEM image of the fern-like La3+CuO nanoleaves, (b) TEM image of the La3+CuO nanorod in a fern-like La3+-CuO nanoleaves, where black dots are La3+ nanoparticles. (c) XPS spectrum of fern-like La3+CuO nanoleaves with molar ratio of lanthanum nitrate to copper acetate of 0.01; (d) the highresolution scans of Cu 2p3/2 and (e) La 3d.

created using serial dilution phosphate buffer solutions. By mixing a stock solution of 0.1 mol/L NaH2PO4 and 0.1 mol/L Na2HPO4, a phosphate buffer solution (PBS) 0.1 mol/L was created. HCl or NaOH was used to modify the pH. The remaining materials were analytical reagent grade. All solutions were created using double distilled deionized water. Additional purification was not implemented for the chemicals used. 2.2. Apparatus KBr discks on a JASCO FT/IR-460 PLUS instrument was used to record FT-IR spectra. A Philips analytical PC-APD X-ray diffractometer with graphite monochromatic Cu and Kα radiation (α1, λ1 = 1.54056 Å, α2, λ2 = 1.54439 Å) was used for X-ray powder diffraction (XRD) in order to clarify the products’ arrangement. KYKY, EM 3200 scanning electron microscope (SEM) was used to analyze nanoleaves’ surface morphology. LEO, LEO912-AB transmission electron microscope (TEM) was used to analyze nanoleaves’ morphology. The XPS measurement was performed with Al-Kα 1486.6 eV X-ray lab source using Omicron energy analyzer (EA-125). The EDX, energy dispersive X-ray spectrometry is a prominent nondestructive tool used for analysis such as chemical composition analysis. SAMA 500 Electro analyzer that was controlled using a personal computer at SAMA Research Center, Iran was used for electrochemical determination. A Pt wire auxiliary electrode, a saturated calomel reference electrode (SCE) and a glassy carbon working electrode (GCE, modified or unmodified) formed the three electrochemical cell system.

Fig. 3. CV acquired at potential sweep rate 50 mV s−1 for a 450.0 μM tramadol in PBS (pH 7.0), at the (a) La3+-CuO/MWCNTs/GCE, (b) MWCNTs/GCE, (c) La3+-CuO/GCE and (d) bare GCE.

2. Experimental 2.1. Reagents and solutions

2.3. La3+-doped fern-like CuO nanoleaves preparation

Copper acetate (Cu(CH3COO)2.2H2O), lanthanum nitrate (La (NO3)3.6H2O), thiourea ((NH2)2CS) and ammonia (25% NH3) were procured from Merck and implemented as received. Tramadol and acetaminophen was bought from Sigma-Aldrich and implemented as received. By dissolving a suitable amount of acetaminophen and tramadol in water and diluting the mixture to 100 mL with distilled water using a 100 mL volumetric flask, a tramadol and acetaminophen solution of 0.01 M was prepared. The resulting solution was stored in a refrigerator in a dark environment. Additional dilute solutions were

A separate solution consisting of 0.46 mol of copper acetate in 80 mL of deionized water, different concentration of lanthanum nitrate (0, 0.0046, 0.0092, 0.0184 and 0.0364 mol) in 80 mL of deionized water, 0.18 mol of thiourea in 80 mL of deionized water and finally 19.76 mL of ammonia in 80 mL of deionised water was used to prepare La3+-doped fern-like CuO nanoleaves. The next stage was to add the copper acetate solution in a beaker within the reaction bath, with the addition of thiourea and lanthanum nitrate solution within the common reaction bath. Lastly ammonia solution was added slowly and dropwise 564

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Scheme 1. Probable oxidation mechanism for tramadol.

the powdered tablet that was dissolved in deionized distilled water was stirred intensively for a 15 min time period to make sure the tablets were totally dissolved. In order to acquire a clear filtrate, the resulting concoction was filtered using a filter paper. Various diluted solution volumes were put into a 25 mL volumetric flask and diluted to the mark with PBS pH 7.0. The proposed method was used to analyze the acetaminophen and tramadol contents by utilizing the standard addition method.

into the mixture, the resulting concoction was stirred for a 5 min time period. The bath temperature was increased to 80 °C for 1 h. Next, the precipitates were created and stored overnight before being filtered. Ethanol was then used to wash the precipitates. The resulting powders were preserved for a number of days at ambient conditions. 2.4. Modified electrode preparation Before the surface was modified, the GCE was cautiously polished using 0.3 μm and 0.05 μm alumina slurries to acquire a surface resembling a mirror. The electrode was rinsed using water upon sonication in water and ethanol successively for 20 s. An infrared lamp was then used to dry the electrode. By casting 4 μL of MWCNT suspension (1.0 mg MWCNT + 1.0 mL H2O) on the cleansed GCE surface, the MWCNTs/ GCE was prepared. An infrared heat lamp was used to evaporate the solvent. Identical procedures were adopted to fabricate La3+-CuO/ MWCNTs/GCE with the addition of 4 μL of fern-like La3+-CuO nanoleaves suspension (1.0 mg fern-like La3+-CuO nanoleaves + 1.0 mL H2O) on MWCNTs/GCE surface. In order to achieve the optimal ratio of MWCNTs mass and La3+CuO mass, different ratios of MWCNTs mass (0.0, 0.2, 0.6, 1.0, 1.4, 1.8 and 2.0 mg) and La3+-CuO mass (2.0, 1.8, 1.4, 1.0, 0.6, 0.2 and 0.0 mg) were investigated. The recommended ratio was 1:1 for MWCNTs and La3+-CuO, respectively. The lowest potential and highest peak of tramadol by the developed La3+-CuO/MWCNTs/GCE, according to DPV responses.

3. Results and discussion 3.1. Fern-like La3+-CuO nanoleaves surface characterization The FT-IR spectra of fern-like La3+-CuO nanoleaves sample in the 400–4000 cm−1 is shown in Fig S1. This spectrum possessed formidable vibrational bands in the low frequency region of approximately 501 and 489 cm−1, which was assigned to vibration of the CueO bands, thus determining the presence of CuO in the system. While the lanthanum is substituted, there is a minor alteration in the CueO vibration band. The OeH groups of the absorbed H2O molecules symmetric vibration is thought to be responsible for the absorption evident at ˜3447 cm−1 [43]. Fig. S2 present a XRD spectrum of the fern-like La3+-CuO nanoleaves. The eleven attribute peaks take place at 2θ of 36.07°, 39.11°, 48.87°, 53.1°, 58.42°, 61.29°, 66.88°, 68.01° and 75.33° for CuO nanoparticles and are marked by relevant indices (-111), (111), (-202), (020), (202), (-113), (022), (220) and (004), respectively (JCPDS Card no. 89-5895). This is a clear indication that nanoparticles are genuine CuO nanoparticles with monoclinic structure. There were no signs of diffraction peaks for impurities such as cubic structure of Cu2O or La2O3. When the dopants are added, it is possible for the La3+ ions to co-operate with the matrix of CuO particles to form La-Cu-O solid solutions since the radius of La3+ is bigger than that of Cu2+. The difference in the ionic radii of the host and the dopant atom lead to changes in the lattice parameters of the system as the dopant concentration increases but, no characteristic lanthanum peaks were determined [43]. The breadth of diffraction peaks is a sign that the average crystallite size (t) and nano-sized nature of the product are derived via the DebyeScherrer formula giving 70.0 nm. t = 0.9 λ / β cos (θ) where λ is the Xray radiation (1.54056 Å for Cu lamp) wavelength, θ is the diffraction angle and β is the full width at half-maximum (FWHM) [44]. We found that the molar ratio of the reagents lanthanum nitrate to copper acetate in the solution have the predominant effect on the morphology of the resulting fern-like La3+-CuO nanoleaves products.

2.5. Real samples preparation A refrigerator was used to keep urine samples upon collection. A 20 min centrifuging process at 2000 rpm was implemented on 10 mL of the sample. A 0.45 mm filter was used to filter the supernatant. A phosphate buffer solution of pH 7.0 was used to dilute the filtered result 5 times. The resulting solution was then transported into the volumetric cell for analysis with no need for additional pretreatment. To determine the tramadol and acetaminophen sample content, the standard addition method was implemented. Tramadol and acetaminophen commercial pharmaceutics tablets were bought from a drugstore in Kerman, Iran (Daroupakhsh Company). Each of the tablets had a dose of 50 and 300 mg tramadol and acetaminophen respectively, as significant components that were electrochemically active without other typically prevalent additive drugs as guaranteed by the manufacturer in the accompanying informational leaflet. To create each pharmaceutical formulation, six of the tablets were thoroughly grinded and homogenized. Then, 100 mg of 565

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Fig. 4. (a) CVs of La3+-CuO/MWCNTs/GCE in pH 7.0 in the presence of tramadol (250.0 μM) at various scan rates (from inner to outer curve): 10, 20, 30, 40, 50, 60, 70, 80 and 90 mV/s. (b) The plot of peak currents vs. υ1/2. (c) LSV (at 10 mV s−1) of La3+-CuO/MWCNTs/GCE in 0.1 M PBS (pH 7.0) containing 250.0 μM tramadol. The points are the data used in the Tafel plot. (d) The Tafel plot derived from the LSV.

the aggregation is also seen (Fig. 1(c)). When the La3+/Cu ratio is increased to 0.04, the products show a fern-like nanoleaves with many branches and spherical particles (Fig. 1(d)). Further increasing the La3+/Cu ratio to 0.08 does not produce fern-like nanoleaves, but an irregular aggregation of spherical particles with a diameter of about 60 nm are produced (Fig. 1(e)). The results reveal that the morphologies of the resulting products can be controlled by changing the ratio of La3+/Cu. According to Fig. 1(b), every fern-like nanoleaf consists of a La3+-

When the molar ratio of lanthanum nitrate to copper acetate in the solution (represented by La3+/Cu ratio) is adjusted, while the amount of copper acetate to 0.46 mol is fixed, products with obviously different morphologies are obtained. In the absence of lanthanum nitrate (i.e., La3+/Cu = 0), the products show a fern-like nanoleaves, but growth of branch < growth of trunk, as shown in Fig. 1(a). When the La3+/Cu ratio is increased to 0.01, fern-like nanoleaves are formed as the products corresponding to the ones shown in Fig. 3(b). When the La3+/Cu ratio is increased to 0.02, the products show a fern-like nanoleaves, but 566

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Fig. 5. DPVs of La3+-CuO/MWCNTs/GCE in 0.1 M (pH 7.0) containing different concentrations of tramadol (from inner to outer curve): 0.5, 1.0, 5.0, 10.0, 20.0, 40.0, 60.0, 80.0, 100.0, 200.0, 300.0, 400.0, 500.0, 600.0, 700.0, 800.0 and 900.0 μM of tramadol. Inset: Plot of the electrocatalytic peak current as a function of tramadol concentration in the range of.0.5–900.0 μM.

Fig. 6. DPVs of La3+-CuO/MWCNTs/GCE in 0.1 M PBS (pH 7.0) containing different concentrations of tramadol and acetaminophen in μM, from inner to outer: 200.0 + 200.0, 300.0 + 300.0, 350.0 + 400.0, 400.0 + 500.0, 475.0 + 600.0, 525.0 + 700.0, 575.0 + 800.0, and 625.0 + 900.0 respectively. Insets: plot of Ip vs. tramadol concentration and plot of Ip vs. acetaminophen concentrations. Table 1 Determination of tramadol and acetaminophen in tramadol tablets, acetaminophen tablets and urine samples. All the concentrations are in μM (n=5). Sample

Tramadol tablets

Acetaminohen tablets

Urine

Spiked

Found

Recovery (%)

R.S.D. (%)

Tramadol

Acetaminophen

Tramadol

Acetaminophen

Tramadol

Acetaminophen

Tramadol

Acetaminophen

0.0 2.5 5.0 7.5 10.0 0.0 5.0 10.0 15.0 20.0 0.0 5.0 15.0 25.0 35.0

0.0 7.5 12.5 17.5 22.5 0.0 2.5 5.0 7.5 10.0 0.0 5.0 10.0 15.0 20.0

5.0 7.3 10.2 12.7 14.7 – 4.9 10.2 14.8 20.2 – 4.9 15.4 24.8 35.3

– 7.6 12.6 17.3 23.3 7.5 9.9 12.7 14.9 17.7 – 5.1 9.8 15.3 19.5

– 97.3 102.0 101.6 98.0 – 98.0 102.0 98.6 101.0 – 98.0 102.6 99.2 100.8

– 101.3 100.8 98.8 103.5 – 99.0 101.6 99.3 101.1 – 102.0 98.0 102.0 97.5

2.1 2.7 1.8 2.2 3.2 – 2.4 3.1 1.7 2.6 – 2.1 1.6 3.2 3.1

– 2.3 2.9 3.3 1.7 3.3 2.5 1.9 3.1 2.2 – 2.9 3.3 1.8 2.6

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Table 2 Comparison between various electroanalytical methods for the determination of tramadol with the proposed method. Method

Modifier

Detection limit

Linear working range

Ref.

FIA-AMP DPV DPV DPV SWV DPV

Boron-doped diamond electrode Poly(Nile blue) Carbon nanoparticles MWCNT Nano-molecularly imprinted polymer MWCNT and fern-like La3+-CuO nanoleaves

0.04 μM 0.5 μM 1.0 μM 0.361 μM 0.004 μM 0.014 μM

0.08–10.0 μM 1.0–310.0 μM 10.0–1000.0 μM 2.0–300.0 μM 0.01–20.0 μM 0.5–900.0 μM

[1] [2] [50] [51] [52] This work

CuO nanorod central trunk and numerous La3+-CuO regularly structured nanoplates in the form of side branches. The dimensions of the central La3+-CuO nanorod in the fern-like nanoleaves are approximately 1 μm long with a diameter of 60 nm. The dimensions of the La3+-CuO nanoplate side branching are 120 nm in length, 50 nm in width and 50 nm thick. The larger and flat La3+-CuO nanoplates are structured in opposing pairs along the central La3+-CuO nanorod in fern-like La3+-CuO nanoleaf. The fern-like La3+-CuO nanoleaf consists of a more complicated geometry in comparison to the 1D La3+-CuO nanorods and the 2D La3+-CuO nanoplates. The fractal growth of fernlike La3+-CuO nanoleaves is caused by the diffusion limited aggregation. The La3+-CuO nanoparticles are likely to aggregate into greater clusters when located in water. The La3+-CuO nanoparticles have the ability to self-assemble into a fern-like La3+-CuO nanoleaf on the condition that the number of La3+-CuO nanoparticles is large enough according to Monte Carlo simulations carried out in the frame of diffusion limited aggregation theory. The fern-like La3+-CuO nanoleaves are more identical to the fern when comparing star-like, comb-like and leaf-like La3+-CuO hierarchical architectures [45–47]. Ferns are naturally grown plants with broad and flat leaves along its stem. Complicated geometries are the most discerning feature of hierarchical La3+CuO nanoleaves. It is well-established that naturally grown fern fractional dimension has a range of 1.0–2.0. In addition, the morphology of the fern-like La3+-CuO nanoleaves was characterized by transmission electron microscopy (TEM) (Fig. 2(a)). Fig. 2(b) shows the TEM image of the La3+-CuO nanorod of a fern-like La3+-CuO nanoleaf. It is clear that the diameter of the La3+CuO nanorod and La3+ nanoparticles is about 60 nm and 10 nm, respectively. Fig. 2(c) depicts the XPS spectra of fern-like La3+-CuO nanoleaves. Fig. 2(d) reveal the appearance of characteristic peaks of Cu-2p3/2 at 929.27 eV corresponding to Cu2+. Fig. 2(e) depicts a core scan of La3d2/5 at 834.67 eV and La-3d3/2 at 851.86 eV [48]. Additionally, two satellite peaks neighboring to core levels are attributed to the relocation of electrons of O-2p to an unoccupied La 5f, suggesting the presence of La3+ oxidation state. The architecture of the resulting products was further confirmed via EDX analysis. Cu and La products are presented in Fig. S3.

times) in the anodic peak current at the MWCNTs/GCE and nearly 3.77 μA (almost 9.9 times) in the anodic peak current at the La3+-CuO/ MWCNTs/GCE, which are due to the increase in the surfaces area of La3+-CuO/GCE and MWCNTs/GCE, and due to the high surface area and functionality in La3+-CuO/MWCNTs/GCE as compared with unmodified GCE. Thus, increases in sensor sensitivity stemmed from La3+CuO/MWCNTs which was to be expected. 3.3. pH effect The pH influence of accompanying electrolyte on anodic peak current and potential was examined to acquire the maximum sensitivity in tramadol solution. In these studies, cyclic voltammetric analysis was conducted on numerous buffered solutions in pH ranges of 3.0–9.0 for tramadol solutions. There were no detectable peaks for tramadol in the 3.0 and 4.0 pH. When the pH was increased from 5.0 to 9.0, the best peak current was at pH 7.0. Thus, for the following voltammetric analysis, the 0.1 M phosphate buffer solution with pH 7.0 was selected as the accompanying electrolyte. The presumed tramadol oxidation mechanism is presented in Scheme 1. 3.4. Potential sweep rates effect The influence of scan rate on the oxidation peak current of tramadol was investigated on the La3+-CuO/MWCNTs/GCE by cyclic voltammetry. According to Fig. 4(a), peak current intensity is directly proportional to scan rate i.e. increases in scan rate entail increases in peak current intensity. Moreover, current is directly proportional to scan rate square root at the range 10–90 mVs−1 as presented in Fig. 4(b) which is a strong indication that tramadol redox reaction is controlled by diffusion. According to these results, oxidation peak potential had a positive shift when scan rate was increased. Furthermore, in the course of reaction among La3+-CuO/MWCNTs/GCE and tramadol, there are kinetic limitations at higher scan rates. Data from rising sections i.e. Tafel regions of current-voltage curves acquired at 10 mVs−1 were used to plot analyte Tafel curves. This is shown in Fig. 4(c). The Tafel regions of the current potential curves are influenced by the electron transfer kinetics of the electrode reactions. Results show that a 0.1017 V Tafel slope, indicating one electron rate determining step (RDS) for the electron process [49] for charge transfer coefficient (α) of 0.42 as shown in Fig. 4(d).

3.2. Electrochemical behavior of tramadol at the surface of various electrodes

3.5. Tramadol voltammetric determination

This paper investigates the electrochemical conduct of tramadol at the unmodified GCE and modified GCEs. CV obtained at potential sweep rate 50 mV s−1 for a 450.0 μM tramadol in PBS (pH 7.0), at the unmodified GCE (Fig. 3, curve d), La3+-CuO/GCE (Fig. 3, curve c), MWCNTs/GCE (Fig. 3, curve b) and La3+-CuO/MWCNTs/GCE (Fig. 3, curve a). It is evident that, the oxidation of tramadol at MWCNTs/GCE and La3+-CuO/MWCNTs/GCE surfaces was conducted at the potential 750 mV vs. SCE, that is around 62 mV and 120 mV more negative than that observed in the case of the La3+-CuO/GCE and unmodified GCE, respectively. A comparison of oxidation peak currents for tramadol at the unmodified GCE, MWCNTs/GCE and La3+-CuO/MWCNTs/GCE indicate an enhancement of nearly 2.07 μA (almost 5.4 times) in the anodic peak current at the La3+-CuO/GCE, nearly 2.65 μA (almost 7.0

A Tramadol calibration curve was acquired via differential pulse voltammetric (DPV) measurements within optimum experimental conditions. Usual DPVs for various tramadol concentrations are presented in Fig. 5. Tramadol slope value of 0.007 μA/μM resulted in a linear range of 0.5–900.0. The detection tramadol limit was 0.014 μM. 3.6. Determination of tramadol and acetaminophen simultaneously As previously mentioned, tramadol and acetaminophen, exist together in numerous pharmaceutical structures. Thus, the next attempt was to determine acetaminophen and tramadol simultaneously. Hence, 568

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naltrexone, heroin, papaverine, buprenorphine and thebaine hardly caused any significant change of peak current. For La3+-CuO/ MWCNTs/GCE the higher variation of peak current occurred in the presence of papaverine (7.21%), for the other drugs this variation was less than 1.98%. This could be explained by a good selectivity of La3+CuO/MWCNTs/GCE for tramadol (Fig. 4S).

the suggested DPV approach was conducted for determining acetaminophen and tramadol simultaneously in synthetic samples by utilizing La3+-CuO/MWCNTs/GCE. In this regard, by concurrently increasing concentrations, both analytes were determined, as shown in Fig. 6. The relative standard deviations were 1.8% and 2.1% for seven consecutive determinations of 200.0 μM of tramadol and acetaminophen respectively. Therefore, it was clarified that when implementing the suggested DPV approach, acetaminophen and tramadol simultaneous determination has the same efficacy as when individually determined. Results also indicated that the recommended electrode can be effectively utilized for simultaneously determining acetaminophen and tramadol.

4. Conclusion

In order to demonstrate the pragmatic application of the proposed method tramadol and acetaminophen were determined in tramadol tablets, acetaminophen tablets and urine samples, at La3+-CuO/ MWCNTs/GCE. Every sample was treated according to Section 2.5. Five parallel determinations were carried for each sample. Table 1 presents the results. The recoveries were 97.3%–103.5% and the RSD was lower than 3.3%. The obtained results prove the applicability of the proposed method in real samples.

To summarize, fern-like La3+-CuO nanoleaves were successfully synthesized using a single step facile method. The morphology of the synthesized La3+-CuO nanostructures revealed leaf like structure. A novel sensor was created to simultaneously determine tramadol and acetaminophen employing differential pulse voltammetry by utilizing fern-like like La3+-CuO nanoleaves and carbon nanotube as modifiers in GCE. The La3+-CuO/MWCNTs/GCE modified electrode displayed favorable electrocatalytic tramadol oxidation in physiological conditions with + 750 mV operating potential. The detection limit (0.014 μM), sensitivity (0.028 μA/μM), and linear response range (0.5–900.0 μM) for the La3+-CuO/MWCNTs/GCE adjusted electrode provides an efficient means for tramadol electrochemical determination. Finally, to determine tramadol and acetaminophen in pharmaceutical formulations, and urine samples; the developed sensor was utilized with successful results.

3.8. Comparison of proposed method with literature methods

Appendix A. Supplementary data

Table 2 presents a comparison of La3+-CuO/MWCNTs/GCE analytical performance created in this research with other sensors involved in tramadol analysis [1,2,40–42]. The proposed method was inferior in terms of detection limit in comparison to previously reported methods in the literature with the exception of one provided in Ref. [42]. Although, it is noteworthy that the [42] method is indirect in estimating tramadol and does not utilize simultaneous determination with other compounds. The proposed method is superior as it is simple, utilizes simultaneous tramadol and acetaminophen determination and does not need any pre-treatment processes. This proves that La3+-CuO/ MWCNTs/GCE possesses favorable analytical conduct for tramadol and acetaminophen simultaneous determination in terms of an extremely low detection limit, wide linear dynamic range, excellent repeatability and reproducibility and high sensitivity compared to the methods mentioned in the literature.

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.snb.2019.01.069.

3.7. Sample analysis

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3.9. Stability, repeatability and selectivity of modified electrode La3+-CuO/MWCNTs/GCE long term stability was assessed for a period of three weeks. Prior to not using the modified electrode for three weeks while being stored at atmosphere, the tests were repeated. Based on cyclic voltammograms, there were no changes in tramadol oxidation peak potential with the exception of a reduction of less than 2.5% in comparison to first response. The modified electrode’s antifouling characteristics regarding the oxidation of tramadol and relevant oxidation products were examined by recording CVs. At the vicinity of tramadol, upon potential cycling for 15 times at 50 mV s−1 scan rate, voltammograms were recorded. By examining the results, it is evident that there are no changes in peak potentials while there is a current reduction of less than 2.3%. Based on these results, by applying a modified La3+-CuO/MWCNTs/GCE, there will be enhanced sensitivity and a reduction in analyte and relevant oxidation product fouling effects. The selectivity of La3+-CuO/MWCNTs/GCE was checked with some analogs, such as dopamine, morphine, oxymorphone, naltrexone, heroin, papaverine, buprenorphine and thebaine were chosen as objective molecules to investigate the influence on the La3+-CuO/ MWCNTs/GCE. According to the results for the La3+-CuO/MWCNTs/ GCE, a 10-fold excess of dopamine, morphine, oxymorphone, 569

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