Voltammetric detection of sumatriptan in the presence of naproxen using Fe3O4@ZIF-8 nanoparticles modified screen printed graphite electrode

A novel electrochemical sensing platform was designed and prepared for the simultaneous detection of sumatriptan and naproxen by exploiting the prowess of the Fe3O4@ZIF-8 nanoparticles (NPs); as-synthesized Fe3O4@ZIF-8 NPs were characterized by energy-dispersive X-ray spectroscopy, fourier transform infrared spectroscopy, X-ray diffraction, field emission scanning electron microscopy (FESEM), transmission electron microscopy and thermal gravimetric analysis. The immobilized Fe3O4@ZIF-8 NPs on a screen printed graphite electrode (SPGE) was evaluated electrochemically via cyclic voltammetry, linear sweep voltammetry, and differential pulse voltammetry as well as chronoamprometery means; Fe3O4@ZIF-8/SPGE exhibited good sensing performance for sumatriptan in a range of 0.035–475.0 µM with detection limit of 0.012 µM. Also, Fe3O4@ZIF-8/SPGE exhibited good sensing performance for naproxen in a range of 0.1–700.0 µM with detection limit of 0.03 µM. The modified electrode showed two separate oxidative peaks at 620 mV for sumatriptan and at 830 mV for naproxen with a peak potential separation of 210 mV which was large enough to detect the two drugs simultaneously besides being stable in the long-run with considerable reproducibility. Real sample analyses were carried out to identify the function of fabricated electrode in sensing applications wherein trace amounts of sumatriptan and naproxen could be identified in these samples.

www.nature.com/scientificreports/ Despite the increasing application of the triptans, the non-steroidal anti-inflammatory drugs are still distributed at the highest frequency to treat acute migraines such as naproxen as effective nonspecific analgesic and anti-inflammatory medication, prescribed for diverse pains and inflammatory syndromes, namely migraines 8 . In this impediment, the drug's analgesic effects relieve the headache on one hand, while the anti-inflammatory effects decrease the neurogenic inflammations in the trigeminal ganglion on the other hand. In general, involuntary naproxen intake as residues in foods brings about health risks for individuals, comprising allergies, serious gastrointestinal lesions, alterations in renal function as well as nephrotoxicity 9 . The vital contribution of naproxen in humans' health emphasizes its determination in biological samples.
Given the complimentary mode of sumatriptan and naproxen action, their integrated application would present more desirable clinical advantages compared to their single application in acute migraine therapies. Hence, the simultaneous detection of these medications in biological fluids and pharmaceutical formulations is very important 24 .
Among the various methods of detection drugs, electrochemical methods are noteworthy candidates for analyzing drugs, as they are versatile, portable, and capable of system miniaturization system, with no compromise in terms of sensitivity and selectivity 25 . The electrochemical methods employ low-cost instruments in comparison to the instrumentation needed in chromatographic or spectrophotometric methods, while the low detection limit and lower reagent usage are additional beneficial attributes 26,27 .
Currently, screen printed electrodes (SPEs) are garnering attention as they have noticeably challenged the traditional three electrode cell systems. Such devices can be accessed through printing on a plastic or ceramic support a series of inks which contain the components of the working, reference as well as auxiliary electrode along with the necessary connectors. The appliance of SPEs offers as an uncomplicated, disposable, nontoxic and inexpensive option compared with other solid electrodes, and employed to quantify a diverse set of substances 28 . Their versatile design and the option to employ a broad range of printing ink compositions, along with the convenient improvement of their surface are regarded as salient features of such devices. Moreover, it is easy to adapt them to flow and automated systems, and their easy connection to mobile instruments expedite in place analyses 29 .
The use of unmodified SPEs for the electrochemical detection generally results in low sensitivity and selectivity due to the drawbacks of unmodified electrodes including loss of surface passivation, high background noise, heterogeneous surface, non-repeatability of surface conduct, overpotential requirement, slow kinetics of electrochemical reactions of some compounds onto the surface of the electrode, and may incur large interferences from other existing electroactive species in real samples limiting the applicability of unmodified electrodes for the analytical usages.
Chemically modified electrodes (CMEs) based electrochemical sensors reflect a future trend in analytical chemistry 30 . In a variety of contexts, the direct electrochemical detection on a "bare" or unmodified electrode takes place just at higher cathodic or anodic potentials. However, a considerable passivation effect of the electrode, brought on by species formed over the electrochemical process, would poison the electrode thus necessitating the modification of the electrode's surface to solve or diminish such challenges. Furthermore, the modification of the surface increases the electrode kinetics while enhancing the detection sensitivity as well as selectivity 31,32 .
To date, a wide range of electrode modifiers such as metal and metal oxide NPs, conducting polymers, carbon nanotubes, graphene, ordered mesoporous carbon, and so on have been considered as modifiers in electrochemical sensors. Recently, metal organic frameworks (MOFs), or as they are often termed coordination networks or polymers, including metal ions or clusters of metals as nodes and organic units connected by coordinate bonds, are getting significant attention in applied sciences. MOFs are widely considered desirable candidates to modify the electrode surface because of their unprecedented features, such as considerable surface area, adjustable pore sizes, flexible structure, chemical integrity and convenient functionalization as well as the design 33,34 . Zeolitic imidazolate frameworks (ZIFs), known as a nitrogen containing subclass of MOFs, are novel porous inorganic-organic hybrid crystalline materials consisting of metal ions or metal clusters bridged tetrahedrally by imidazolate-type linkers 35 . ZIFs are good candidates in the field of electrochemical sensing due to their good dispersion and high adsorbability to small molecules 36 .
Magnetite (Fe 3 O 4 ) as one of the most commonly used magnetic nanomaterials have attracted researchers from different fields including catalysts, absorbents, sensors, wastewater treatments, magnetic resonance imaging (MRI), as well as drug delivery, due to their multifunctional properties such as small size, biocompatibility, catalytic activity, superparamagnetism, low toxicity, and easy preparation. Fe 3 O 4 NPs have the capability to enhance electrode conductivity and facilitate electron transfer 37 . Also, the Fe 3 O 4 @ZIF-8 exhibits synergistic effect and thus improve the performance for electrochemical sensor construction.
Based on above considerations, herein, a sensitive and simple voltammetric sensor is described constructed as Fe 3 O 4 @ZIF-8/SPGE to simultaneously detect sumatriptan and naproxen. It exhibited excellent electrochemical performance with lower detection limit, extended linear range, good stability and reproducibility. Moreover, the applicability of this sensor toward sumatriptan and naproxen detection in real samples was evaluated. Furthermore, to the best of our knowledge, the simultaneous detection of sumatriptan and naproxen via electrochemical means has been unprecedented yet. Chemie, the Netherlands) helped to measure electrochemicals. The use of General Purpose Electrochemical System (GPES) software aimed at controlling the experimental conditions. Moreover, SPGE (DropSens; DRP-110: Spain) possessed 3 typical graphite counter, unmodified graphite working, and silver pseudo-reference electrodes. Metrohm 710 pH meter was utilized for pH measurements. EDS was performed using the MIRA3 instrument. Measurement of FT-IR spectra was carried out using a Shimadzu 8400 spectrometer. Examination of XRD patterns was accomplished with XRD device model X'Pert Pro made in the Netherlands. The samples' morphology was observed through a FESEM-FEI Nanosem 450 field emission scanning electron microscope (FE-SEM) as well as a Philips EM208S 100 kV transmission electron microscope (TEM) at 120 kV, correspondingly. TGA was measured by using STA 503 instrument. The surface area along with the adsorption-desorption isotherm was determined on a BELSORP MINI II at 77 K with the use of liquid nitrogen as the coolant, while degassing of the samples at 473 k for 1. Sumatriptan, naproxen and other analytical grade reagents were acquired from Merck (Darmstadt, Germany). Orthophosphoric acid and the associated salts with a pH ranging higher than 2.0-9.0 have been utilized to prepare the buffer solutions. were ground. Next, the preparation of tablet solution was achieved by dissolving 50 mg of the powder in 25 mL water using ultrasonication. Later, varying quantities of the diluted solution were delivered into a 25 mL volumetric flask, diluted to the mark with PBS (pH 7.0) and the analysis were performed using modified electrode. Five naproxen tablets (labeled 500 mg per tablet, Pharmashimy Company, Iran) were ground. Next, the preparation of tablet solution achieved by dissolving 500 mg of the powder in 25 mL water with ultrasonication. Later, the varying quantities of the diluted solution were delivered into a 25 mL volumetric flask, followed by dilution to the mark with PBS (pH 7.0) and analysis were performed using modified electrode.

Result and discussions
Characterizations. EDX analyses of Fe 3 O 4 @ZIF-8 NPs. The chemical compositions of Fe 3 O 4 @ZIF-8 NPs analysed by EDS that shown in Fig. 1. This pattern displayed that this NP is pure. It can be seen that the Fe, Zn, C, O and N exist in Fe 3 O 4 @ZIF-8 at the ratio of 40.1, 23.7, 22.1, 7.2 and 6.9 (%), respectively (Fig. 1).   (Fig. 3).

Morphology of Fe 3 O 4 @ZIF-8.
The morphologies of Fe 3 O 4 @ZIF-8 are depicted in Fig. 4a,b. In details, the micrograph of NPs shows that the morphology has a hexagonal shape and these rough surfaces have average size 41.42 nm. As shown in Fig. 4c Fig. 5. The first step was observed at 387 °C, that correspond to the removal of solvent molecules or guest molecules occluded within sample and is observed for only 2% weight loss up to 500 degrees. The second step, which has a steeper slope, related to the decomposition of the NPs, which occured at a temperature of 569 °C and lasts up to 800 °C. From above TGA data it was affirmed that the sample has extremely high thermal stability.     Fig. 6a. The BJH (Barrett-Joyner-Halenda) analyses indicate that the average diameter of the NPs is 3.79 nm, showing that porosity is present in the nanoscale (Fig. 6b).

Electrochemical analysis. Electrochemical features of sumatriptan on the Fe 3 O 4 @ZIF-8/SPGE.
To study electrochemical behaviours of sumatriptan, which was supposed to show dependence on pH, obtaining an optimum pH-value for the acceptable outcomes is important. Thus, the modified electrode was employed in conducting the experiments in 0.1 M phosphate buffer solution (PBS) in various pH-values between 2.0 and 9.0. Eventually, the most desirable results were considered for electrooxidation of sumatriptan at the pH of 7.0.  Table 1.
Scan rate effect. The association between peak current and scan rate would supply helpful information considering the underlying electrochemical mechanisms. Therefore, the scan rate effects on the peak current of 100.0 μM of sumatriptan were examined using LSV, at a range of 10-600 mVs −1 in PBS (0.1 M, pH 7), according to Fig. 8. The electrode response of sumatriptan was a diffusion-controlled procedure, as the oxidation peak current corresponded to the square root of the scan rate (Fig. 8 inset). Figure 9, indicates a Tafel plot taken from data which were collected from the current rising part against the voltage curve recorded at 10 mV s −1 scan rate. It is notable that this part of voltammogram, called the Tafel region, was under the influence of the electron transfer kinetics of the substrate (sumatriptan) and Fe 3 O 4 @ZIF-8/SPGE. From the Tafel plot slope, the number of electrons engaged in the rate-identifying stage can be estimated. A   www.nature.com/scientificreports/ Cottrell equation was recommended to perform electroactive moiety chronoamperometric analyses according to the mass transfer restricted conditions 40 : Figure 10A indicates the experimental findings regarding I versus t −1/2 , which shows the most acceptable fit for the sumatriptan distinct concentrations. Then, the ultimate slopes relative to the straight lines in Fig. 10A could be depicted versus sumatriptan concentrations (Fig. 10B). Thus, D mean value equaled to 9.7 × 10 −5 cm 2 /s regarding Cottrell equation and resultant slopes.  Step potential = 0.01 V and pulse amplitude = 0.025 V). Two separated oxidation signals were apparent having potentials of ~ 620 mV (sumatriptan) and 830 mV (naproxen), which seemed adequate to simultaneously detect sumatriptan and  www.nature.com/scientificreports/ naproxen. The current-concentration curves associated with sumatriptan and naproxen can be observed in Fig. 12A,B.
Stability and repeatability of Fe3O4@ZIF-8/SPGE. The stability of Fe 3 O 4 @ZIF-8/SPGE was evaluated using DPVs of the oxidation of 50.0 µM sumatriptan in first day and after two weeks (each measurement was done 5 times and the mean value was used). A 2.7% deviation was identified with compression of the first oxidation signal of sumatriptan following 2 weeks, indicating good stability of Fe 3 O 4 @ZIF-8/SPGE as a voltammetric sensor. Examination of the Fe 3 O 4 @ZIF-8/SPGE antifouling features regarding sumatriptan oxidation and the corresponding products was carried out through DPV for the Fe 3 O 4 @ZIF-8/SPGE in first use and after successive fifteenth uses for 50.0 µM sumatriptan. The currents were reduced by lower than 2.4%, while the peak potential faced no alterations.
Real samples analysis. Fe 3 O 4 @ZIF-8/SPGE performance as a new electrochemical sensor was used to analyze sumatriptan and naproxen in tablet samples. The results showed a sensitive sensor to analyze sumatriptan and naproxen in actual samples. Also, the data in Table 2 indicate that the results obtained by utilizing Fe 3 O 4 @ZIF-8/ SPGE are in good agreement with those declared in the label of the preparations. Thus, the modified electrode can be efficiently used for individual or simultaneous determination of sumatriptan and naproxen in pharmaceutical preparations. The voltammograms of the sumatriptan tablet analysis are shown in Fig. 13.

Conclusions
In this work, a Fe 3 O 4 @ZIF-8 NPs has been utilized as a novel electrode modifier material for the detection of sumatriptan. Electrochemical sensing assays indicated the obvious catalytic abilities of Fe 3 O 4 @ZIF-8/SPGE in oxidizing the sumatriptan. An extensive linear range (0.035-475.0 µM), low detection limit (0.012 µM), high sensitivity (0.1013 μA μM −1 ), good stability as well as repeatability have been obtained through the development of sensor to analyze sumatriptan. Also, the simultaneous detection of sumatriptan and naproxen was also performed by means of the DPV method; peak separation of about 210 mV clearly allows the simultaneous detection of these drugs. Finally, sumatriptan and naproxen analyses in real samples validated the potential utility of this sensor and good recoveries (98-103.7%) were obtained from different spiked values.