Green Chemistry Letters and Reviews

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Biogenic green synthesis of metal oxide

nanoparticles using oat biomass for ultrasensitive
modified polymeric sensors

Salma A. Al-Tamimi

To cite this article: Salma A. Al-Tamimi (2021) Biogenic green synthesis of metal oxide
nanoparticles using oat biomass for ultrasensitive modified polymeric sensors, Green Chemistry
Letters and Reviews, 14:2, 166-179, DOI: 10.1080/17518253.2021.1895326

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GREEN CHEMISTRY LETTERS AND REVIEWS
2021, VOL. 14, NO. 2, 166–179
https://doi.org/10.1080/17518253.2021.1895326

LETTER

Biogenic green synthesis of metal oxide nanoparticles using oat biomass for
ultrasensitive modified polymeric sensors
Salma A. Al-Tamimi
Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia

ABSTRACT ARTICLE HISTORY

This study describes Green synthesis of two metal oxide nanoparticles MnO2NPs and CuONPs using Received 28 August 2020
the oat biomass. The electrocatalytic activity of the synthesized metal oxide nanoparticles was Accepted 20 February 2021
investigated by fabricating two modified sensors enriched with MnO2NPs and CuONPs as a
KEYWORDS
coated layer on the surface of the sensors and utilized to quantify antibacterial drugs Cephalexin; cefazolin;
cephalexin (CPX) and cefazolin (CFZ) in their commercial products and biosamples. The tested modified sensors; metal
drugs were incorporated with the precipitating agents phosphomolybdic acid and oxide nanoparticles; coated
phosphotungstic acid to form CPX-PM and CFZ-PT as electroactive materials, respectively. wire sensors
Conductivity enhancement of the fabricated modified sensors CPX-PM-MnO2NPs and CFZ-PT-
CuONPs was determined and the outcomes compared to the results obtained from the
conventional types of the same sensors. Linear relationships were recorded between the
sensory potentials of the enriched metal oxide nanoparticles in the ranges of 1.0 × 10-8-1.0 ×
10-2 and 1.0 × 10-10-1.0 × 10-2 mol L-1 with lower limits of detection 5.6 × 10-9 and 5.7 × 10-11
mol L-1 for CPX-PM-MnO2NPs and CFZ-PT-CuONPs with respect to 1.0 × 10-6-1.0 × 10-2 mol L-1
of their conventional coated wire types. The fabricated sensors provide excellent sensitivity and
selectivity towards the determination of CPX and CFZ in its commercial and biosamples.

1. Introduction Currently, nanomaterials have gained much attention

Nanotechnology is a term concerned with the utility of in electrochemical and sensing applications, due to their
the techniques or nanomaterials in various applications. unique physical and chemical properties such as high
It is an innovative facilitating technology with the poten- mechanical strength, large surface area, excellent elec-
tial to engineer novel materials has the ability to trocatalytic potential, and conductivity. The nanoscale
introduce new nano-specific features of products, instru- materials reveal significant and amazing characteristics
ments, and systems in wide-ranging professional and which are considered as a possible key to solving
consumer applications (1). many global and environmental problems (2).

CONTACT Salma Al-Tamimi [email protected] Department of Chemistry, College of Science, King Saud University, P.O. Box 22452, Riyadh 11495,
Saudi Arabia
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
 GREEN CHEMISTRY LETTERS AND REVIEWS 167

Scientists are still trying to improve their research Cephalexin (CPX) is a semi-synthetic antibiotic that
area, where, the extraordinary features of nanomaterials belongs to the cephalosporin group, which is a medi-
can be potentially modified our life cycle. The unique cation used in the treatment of various bacterial infec-
characteristics of these nanomaterials and the multi- tions (Figure 1). Its action is conducted by stopping
functional properties of metal oxides play an important the bacterial cell growth. Various analytical methods
role in the fabrication of various modified chemo and were reported in the literature for the quantification of
biosensors (3–4). Cephalexin monohydrate in its commercial products
The unique physical and chemical characteristics of such as reversed-phase high-performance liquid chrom-
metal oxide nanoparticles, including a large specific atography (23), UV–spectrophotometry (24), spectrofl-
surface area, ability of strong adsorption, high catalytic uorimetry (25). Also, electrochemical methods were
efficiency, and biocompatibility, they have been addressed including, voltammetry (26) and potentiome-
reported for many applications such as biomedical appli- try (27–28).
cations (5), catalysis (6), drug delivery systems (7), and Cefazolin sodium (CFZ) is a first-generation cephalos-
sensing technology (8). The last decades have also porin (Figure 1), which is active mainly against
seen phenomenal advancement in the synthesis of Gram-positive and Gram-negative organisms. It is mainly
metal oxides nanoparticles using various chemical and recommended to treat various bacterial infections,
biogenic methods (9–10). Accordingly, eco-friendly, including skin, bone, lung, joint, stomach, and urinary
benign methods are necessary to be ascribed for syn- tract (29). Furthermore, it is also used before surgical
thesis of nanomaterials. Indeed, the formation of operations (30). Methods of analysis have been reported
energy-efficient, low-cost, and nontoxic metal oxides for CFZ quantification in commercial formulations
nanoparticles using plant extracts, and microorganisms including, spectroscopic analysis using spectropho-
have been reported (11–12). tometry and spectrofluorimetry (31–32), chemilumines-
The Oat (Avena sativa L.) is a species of cereal grains cence (33), densitometry (34) and high-performance
usually grown worldwide to provide a potential food liquid chromatography (35). Few reports were con-
staple for people in many countries. It is commonly cerned with the electrochemical determination of CFZ
eaten or administered as a medicinal supplement for using voltammetry and potentiometry (26–36).
its high health benefits (13). The use of oat biomass or Despite these analytical techniques provide sensitive
extract can be useful for biogenic preparation of nano- detection, they still have certain drawbacks such as
particles (14–15). expensive instrumentations, consuming a long time of
In recent years, the researchers started employing analysis and may require a tedious precondition
metal oxide nanoparticles based sensors in the esti- procedure.
mation and quantification of medical drugs. The unique Nowadays, numerous polymeric potentiometric
advanced physicochemical features of metal oxide nano- sensors have been developed for the determination of
particles such as manganese dioxide nanoparticles drug species, mainly for quality control of commercial
(MnO2NPs) and copper oxide (CuONPs), encourage preparations. Because of their sensitivity, selectivity
their use in various applications such as semiconductors, and simplicity, potentiometric sensors are among the
drug delivery systems, and biomedical properties (16– most commonly applied electrochemical techniques
20). The literature review revealed various reported for various rapid measurements of drugs (37). Although
articles that discussed the role of MnO2NPs and few reports were addressed for the determination of CPX
CuONPs in electrochemical sensors (21–22). and CFZ, those developed sensors showed poor

Figure 1. Chemical structures of cephalexin and cefazolin.

168 S. A. AL-TAMIMI

reproducibility, narrow concentration ranges and high Kyoto, Japan) was employed to investigate the crystal-
detection limits. Therefore, the objective of this study line nature of the synthesized MnO2NPs and CuONPs.
is to synthesize MnO2 and CuO nanoparticles using oat Furthermore, Transmission electron microscope (TEM)
biomass as a green reducing agent. Various spectro- (JEM-2100F, JEOL Ltd, USA) and Scanning electron
scopic and microscopic techniques were used to microscope (SEM) (JSM-7610F; JEOL, USA) was used to
confirm the synthesis of MnO2 and CuO nanoparticles. characterize the surface morphology and particle size
The synthesized metal oxides were used to fabricate using an accelerating voltage of 100 kV. Additionally,
simple and ultrasensitive new CPX-PM-MnO2NPs and all potentiometric measurements were performed
CFZ-PT-CuONPs coated wire membrane sensors for the using a digital pH-mV (HANNA, model 211) with a fabri-
determination of CPX monohydrate and CFZ sodium in cated indicator sensor in conjunction with Ag/AgCl as a
their commercial products and biosamples. In addition, reference electrode. The pH adjustment was carried out
a comparative study was performed between the using pH-meter (Metrohm model 744, Romania).
modified sensors and their conventional types with
respect to the potential response, selectivity, the
2.3. Plant gathering and oat biomass
quantification range and the detection limit. The
preparation
suggested potentiometric method was also validated
according to the International council for harmonization The seeds of oat (Avena Sativa L) were collected and
of technical requirements for pharmaceuticals for identified by prof. Hesham Oraby, Crop Department of
human use (ICH) guidelines (38). Agriculture, Zagazig University, Egypt. The collected
seeds were washed with deionized water and dried at
80°C for 15 days. The dried oat seeds (0.5 kg) were
2. Experimental ground and sieved through a sieve with a nominal
2.1. Chemicals mesh aperture of 180 μm to obtain a homogenous
powder.
Pure grade of cephalexin and cefazolin was gifted by
Memphis Co. for Pharmaceutical and Chemical Indus-
tries (Cairo, Egypt). Commercial cephalexin 2.4. Green synthesis of MnO2 nanoparticles
(Keflex®500 mg/tablets) and (Zinol 500 mg/vial) were Green synthesis of MnO2NPs was conducted by mixing
purchased from local drug markets. The used chemicals 10 g of oat powder with 250 mL of distilled water and
and reagents such as tetrahydrofuran (THF), acetic acid, boiled for 10 min and centrifuged at 3500 rpm for
ortho-nitrophenyloctyl ether (o-NPOE), high molecular 10 min. Then 25 mL of aqueous solution manganese
weight polyvinyl chloride (PVC), acetone 99.9%, metha- acetate (1.0 × 10−5 mol L−1) at alkaline pH 8 was mixed
nol 99.9%, ethanol 99.9%, acetonitrile, hydrochloric with 100 mL of the oat biomass under continuous stir-
acid 37%, phosphomolybdic acid (PMA) and phospho- ring for 1 h at ambient temperature. After centrifugation,
tungstic acid (PTA) were supplied by (Sigma Aldrich, the obtained precipitate was washed with deionized
Hamburg, Germany). Manganese acetate 99.9%, water followed by ethanol three times and dried at
copper sulfate 99.0%, potassium monobasic phosphate, 100°C (Scheme 1(a)).
zinc sulfate (ZnSO4.7H2O), potassium dibasic phosphate,
sodium acetate and sodium hydroxide 99.9% were pur-
chased from (WinLab, East Midlands, UK). Multi-Serum 2.5. Green synthesis of CuO nanoparticles
Normal, Randox Laboratories (Crumlin, Antrim, UK) is The green synthesis of CuONPs was carried out by
the suppliers of commercial serum samples. adding a quantity of 1.0 × 10−2 mol L−1 copper sulfate
solution (10 mL) to 30 mL of aqueous oat biomass and
mixed well under magnetic stirring. Then, the solution
2.2. Characterization and instruments
was heated at 80 °C in a water bath for 60 min. The
UV 2450 Spectrophotometer (Shimadzu Corporation, change of color solution from brownish-yellow to dark
Kyoto, Japan) in the range of 200–800 nm was used to brown revealed the formation of CuONPs (Scheme 1(b)).
study the UV–Vis spectra of the prepared metal oxide
nanoparticles. Spectrum BX spectrometer, (PerkinElmer,
2.6. Preparation of standard drug solution
Waltham, USA) was applied to determine the possible
functional groups that are responsible for the reduction Standard aqueous CPX and CFZ solutions of 1.0 ×
process to form the metal oxide nanoparticles. X-ray 10−2 mol L−1 were prepared by dissolving 0.347 g and
diffraction (XRD) (Shimadzu XRD-6000 diffractometer, 0.476 of CPX and CFZ in 100 mL distilled water. Testing
 GREEN CHEMISTRY LETTERS AND REVIEWS 169

Scheme 1. Illustration of (a) preparation of MnO2NPs and (b) preparation of CuONPs using oat biomass.

solutions for experimental studies with various concen- 2.9. Calibration graphs
trations were prepared using the same solvent for
The calibration graphs of the fabricated conventional
serial dilutions.
and modified sensors were constructed by plotting the
potential readings of each sensor vs. -logarithm of
2.7. Preparation of electroactive materials drug concentrations. Approximately, 20 mL of 1.0 ×
10−10–1.0 × 10−2 mol L−1 CPX or CFZ standard solution
The electroactive materials of CPX-PM and CFZ-PT were was analyzed using the fabricated sensors separately in
prepared by adding 50 mL of 1.0 × 10−2 mol L−1 of each conjunction with Ag/AgCl as a reference electrode.
CPX and CFZ solution to the same volume of 1.0 × Between each measurement, the surface of the sensors
10−2 mol L−1 of PMA and PTA, respectively. A light should be washed carefully with distilled water and
yellow precipitate of CPX-PM and a white precipitate dried with tissue paper.
of CFZ-PT were formed. The obtained solutions were
filtered and washed thoroughly three times using dis-
tilled water and left aside to dry in room temperature 2.10. Optimization of potential readings
for 12 h. conditions
The potential readings of the fabricated sensors can be
greatly affected by the pH of the testing solution. To
2.8. Sensor fabrication and membrane
investigate the pH effect, 1.0 × 10−4 mol L−1 of CPX or
composition
CFZ test solution was acidified by adding a few drops
Four different coated wire sensors CPX-PM, CPX-PM- of 0.1 mol L−1 hydrochloric acid. After increasing the
MnO2NPs, CFZ-PT and CFZ-PT-CuONPs were fabricated pH using 0.1 mol L−1 sodium hydroxide, the potential
by mixing 10 mg of ion-pair CPX-PM or CFZ-PT with readings were determined using the fabricated
190 mg of high molecular weight polyvinyl chloride
(PVC) and 0.35 mL of plasticizer o-NPOE in the presence
of 5 mL of THF. The mixed solution of each electroactive
material was allowed to evaporate slowly in a Petri dish
(3 cm in diameter) at room temperature until an oily
membrane solution was formed. An aluminum wire
was cleaned and washed with acetone, then immersed
many times in the membrane solution to fabricate the
conventional CPX-PM and CFZ-PT sensors. The
modified sensors were fabricated by coating the
surface of the sensor with a modified coated membrane
cocktail containing MnO2NPs or CuONPs (5 mg). A poly-
meric CPX-PM-MnO2NPs or CFZ-PT-CuONPs was used to
form a thin layer on the surface of the sensor then after
drying the sensor immersed several times in the coated Scheme 2. The preparation steps of modified coated wire
membrane mixture to form thick coated wire membrane sensors using polymeric coated membrane cocktail containing
as shown in Scheme 2. CPX-PM-MnO2NPs or CTZ-PT-CuONPs as modified ion-pairs.
170 S. A. AL-TAMIMI

conventional and modified sensors separately in con- serum samples using a spiking technique. The pH of
junction with Ag/AgCl as a reference electrode and a the samples was adjusted using acetate buffer pH 3
combined glass electrode for detecting pH values. The (CPX) or pH 2 (CFZ). To the previously adjusted serum
pH values were plotted as a function of potential read- samples, an accurate amount of the tested CPX or CFZ
ings of each sensor and the pH graphs were obtained. was added. Approximately, 1.0 mL of each previously
A separate solution method (39) was applied to evalu- spiked sample was mixed with 1.0 mL acetonitrile,
ate the selectivity of the fabricated sensors towards the 0.1 mL of 0.1 mol L−1 sodium hydroxide and 1.0 mL
determination of CPX and CFZ solutions. The same molar ZnSO4 ·7H2O (5.0%, w/v) for deproteination. The
concentration (1.0 × 10−3 mol L−1) of CPX or CFZ sol- sample was centrifuged at 2500 rpm for 15 min and
ution and interfering species was analyzed and the filtered.
selectivity of the fabricated sensors was expressed as tol-
erable values which were calculated using the previously
reported equation (40). 3. Results and discussion
Furthermore, the dynamic response time and lifetime of
3.1. Characterization of MnO2 and CuO
the fabricated sensors should be determined by measuring
nanoparticles
the potential response time of the investigated drugs using
the concentration range 1.0 × 10−10–1.0 × 10−2 mol L−1. Different spectroscopic methods were used to character-
ize the green synthesized MnO2 and CuO nanoparticles.
UV–Vis spectroscopy is an utmost reliable and useful
2.11. Analysis of CPX and CFX in pharmaceuticals
method suitable for characterizing and confirming the
Ten tablets of Keflex® (500 mg/tablets) were ground to a shape, size and stability of the biogenic green syn-
fine powder and an amount 0.347 g equivalent to obtain thesized metal oxide nanostructures in their aqueous
1.0 × 10−2 mol L−1 CPX standard solution was dissolved suspensions (41). UV–Vis spectra of MnO2NPs and
in 100 mL distilled water. Testing solutions in the range CuONPs demonstrated two broad absorption peaks at
of 1.0 × 10−8−1.0 × 10−2 mol L−1 were prepared using 387 and 270 nm, respectively (Figure 2). This can be
serial dilutions with distilled water. The potential readings due to photo excitation of electrons from the valence
of modified CPX-PM-MnO2NPs were recorded to deter- band to the conduction band. Eg = hυ = hc/λ formula
mine CPX in its tablets. To determine of CFZ in its injections was used to calculate the band gap of nanoparticles,
Zinol® (500 mg/vial), the powder of five vials mixed well where h is Planck’s constant, c is the velocity of light
and accurate amount 0.476 g equivalent to obtain 1.0 × and λ is the wavelength. The band gaps of MnO2NPs
10−2 mol L−1 CFZ standard solution was dissolved in and CuONPs were found to be 3.45 and 3.36 eV, respect-
100 mL distilled water and serial dilutions to obtain con- ively. The bandgap values confirmed that these nano-
centration range 1.0 × 10−10–1.0 × 10−2 mol L−1 was per- particles are semiconductors. The results obtained
formed and the fabricated CFZ-PT-CuONPs was applied were in agreement with those previously reported in
to determine CFZ in its pharmaceutical injections. (42–43).
The FTIR analysis of MnO2NPs and CuONPs was
carried out in the range 400–4000 cm–1. The absorption
2.12. Analysis of CPX and CFZ in biosamples
bands for MnO2NPs were 3430, 2928, 2862, 1597, 1071,
The fabricated modified CPX-M-MnO2NPs and CFZ-PT- and 527 cm–1. The noticed band at 3430 cm–1 is
CuONPs sensors were used to detect CPX and CFZ in related to the O–H bond stretching vibration. The

Figure 2. UV–vis spectra of MnO2 NPs and CuONPs using wavelength scan range 200–400 nm.
 GREEN CHEMISTRY LETTERS AND REVIEWS 171

recorded bands at 2928 and 2862 cm–1 revealed the To estimate and detect the crystalline forms of the
presence of medium C–H stretching vibration bands. green synthesized metal oxide nanoparticles, XRD diffr-
The observed absorption bands around 1597 cm–1 indi- actometer with Cu-kα at (k = 1.5406 Å) with accelerating
cated the presence of an O–H vibrating mode of voltage 220/50 Hz was used to determine the crystal
adsorbed water. A strong peak at 1071 cm–1 was structure of MnO2NPs and CuONPs. The XRD analysis
recorded which is attributed to C–O of secondary of MnO2NPs showed diffraction peaks at 2θ = 38.2°,
alcohol in cellulose and other carbohydrates present in 40.0°, 44.3°, 48.7°, 56.4°, 63.2°, 66.3°, and 72.2° corre-
oat biomass. The observed band at 534 cm–1 sponding to MnO2 (110), (101), (200), (111), (211),
confirmed the formation of O–Mn–O stretching (220), (002) and 310, respectively. However, CuONPs, dis-
vibration (Figure 3(a)). played different peaks at 2θ = 29.2°, 31.5°, 33.2°, 35.7°,
FTIR spectrum of CuONPs showed two significant 42.3°, 45.2°, 51.3°, 62.1°, 73.5° 83.2°, and 84.2° for CuO
bands at 3432 and 2928 cm−1 which corresponding to (110), (002), (111), (202), (020), (202), (113), (311), (220),
O–H and C–H stretching vibrations, respectively. The (311), and (004) plane orientation. The results are in
recorded absorption band at 2369 cm−1 indicated the agreement with JCPDS (044-0141) and (JCPDS 80-1268)
presence of carbon dioxide (CO2–stretching) vibration. values of MnO2 and CuO, respectively, and indicated
The O–H stretching mode of water is confirmed by the that the formed particles are crystalline and in nanoscale
appearance of absorption band at 1622 cm−1. Character- dimensions. All diffraction peaks can be indexed as
istic bands of CuO are ranging from 1000 to 400 cm−1. typical monoclinic in structure and no other phases
The observed bands around 842 and 624 cm−1 can be were observed (Figures 4a and 4b). The particle size of
attributed to the formation of Cu-O (Figure 3(b)). MnO2 and CuO nanoparticles have been estimated

Figure 3. FT-IR spectra of (a) MnO2NPs and (b) CuONPs at wavenumber from 4000 to 400 cm−1.

Figure 4. XRD patterns of (a) MnO2NPs and (b) CuONPs.

172 S. A. AL-TAMIMI

from XRD pattern by using the following Debye–Scher- were fabricated by mixing the active materials CPX-PM
rer equation: D = 0.9λ/β cosθ. Where λ of the XRD detec- or CFZ-PT with (o-NPOE) as a solvent mediator in the
tion was 0.15406 nm, β represents the full width at half presence of PVC. In this study, ortho-nitrophenyloctyl
maximum, θ is the diffraction angle, and D is the diam- ether (o-NPOE) acts as a fluidizer facilitating hom-
eter of the particle. The particle diameter for MnO2 ogenous dissolution of the ion-pairs and allowing their
and CuO nanoparticles were found to be 52.3 and diffusion mobility inside the membranes. The membrane
66.8 nm, respectively. selectivity towards the tested analytes is greatly affected
Further investigations were carried out using TEM by using o-NPOE of high dielectric constant (ɛ = 24) that
and SEM microscopes, to study the surface morphology, enhances the dissolution of ion pairs within the active
shape and size of the synthesized nanoparticles. The membranes and consequently increases their partition
picked images of MnO2NPs and CuONPs using TEM coefficient in the prepared membranes and improves
confirmed that the prepared nanoparticles are uniformly the mechanical feature of the membranes (44).
distributed with rode and spherical particles in shape for The potential response and the critical characteristic
MnO2NPs and CuONPs, respectively (Figures 5a and 5c). performance of the fabricated CPX-PM, CFZ-PT, CPX-
The prepared nanoparticles were found to be in the PM-MnO2NPs and CFZ-PT-CuONPs were summarized in
range of 50–-100 nm. The obtained results were in Table 1. The results demonstrated that the above-men-
agreement with those estimated from XED analysis. tioned sensors displayed Nernstian responses with
The surface morphology of the as-prepared MnO2NPs slopes 52.12 ± 0.8, 51.60 ± 0.5, 57, 39 ± 0.3 and 58.65 ±
and CuONPs, was investigated under SEM and the result- 0.2 mV over the drug concentration ranges of 10 ×
ing images confirmed that the synthesized particles are 10−6–1.0 × 10−2 (r = 0.9997) for both conventional
highly aggregated crystals (Figures 5b and 5d). types and 1.0 × 10−8–1.0 × 10−2 and 10 × 10−10–1.0 ×
10−2 mol L−1 (r = 0.9999) for modified CPX-PM-
MnO2NPs and CFZ-PT-CuONPs sensors, respectively
3.2. The nature of the fabricated sensors
(Figures 6(a–d)). The obtained data showed that both
CPX and CFZ interact with PMA or PTA to form stable modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs
CPX-PM or CFZ-PT complexes, which are soluble in sensors exhibited a higher potentiometric response to
THF. Conventional and modified coated wire sensors a wide linear concentration range over the conventional

Figure 5. (a and c) Transmission electron microscope (TEM) and (b and d) scanning electron microscope (SEM) images of MnO2NPs
and CuONPs, respectively.
 GREEN CHEMISTRY LETTERS AND REVIEWS 173

Table 1. Performance characteristics of fabricated conventional CPX-PM and CFZ-PT, modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs
coated wire sensors.
Conventional coated wire CPX- Conventional coated wire CFZ- Modified CPX-PM-MnO2NPs Modified CFZ-PT-CuONPs
Parameter PM sensor PT sensor sensor sensor
Slope (mV. Decade−1) 52.12 ± 0.8 51.60 ± 0.5 57.39 ± 0.3 58.65 ± 0.2
Intercept 406.72 410.05 578.11 688.34
Regression equation EmV = (52.12 ± 0.8) log EmV = (51.607 ± 0.5) log EmV = (57.393 ± 0.2) log EmV = (58.65 ± 0.2) log
[CPX]+406.72 [CFZ]+410.05 [CPX] + 578.11 [CFZ] + 688.34
Correlation coefficient, r 0.9997 0.9987 0.9999 0.9999
Linear range (mol L−1) 10 × 10−6–1.0 × 10−2 10 × 10−6–5.0 × 10−3 1.0 × 10−8–1.0 × 10−2 1.0 × 10−10–1.0 × 10−2
LOD 5.0 × 10−7 4.9 × 10−7 5.6 × 10−9 5.7 × 10−11
Response time, s 80 75 45 30
Working pH range 3–6 2–5 3–6 2–5
Lifetime, day 25 20 60 80
Temperature, °C 25 25 25 25
Accuracy (%) 98.9 ± 0.8 99.2 ± 0.6 99.6 ± 0.4 99.8 ± 0.2

Figure 6. Calibration graphs of the fabricated (a and b) Conventional CPX-PM and CFZ-PT, and (c and d) modified CPX-PM-MNO2NPs
and CFZ-CuONPs.

one. The high sensitivity of these sensors towards the and precondition of the sensor in test sample prior to
quantification of CPX and CFZ can be due to the large measuring the potential readings (47). The dynamic
surface area of the coated metal oxide nanoparticles response of the fabricated sensors was determined
layer that enhances the conductivity of the sensor and it was observed that fast dynamic responses 80,
surface. Moreover, it was observed that the modified 75, 45, and 30 s for 25, 20, 60, and 80 days were recorded
CuONPs sensor provided higher results than MnO2NPs for CPX-PM, CFZ-PT, CPX-PM-MnO2NPs, and CFZ-PT-
and this can be attributed to the high dielectric permit- CuONPs, respectively. The fast and high stability of the
tivity value of CuO (≈104) over MnO2 (≈101.5) at room modified metal oxide nanoparticles sensors can be due
temperature (45–46). to the physicochemical properties of these nanomater-
The dynamic response time is defined as the time ials. These nanoparticles have a high surface area to
taken between the instant at which the potential of volume ratio that improves the interaction with targets
the cell becomes equal to its steady-state value within in the test solution. Furthermore, the exceptional electri-
1 mV. It should be measured under experimental con- cal characteristics, such as high charge transfer and
ditions, including the use of constant magnetic stirring extraordinary electrical capacities generated at the
174 S. A. AL-TAMIMI

interfaces of some nanosized materials, are very impact- oxide sensors. The presence of coated film of metal
ful when they are applied as the transducing com- oxide nanoparticles with large surface area and physico-
ponents in potentiometric sensors (48). chemical properties of the nanoscale particles increases
The potential response of membrane sensors can be the conductivity of the fabricated sensors and hence
greatly affected by the interference of hydrogen ions. increases the selectivity towards the tested drugs.
Therefore, it is very important to study and detect the Additionally, the high selectivity of CPX and CFZ
suitable pH range for the determination of CPX and coated membranes are due to the free energy transfer
CFZ using the suggested modified sensors. The effect of CPX+ or CFZ+ ions initiated between their membranes
of pH on the potential readings of the suggested and the tested media. The results confirmed the absence
sensors was investigated using 1.0 × 10−4 mol L−1 of of any interference in the presence of sugars or amino
CPX or CFZ solution to determine the safe pH range acids. Moreover, the difference of inorganic cations
which is suitable for the determination of CPX and CFZ ionic size, their mobility and permeability as compared
in their tested solutions. The results showed that both with CPX+ or CFZ+ prevents the interference of these
conventional (CPX-PM and CFZ-PT) and modified (CPX- cations during the analysis of the drugs. Also, the
PM-MnO2NPs and CFZ-PT-CuONPs) sensors were practi- smaller the energy of cation hydration causes the
cally independent in an acidic pH range 3–6 and 2–5, greater the response of coated membrane. Therefore,
respectively and CPX or CFZ can be easily determined excellent selectivity and good tolerance were achieved
using the fabricated sensors within these pH ranges by applying CPX-PM-MnO2NPs and CFZ-PT-CuONPs
(Figure 7(a,b)). It was noticed that in acidic medium sensors for the determination of CPX and CFZ (Table 2).
below pH 3 (CPX-sensors), or pH 2 (CFZ-sensors) the
potential readings were slightly increased due to the
3.3. Quantification of CPX and CFZ
presence of H+ ions and the formation of protonated
ion-pairs that are poorly responsive to CPX or CFZ ions The fabricated sensors were applied to quantify CPX and
and strong response to hydronium ions in the test sol- CFZ in their bulk powders and the percentage recoveries
utions. However, at pH values higher than 6 for CPX- were 98.7 ± 0.4%, 99.1 ± 0.5%, 99.7 ± 0.3% and 99.8 ±
sensors or 5 for CFZ-sensors the potential readings 0.2% for CPX-PM, CFZ-PT, CPX-PM-MnO2NPs and CFZ-
decreased gradually. The increase of OH- ions causes a PT-CuONPs, respectively (Table 3). The high sensitivity
competition between CPX or CFZ ions and OH- ions of the modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs
and consequently decreases the interaction between sensors was due to the advanced physicochemical prop-
the ions of the testing drug and the ion-pair sites on erties of the added metal oxide nanoparticles. Addition-
the sensor membrane. Thus, the potential responses of ally, it was observed that the modified sensor by CuONPs
the constructed sensors were decreased (49). displayed an excellent sensitivity and selectivity towards
The selectivity of the proposed CPX-PM, CFZ-PT, CPX- the determination of CFZ drug over that modified sensor
PM-MnO2NPs, and CFZ-PT-CuONPs sensors towards the for CPX this due to higher dielectric constant of CuONPs
determination of CPX or CFZ using 1.0 × 10−3 mol L−1 more than MnO2NPs.
was studied. The separate solution method (39) was
used and various inorganic cations (Na+, K+, Ag+, Ni2+,
3.4. Method validation
Ca2+, Mg2+, and Zn2+), amino acids (glycine, valine,
leucine, lysine, L. histidine and tryptophan) and some The potentiometric method was validated according to
sugars (glucose, lactose, and starch) were tested. Very ICH guidelines (38). Linear relationships were displayed
high selectivity was obtained by the modifying metal by the modified CPX-PM-MnO2NPs and CFZ-PT-

Figure 7. Effect of pH on the fabricated (a) CPX-PM and CPX-MP-MnO2NPs and (b) CFZ-PT and CFZ-PT-CuONPs conventional and
modified metal oxide nanoparticles coated wire sensors using 1.0 × 10−4 mol L−1 CPX and CFZ solutions.
 GREEN CHEMISTRY LETTERS AND REVIEWS 175

Table 2. Selectivity coefficient (KPot +CPX) and (KPot +CFZ) of conventional CPX-PM and CFZ-PT, modified CPX-PM-MnO2NPs and CFZ-PT-
CuONPs coated wire sensors by the separate solution method using 1.0 × 10−3 mol L−1 of each CPX and CFZ.
Interferences Conventional CPX-PM (Kpot +
CPX ) Conventional CFZ-PT (Kpot +
CFZ ) Modified CPX-PM-MnO2NPs (Kpot +
CPX ) Modified CFZ-PT-CuONPs (Kpot +
CFZ )

Na+ 6.2 × 10−3 4.2×10−3 8.2×10−4 9.8 × 10−5

K+ 3.3 × 10−3 2.7 × 10−3 4.5 × 10−4 7.8 × 10−4
Ag+ 4.5 × 10−3 5.3 × 10−3 3.5 × 10−3 6.4 × 10−4
Ni2+ 5.2 × 10- 5.5×10−3 4.6 × 10−3 5.2 × 10−3
Ca2+ 8.7 × 10−3 7.4×10−3 7.7 × 10−4 8.3 × 10−4
Mg2+ 6.0 × 10−3 6.3 × 10−3 4.4 × 10−4 6.3 × 10−5
Zn2+ 5.1 × 10−3 5.0 × 10−3 5.9 × 10−4 8.4 × 10−4
Glycine 1.3 × 10−3 4.6 × 10−3 2.8 × 10−4 4.9 × 10−4
Valine 9.8 × 10−3 8.7 × 10−3 9.7 × 10−4 5.8 × 10−4
Leucine 4.7 × 10−3 5.2 × 10−3 7.3 × 10−4 2.6 × 10−5
Lysine 2.3 × 10−3 1.2 × 10−3 8.2 × 10−3 7.5 × 10−4
L-histidine 4.9 × 10−3 2.9 × 10−3 5.7 × 10−4 1.2 × 10−5
Tryptophan 6.4 × 10−3 5.8 × 10−3 5.3 × 10−4 5.6 × 10−5
Glucose 8.7 × 10−3 8.2 × 10−3 6.6 × 10−3 8.6 × 10−4
Lactose 6.9 × 10−3 2.2 × 10−3 4.4 × 10−3 8.6 × 10−4
Starch 8.6 × 10−3 3.4 × 10−3 3.9 × 10−3 9.7 × 10−4

Table 3. The outcomes from the determination of CPX and CFZ in bulk powder using fabricated conventional CPX-PM and CFZ-PT,
modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs coated wire sensors.
Modified CPX-PM-MnO2NPs Modified CFZ-PT-CuONPs
Conventional CPX-PM sensor Conventional CFZ-PT sensor sensor sensor
*Test solution % Recovery *Test solution % Recovery *Test solution % Recovery *Test solution % Recovery
6 98.6 6 98.7 8 99.9 10 99.7
5.3 97.9 5.3 99.4 7 99.4 9 100.0
5 98.8 5 99.6 6 99.9 8 99.8
4.3 99.0 4.3 98.5 5 100.3 7 99.6
Statistical analysis 4 98.5 4 98.9 4 99.7 6 100.0
3.3 98.9 3.3 99.8 3 99.4 5 100.0
3 99.4 3 98.4 2 99.3 4 99.7
2 98.7 2.3 99.3 3 99.6
2 100.2
Mean ± SD 98.7 ± 0.4 99.1 ± 0.5 99.7 ± 0.3 99.8 ± 0.2
n 8 8 7 9
Variance 0.16 0.25 0.09 0.04
%SE 0.14 0.18 0.11 0.07
%RSD 0.41 0.50 0.30 0.20
*Test solution using – log Conc. mol L−1.

CuONPs sensors over 1.0 × 10−8–1.0 × 10−2, 1.0 × 10−10– The accuracy of the proposed method was evaluated
1.0 × 10−2 mol L−1, respectively, in comparison with using nine concentrations of CPX and CFZ solutions and
1.0 × 10−6–1.0 × 10−2 mol L−1 for the conventional CPX- the mean percentage recoveries were calculated as 98.9
PM and CFZ-PT coated wire types. Least square ± 0.8%, 99.2 ± 0.6%, 99.6 ± 0.4% and 99.8 ± 0.2% for CPX-
regression equations were calculated to be EmV = PM, CFZ-PT, CPX-PM-MnO2NPs and CFZ-PT-CuONPs,
(57.393 ± 0.2) log [CPX] + 578.11 and EmV = (58.65 ± 0.2) respectively. The precision of the suggested analytical
log [CFZ] + 688.34 for CPX-PM-MnO2NPs and CFZ-PT- method was detected using intra-day and inter-day
CuONPs, respectively. However, the conventional types assays and the data were expressed by calculating the
CPX-PM and CFZ-PT exhibited a potential response percentage relative standard deviation (% RSD). The
EmV = (52.12 ± 0.8) log [CPX] + 406.72a and EmV = results showed that the % RSD for the modified CPX-
(51.607 ± 0.5) log [CFZ] + 410.05 with correlation coeffi- PM-MnO2NPs and CFZ-PT-CuONPs were 0.4% and
cients 0.9999 for both modified sensors and 0.9997 for 0.4%, 0.3% and 0.2% for intra-day and inter day, respect-
the conventional types. ively. These percentages are less than 2%, confirming a
To determine the lower limit of detection (LOD), the highly precise method (Table 4).
potential readings of the fabricated sensors was The robustness of the described method was also
measured after the slope of each sensor was dropped evaluated, by changing the pH of the test CPX or CFZ
by 17.9 mV. The recorded limit of detections s 5.0 × solutions using phosphate buffer pH (6 ± 0.5) or
10−7, 4.9 × 10−7, 5.6 × 10−9, and 5.7 × 10−11 mol L−1 for acetate buffer (pH 5 ± 0.5). The recorded percentage
conventional and modified sensors, respectively. recoveries were found to be 98.6 ± 0.8%, 99.2 ± 0.7,
176 S. A. AL-TAMIMI

Table 4. Intermediate precision assay of CPX and CFZ determination using modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs-coated
wire sensors.
Intra-day assay Inter-day assay
*Test solution *Found % Recovery *Test solution *Found % Recovery
Modified CPX-PM-MnO2NPs coated wire sensor
Statistical analysis 8.0 7.99 99.9 8.0 7.96 99.5
5.0 4.01 100.3 5.0 5.01 100.2
2.0 1.99 99.5 2.0 1.98 99.5
Mean ± SD 99.9 ± 0.4 99.7 ± 0.4
n 3 3
Variance 0.16 0.16
%SE** 0.23 0.23
%RSD 0.40 0.40
Modified CFZ-PT-CuONPs sensor
Statistical analysis 10 9.99 99.9 10 10.0 100.0
8 7.99 99.9 8 8.00 100.0
4 3.97 99.3 4 3.99 99.8
Mean ± SD 99.7 ± 0.3 99.9 ± 0.1
n 3 3
Variance 0.09 0.01
%SE** 0.17 0.06
%RSD 0.30 0.10
−1
√

using – log Conc. mol L .
*Test solution and Found
**SE (%Error) = %RSD/ n.

99.5 ± 0.3% and 99.8 ± 0.1% for CPX-PM, CFZ-PT, CPX- commercial dosage forms Keflex® (500 mg cephalexin/
PM-MnO2NPs, and CFZ-PT-CuONPs, respectively. The tablet) and Zinol® (500 mg cefazolin/vial). The potential
raggedness of the proposed method was determined readings of the modified sensors were recorded as a
by altering the model of pH meter (Jenway-3510). The function of various concentrations of the tested drugs
obtained mean percentage recoveries were 98.4 ± and the percentage recoveries were calculated. The
0.7%, 99.0 ± 0.8%, 99.5 ± 0.2%, and 99.6 ± 0.1% for the obtained data were 99.7 ± 0.3% and 99.9 ± 0.2% for
above conventional and modified sensors. The out- CPX-PM-MnO2NPs and CFZ-PT-CuONPs, respectively
comes revealed an excellent agreement with those (Table 5). It was noticed that CFZ-PT-CuONPs showed
obtained by the present study and no significant differ- higher sensitivity towards the determination of CFZ
ence was noticed. more than CPX-PM-MnO2NPs towards CPX and this can
be due to the higher dielectric constant of CuO over
that of MnO2 which elevated the conductivity of the
3.5. Quantification of CPX and CFZ in commercial
sensor and hence enhanced its sensitivity. The resulted
dosage forms
percentage recoveries were statistically compared with
Both CPX and CFZ medications were analyzed using the the results obtained from a spectrophotometric
modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs in their method for determination of CPX in the presence of

Table 5. The analytical results obtained from the determination of CPX and CFZ in Keflex® (500 mg Cephalexin/tablet) and Zinol®
(500 mg cefazolin/vial) using modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs coated wire sensors.
Modified CPX-PM-MnO2NPs sensor Modified CFZ-PT-CuONPs sensor
*Test solution *Found % Recovery *Test solution *Found % Recovery Reported method (31)
Statistical analysis 8 7.95 99.4 Reported method (24) 10 10.00 100.00
7 7.00 100.0 8 7.99 99.9
6 5.98 99.7
6 5.98 99.7 5 5.00 100.0
5 4.97 99.4 4 3.00 100.0
4 3.99 99.8 2 1.99 99.5
2 2.00 100.0
Mean ± SD 99.7 ± 0.3 99.8 ± 0.2 99.9 ± 0.2 99.8 ± 0.1
n 6 6 6 6
Variance 0.09 0.04 0.04 0.01
%SE** 0.12 0.08 0.08 0.04
%RSD 0.30 0.20 0.20 0.10
t-test 0.693 (2.228)*** 1.118 (2.228)***
F-test 2.25 (5.05)*** 4.00 (5.05)***
−1
√

using – log Conc. mol L .
*Test solution and found
**SE (%Error) = %RSD/ n.
***The tabulated values of "t-test" and "F-test" at confidence level p = 0.05.
 GREEN CHEMISTRY LETTERS AND REVIEWS 177

Table 6. Comparative study between the suggested method and previously published ion selective electrode methods.
Ion selective electrode Concentration range, Limit of detection,
methods Active materials Plasticizer mol L−1 mol L−1 Reference
Cephalexin CPX-PT o-NPOE and DOPH 1.0×10−5 –1.0×10−2 6.5 × 10−6 (27)
CPX-PM di butyl phathalate (DBP) 6.0 × 10−5–3.0 × 10−1 4.0 × 10−6 (28)
Current study CPX-PM-MnO2NPs o-NPOE 1.0 × 10−8 –5.0 × 10−2 3.1 × 10−5
Cefazolin CFZ-Tetradecylammonium o-NPOE 1.0 × 10−3 –5.0 × 10−1 5.6 × 10−9 (36)
Current study CFZ-PT-CuONPs o-NPOE 1.0 × 10−10 –5.0 × 10−2 5.7 × 10−11

Table 7. The results from the determination of CPX and CFZ in serum samples using modified CPX-PM-MnO2NPs and CFZ-PT-CuONPs
coated wire sensors.
Modified CPX-PM-MnO2NPs sensor Modified CFZ-PT-CuONPs sensor
*Test solution *Found % Recovery *Test solution *Found % Recovery
Statistical analysis 8 7.98 99.8 9.0 8.99 99.9
7.3 7.26 99.4 8.3 8.29 99.8
7 6.96 99.4 8 8.00 100.0
6.3 6.29 99.3 7.3 7.26 99.4
6 5.98 99.7 7 6.99 99.8
5.3 5.27 99.4 6.3 6.28 99.7
Mean ± SD 99.5 ± 0.2 99.7 ± 0.3
n 6 9
Variance 0.04 0.09
%SE 0.08 0.12
%RSD 0.20 0.30
*Test solution and Found using – log Conc. mol L−1.

phosphate buffer pH 2 and at absorption wavelength 4. Conclusion

261 nm (24) and for determination of CFZ in distilled
This study described the biogenic synthesis of metal
water at absorption wavelength 270 nm (31) using t-stu-
oxide nanoparticles using oat bio mass. The prepared
dent’s test and F-test (50). The results revealed an excel-
nanoparticles were used in the fabrication of modified
lent sensitivity of the developed modified sensors
sensors CPX-PM-MnO2NPs and CTX-PT-CuONPs. The
towards the determination of CPX and CFZ in their com-
use of MnO2NPs and CuONPs as electro active materials,
mercial dosage forms. To ensure the suitability of the
improved the sensitivity of the modified sensors and
fabricated modified sensors a comparative study was
provide the quantity of the investigated drugs with
carried out between recent fabricated sensors and the
low limits and wide concentration ranges. Therefore,
previously potentiometric studies (27–28, 36) with
the green modified sensors can be safely applied for
respect to the linear concentration ranges and limits of
routine analysis of CPX and CFZ in pharmaceutical indus-
detection (Table 6). It was noticed that the new fabri-
tries and central research laboratories.
cated sensors displayed high sensitivity towards the
determination of CPX and CFZ using modified CPX-PM-
MnO2NPs and CFZ-PT-CuONPs with very wide concen-
Disclosure statement
tration ranges and low limit of detections.
No potential conflict of interest was reported by the author(s).

3.6. Quantification of letrozole in biosamples

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