Mouhamed et al. BMC Chemistry(2024) 18:148
https://doi.org/10.1186/s13065-024-01247-7

BMC Chemistry

RESEARCH

Open Access

Bimetallic MOF-based electrochemical sensor
for determination of paracetamol in spiked
human plasma
Aya A. Mouhamed1*, Ahmed H. Nadim1, Amr M. Mahmoud1, Nadia M. Mostafa1 and Basma M. Eltanany1
Abstract
Metal-organic frameworks (MOFs) with their exceptional properties have the potential to revolutionize the fieldof electrochemistry and pave the way for new and exciting applications. MOFs is an excellent choice as an active
electrocatalyst component in the fabrication of electrochemical sensors. Here, bimetallic NiCo-MOFs, monometallic
Ni-MOFs, and Co-MOFs were fabricated to modify the carbon paste electrode. Moreover, the ratio between Co
and Ni within the bimetallic MOFs was optimized. Our aim in this work is to synthesize different compositions
from bimetallic MOFs and systematically compare their catalytic activity with mono-metallic MOFs on paracetamol.
The structure and properties of the 2D NiCo-MOFs were characterized by scanning electron microscope, X-ray
photoelectron spectroscopy, Fourier transform infrared, and electrochemical method. Bimetallic Ni0.75Co0.25-MOFs
modified carbon paste sensor displayed the optimum sensing performance for the electrochemical detection ofparacetamol. A linear response over the range 6.00 × 10− 7 to 1.00 × 10− 4 M with a detection limit of 2.10 × 10− 8
M was obtained. The proposed method was applied to detect paracetamol in spiked human plasma and to
determine paracetamol in the presence of its major toxic impurity, p-aminophenol. These findings suggest theconsiderable potential use of the newly developed sensor as a point-of-care tool for detecting paracetamol andp-aminophenol in the future.
Keywords Bimetallic metal-organic framework, Monometallic metal-organic framework, Carbon paste electrode,
Electrochemical sensor, Paracetamol, p-aminophenol

Introduction
Electrochemical sensors are a remarkable class of sensors in which the electrode is the transducer element.
These sensors (which appeared in the second half of thetwentieth century) are now found in a wide range of commercial applications [1]. These sensors use the electrons
to acquire signals, which is considered a clean model*Correspondence:
Aya A. Mouhamedaya.ahmed@pharma.cu.edu.eg
1
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy,
Cairo University, Kasr El-Aini St, Cairo 11562, Egypt

for analytical applications, with no generation of waste.
In addition, they are miniaturized for use in portabledevices, which allows for analyses with micro volumesof samples [1, 2]. Electrocatalysis is crucial for modern
energy storage and conversion [3]. Advanced electrocatalysts help to decrease energy consumption in electrochemical processes [4]. Metal-organic frameworks(MOFs) which were reported in 1995 by Yaghi et al. [5],have shown great promise as electrocatalysts in recent
years [4]. They represent a class of solid porous materials,
which consist of metal nodes, and polydentate organic
linkers [6]. They are considered a subset of coordination
polymers and can be extended into one, two, and three© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use,sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) andthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in thisarticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not includedin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The
Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available
in this article, unless otherwise stated in a credit line to the data.

Mouhamed et al. BMC Chemistry(2024) 18:148

Fig. 1 Chemical structure of PAR and p-AP

Fig. 2 Differential pulse voltammograms of PAR using potassium ferro/
ferricyanide solution (0.01 mM) in PBS buffer at solid CPE with/without
NiCo-MOFs

dimensions [7]. MOFs have a wide diversity of skeleton
and pores, network topology, surface functionalities,
and charge mobility that result in tunable porosity [8].
They also introduce exciting new avenues for creativity
in designing ligands, assembling crystal engineering [9],chemical separations, photocatalysis [10, 11], electrocatalysis [12], and energy storage materials candidates [7,13]. Several strategies were developed to enhance the catalytic activity, such as element doping [14, 15], coordination structures optimization, and or defects construction[16–18]. Another strategy is the regulation of the numberof accessible active sites of MOFs by different methods
such as morphology engineering [19–21]. Unlike monometallic compounds, bimetallic MOFs provide numerous
benefits for use as electrode components or as precursors in the production of advanced composites due tohigher stability and efficiency [22]. Many experimental
results proved that the inclusion of cobalt (Co) and nickel(Ni) transition elements creates more electrochemically
active sites and increases catalytic activity [23, 24]. In
2016, Zhao et al. published a study of the electrocatalytic performance of NiCo bimetal-organic frameworknanosheets on the oxygen evolution reaction [25].
Paracetamol (PAR), N-(4-hydroxyphenyl) acetamide(Fig. 1a) is commonly used as a painkiller and antipyretic.
It is a suitable alternative for aspirin-sensitive patients[26]. PAR is usually used to relieve moderate pain, such

Page 2 of 11

as headaches caused by the flu, joint pain, and migraines[27]. The normal dose of PAR is not harmful to thehuman body [28]. However, PAR is a substrate of oxidative metabolism by Cytochrome P450 2E1 (CYP2E1),
generating the toxic metabolite N-acetyl-p-benzoquinone
imine (NAPQI). Overdosage of PAR can lead to hepatic
necrosis through the diminution of cellular glutathionelevels by forcing NAPQI to interact with nucleophilic cellular macromolecules [28]. The widespread availability
and usage of PAR increase the incidence of accidental or
intentional overdoses globally [29]. Each year, PAR overdoses result in approximately 56,000 emergency room
visits, 33,000 hospitalizations, and 500 deaths [29].
Like many other drugs, PAR undergoes degradation
during storage. The manufacturing process also introduces some impurities [30]. Para-aminophenol (p-AP),(Fig. 1b) is the primary PAR impurity. It is nephrotoxic
and can cause teratogenicity [31].
Therefore, a simple, sensitive, and precise method ofdetermining PAR in the presence of p-AP is significant
for personal health care. Compared to traditional spectrophotometry [32]or chromatography [33], the electrochemistry technique is simple, has a fast response, highsensitivity, and low cost [34–36]. The detection of PAR
by electrochemical sensors has attracted much interestin recent years. Various designs were detected including screen-printed electrodes [37], carbon-based electrodes [38], and nanomaterial-modified electrodes [39],to enhance sensitivity and selectivity towards PAR. The
choice of electrode materials is critical for the sensor’s
performance. Carbon-based materials such as graphene,carbon nanotubes, and carbon nanofibers have been
widely investigated due to their high conductivity, large
surface area, and electrocatalytic properties [40]. Surfacefunctionalization techniques, such as electrodeposition,
molecular imprinting [38], and electropolymerization[38], have been employed to enhance the selectivity ofelectrochemical sensors toward PAR. Electrochemical
detection methods for PAR include voltammetric techniques, such as cyclic voltammetry (CV) and differential
pulse voltammetry (DPV), which are commonly used
for their high sensitivity and ease of implementation insensor devices [41]. Efforts have been made to miniaturize electrochemical sensors for PAR detection, to be
integrated into portable devices for on-site analysis [42].
Several strategies have been developed to enhance theselectivity of electrochemical sensors for PAR detection
by minimizing interference from other electroactive species found in real samples [42]. This includes the use of
selective electrode materials, signal processing, and sample pretreatment techniques [43, 44].
In our presented study, novel functional nanomaterials
have been developed to create modified electrodes for thesensitive and specific electrochemical detection of PAR

Mouhamed et al. BMC Chemistry(2024) 18:148

Fig. 3 Differential pulse voltammograms of PAR on the Ni-MOFs/CPE, CoMOFs/CPE, Ni0.25Co0.75-MOFs/CPE, Ni0.5Co0.5-MOFs/CPE, and Ni0.75Co0.25MOFs/CPE using scan rate 40 mV/s and pH 7.4

Page 3 of 11

in the presence of its primary impurity, p-AP. Bimetallic NiCo-metal-organic frameworks (NiCo-MOFs) wereused to modify carbon paste electrodes (CPE), whichwere synthesized and subsequently compared for catalytic activity with monometallic Ni-MOFs/CPE and CoMOFs/CPE using PAR as a representative drug model.
Results revealed that NiCo-MOFs/CPE exhibited significant electrocatalytic performance in the redox process of
PAR compared to both monometallic Ni-MOFs/CPE and
Co-MOFs/CPE. Furthermore, the developed sensor was
successfully employed for PAR detection in pharmaceutical formulations and spiked human plasma samples.
MOFs-modified sensors can maintain their sensing
performance over extended periods due to their known
structure stability and this ensures reliable and continuous monitoring of PAR levels without significant degradation. MOFs-modified sensors can be integrated into
portable and miniaturized devices for on-site detectionof PAR. This has implications in point-of-care diagnostics, where rapid and sensitive detection of paracetamol
levels is crucial for patient care.

Experimental
Materials and reagents

Fig. 4 Differential pulse voltammograms of PAR on different percentagesof Ni0.75Co0.25-MOFs (1%, 2%, 5%,10%) using scan rate 40 mV/s and pH 7.4

Polyvinyl pyrrolidine K30 (PVP), purified terephthalicacid (PTA), nickel (II) sulfate hexahydrate, cobalt (II)chloride hexahydrate, dimethyl formamide (DMF),
sodium hydroxide, graphite, phosphate-buffered saline(PBS) tablets, and p-aminophenol were purchased from
Sigma-Aldrich. PAR was obtained from the Egyptian
Drug Authority (EDA) (with a certified purity of 99.58%± 1.01). Ethanol of HPLC grade was supplied from Fisher
Scientific (Loughborough, Leicestershire, UK). Deionizedwater was prepared by double distillation (Agela Technologies Wilmington, USA). Blank human plasma was
supplied from the Holding Company for Biological Products and Vaccines (VACSERA, Egypt).
Instrumentation

A PC-controlled electrochemical analytical workstation (Metrohm Autolab potentiostat/ galvanostat
PGSTAT204) supplied with NOVA software for electrochemistry was applied for all voltammetric measurements. The used reference electrode was Ag/AgCl, whilea Pt wire was utilized as a counter electrode. The working electrode used was CPE. For the analysis of spiked
human plasma, the samples were mixed using a vortex(VELP Scientifica, Europe), and then centrifuged using
a Centurion K241R centrifuge (UK). The solution’s pH
was adjusted using Jenway digital ion analyzer model
3330 with Jenway pH glass electrode (Essex, UK). The
SEM image of Ni0.75: Co0.25-MOFs was obtained using
Fig. 5 SEM image of cauliflower-like Ni0.75Co0.25-MOFs

Mouhamed et al. BMC Chemistry(2024) 18:148

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Fig. 6 EDX spectrum of Ni0.75 Co0.25-MOFs

Fabrication of MOFs
Fabrication of monometallic Ni-MOFs and Co-MOFs

A solvothermal method was used to prepare Ni-MOFs[12]. Thus, NiSO4.6H2O (0.144 g), PTA (0.25 gm), and
PVP (0.5 gm) were poured in DMF (30 mL), then 3mL
0.4 M NaOH was added dropwise while stirring for20.0 min. A faint green colloidal suspension was obtained
and then subjected to a solvothermal reaction for 8 h at
100 °C inside a 50-mL Teflon autoclave. Next, the product was cooled down to room temperature, followed bycentrifugation at 4000 rpm for 14.0 min to obtain the precipitate then washed with DMF and ethanol, and finallydried at 65 °C for 1 h under vacuum condition. Moreover,
Co-MOFs was prepared by the same procedure using
CoCl2.6H2O.
Fig. 7 Effect of pH on the cathodic peak current (Ip)the ZEISS EVO scanning electron microscope in Hamburg, Germany. The structure of Ni0.75: Co0.25-MOFs
was characterized through XPS, K-ALPHA (Thermo
Fisher Scientific, USA) utilizing monochromatic X-ray
Al K-alpha radiation − 10 to 1350 eV, spot size 400 μm,
at specified pressure 10−9 mbar with full spectrum passenergy 200 eV and narrow spectrum at 50 eV. Fouriertransform infrared spectrum (FT-IR) of the NiCo- MOFs
was obtained by an FTS- 3000 spectrometer in the range
from 4000 to 400 cm− 1.

Fabrication of bimetallic Ni/Co-MOFs

Different molar ratios of Ni and Co were prepared (1:1),(3:1), and (1:3) then the same procedures were applied toprepare different bimetallic NiCo-MOFs as mentionedin.
Fabrication of MOFs modified carbon paste electrodes

The working modified electrodes were prepared as follows: 190.00 mg graphite was weighed and placed in
mortar. Then 10.0 mg of synthesized Ni-MOFs, CoMOFs, Ni0.25Co0.75−MOFs, Ni0.5Co0.5−MOFs, andNi0.75Co0.25−MOFs mixed at least for 5.0 min using 0.50

Mouhamed et al. BMC Chemistry(2024) 18:148

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Scheme 1 Electrochemical oxidation mechanism of PAR

Fig. 8 Cyclic Voltammograms of 0.1mM PAR in 10 mM PBS (pH 7.4) on
the Ni0.75Co0.25-MOFs /CPE at different scanning rates: 10, 20, 40, 60, 80,
and 100 mV/s

mL paraffin oil. Each modified paste was filled in the electrode body and a copper wire was used for electrode connection. The CPE was prepared in the same procedure
without MOFs mixing. The new surface of the paste electrode surface was simply renewed by scraping off about
3.0 mm of its old surface and polishing the new surface
with a piece of tracing paper. Modified CPE sensors withvaried MOFs composition can be recorded as Ni-MOFs/
CPE, Co-MOFs/CPE, Ni0.25Co0.75-MOFs/CPE, Ni0.5Co0.5-MOFs/CPE, and Ni0.75Co0.25 -MOFs/CPE.
ProcedureStandard solution

Stock standard solution of PAR was prepared by accurately weighing 0.38 g of pure drug and transferring it
to a 100-mL volumetric flask then dissolved in 50-mL
distilled water and completed to the mark with distilledwater. Then one mL from the prepared solution wastransferred into a 25-mL volumetric flask and completed
to the mark with distilled water to obtain a PAR solutionof concentration equal to 10–3M.
Operational conditions of electrochemical measurements

Fig. 9 A plot of logarithm of anodic peak current (log Ip) of PAR as a function of the logarithm of scan rate (log ʋ) using cyclic voltammetry

Cyclic wave voltammograms were obtained by scanningthe potential over a range of -0.1 to 1.2 V, starting from
0. A carbon paste electrode (CPE) was used versus thereference electrode Ag/AgCl, with a platinum wire as acounter electrode. All determinations were carried out atroom temperature. DPV measurements were conductedby scanning the potential over a range of -0.4 to 1.0 V ata scan rate of 40 mV/s. The sample width, modulation
amplitude, pulse width (modulation time), pulse period(interval), and quiet time were set to 17.0 ms, 40.0 mV,
50.0 ms, 600.0 ms, and 5.0 s, respectively. These parameters were carefully chosen to ensure accurate and reliablemeasurements.
Construction of calibration curve

Fig. 10 A plot of the anodic peak current (Ip) of PAR as a function of thesquare root of scan rate (ʋ1/2)

Aliquots of PAR were transferred from the stock solution
to 25-ml volumetric flasks. The volumes were then accurately completed using PBS pH 7.4 to produce the desired
final concentrations ranging from 0.60 µM to 100.00 µM.
DPV was produced between -0.4 and 1.0 V. The current
peak height confidently recorded for each sample wasplotted against its corresponding concentration to determine the calibration curve and regression equation.

Mouhamed et al. BMC Chemistry(2024) 18:148

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using filter paper to remove impurities and fillers in thetablet.
A specific volume of this solution was transferred to a
volumetric flask (25 mL) and diluted with PBS (pH = 7.4).
Finally, the obtained concentrations were analyzed to calculate the recovery percentage.
Analysis of PAR in spiked human plasma

Fig. 11 DPVs of different concentrations of PAR on the Ni0.75Co0.25-MOFs/
CPE in 0.1 M PBS (pH = 7.4)

Fig. 12 The peak current plot as a function of the concentration of PAR

Method validation

The developed method was successfully validated following ICH guidelines [45] for linearity, accuracy, precision, detection, and quantification limits, confirming its
suitability for the intended use. Linearity was thoroughly
investigated under optimal electrochemical conditions
by analyzing six different concentrations of PAR. Accuracy was rigorously assessed by calculating the percentage recovery of three different concentrations. Intra-day
and inter-day precision were evaluated and reported as%RSD.
Application procedure
Analysis of PAR in real samples

For the preparation of the real sample of PAR tablet(labelled 500 mg), ten PAR tablets were crushed. Then,
5.09 mg of this powder was dissolved in 25.00 mL ofdeionized water under ultra-sonication to prepare a concentration of 10− 3 M. The resulting sample was filteredA standard stock solution of 1.00 mM PAR was preparedby dissolving 3.80 mg of pure PAR powder in 25.00 mL of
distilled water. From this solution, various working standard solutions were prepared. Then, 500.00 µL was withdrawn from each working solution and added separately
to 500.00 µL of plasma in a 10-mL centrifuge tube. Protein precipitation was efficiently achieved by adding 1.50
mL of acetonitrile. The mixtures were blended using avortex mixer for 5.0 min at 4000 rpm, followed by a carefully timed centrifugation for 15.0 min at 4000 rpm. The
supernatant was transferred and evaporated to complete
dryness utilizing the rotatory vacuum concentrator at 60.
Samples were reconstituted in 25.00 mL of PBS to obtainthe final desired concentrations of 1.00 × 10–5, 4.00 × 10–5,
6.00 × 10–5, 8.00 × 10–5, and 1.00 × 10–4 M. DPV was generated for those spiked samples in the range from -0.4 to
1.0 V. To construct a calibration curve, the current peakheights of the measured concentrations were used andcorrelated with their corresponding concentrations. To
evaluate the accuracy, the percentage recovery of threedifferent concentrations was calculated.

Results and discussion
Compared to traditional porous materials, the most
attractive advantage of MOFs is that their catalytic
activity can be enhanced using different metal ions andorganic linkers. Purified terephthalic acid (PTA) wasused as a ligand. Nickel sulfate and cobalt chloride wereused as ion sources to synthesize 2D MOFs through asolvothermal method [12]. PVP was assembled as a polymer in the fabrication of MOFs to prevent aggregationand provide a larger surface area and more active sites tointeract with the PAR. To investigate the redox propertyof the CPE sensor modified with the porous NiCo-MOFs,
a DPV study was conducted on plain CPE and NiCoMOFs/CPE sensors as shown in Fig. 2. The NiCo-MOFs/
CPE sensor exhibited better-defined oxidation andreduction properties of the ferro/ferri cyanide solution
than the plain CPE sensor. The synthesized bimetallic
NiCo-MOFs have more catalytic activity than monometallic Ni-MOFs and Co-MOFs, Fig. 3 and Figure S1. The
catalytic performance of different molar ratios of Ni and
Co were examined (Ni0.25Co0.75, Ni0.5Co0.5, Ni0.75Co0.25)
and compared, results are shown in Fig. 3. The molar
ratio of Ni0.75Co0.25-MOFs was revealed to have the mostcatalytic activity, Fig. 3. Then several percentages of theMouhamed et al. BMC Chemistry(2024) 18:148

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acid, respectively [46]while the broad peaks in the spectral range of 3150–3400 cm− 1 may be due to acidic OH ofcarboxylic groups [47]. The peaks at 1161 and 1099 m− 1
are attributed to the in-plane stretching vibration of C-H
while the peaks at 756 and 813 cm− 1 are assigned to theout-of-plane bending vibration of C-H [48]. The absorptions around 466, 524, 559, and 609 cm− 1 are related tometal–oxygen–hydrogen bending vibration (Ni-O or
Co-O or Ni-Co-O bond) [47].
Electrochemical characterization

Fig. 13 Differential pulse voltammograms of PAR and p-AP on the
Ni0.75Co0.25-MOFs/CPE in 10 mM PBS (pH 7.4)

optimized molar ratio Ni0.75Co0.25-MOFs (1%, 2%, 5%,
and 10%) were carried out. The best results were achieved
by applying 5% Ni0.75Co0.25-MOFs to CPE where a highcurrent was obtained, Fig. 4.
Surface characterization of bimetallic Ni0.75Co0.25-MOFs/
CPE

The morphology of the synthesized NiCo-MOFs was
examined using SEM. A cauliflower-shaped structure aggregates were obtained with average length of
5.4 ± 1.3 μm and width of 3.1 ± 0.74 μm of the cluster Fig.
5. Moreover, energy dispersion X-ray (EDX) analysis wasused for the elemental analysis. The elemental mappingof NiCo-MOFs confirmed the presence of Ni, Co, C, andO in the structure Fig. 6. This was also confirmed by the
XPS technique that was used to analyze the elemental
structure of NiCo-MOFs. The survey spectrum clearly
showed the presence of Ni, Co, O, N, and C elements.
The high-resolution XPS spectra were obtained. The
Co(2p) high-resolution XPS spectrum shows three peaks
at 780.4, 785.3, and 797.0 eV corresponding to Co2+ oxidation state. Similarly, Ni(2p) high-resolution XPS spectrum showed peaks at 855.6, 861.1, and 873.6 eV that
could be assigned to Ni2+ oxidation state. Such results
showed electronic interactions between Co and Ni atoms
found in Ni0.75Co0.25-MOFs which would improve theelectro-catalytic properties of MOFs. The C(1s) spectra
showed peaks at around 283.9, 284.1, and 287.6 eV corresponding to C = C, C = O, and O-C = O. The N(1s) spectra had two major peaks at 399.58 eV for pyridinic-N and
401.1 eV for pyrrolic-N indicating the formation of MOFs
on the PVP polymer. From the infrared spectrum of
Ni0.75Co0.25−MOFs (Figure. S2), it can be observed that a
new characteristic absorption peak appears at 1377 cm− 1
and 1577 cm− 1 which corresponded to asymmetric andsymmetric stretching modes of coordinated carboxylic

Electrochemical Impedance Spectroscopy (EIS) of different electrodes was often performed using [Fe (CN)6]−3/[Fe (CN)6]−4 redox probes [49–51]. As shown in Figure
S3, the different sizes of the semicircle for each curve,
it can be concluded that the Charge transfer resistance(Rct) of Ni 0.75Co0.25-MOFs/CPE was significantly lower
than that of CPE. The Rct of CPE and Ni 0.75Co0.25-MOFs/
CPE were 1.15, 0.788 kΩ. This suggests that Ni 0.75Co0.25MOFs was successfully coated on the electrode surface,
and the introduction of conductive Ni 0.75Co0.25-MOFs
was a reliable way to reduce the Rct of CPE and thus promote electron transfer.
Electrochemical performance of PAR on the Ni0.75Co0.25MOFs/CPE surface
The effect of buffer and pH

To obtain better electrochemical sensing performance,
the detection conditions were optimized using CV.
Firstly, three types of buffers were tried: acetate, Britton-Robinson Buffer (BRB), and PBS each at pH 7.0. The
peak potential of PAR was maximum with the PBS buffer. Then, the pH ranges between 5.0 and 7.0 throughPBS buffer were studied to determine the impact ofthe pH value of the electrolyte on the response of PAR.
Because the pKa value is 9.5 for PAR, therefore it carries a positive charge at pH values lower than their pKa
values [52]. As shown in Fig. 7, the oxidation peak current of PAR increased as pH values increased from 5.0 to
7.0 as at lower pH, PAR is more protonated, meaning it
has gained a hydrogen ion (H+) and exists in a charged
form. This may hinder its oxidation process, resulting inlower peak currents. As the pH increases to pH 7.0 (Neutral), PAR becomes less protonated and more in its neutral form. This neutral form enhanced electrochemical
activity, leading to higher oxidation peak currents [53].
For achieving higher sensitivity, pH 7.4 was selected as
an optimal pH to electrochemically detect PAR on the
Ni0.75Co0.25-MOFs/CPE.
The effect of scanning rate

The impact of the scanning rate was studied on theanodic oxidation peak of PAR using CV. The CV curvesof 0.1mM PAR on the Ni0.75Co0.25-MOFs/CPE were

Mouhamed et al. BMC Chemistry(2024) 18:148

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Table 1 Validation parameters obtained by the developed DPV
method for determination of PAR in the presence of p-AP

Table 2 A comparison of analytical performance for PAR inelectrodes modified with different materials

Parameter
LOD (µM)
Linearity range (µM)
SlopeIntercept
Correlation coefficient (r)Accuracy (mean ± SD)
Precision(%RSD) a(%RSD) b

Modified electrodes

Method2D Ni-MOFs/rGO/GCE

DPV

MoS2/Ni-MOF/SPGEDPVParacetamol
0.02
0.60–100.00
0.05410.61010.9998100.71 ± 1.30
0.32
1.09

2D NiCu-CAT/GCE

DPVa Intraday precision [average of three different concentrations of three replicate
each (n = 9) within the same day]

HKUST-1/GCE

DPVb Interday precision [average of three different concentrations of three replicate
each (n = 9) repeated on three successive days]

Cu(tpa)-GO/GCE

DPV

Ni0.75: Co0.25-MOFs/CPE

DPVplotted in Fig. 8, with scanning rates ranging from 10.0
to 100.0 mV/s. Figure 9 demonstrates a clear linear relationship between the logarithm of peak current (IP) andthe logarithm of scan rate (ʋ), the equation of regressionlog IP = 0.6995 log ʋ − 6.3203 (r = 0.9976), showed thatthe slope is higher than the theoretical value of 0.50. This
indicates that the anodic reaction at the electrode surface
is a process controlled by diffusion, with some adsorption character. This regression equation IP=1.4038 ʋ1/2
− 2.3087 (r = 0.9948), demonstrated that there is a direct
proportionality between, the peak current (IP) and theParacetamol
Linear
Detecrange
tion
(µM)
limits
(µM)
0.04–
0.01
50.00
1.00–
400.005.00–
190.0012.50–
0.09
375.001.00–
0.36
100.000.60–
0.02
100.00

Reference

[57]
[58]
[59]
[60]
[61]
This
work

square root of the scan rate (ʋ1/2) within the range of scanrate from 10.0 to 100.0 mV/s, as shown in Fig. 10.
Moreover, as shown in Figure S4, during our study,
the long-term stability of the developed sensor wasassessed. The electrode was stored in the presence of air
and measured every five days for two months to record
the data regarding the change in the peak current values. The results show a loss of only 10.42% in the current value. Although bimetallic MOFs showed enhanced

Fig. 14 Schematic representation of monometallic and bimetallic MOFs synthesis and voltammetric measurements of PAR

Mouhamed et al. BMC Chemistry(2024) 18:148

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Table 3 Results of PAR analysis in real samples form by thedeveloped DPV method
Product

Panadol® tablets
each tablet is labeled to contain 500 mg of PAR
Batch no.11,565,448

Taken Concentra- Drug prodtion (µM)
uct Recovery%*±SD of theclaimed amount
25.00
99.81 ± 0.74
100.0098.77 ± 0.70

Table 4 Analysis results of plasma samples spiked with different
concentrations of PAR
Parameter
Linearity range
SlopeIntercept
Correlation coefficient (r)Accuracy
Precision(%RSD)
Intraday precision (Repeatability)
Interday precision (Intermediate precision)

PAR spiked in plasma
1.00 × 10− 5 M-1.00 × 10− 4M
0.1032
2 × 10− 7
0.9992102.04 ± 0.49
0.89
0.96

Table 5 Results of the proposed DPV method accuracy in spiked
human plasma samples
Prepared concentration (M)3.00 × 10− 5
5.00 × 10− 5
7.00 × 10− 5
Mean ± SD

Found concentration(M)3.05 × 10− 55.13 × 10− 5
7.13 × 10− 5

Table 6 Statistical comparison of the results obtained by the
proposed and official methods for the analysis of PAR in its pure
form
Value
Mean
SD
VariancenStudent’s t-test
F value

Proposed method
99.89
1.50
2.25
6
2.074 (2.262)
2.848 (6.26)

Official method [27]101.480.89
0.79
5Analytical performance of PAR
Calibration curve and detection limit

The DPV method was used to measure the PAR peakcurrent and was found to be linear within the range of
0.60–100.00 µM under the optimum electrochemical
conditions as presented in Fig. 11, and Fig. 12 with thesensitivity of 0.0564 µA µΜ−1 cm− 2 and a low detection
limit of 0.02 µM as mentioned in Table 1. A comparison
between the detection limits/analytical range reported
for PAR on various electrode systems [57–61] and thatobserved in the present work has been performed asshown in Table 2.

*

Recovery%
101.90102.59101.63102.04 ± 0.49

characteristics in terms of catalytic activity, they have alimitation of being commonly aggregated and difficulty
controlling the pore structure. They lack the backbone toguard against structure deformation or aggregation. Thatshall direct our plans in future work to a template-assisted
synthesis and controlled fabrication of “quasi-MOFs” [54].
Suggested mechanism of PAR electrochemical oxidation

The number of electrons involved in the reaction for an
irreversible electrochemical process is calculated using
the Laviron Eqs. [55, 56]
E = E ◦ +2.303RT /αnF, [log R at K ◦ /αnF ] + 2.303RT /αnF (log v)

All symbols have their standard meaning. For the system
under study, using slope (0.0556), generated from linear
plot of potential against log scan rate αn was calculated
to be 1.032 for PAR at Ni0.75Co0.25-MOFs/CPE. Since anirreversible electron transfer α assumed to be 0.5 [56],therefore “n” value was calculated to be 2.064 PAR, whichis consistent with 2 electron transfer processes involvedin the oxidation of PAR at the modified electrode.
Scheme 1 illustrates the possible electrochemical oxidation mechanism of PAR.

Method validation

By examining three different concentration levels of
PAR and calculating the percentage recovery, the suggested method was found to be accurate. The suggested
method was precise based on the assessment of intra-day
and inter-day precision, with % RSD values within theaccepted range of less than 2%. The results of LOD, accuracy, and precision are shown in Table 1. As shown in
Fig. 13, the method studied was also considered specificfor its ability to efficiently detect PAR with uniform peakwithout interfering with its main impurity p-AP.
Analytical applications
Analysis of PAR in the real samples

As our research was aimed at evaluating a new approachin practice, Ni0.75Co0.25-MOFs/CPE was used for PAR
detection in its commercial tablet. As seen in Table 3, therecovery of PAR is from 98.77 to 99.81%, indicating thepossible use of our electrochemical sensor to detect PAR
in actual samples.
Analysis of PAR in spiked human plasma

Tables 4 and 5 summarize the results of the accuracy andprecision of the analysis of spiked human plasma samples
by the suggested method. Our developed method wasable to detect concentrations as low as 10− 5M, which islower than the previously reported Cmax value [62]. Thisconfirms that our method is suitable for analyzing PAR inreal human plasma samples.

Mouhamed et al. BMC Chemistry(2024) 18:148

Statistical data analysis

The results obtained by Ni0.75Co0.25-MOFs/CPE werecompared with those obtained by applying the official
method for the determination of the PAR pure sample[27]. The t-test and F-value [63]were used to compare themean and variance between the two methods where no
significant difference in the results was found (Table 6).
The schematic representation of the electrochemical
platform of MOFs synthesis and voltammetric measurements of PAR is summarized in Fig. 14.

Conclusion
Bimetallic NiCo-MOFs with complex composition andstructure show superior catalytic activity compared totheir monometallic counterparts Ni-MOFs and CoMOFs. An electrochemical sensing platform based on 2D
Ni0.75Co0.25-MOFs/ CPE was successfully fabricated andemployed in the detection of PAR in the presence of p-AP
with a peak potential separation of 280.0 mV. Good electrochemical performance was attributed to the porous
structure of MOFs, the good electrocatalytic activity,
and the synergetic effect of Ni and Co. The constructed
electrochemical sensor showed good selectivity and highsensitivity for PAR under optimized experimental conditions. The developed Ni0.75Co0.25-MOFs/CPE had abroad linearity range (0.60–100.00 µM) and a low limit
of detection of 0.02 µM, this allows its use for pharmacokinetic studies in the future. In addition, the analysisof real samples and human plasma samples revealed thesuccessful applicability of the developed sensor as a pointof care in determining PAR. This work also provided asimple and general strategy for constructing MOFs-based
electrochemical sensors.
Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s13065-024-01247-7.
Supplementary Material 1
Acknowledgements
Not applicable.
Author contributions
A. A. M. Data curation, Software, Validation, and Writing- Original draft
preparation. A. H. N. Software, Investigation, Writing- Reviewing and Editing.
(A) M.M. Conceptualization, Methodology, Software, Reviewing, Editing.N.
M.M. Conceptualization, Writing- Reviewing and Editing. (B) M. E. Investigation,
Writing- Reviewing and Editing. All authors reviewed the manuscript.
Funding
No funding was received for this study.
Open access funding provided by The Science, Technology & Innovation
Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank
(EKB).
Data availability
The datasets used and/or analysed during the current study are available fromthe corresponding author on reasonable request.

Page 10 of 11

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 3 April 2024 / Accepted: 12 July 2024

References
1. Simões FR, Xavier MG. 6 - Electrochemical sensors. In: Da Róz AL, Ferreira M,
de Lima Leite F, Oliveira ON, editors. Nanoscience and its applications. William
Andrew Publishing; 2017. pp. 155–78.
2. El-Hadi HRA, Eissa MS, Eltanany BM, Zaazaa HE, Arafa RM. Greenness andwhiteness assessment of a sustainable voltammetric method for difluprednate estimation in the presence of its alkaline degradation product. Sci Rep.
2024;14:12088.
3. Shah R, Ali S, Raziq F, Ali S, Ismail PM, Shah S et al. Exploration of metal organic
frameworks and covalent organic frameworks for energy-related applications. Coord Chem Rev. 2023;477.
4. Li Z, Song M, Zhu W, Zhuang W, Du X, Tian L. MOF-derived hollow heterostructures for advanced electrocatalysis. Coord Chem Rev. 2021;439.
5. Yaghi OM, Li G, Li H. Selective binding and removal of guests in a microporous metal–organic framework. Nature. 1995;378:703–6.
6. Alzahrani FM, Alsaiari NS, Katubi KM, Amari A, Tahoon MA. Synthesis,characterization, and application of magnetized Lanthanum (III)-Based MetalOrganic Framework for the Organic dye removal from Water. Adsorpt Sci
Technol. 2022.
7. Dutt S, Kumar A, Singh S. Synthesis of Metal Organic frameworks (MOFs)
and their derived materials for Energy Storage Applications. Clean Technol.
2023;5:140–66.
8. Beitollahi H, Van Le Q, Farha OK, Shokouhimehr M, Tajik S, Nejad FG, et al.
Recent electrochemical applications of metal-organic framework-basedmaterials. Cryst Growth Des. 2020;20:7034–64.
9. Xie LS, Skorupskii G, Dincǎ M. Electrically Conductive Metal-Organic frameworks. Chem Rev. 2020;120:8536–80.
10. Laurier KGM, Vermoortele F, Ameloot R, De Vos DE, Hofkens J, Roeffaers MBJ.
Iron (III)-based metal-organic frameworks as visible light photocatalysts. J Am
Chem Soc. 2013;135:14488–91.
11. Fateeva A, Chater PA, Ireland CP, Tahir AA, Khimyak YZ, Wiper PV, et al. A waterstable porphyrin-based metal-organic framework active for visible-light
photocatalysis. Angewandte Chemie - Int Ed. 2012;51:7440–4.
12. Raptopoulou CP. Metal-organic frameworks: synthetic methods and potential
applications. Materials. 2021;14:1–32.
13. Deng T, Zhang W, Arcelus O, Wang D, Shi X, Zhang X et al. Vertically co-oriented two-dimensional metal-organic frameworks for packaging enhanced
supercapacitive performance. Commun Chem. 2018;1.
14. Wu Y, Tian J, Liu S, Li B, Zhao J, Ma L, et al. Bi-microporous Metal-Organic
frameworks with cubane [M4(OH)4 ] (M = Ni, Co) clusters and pore‐spacepartition for electrocatalytic methanol oxidation reaction. Angew Chem.
2019;131:12313–7.
15. Xue Z, Li Y, Zhang Y, Geng W, Jia B, Tang J et al. Modulating electronic
structure of Metal-Organic Framework for efficient Electrocatalytic Oxygen
Evolution. Adv Energy Mater. 2018;8.
16. Shan Y, Zhang G, Shi Y, Pang H. Synthesis and catalytic application of defective MOF materials. Cell Rep Phys Sci. 2023;4.
17. Heidary N, Chartrand D, Guiet A, Kornienko N. Rational incorporation of
defects within metal-organic frameworks generates highly active electrocatalytic sites. Chem Sci. 2021;12:7324–33.
18. Khalil IE, Xue C, Liu W, Li X, Shen Y, Li S et al. The role of defects in MetalOrganic frameworks for Nitrogen Reduction reaction: when defects switch tofeatures. Adv Funct Mater. 2021;31.
19. Bai Y, Liu C, Shan Y, Chen T, Zhao Y, Yu C et al. Metal-Organic frameworks
nanocomposites with different dimensionalities for Energy Conversion andStorage. Adv Energy Mater. 2022;12.

Mouhamed et al. BMC Chemistry(2024) 18:148

20. Hai G, Jia X, Zhang K, Liu X, Wu Z, Wang G. High-performance oxygen evolution catalyst using two-dimensional ultrathin metal-organic frameworks
nanosheets. Nano Energy. 2018;44:345–52.
21. Chao S, Xia Q, Wang Y, Li W, Chen W, Pristine S. N-containing Mn-based metalorganic framework nanorods enable efficient oxygen reduction electrocatalysis. Dalton Trans. 2020;49:4336–42.
22. Zhou Y, Abazari R, Chen J, Tahir M, Kumar A, Ikreedeegh RR et al. Bimetallic
metal–organic frameworks and MOF-derived composites: recent progress onelectro- and photoelectrocatalytic applications. Coord Chem Rev. 2022;451.
23. Li H, Qian X, Xu C, Huang S, Zhu C, Jiang X, et al. Hierarchical porous Co9S8/
Nitrogen-Doped Carbon@MoS2 polyhedrons as pH Universal Electrocatalysts
for highly efficient hydrogen evolution reaction. ACS Appl Mater Interfaces.
2017;9:28394–405.
24. Dong Y, Zhou M, Zhang L. 3D multiporous Co, N co-doped MoO2/MoC
nanorods hybrids as improved electrode materials for highly sensitive simultaneous determination of acetaminophen and 4-aminophenol. Electrochim
Acta. 2019;302:56–64.
25. Zhao S, Wang Y, Dong J, He CT, Yin H, An P et al. Ultrathin metal-organic
framework nanosheets for electrocatalytic oxygen evolution. Nat Energy.
2016;1.
26. Sweetman SC. Martindale: the complete drug reference. 36th edition. London: Pharmaceutical Press; 2009.
27. The British Pharmacopoeia. The Stationary Office, London; 2016.
28. Brunton LL, Hilal-Dandan R, Knollmann BC. The pharmacological basis ofTherapeutics. 13th edition. 2017.
29. Zhang Y, Huang Z, Wang L, Wang C, Zhang C, Wiese T, et al. Point-of-caredetermination of Acetaminophen levels with Multi-hydrogen Bond manipulated single-molecule recognition (eMuHSiR). Anal Chem. 2018;90:4733–40.
30. Braimah HY, Tijjani AB, Amos SC. Impurity profiling of paracetamol dosage
forms used IN Maiduguri Metropolis. World J Pharm Res. 2019;8:1659–85.
31. El Sherbiny D, Wahba MEK. Analysis of some pharmaceuticals in the presenceof their synthetic impurities by applying hybrid micelle liquid chromatography. Open Chem. 2020;18:377–90.
32. Tan C, Gao N, Zhou S, Xiao Y, Zhuang Z. Kinetic study of acetaminophen
degradation by UV-based advanced oxidation processes. Chem Eng J.
2014;253:229–36.
33. Youssef SH, Mohamed D, Hegazy MAM, Badawey A. Analytical methods forthe determination of Paracetamol, pseudoephedrine and brompheniraminein Comtrex tablets. BMC Chem. 2019;13.
34. Bakker E. Ion-selective electrodes: Liquid membrane. Encylopedia of Analytical sciences-Second Edition. Elsevier; 2005. pp. 509–14.
35. Nahorniak M, Pasetto P, Greneche JM, Samaryk V, Auguste S, Rousseau A, et al.
Two-step single-reactor synthesis of oleic acid- or undecylenic acid-stabilized
magnetic nanoparticles by thermal decomposition. Beilstein J Nanotechnol.
2023;14:11–22.
36. Adeyemi Oladipo A. Cu0-doped graphitic carbon quantum dots for rapid
electrochemical sensing of glyphosate herbicide in environmental samples.
Microchem J. 2024;200.
37. Bahar SL, Permatasari LM, Madurani KA, Kurniawan F. Determination of
Paracetamol using screen-printed carbon electrode. Int J Health Sci.
2022;1968–77.
38. Peng Y, Wu Z, Liu Z. An electrochemical sensor for Paracetamol based onan electropolymerized molecularly imprinted o-phenylenediamine film ona multi-walled carbon nanotube modified glassy carbon electrode. Anal
Methods. 2014;6:5673–81.
39. Atta NF, Galal A, Azab SM. Electrochemical Determination of Paracetamol
Using Gold Nanoparticles-Application in tablets and human fluids. Int J
Electrochem Sci. 2011.
40. Kang X, Wang J, Wu H-X, Liu W, Aksay I, Lin Y. A graphene-based electrochemical sensor for sensitive detection of Paracetamol. Talanta. 2010;81:754–9.
41. Rezaei B, Irannejad N. Electrochemical detection techniques in biosensor
applications. Electrochemical biosensors. Amsterdam: Elsevier; 2019. pp.
11–43.
42. Beitollahi H, Mohammadi S, Safaei M, Tajik S. Applications of electrochemical sensors and biosensors based on modified screen printed electrodes: areview. Anal Methods. 2020;12.
43. Han T, Mattinen U, Bobacka J. Improving the sensitivity of solid-contact
ion-selective electrodes by using Coulometric Signal Transduction. ACS Sens.
2019;4:900–6.
44. Shao Y, Ying Y, Ping J. Recent advances in solid-contact ion-selective electrodes: functional materials, transduction mechanisms, and development
trends. Chem Soc Rev. 2020;49.

Page 11 of 11

45. ICH Guideline Validation of analytical procedures: text and methodology,
Q2 (R1. ), International Conference of Harmonization (ICH) of TechnicalRequirements for Registration of Pharmaceuticals for Human Use. Geneva,
Switzerland; 2005.
46. Salama RS, Abd El-Hakam S, Elsayed Samra S, El-Dafrawy SM, El-Hakam SA,
Samra SE, et al. Adsorption, Equilibrium and kinetic studies on the removalof methyl orange dye from aqueous solution by the use of copper metalorganic framework (Cu-BDC) Adsorption, Equilibrium and Kinetic studies on
the removal of Methyl Orange Dye from Aqueous Solution by using of Copper Metal Organic Framework (Cu-BDC). Int J Mod Chem. 2018;10:195–207.
47. Radhika MG, Gopalakrishna B, Chaitra K, Bhatta LKG, Venkatesh K, Sudha
Kamath MK et al. Electrochemical studies on Ni, Co & Ni/Co-MOFs for highperformance hybrid supercapacitors. Mater Res Express. 2020;7.
48. Wang Y, Wu Y, Xie J, Hu X. Metal-organic framework modified carbon paste
electrode for lead sensor. Sens Actuators B Chem. 2013;177:1161–6.
49. Mouhamed AA, Eltanany BM, Mostafa NM, Elwaie TA, Nadim AH. Designof screen-printed potentiometric platform for sensitive determination of
mirabegron in spiked human plasma; molecular docking and transducer
optimization. RSC Adv. 2023;13:23138–46.
50. Chen JY, Weng YX, Han YH, Ye RH, Huang DH. A novel pencil graphite
electrode modified with an iron-based conductive metal-organic framework
exhibited good ability in simultaneous sensing bisphenol A and bisphenol S.
Ecotoxicol Environ Saf. 2024;272.
51. Ye RH, Chen JY, Huang DH, Wang YJ, Chen S. Electrochemical Sensor basedon glassy-Carbon Electrode modified with dual-ligand EC-MOFs supported
on rGO for BPA. Biosensors.2022;12(367).
52. Prescott L. Kinetics and metabolism of Paracetamol and phenacetin. Br J Clin
Pharmacol. 1980;10 2:291–8.
53. Awad MI, Sayqal A, Pashameah RA, Hameed AM, Morad M, Alessa H, et al.
Enhanced paracetamol oxidation and its determination using electrochemically activated glassy Carbon Electrode. Int J Electrochem Sci. 2021;16:1–15.
54. Laviron E. The Use of Linear potential sweep voltammetry and of A.C.
Voltammetry for the study of the Surface Electrochemical reaction of strongly
Adsorbed systems and of Redox Modified electrodes. J Electroanal Chem.
1979;100:263–70.
55. Atty SA, Ghany MFA, Hussein LAA, Magdy N, Yamani HZ. TiO2 nanoparticles
and ionic liquid platform for selective electrochemical determination ofindacaterol in pharmaceutical formulations and human fluids: application tocontent uniformity. J Iran Chem Soc. 2019;17:383–95.
56. Chen L, Wang HF, Li C, Xu Q. Bimetallic metal-organic frameworks and theirderivatives. Chem Sci. 2020;11:5369–403.
57. Wu M, Wang L, Xu F, Ma G. Preparation of Ni-MOF superstructure-reduced
graphene oxide composite for enhanced electrochemical sensing of acetaminophen. Ionics. 2022;28:5571–80.
58. Dourandish Z, Sheikhshoaie I, Maghsoudi S. Molybdenum Disulfide/
Nickel-Metal Organic Framework Hybrid Nanosheets Based Disposable
Electrochemical Sensor for determination of 4-Aminophenol in Presence of
Acetaminophen. Biosensors. 2023;13.
59. Wang J, Liu S, Luo J, Hou S, Song H, Niu Y et al. Conductive Metal-Organic
frameworks for Amperometric Sensing of Paracetamol. Front Chem. 2020;8.
60. Sofi FA, Bhat MA, Majid K. Cu2+-BTC based metal-organic framework: a redox
accessible and redox stable MOF for selective and sensitive electrochemicalsensing of acetaminophen and dopamine. New J Chem. 2019;43:3119–27.
61. Wang X, Wang Q, Wang Q, Gao F, Gao F, Yang Y, et al. Highly dispersible andstable copper Terephthalate Metal-Organic Framework–Graphene Oxide
Nanocomposite for an Electrochemical sensing application. ACS Appl Mater
Interfaces. 2014;6:11573–80.
62. Raffa RB, Pawasauskas J, Pergolizzi JV, Lu L, Chen Y, Wu S, et al. Pharmacokinetics of oral and intravenous paracetamol (Acetaminophen) when coadministered with intravenous morphine in healthy adult subjects. Clin Drug
Investig. 2018;38:259–68.
63. Hassan AM, Kelani KM, Hegazy MA, Nadim AH, Tantawy MA. A probe of newmolecularly imprinted solid-phase extraction coupled with HPLC-DAD andatomic absorption spectrophotometry for quantification of tetracycline HCl,metronidazole and bismuth subcitrate in combination with their official
impurities: application in dosage form and human plasma. J Chromatogr B
Analyt Technol Biomed Life Sci. 2024;1234.

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