Journal of Chromatography A 1639 (2021) 461891

Contents lists available at ScienceDirect

Journal of Chromatography A
journal homepage: www.elsevier.com/locate/chroma

High-temperature liquid chromatography for evaluation of the

efficiency of multiwalled carbon nanotubes as nano extraction beds
for removal of acidic drugs from wastewater. Greenness profiling and
comprehensive kinetics and thermodynamics studies
Lateefa A. Al-Khateeb a,∗, Mona A. Al-zahrani a, Mohamed A. El Hamd b,c,
Mahmoud El-Maghrabey d,e,∗, Fatimah A. Dahas a, Rania El-Shaheny d,f
a
Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
b
Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University 83523, Qena, Egypt
c
Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Al Dawadmi, 11961, Shaqra, Kingdom of Saudi Arabia
d
Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
e
Department of Analytical Chemistry for Pharmaceuticals, Course of Pharmaceutical Sciences, Graduate School of Biomedical Science, Nagasaki University,
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
f
Course of Pharmaceutical Sciences, Graduate School of Biomedical Science, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

a r t i c l e i n f o a b s t r a c t

Article history: The retention behavior of a series of acidic drugs, namely ketoprofen (KET), naproxen (NAP), diclofenac
Received 26 September 2020 (DIC), and ibuprofen (IBU), on the heat-resisting ZORBAX 300SB-C18 column, was studied thermodynam-
Revised 3 January 2021
ically using high-temperature liquid chromatography (HTLC). A perfect correlation of the compounds’
Accepted 5 January 2021
lipophilicity and the calculated thermodynamic indicators evidenced its contribution to the retention
Available online 8 January 2021
behavior. Besides, the steric fitting has a subsidiary effect on IBU retention. Isocratic HTLC separation
Keywords: of the four compounds was achieved using an aqueous mobile phase containing 30% acetonitrile-0.2%
MWCNTs acetic acid-0.2% triethylamine at 60 °C. This method has been utilized to monitor the adsorption effi-
HTLC ciency of multiwalled carbon nanotubes (MWCNTs) for the removal of the four NSAIDs from water. Dif-
Adsorption kinetics and thermodynamics ferent variables affecting the remediation process have been optimized such as the time of contact, pH,
Extraction beds ionic strength, temperature, and the mass of MWCNTs. The kinetics and thermodynamics of the adsorp-
Wastewater treatment
tion were investigated. The adsorption was evidenced to take place via pseudo-second-order kinetics and
Green protocol
the intraparticle diffusion is the rate-controlling step. The thermodynamic investigation showed that the
adsorption process is exothermic and enthalpy-driven, and the adsorption is more extensive at a lower
temperature. The MWCNTs showed excellent adsorption efficiency of about 76.4 to 97.6% at the optimum
conditions. The obtained results are promising and encouraging for the full-scale application of MWCNTs
for remediation of NSAIDs-related water pollution. The green analytical chemistry metric “AGREE” and
the analytical eco-scale score tool confirmed that the developed protocol is greener and more favorable
to the environment and user than most of the reported literature.
© 2021 Elsevier B.V. All rights reserved.

1. Introduction tric constant and the surface tension of the mobile phase influ-
ence the retention of solutes, and they are inversely dependent on
Alongside the classical factors that govern the LC methods, in- the temperature. Elevated temperature causes a decrease of the
cluding the components, pH, and ionic strength of the mobile dielectric constant, the viscosity, and the surface tension of the
phase and the nature, particle size, and dimensions of the sta- mobile phase, and an increase of the diffusivity of the solutes.
tionary phase, the temperature is another factor that has an in- The less viscous mobile phase leads to decreased back pressure
tense effect on the LC technique development. Both the dielec- that permits greater flow rate and speed. Further, the improved
solute diffusivity is associated with better mass transfer and im-
∗
proved column efficiency [1]. These remarkable advantages initi-
Corresponding authors.
E-mail addresses: laalkhatib@kau.edu.sa (L.A. Al-Khateeb), mh-
ate the theory of high-temperature liquid chromatography (HTLC)
elmaghrabey@nagasaki-u.ac.jp, dr_m_hamed@mans.edu.eg (M. El-Maghrabey). that is conducted at high temperatures ranging from 50–150 °C.

https://doi.org/10.1016/j.chroma.2021.461891
0021-9673/© 2021 Elsevier B.V. All rights reserved.
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
Recently, the development of heat-resistive stationary phases led
to a significant increase in the applications of HTLC as a power-
ful chromatographic technique offering short analysis time, great
selectivity, and excellent column efficiency [1,2]. Therefore, in this
study, we explored the retention and the thermodynamic behav-
ior of a series of acidic drugs belonging to the non-steroidal anti-
inflammatory drugs (NSAIDs) group on the ZORBAX 300SB-C18 col-
umn. This study gave rise to an efficient and precise HTLC method.
Thus, we utilized the developed HTLC method to follow up the
remediation of NSAIDs-related water pollution via adsorption on
multiwalled carbon nanotubes (MWCNTs).
NSAIDs are among the most administered medicines world-
wide. They are acidic compounds with anti-inflammatory,
painkilling, and antipyretic effects and they are first step medicines
in the WHO analgesic ladder for pain management [3–5]. They
act by inhibiting the cyclooxygenase enzymes (COX-1 and COX-2),
thus, reducing the production of prostaglandins that are involved
in inflammations and thromboxane that is involved in blood clot-
ting [6,7]. However, some side effects are linked to the long-term
use of NSAIDs such as upper gastrointestinal irritation, gastric
ulceration, heartburn, and hemorrhage, as well as cardiovascular
disorders [4,8,9].
More than 30 million tons of NSAIDs are consumed daily
throughout the world and the rate of their consumption increases
largely each year by about 11.9%. This huge rate of consumption
leads to the release of a large quantity of unused overtime drugs
to the environment where a small portion of the expired drugs is
collected for incineration while the larger portion is disposed to
the waste discarding spot or flushed down via the toilet. The re-
sistance of the NSAIDs to chemical or biological decomposition in
wastewater treatment plants leads to their escaping into the drink-
ing water cycle. As a result, these drugs are frequently detected
in ng/L to μg/L levels in river water and sewage treatment plant
discharges [10]. Experiencing residual amounts of pharmaceutical
compounds in drinking water is associated with risks to human
health [11]. Moreover, the presence of NSAIDs such as ketoprofen
(KET), naproxen (NAP), diclofenac (DIC), and ibuprofen (IBU) in the
surface water and wastewater treatment plants represents a threat
to aquatic life [10,11]. A report of the WHO revealed the detec-
tion of many pharmaceutical compounds in treated drinking water
and more compounds have been distinguished in untreated waters,
e.g. wastewater, surface water, and groundwater, that is mainly at-
tributed to frequently administered pharmaceuticals including the
NSAIDs [11].
In consequence, there is a strong necessity for enhancing the
water purification technologies to guarantee the purity of drinking
water. The current techniques for purification involve the introduc-
tion of purification tag [12], UV-irradiation, photocatalytic degra-
dation, specific oxidation treatments [13,14], ozonation [15], and
non-thermal plasma treatment [16]. These methods have various
drawbacks such as lengthy procedures and high costs. In addition,
the water treatment process uses chemicals, such as hydrochloric
acid, ammonia, chlorine, ozone, permanganate, alum, ferric salts,
coagulating agents, and resins, which can produce residuals or by-
products that contaminate the water sources [17]. Thus, numer-
ous nanotechnology approaches were introduced for efficient and
safe water purification. Among these, nano adsorbents are promis-
ing for future full-scale applications since they are commercially
available, have reasonable costs, and compatible with the existing
infrastructures [18,19]. In this study, we examine the efficiency of
MWCNTs for remediation of NSAIDs-related water pollution via ad-
sorption. The model compounds in this examination are KET, NAP,
DIC, and IBU. Carbon nanotubes show a superb aptitude to remove
different contaminants from water [20] such as dyes [21], benzoic
acid [22], polycyclic aromatic hydrocarbons [23], ciprofloxacin [24],
estrogenic compounds [25], and heavy metals [26]. However, no
2
Journal of Chromatography A 1639 (2021) 461891
study is reported for the simultaneous removal of KET, NAP, DIC,
and IBU from wastewater using MWCNTs as a new efficient adsor-
bent.
Working within the frame of environmental protection and re-
mediation motivated us to be highly committed to the develop-
ment of analytical methods that are inherently green [27]. Thus,
we conducted a greenness profiling to evaluate the entire approach
applied in this investigation using the most updated analytical
chemistry metric; Analytical Greenness (AGREE) [28], as well as the
analytical eco-scale score approach [29].
Thus, this study aims to (i) investigate the thermodynamic and
retention behavior of the four acidic drugs using HTLC mode, (ii)
optimize the adsorption conditions for maximum removal of these
NSAIDs from wastewater using MWCNTs, (iii) investigate the kinet-
ics and thermodynamics of the adsorption process, (iv) apply of
the developed approach for purification of real wastewater sam-
ples, and (v) conduct greenness profiling of the whole strategy to
evaluate its environmental safety.
2. Experimental
2.1. Chemicals and solutions
Analytical grade powder of IBU, KETO, NAP, and DIC sodium
salt (99.99% purity) was bought from Sigma–Aldrich (Mississauga,
ON, Canada). HPLC-grade acetonitrile (ACN), methanol (MeOH)
(BDH Ltd., Poole, UK), acetic acid, and trimethylamine (Sigma–
Aldrich) were used. Multiwalled carbon nanotubes, MWCNTs, (CNT
l-MWNT-2040, purity > 97%) were purchased from Shenzhen
Nano-Technologies, China. Deionized water was taken from a Milli-
Q Plus system (Millipore, Bedford, MA, USA). MWCNTs were pre-
treated via sonication in acetone for 2.0 h to eliminate any com-
pounds adsorbed during the production, then filtered and repeat-
edly rinsed with acetone then transferred to a drying oven ad-
justed to 110 °C to vaporize the acetone. Stock solutions of each
drug (1 mg/mL) were separately prepared in MeOH. Proper dilu-
tion of the stock solutions with deionized water was done to pre-
pare the working standard solutions.
2.2. Characterization of the MWCNTs
The morphological features of the MWCNTs were elucidated us-
ing a scanning electron microscope SEM (JEOL JEM-1230) operat-
ing at 120 kV attached to a CCD camera. X-ray diffraction (XRD)
curve was obtained using X’Pert Explorer, PANalytical diffractome-
ter (Malvern, UK). Automated gas sorption system NOVA 2200e
(Quantachrome, USA) was used for nitrogen adsorption/desorption
isotherms measurement at 77 K to determine the specific surface
area of MWCNTs utilizing the Brunauer-Emmett-Teller (BET) equa-
tion [30]. Further, the pore size distribution was measured by the
Barrett–Joyner–Halenda (BJH) technique that is commonly used for
mesoporous materials [31] like MWCNTs. The desorption branch
of the adsorption/desorption isotherms was used for these calcu-
lations.
The point of zero charge (PZC) for the MWCNTs has been cal-
culated by applying the next steps: 100 mL of deionized water
was boiled in a cotton-capped flask for 20 min to expel CO2 . Af-
ter cooling, 10 mL of the CO2 -free water was put in a small flask
and mixed with 0.5 g of the MWCNTs. The flask is rapidly closed
and kept under continuous shaking for 2 days at ambient temper-
ature (20 °C). The pH of the slurry was measured and it is the PZC
[32].
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
2.3. HTLC method and instrumentation
The separation of the four drugs was implemented using an Ag-
ilent 1200 series liquid chromatograph (Agilent Technologies, Wal-
dron, Germany) supplied with a quaternary pump, autosampler,
and diode array detector (DAD). The instrument was interfaced to
a computer to obtain and analyze the data. An analytical reversed-
phase column ZORBAX 300SB-C18 (5 μm particle size, 4.6 ID x
150 mm) from Agilent Technologies, USA was used. A preheating
stainless-steel tubing (100 cm × 0.005 mm ID) was attached to the
inlet of the column and placed inside the column oven. Besides, a
stainless-steel tube (100 cm × 0.005 mm ID) was attached to the
outlet of the analytical column outside the oven for cooling of the
mobile phase to room temperature prior to getting in the DAD.
The mobile phase consisted of 30% ACN-0.2% triethylamine-0.2%
acetic acid in water and run in an isocratic mode at 1.0 mL/min.
The mobile phase was passed for 60 min through the HTLC system
for conditioning, then the column oven temperature was raised
to 60 °C and equilibrated for 30 min. The analysis was done at
240 nm using an injection volume of 10 μL.
2.4. Procedure for calibration graphs
Increasing amounts of the standard solutions of KET, NAP, DIC,
and IBU were measured to yield final concentrations of 0.1–500,
0.05–10, 0.5–100, and 0.6–100 mg/L, respectively, and placed in
a group of 10 mL calibrated flasks. The mobile phase was used
to make up the solutions to the final volume prior to thorough
mixing. Ten μL were injected in triplicate into the HTLC system
and analyzed under the optimum chromatographic conditions. The
mean peak areas were plotted versus the concentration of the drug
(mg/L) to develop the calibration curves and the regression equa-
tions were calculated.
2.5. Adsorption experiments
Experiments were done to investigate the influence of vari-
ous factors, e.g. contact time, pH, ionic strength, temperature, and
MWCNTs mass, on the adsorption capacity of MWCNTs, and to in-
spect the kinetics and thermodynamics of the adsorption process.
A set of 10 mL solutions comprising 5.0 mg/L of the four NSAIDs
was prepared, placed in a set of 25 mL glass vials, and used to
perform the following experiments by varying the intended fac-
tor in turn while keeping the other factors fixed. The pH of the
solutions was adapted to the requisite value (2.0–11.0) and their
temperature was adjusted to the specific temperature (281, 298, or
333 K). MWCNTs (10–200 mg) were added to the vials and allowed
to stand for variable contact times (1–120 min). At specific times,
the solutions were filtered to collect the purified water. The pH of
the samples was properly adjusted to 7.0 before chromatographic
analysis. The remaining concentrations of the four NSAIDs were de-
termined using the HTLC method and the amount adsorbed (qt )
can be estimated by applying the following formula in Eq. (1):
(C0 − Ct )V
qt = (1)
m
Where qt is the quantity of NSAID adsorbed by the MWCNTs
(mg/g) at time t, C0 is the initial concentration (mg/L), Ct is the
concentration (mg/L) of NSAID at time t, V is the initial solution
volume (L), and m is the mass of MWCNT (g).
The % adsorbed of NSAID was determined using Eq. (2):
C0− Ct
% Adsorbed = × 100 (2)
C0
3
Journal of Chromatography A 1639 (2021) 461891
2.6. Real water samples
Two samples were investigated to test the efficacy of MWCNTs
for the elimination of the four NSAIDs from real environmental wa-
ter. A tap water sample was obtained from our laboratory and a
wastewater sample was obtained from the Membrane Bio-Reactor
Sewage Treatment Plant (60 0 0 m3/day, MBR 60 0 0 STP) of King Ab-
dulaziz University, Jeddah, Saudi Arabia. The two samples were fil-
tered through a 0.45 μm Millipore membrane filter and kept in
Teflon® bottles at 5 °C in the dark. The samples were analyzed by
the HTLC method for their NSAIDs content and none of the NSAIDs
was detected indicating that these samples are not polluted with
the targeted pharmaceuticals. Then, the wastewater treatment ex-
periment was performed adopting the spiking technique by the ad-
dition of NSAIDs solutions to the samples to achieve a 5.0 mg/L
final concentration. Then, the pH of each sample was adjusted to
pH 2.0. Then, 10 mL of each sample was transferred to a glass vial,
in which they were mixed with 100 mg MWCNTs and left in con-
tact for 30 min. Thereafter, the solution was filtered and analyzed
for its NSAIDs content. For comparison, the same steps were re-
peated to analyze the un-purified sample by omitting the addition
of MWCNTs. The % adsorption was calculated by comparison of
the NSAIDs’ concentration found before and after treatment with
MWCNTs.
3. Results and discussion
3.1. HTLC method optimization
Different factors affecting the separation of IBU, KETO, NAP, and
DIC were explored to achieve the best resolution, sensitivity, and
peak efficiency within a minimum time. The optimum detection
wavelength that allowed sensitive and simultaneous detection of
the four compounds was 240 nm. The mobile phase composition
was changed using different percentages of ACN to show the in-
fluence of organic solvent concentration on the separation process.
30% ACN was the most suitable concentration since higher concen-
trations lead to the overlapping of the chromatographic peaks of
KET and NAP, while lower concentrations cause long analysis time.
However, at this point, the analysis time was about 30 min. Thus,
we studied the influence of temperature on the separation process
to decrease the run time. Since the used column is heat resistant,
we studied the temperature in the range of 30–65 °C and we found
that elevation of the mobile phase temperature leads to a remark-
able reduction of the retention of the four compounds. This is at-
tributed to the decrease of the viscosity of the mobile phase at
high temperatures that enhances its diffusivity and elution power
[2]. We selected 60 °C as the optimal temperature to separate the
four analytes in an acceptable time not exceeding 16 min. A study
of the influence of the flow rate of the mobile phase showed that
a flow rate of 1.0 mL/min is the optimum for reasonable retention
time (tR ) and column efficiency. Good separation of the four an-
alytes under the optimum chromatographic conditions is demon-
strated in Fig. 1A. Table 1 collects the chromatographic parameters
for the four compounds under the optimum conditions.
3.2. Thermodynamic study of the acidic analytes by htlc
The retention of KET, NAP, DIC, and IBU on the ZORBAX 300SB-
C18 column was studied at increasing temperatures from 30 to
65 °C. The van’t-Hoff plots were generated for each compound by
plotting Ln k versus 1/T [33,34] as per Eq. (3):
S ◦ H ◦
ln k = − (3)
R RT
Where k is the retention factor, R is the gas constant (8.314 J.
mol−1 .K − 1 ), T is the absolute temperature, H° and S° are
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al. Journal of Chromatography A 1639 (2021) 461891

Fig. 1. (A) Representative chromatogram showing the separation of the four NSAIDs (5.0 mg/L) under the optimum chromatographic condition (1 = KET; 2 = NAP; 3 = DIC;
4 = IBU), (B) van’t Hoff plots of the four NSAIDs on the column, (C) and (D) are the correlations between experimental H˚ and G˚, respectively, and log P for the four
studied compounds, and (E) selectivity plots for distinguished pairs of analytes.

Table 1 H°/R and the intercept = S°/R. The change in Gibb’s energy
Chromatographic parameters for the separation of the four NSAIDs by the devel-
(G°) can be determined using Eq. (4) [35]:
oped HTLC method.

Parameter KET NAP DIC IBU G◦ = H◦ − TS◦ = −RT(Lnk ) (4)
Retention time, tR 5.0 5.4 10.6 15.3
The obtained results are abridged in Table 2. The enthalpies for
Number of theoretical plates, N 23,153 21,403 24,375 25,362
Peak symmetry 0.87 0.90 0.96 0.88 the four analytes are negative values (Table 2) which indicates that
Retention factor, k 4.029 4.424 5.0 14.57 their transfer from the mobile phase to the stationary phase is an
Resolution, Rs KET/NAP NAP/DIC DIC/IBU exothermic process. Furthermore, the S° values are all negative
1.68 14.44 8.45
for the four compounds because of the increase of the ordering
of the molecules by moving from the mobile phase to the sta-
the enthalpy and entropy of the transfer of solutes from the mo- tionary phase. However, the change in enthalpy is much greater
bile phase to the stationary phase, respectively. Linear plots were than the change in entropy (Table 2) indicating that the enthalpy
achieved for all compounds with acceptable correlation coefficients is the dominant energy term. Thus, the free energy (G°) is a neg-
(Table 2 and Fig. 1B). It is clear that the four curves are parallel ative value for the four compounds (Table 2) indicating a sponta-
which indicates that the retention mechanism and the separation neous exergonic process because of the leading enthalpy involve-
selectivity were not changed with the temperature change. ment [33].
The thermodynamic data, including the enthalpy and entropy, A perfect correlation between the H° of the four solutes and
were determined from the van’t-Hoff plots where the slope= – their lipophilicity (log P) is clear in Fig. 1C. This indicates that as

4
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al. Journal of Chromatography A 1639 (2021) 461891

Table 2
Thermodynamic figures for the separation of the investigated drugs by the HTLC method.

Stern-Volmer plot data KET NAP DIC IBU

Enthalpy change, H° (kJ/mol) −9.72485 −11.8974 −16.7237 −14.7736

Entropy change, S° (J/K. mol) −15.7062 −21.5083 −30.1446 −21.1348
Gibb free energy change, G° (kJ/mol) at 333 K −4.49 −4.74 −6.69 −7.74
Correlation coefficient 0.986 0.971 0.970 0.976
Selectivity plot data KET/NAP NAP/DIC DIC/IBU
Partial molar enthalpy, Hd 0 (kJ/mol) −1.432 −5.58 2.8
Correlation coefficient 0.8272 0.9779 0.9824

Table 3
Linearity data for KETO, NAP, DIC, and IBU using the proposed HTLC method.

Analytes Linear range (mg/L) Regression equationa r LOD, μg/L (ng on column) LOQ (μg/L)

KET 0.1–50.0 y = 45.3 x – 4.1 0.997 20 (0.2) 61

NAP 0.05–10.0 y = 230.5 x + 11.3 0.996 11 (0.11) 32
DIC 0.5–100.0 y = 23.7 x + 6.9 0.999 134 (0.13) 405
IBU 0.6–100.0 y = 13.9 x + 3.9 0.999 183 (0.18) 555
a
y is the peak area and x is the concentration of analyte (mg/L).

Table 4
The accuracy and precision results for the studied NSAIDs using the developed HTLC method.

Analyte Concentration (mg/L) Accuracy (%) Intra-day Precision (%RSD) Inter-day Precision (%RSD)

KET 2.0 98.7 1.1 1.5

10.0 99.2 0.8 1.1
50.0 100.2 1.0 2.6
NAP 0.1 102.8 0.4 0.5
2.0 103.6 0.3 1.7
10.0 99.1 0.5 1.3
DIC 1.0 103.1 1.0 1.6
10.0 98.4 0.9 1.9
100.0 100.6 0.8 1.0
IBU 1.0 94.3 2.2 2.0
10.0 98.1 1.0 2.6
100.0 100.0 0.8 2.8

the lipophilicity of the compound increased, the H° value be-
came more negative (more exergonic) due to a greater tendency
to move from the polar mobile phase to the non-polar stationary
phase. On the other hand, a plot of G° versus log P of the stud-
ied compounds (Fig. 1D) shows that IBU has an unexpectedly low
value of G°. The structure of IBU lacks heteroatoms substituents
that exist in the other three compounds and contains a single ben-
zene ring with a short branched (isobutyl) substituent in contrary
to the three compounds containing two benzene rings. This prob-
ably leads to a better steric fit resulting in lower unpredicted G°
[33].
3.3. The selectivity of the chromatographic system
The selectivity plots were generated to illustrate the transfer of
the solute in the HTLC system. Graphs of Ln α versus 1/T were
plotted where α is the selectivity factor between adjacent analytes’
peaks that is calculated as the ratio of their retention factors k. The
slope of the obtained graph = -Hd 0 /R, (Hd 0 is the partial mo-
lar enthalpy of the transfer of each two adjacent analytes from the
mobile phase to the stationary phase) [34]. The obtained selectivity
plots (Fig. 1E) are linear indicating independence on phase ratio. It
can be distinguished that the selectivity decreased as the temper-
ature increased for pairs having heteroatoms substituents in their
structures, i.e. NAP/DIC and KET/NAP pairs. Therefore, the Hd 0 for
the transfer of the heteroatoms: nitrogen, oxygen, and chlorine dif-
fers remarkably on this column. The Hd 0 values for NAP/DIC and
KET/NAP are −5.58 and −1.43 KJ/mol, respectively. The more nega-
tive Hd 0 values for NAP/DIC revealed stronger interaction with
the stationary phase. On contrary, the selectivity increased with
the increase of the temperature in the case of DIC/IBU pair with
Hd 0 = 2.8 KJ/mol. The results of the column selectivity study are
summarized in Table 2.
3.4. HTLC method validation
To assess the reliability of the established HTLC method for
analysis of the four investigated drugs, different parameters includ-
ing linearity, range, limit of quantification (LOQ), limit of detection
(LOD), accuracy, precision, and recovery were thoroughly investi-
gated as guided by the ICH Q2R1 guideline [36,37]
Excellent linear relations were accomplished by graphing the
mean peak areas against drug concentration over the ranges of 0.1–
50.0, 0.05–10.0, 0.5–100.0, and 0.6–100.0 mg/L for KET, NAP, DIC,
and IBU, respectively, with correlation coefficient r ≥ 0.996. The
LODs and LOQs were also calculated as 3.3σ /a and 10σ /a, respec-
tively, where (σ ) is the standard deviation (SD) of the response and
(a) is the slope of the regression line. A summary of the obtained
results is presented in Table 3.
The intra- and inter-day precision and accuracy were also stud-
ied by determination of 3 concentrations of each drug on 3 consec-
utive times in a single day and on 3 successive days, respectively.
The results indicated good accuracy and precision where the % re-
covery ranged from 94.3 to 103.6% and the % RSD were ≤ 2.8 for
the four compounds (Table 4).
Further, to validate the reliability of the HTLC method for the
determination of the investigated analytes in water samples from
distinct sources, the recoveries of different known added amounts
of the analytes to wastewater and tap water samples were cal-
culated. As deduced from Table 5, the good % recoveries of the
four compounds ranged from 90.1 to 104.6% with SD not exceeding
6.8 in all cases. Furthermore, to confirm the accuracy and preci-

5
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al. Journal of Chromatography A 1639 (2021) 461891

Table 5 tion of the concentrations of the NSAIDs during the investigation

Recovery of the four NSAIDs form tap water and wastewater samples
of their adsorption from the water on MWCNTs.
by the developed method.
Spiked Wastewater Tap water 3.5. Characterization of MWCNTs
Drug concentration Recovery Recovery
(mg/L) %±SD (n = 3) %±SD (n = 3)
The exterior morphology of the MWCNTs was examined by SEM
KET 0.1 95.3 ± 4.0 93.7 ± 3.0 imaging. As illustrated in Fig. 2A, the MWCNTs are randomly en-
2.0 98.4 ± 2.3 95.8 ± 4.0
10.0 98.5 ± 1.9 94.7 ± 1.6
tangled around each other forming a porous network. The MWC-
50.0 90.1 ± 1.3 100.0 ± 2.0 NTs have a mean diameter between 20 and 40 nm and a mean
NAP 0.05 99.5 ± 4.5 102.0 ± 3.0 length between 5 and 15 μm as certified by the manufacturer. The
0.1 98.4 ± 3.1 99.3 ± 2.3 XRD pattern of the MWCNTs (Fig. 2B) shows the typical (002) and
91.7 ± 2.4 95.6 ± 3.1
2.0
(100) peaks at 2θ of 26.075° and 43.6°, respectively, that charac-
10.0 102.3 ± 4.3 100.6 ± 1.9
DIC 0.5 98.9 ± 1.9 104.6 ± 3.7 terize the MWCNTs [39]. This result confirms the purity and crys-
1.0 98.5 ± 3.6 95.6 ± 3.1 tallinity of the MWCNTs.
10.0 101.4 ± 2.9 99.9 ± 1.8 The nitrogen adsorption/desorption on MWCNTs was studied at
100.0 91.3 ± 1.5 102.6 ± 1.1 77 K. Fig. 2C shows the adsorption/desorption isotherms obtained
IBU 0.6 90.9 ± 6.0 99.7 ± 6.8
by BET analysis. The obtained adsorption/desorption isotherm
1.0 98.1 ± 4.0 98.1 ± 3.1
10.0 94.7 ± 3.2 99.5 ± 2.0 shows an H3-type hysteresis loop that indicates a typical meso-
100.0 97.1 ± 2.3 100.3 ± 1.9 porous structure [40]. The specific surface area for the MWCNTs
was estimated using the BET equation and it equals 410.25 m2 /g.
Fig. 2D illustrates the pore size distribution of the MWCNTs deter-
mined by the BJH method [31]. The MWCNTs have pore size dis-
Table 6 tributed over the range of 2–50 nm with the majority of the pore
Statistical comparison of the results for the determination of NSAIDs in different diameters lay within the region of 2.4–2.9 nm corroborating that
water samples.
their structure is highly mesoporous.
Deionized water Wastewater Tap water The value of PZC for the MWCNTs equals 5.89 which indicates
KET that its surface is acidic in nature [32].
Mean ± SD (n = 9) 99.4 ± 0.8 95.7 ± 4.8 96.8 ± 2.8
Brown-Forsythe test (p)a 0.6683 3.6. Optimization of the adsorption of NSAIDs on MWCNTs
ANOVA test (p)a 0.4164
Dunnett’s test (p)a , b 0.3401 0.5644
NAP 3.6.1. Effect of contact time of water sample with MWCNTs
Mean ± SD (n = 9) 101.8 ± 2.4 97.5 ± 5.4 98.5 ± 2.6 It is demonstrated from the data illustrated in Fig. 3A that the
Brown-Forsythe test (p)a 0.5713 adsorption % of the four NSAIDs on MWCNTs increased gradually
ANOVA test (p)a 0.3814 with time reaching nearly equilibrium after 30 min then more in-
Dunnett’s test (p)a , b 0.3207 0.4818
DIC
crease of the contact time up to 120 min did not produce a signif-
Mean ± SD (n = 9) 100.7 ± 2.4 97.1 ± 5.2 99.4 ± 3.5 icant additional enhancement of the % adsorption. Thus, a contact
Brown-Forsythe test (p)a 0.7039 time of 30 min was chosen as the optimal for the next experimen-
ANOVA test (p)a 0.5440 tations.
Dunnett’s test (p)a , b 0.4566 0.8818
IBU
Mean ± SD (n = 9) 97.5 ± 2.9 96.6 ± 1.7 99.3 ± 1.1 3.6.2. Effect of MWCNTs mass
Brown-Forsythe test (p)a 0.5870 The % adsorption of the four drugs increased significantly by
ANOVA test (p)a 0.3281 increasing the mass of MWCNTs till achieving the maximum ad-
Dunnett’s test (p)a , b 0.8306 0.4865
sorption using 100 mg MWCNTs then a plateau region is attained
a
p > 0.05 means non-significant difference. (Fig. 3B). The improvement in the % adsorption by using larger
b
Dunnett’s multiple comparisons test was performed for every tested matrix masses of MWCNTs is attributed to offering additional surface
versus the control matrix (deionized water).
binding sites to adsorb and eliminate the NSAIDs. For the next ex-
periments, 100 mg MWCNTs was used.

sion of the proposed method for the analysis of targeted NSAIDs in
real water samples, we compared its performance in wastewater
and tap water with that in deionized water as a control matrix.
The equality of variances was evaluated by the Brown-Forsythe
test and it showed that all the tested matrices have no signif-
icant differences in their variances indicating the method preci-
sion (Table 6). After confirming the parametric nature of data, the
means of the different groups were compared with the ANOVA
test. The three groups showed insignificant differences regarding
their means. Then, this was verified via Dunnett’s multiple com-
parisons post hoc test, which was applied to compare the tested
matrices with the deionized water as the control (Table 6). All
the tests were performed as two-sided and at probability p >
0.05 [38]. The validation study demonstrated the excellent perfor-
mance of the developed HTLC method for the determination of the
targeted NSAIDs in water from different sources without signifi-
cant interference. Also, it revealed the suitability of the developed
method to be applied in the next experiments for the determina-
3.6.3. Effect of water sample pH
The impact of the solution pH on the elimination of the stud-
ied drugs by MWCNTs was also explored at 298 K for 30 min us-
ing 100 mg of MWCNTs and 5.0 mg/L of drugs. We found that the
highest % adsorbed of the four NSAIDs (80.8%, 93.8%, 97.8%, and
60.7% for KET, NAP, DIC, and IBU; respectively) was attained at a
low acidic pH value of 2.0. The % adsorption decreased gradually
by rising the solution pH (Fig. 3C). It is worth noting that the pre-
dominant species of the four NSAIDs at basic pH (higher than their
pKa that are 4.5, 4.2, 4.2, and 4.4 for KET, NAP, DIC, and IBU respec-
tively [41]) are the anionic forms. Thus, the anionic species of the
drugs are electrostatically repelled from the MWCNTs because their
surface is acidic (PZC equals 5.89) and it exhibits a negative charge
in alkaline pH. Therefore, the adsorption capacity of the MWCNTs
was reduced gradually by raising the pH. This trend suggested the
possibility of recycling of the MWCNTs by strong alkalization. pH
2.0 was selected as the best pH for the elimination of the four
drugs from water.

6
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
Fig. 2. (A) SEM images for the MWCNTs with different scopes, (B) XRD pattern of the MWCNTs, (C) nitrogen adsorption/desorption isotherms for MWCNTs at 77 K, and (D)
BJH pore size distribution of MWCNTs.
3.6.4. Effect of ionic strength
The adsorption of NSAIDs under four ionic strengths (0.001,
0.0 02, 0.0 04, and 0.0 08 mol/L as KNO3 ) at pH 2.0 indicated that
ionic strength has an insignificant impact on the adsorption of
NSAIDs on MWCNTs as shown in Fig. 3D. This result demon-
strated the potential of the MWCNTs for the elimination of the four
NSAIDs with no substantial influence from the soluble ionic salts
that commonly exist in water.
3.6.5. Effect of sample solution temperature
The influence of the solution temperature (281–333 K) on the
% adsorption of the four drugs from the solution on MWCNTs
was examined. We found that elevating the solution temperature
caused a reduction in the % adsorption of the four compounds
(Fig. 4). Further experiments were performed at room temperature
(298 K) for convenience and simplicity.
7
Journal of Chromatography A 1639 (2021) 461891
3.7. Study of adsorption kinetics
Since an applicable kinetic model is essential to study the
adsorption mechanism, we applied different kinetics models to
investigate their validity to disclose the adsorption of the four
NSAIDs on the MWCNTs. The pseudo-first-order, pseudo-second-
order, fractional power function, and Elovich models were tested
for the best fitting of the experimental data [42] (Table 7).
First, kinetic monitoring of the impact of temperature on the
adsorption of KET, NAP, DIC, and IBU on MWCNTs was done, and
the outcomes were illustrated in Fig. 4. It was found that the ad-
sorption is improved by decreasing the solution temperature which
specifies an exothermic process. It is also marked that the greatest
adsorption capacity is attained within 30 min for the four drugs
at all studied temperatures which could be attributed to the high
hydrophobicity of the studied drugs (log p equals 2.66, 3.2, 4.5,
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al. Journal of Chromatography A 1639 (2021) 461891

Fig. 3. Effect of (A) contact time, (B) MWCNTs mass, (C) pH, and (D) ionic strength on % adsorption of the four NSAIDs (5.0 mg/L for each drug) on MWCNTs.

Fig. 4. Effect of temperature and time on % adsorption of the four NSAIDs (drugs concentration, 5.0 mg/L, 100 mg of MWCNTs, pH 2) on MWCNTs.

8
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al. Journal of Chromatography A 1639 (2021) 461891

Table 7
Results of the application of different kinetic models to fit the adsorption of the four NSAIDs on MWCNTs.

1-Pseudo-first order model

Temperature KET NAP DIC IBU
(K)
qe,exp qe,cal qe,exp qe,cal qe,exp qe,cal qe,exp qe,cal
(mg/g) (mg/g) R2 (mg/g) (mg/g) R2 (mg/g) (mg/g) R2 (mg/g) (mg/g) R2

281 0.419 0.105 0.6535 0.472 0.072 0.7075 0.488 0.037 0.4879 0.380 0.170 0.8659
298 0.368 0.217 0.6431 0.425 0.156 0.8047 0.480 0.084 0.8379 0.325 0.233 0.8638
333 0.286 0.225 0.2118 0.378 0.162 0.5265 0.455 0.095 0.7825 0.225 0.281 0.1772

2-Pseudo-second order model

Temperature KET NAP DIC IBU
(K)
qe,exp qe,cal qe,exp qe,cal qe,exp qe,cal qe,exp qe,cal
(mg/g) (mg/g) R2 (mg/g) (mg/g) R2 (mg/g) (mg/g) R2 (mg/g) (mg/g) R2

281 0.419 0.419 0.9999 0.472 0.474 0.9999 0.488 0.486 0.9999 0.380 0.382 0.9997
298 0.368 0.368 0.9995 0.425 0.428 0.9996 0.480 0.479 0.9998 0.325 0.319 0.9981
333 0.286 0.286 1.0000 0.378 0.378 1.0000 0.455 0.455 0.9999 0.225 0.225 0.9998

3-Elovich model
Temperature KET NAP DIC IBU
(K)
β (mg/ β (mg/ β (mg/ β (mg/
α (mg /g.min) g.min) R2 α (mg/ g.min) g.min) R2 α (mg/ g.min) g.min) R2 α (mg/ g.min) g.min) R2

281 1.22 × 10 22
0.008 0.9216 1.15 × 10 12
0.017 0.9322 3.54 × 10 19
0.011 0.7992 1.76 × 1011
0.0143 0.9296
298 6.27 × 104 0.031 0.9213 1.97 × 106 0.028 0.9841 6.86 × 109 0.021 0.9738 3.88 × 109 0.0139 0.9466
333 3.50 × 1020 0.006 0.6490 6.48 × 109 0.017 0.9019 1.41 × 1011 0.018 0.9441 8.60 × 1023 0.0042 0.6027

4- Fractional power model

Temperature KET NAP DIC IBU
(K)
a b R2 a b R2 a b R2 a b R2

281 0.3812 0.021 0.9126 0.400 0.038 0.9331 0.440 0.024 0.7868 0.3119 0.0410 0.9367
298 0.2354 0.102 0.9176 0.304 0.075 0.9800 0.386 0.048 0.9649 0.2492 0.0489 0.9583
333 0.2624 0.023 0.6462 0.308 0.049 0.8936 0.379 0.042 0.9413 0.2100 0.0197 0.5989

5- Intraparticle diffusion model (C and R2 are for phase 1)

Temperature KET NAP DIC IBU
(K)
K1/K2 C R2 K1/K2 C R2 K1/K2 C R2 K1/K2 C R2

281 0.028/ 0.002 0.346 0.9590 0.023/ 0.006 0.379 0.8453 0.039 /0.002 0.385 0.9997 0.006 /0.006 0.314 0.8572
298 0.030/ 0.004 0.203 0.9508 0.028/ 0.007 0.276 0.9219 0.025 /0.005 0.359 0.8484 0.012 /0.005 0.2406 0.9916
333 0.022 /0.0002 0.229 0.9991 0.023/ 0.004 0.278 0.9805 0.012 /0.005 0.368 0.9511 0.023 /0.0002 0.1778 0.9642

6- Liquid film diffusion model

KET NAP DIC IBU
Temperature (K)
Kfd R2 Kfd R2 Kfd R2 Kfd R2

281 0.0002 0.1231 0.0001 0.6345 0.0002 0.1229 0.0036 0.8659

298 0.0002 0.3282 0.0001 0.7126 0.0002 0.1933 0.0024 0.8638
333 0.0001 0.1173 0.0000 0.4898 0.0002 0.1857 0.0003 0.1772

and 4.0, for KET, NAP, DIC, and IBU, respectively [41,42]), thus, they
tend to migrate from the hydrophilic aqueous solution to the hy-
drophobic surface of the MWCNTs.
The pseudo-first-order and pseudo-second-order models based
on Eq. (5) and (6), respectively were investigated for the best fit-
ting of the obtained experimental data shown in Fig. 4.
ln (qe − qt ) = lnqe − k1 t
t 1 t On the other hand, relating the kinetic models of Elovich and
= +
qt k2 q2e qe
Where k1 (min−1 ) represents the pseudo-first-order rate coeffi-
cient, k2 (g/(mg.min)) is the pseudo-second-order rate coefficient,
and qt and qe are the quantity adsorbed/unit mass at time t and
equilibrium, respectively. Table 7 presents the results obtained ex-
perimentally and theoretically for the two kinetic models. For the
pseudo-first-order model, plots of ln (qe -qt ) against t for the four
drugs at different temperatures (Fig. S1, Supplementary Material)
had poor correlation coefficients. It is also apparent that the cal-
culated values of qe (qe calc ) are far from the experimental values
(qe exp ) as shown in Table 7. Thus, it is established that the ad-
sorption is not following this model. On the contrary, the pseudo-
second-order model leads to excellent linearity for all of the drugs
at each studied temperature (Fig. 5) with high correlation coeffi-
cients (≥0.9981) and highly matched experimental and calculated
(5) qe values (Table 7). These results confirmed that the adsorption
takes place via the pseudo-second-order process.
(6) fractional power Eq. (7) and ((8), respectively) leads to poorer lin-
earity (Fig. S2 and S3, Supplementary Material) and unsatisfactory
correlation coefficients that confirmed the unacceptability of the
two models to define the adsorption process (Table 7).
qt = β ln (αβ ) + β ln t (7)
(qt (mg/g) is the quantity of the drug adsorbed/unit mass of MWC-
NTs at any time t, α and β are Elovich coefficients correspond to
the initial rate of adsorption (g/mg.min)) and the desorption coef-

9
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
Fig. 5. Pseudo-second order kinetic plots for KET, NAP, DIC and IBU adsorption on MWCNTs (drugs concentration = 5.0 mg/L, MWCNTs = 100 mg, pH 2.0).
ficient (mg/(g.min)), respectively. The Elovich coefficients, α , and β
were determined from the slope and intercept of the graph of qt
versus ln t).
ln qt = ln a + b ln t
(qt (mg/g) represents the quantity of drug adsorbed/unit mass of
MWCNTs at time t, a, and b are coefficients with b < 1. The role of
a and b are for the determination of the specific sorption rate at t
equals 1 min).
Thus, depending on the obtained data (Table 7), it is evidenced
that the pseudo-second-order is the most suitable kinetic model to
define the adsorption of the four NSAIDs from an aqueous medium
on MWCNTs.
3.8. Rate-controlling step of the adsorption process
Typically, the uptake of adsorbates from an aqueous medium to
a solid surface involves many successive steps. First, the adsorbates
migrate from the aqueous medium to the boundary layer on the
surface of the solid adsorbent. This step continues till equilibrium
then the adsorbates diffuse across the boundary layer to reach the
outer surface of the solid adsorbent to be adsorbed on its surface
active sites, and ultimately intra-particle diffusion across the pores
of the solid adsorbent [40]. Thus, the control of the entire adsorp-
tion process may occur via one or more rate-determining steps in-
cluding either film diffusion that represents the movement of the
adsorbate to the outer surface of the adsorbent or particle diffu-
sion via movement of the adsorbates into the adsorbent pores [43].
Thus, to explore whether the adsorption process is ruled by one or
more steps, the intra-particle diffusion and the liquid film diffusion
Journal of Chromatography A 1639 (2021) 461891
models were explored adopting Eq. (9) and (10), respectively.
qt = kid t1/2 + C (9)
Where qt is the adsorption capacity at any time (t), kid is the intra-
(8) particle diffusion rate constant (mg/g.min1/2 ), and C (mg/g) is a
constant related to the width of the boundary layer.
ln (1 − F ) = −kfd ∗ t (10)
Where F represents the fractional attainment of equilibrium
(F = qt /qe ) and kfd (min−1 ) is the film diffusion rate coefficient.
If a graph of qt against t1/2 gave a straight line crossing the ori-
gin, this means that the intra-particle diffusion is the single factor
that governs the adsorption process via one diffusion step. Though,
if this plot gave multi-linear lines, it is concluded that two or more
diffusion steps govern the adsorption [44]. Fig. 6 demonstrates the
graphs of qt versus t1/2 for the NSAIDs at different temperatures.
It is distinguished that, the data are correlated by 2 consecutive
straight lines which proposed that the adsorption fitted this model
splendidly. The first straight line represents fast external surface
adsorption or diffusion through the mesopores of the MWCNTs.
This step continues until saturation. The second straight line de-
notes the micropore diffusion where the adsorbates moved slowly
from the mesopores to the micropores of the MWCNTs. The slope
of each linear part expresses the corresponding diffusion step rate,
k1 and k2 , respectively [45]. Since k1 is greater than k2 for the four
NSAIDs at the four studied temperatures (Table 7), it is concluded
that the first step is faster than the second one. By extending the
first linear part to the y-axis (Fig. 6), we can obtain the intercepts
that express the thickness of the boundry layer (c) (Table 7). A
likely reason for divergence of the straight lines from the origin
is the variable rates of mass transfer in the early and last points of
10
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
Fig. 6. Intraparticle diffusion model plots for KET, NAP, DIC and IBU adsorption on MWCNTs (drugs concentration = 5.0 mg/L, MWCNTs = 100 mg, pH 2.0).
adsorption. Additionally, this divergence from the origin evidenced
that the pore diffusion is not the single rate-determining step [44].
The liquid film diffusion model was also tested by graphing -
ln (1–F) versus t. In this model, the boundary layer has a highly
prominent impact on the adsorption throughout the movement
of the adsorbates from the liquid medium to the adsorbent. This
model is considered valid to describe the diffusion process when
a straight line with zero intercepts is obtained. It is observed that
the obtained correlation coefficients are poor (Table 7) and the ob-
tained lines deviate from the origin (Fig. S4, Supplementary Mate-
rial). This result ensured that the film diffusion step does not pre-
dominantly control the adsorption [46].
3.9. Adsorption isotherm
The Langmuir isotherm was utilized in its linearized form to
evaluate the results of the binding of the investigated drugs with
the MWCNTs and to calculate the maximum binding capacity [47].
The data were linearly fitted to the Langmuir equation (Eq. (11))
with high values of correlation coefficient (r2 ≥ 0.9264) as illus-
trated in Fig. S5 (Supplementary Material).
1
 1
1 1
= + 0
qe KL x Q 0 Ce Q
Where; KL is the Langmuir adsorption constant, qe (mg/g) is the
concentration of adsorbate on MWCNTs at equilibrium; Ce [mg/L]
is the concentration of the adsorbate in solution at equilibrium; Q0
(mg/g) is the maximum adsorption capacity of MWCNTs for adsor-
bate.
The maximum adsorption capacities of the four NSAIDs on of
MWCNTs (Q0 ) were determined from the intercept of Langmuir
isotherm resulting in 2.3, 2.5, 4.8, and 1.96 mg/g for KET, NAP, DIC,
Journal of Chromatography A 1639 (2021) 461891
and IBU, respectively. Furthermore, the Langmuir adsorption con-
stant (KL ) can be used as a descriptor of the affinity of the adsor-
bates for the binding sites on the MWCNTs [48]. The KL values of
KET, NAP, DIC, and IBU were calculated from Eq. (11) and the re-
sults are 0.19, 0.46, 0.63, and 0.15 L/mg, respectively. It is evident
that the trends of Q0 and KL showed a clear agreement with the
achieved adsorption percentages of the four drugs at the optimum
conditions.
3.10. Adsorption thermodynamics
The thermodynamics of the adsorption of KET, NAP, DIC, and
IBU on MWCNTs was also investigated over the temperature range
of 281–333 K. The van’t Hoff plot was adopted to evaluate the
changes in enthalpy (H°) and entropy (S°) of the adsorption by
plotting Ln Kc versus 1/T according to Eq. (12) [35]:
S ◦ H ◦
ln Kc = − (12)
R RT
Where Kc is the equilibrium constant, R is the gas constant (8.314 J.
mol−1 .K − 1 ), and T is the temperature (K). The obtained van’t Hoff
(11) isotherms for the four investigated NSAIDs are illustrated in Fig. 7.
The change in the reaction enthalpy can be calculated from the
slope of the acquired line (H°= -slope × R) and the change in the
reaction entropy can be determined from the intercept (S° = in-
tercept × R). The change in Gibb’s energy (G°) can be also deter-
mined using Eq. (4) [35].
Table 8 abridges the obtained thermodynamic data. As observed
in Fig. 7, the obtained van’t Hoff plots show straight lines with
a positive slope indicating exothermic reaction. This means that
heat is released making the net enthalpy change (H°) negative
11
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
Fig. 7. van’t Hoff plots of the four NSAIDs on the MWCNTs.
Table 8
Thermodynamic data for the adsorption of the four NSAIDs on MWCNTs.
Compound Enthalpy change, H° (kJ/mol)
KET −19.92
NAP −24.11
DIC −20.77
IBU −20.14
(Table 8). The negative entropy change (S°) indicates that the sys-
tem becomes more ordered since the adsorption of the molecules
leads to the restriction of their free movement. Thus, the adsorp-
tion is enthalpy-driven as the highly negative H° overpowers the
decrease in entropy S°.
The negative values of both H° and S° suggest that the ther-
modynamic favorability of the adsorption process is reliant on the
temperature. This conclusion is supported by the calculated values
of G° (Table 8). The G° values at 298 K are positive for KET,
NAP, and IBU and negative for DIC only. However, negative values
of G° could be achieved at lower temperatures. The temperature
at which G◦ equals zero can be calculated by substituting G◦ in
Eq. (4) by zero. Below these temperatures, negative values of G°
would be obtained. The calculated results demonstrate that con-
ducting adsorption at temperatures < 260, 290, and 247 K for KET,
NAP, and IBU, respectively, would lead to negative G° for these
compounds. These outcomes confirmed that the adsorption pro-
cess is more likely to be extensive at a lower temperature [35].
3.11. Mechanism of interaction of the NSAIDs with MWCNTs
The interaction of the adsorbates with MWCNTs involves differ-
ent steps where the molecules moved from the bulk solution to
the boundary layer followed by film diffusion then adsorption on
the external surface of the adsorbent. Herein, the adsorption pro-
cess followed pseudo-second-order kinetics. Intraparticle diffusion
is the predominant rate-governing step of the overall adsorption
process. The intraparticle diffusion involves two steps: (i) external
surface adsorption or diffusion through mesopores of the MWCNTs
and (ii) micropore diffusion by the movement of the adsorbates
from the mesopores to the micropores of the MWCNTs.
The hydrophobicity of the organic molecules, expressed by log
P, had a key effect on the adsorption process [49]. The four NSAIDs
are hydrophobic in nature where their log P values are 2.66, 3.2,
Journal of Chromatography A 1639 (2021) 461891
Entropy change, S° (J/K. mol) Gibb free energy change, G° (kJ/mol) at 298 K
−76.81 2.97
−83.06 0.65
−62.33 −2.20
−81.38 4.11
4.5, and 4.0, for KET, NAP, DIC, and IBU, respectively [41,42]. Thus,
hydrophobic interaction is a major player in the adsorption of the
four compounds on the hydrophobic sites uniformly distributed on
the MWCNTs surface. However, the lack of correlation between the
hydrophobicity of the four compounds and their adsorption affinity
to the MWCNTs (the order of % adsorbtion on MWCNTs is DIC >
NAP > KET > IBU) suggested the presence of other types of inter-
action. This behavior is well known for the interaction of organic
molecules and carbon nanotubes [50].
The interaction via π -π bonding of the benzene ring(s) of the
drugs and the aromatic structure of the MWCNTs is another type
of possible interactions, where the π electron orbit around each
carbon atom interacts with the π electrons of the aromatic sys-
tem of the MWCNTs [51]. Thus, since KET, NAP, and DIC have two
aromatic rings in their structures while IBU has one aromatic ring,
it is rational that the three compounds show greater adsorbability
than IBU. Instead, the alkyl-π interaction between the alkyl side
chain of the IBU molecule and the MWCNTs probably takes place,
which is weaker than the π -π bonding interaction [52].
Furthermore, the n-π electron-acceptor-donor interaction can
be recognized as another contributor via the interaction of the lone
pair of electrons on oxygen and nitrogen atoms of the NSAIDs with
the electron-depleted unhybridized p-orbitals of the aromatic π -
bonds in the MWCNTs structure [50,53]. This is another probable
cause for the enhanced adsorption of KET, NAP, DIC relative to IBU,
since IBU has one electron-donating group (-COOH) while each of
the three compounds has two electron-donating groups capable of
n-π interaction.
Hydrogen bonding of the adsorbed molecules with other
molecules in the solution probably contributes also to the adsorp-
tion process [54]. Furthermore, the small size of organic molecules
is responsible for pore filling [49]. Fig. 8 illustrates the mechanisms
involved in the interaction of the four studied compounds with the
MWCNTs.
12
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al. Journal of Chromatography A 1639 (2021) 461891

Fig. 8. Illustration of the mechanisms involved in the adsorption and interaction of KET, NAP, DIC, and IBU with MWCNTs (black dashed arrow denotes n-π interaction, red
arrow denotes hydrophobic interaction, brown arrow denotes alkyl- π interaction, and yellow dashed arrow denotes π -π interactions). (For interpretation of the references
to colour in this figure legend, the reader is referred to the web version of this article.)

3.12. Application for purification of real samples 3.13. Evaluation of the protocol greenness

Application of the developed method for water purification was
demonstrated by assessment of real samples include tap water and
a wastewater sample collected from our institutional treatment
plant. Experimental results showed that none of the four com-
pounds was detected. In consequence, spiking experiments were
performed at a final concentration of 5.0 mg/L of the four com-
pounds. By comparison of the found concentration before and after
treatment with MWCNTs, the % adsorption of the targeted com-
pounds are illustrated in Fig. 9. In the tap water, the % adsorp-
tion ranged from 66.7 to 94.1%, while it was 65.3–92.2% in the
wastewater, which is in good accordance with the results obtained
in deionized water (66.0–96.0%). It is noteworthy that this % ad-
sorption could be increased up to (76.4–97.6%) if the treatment
with MWCNTs is performed at 281 K as shown in Fig. 4. These
results are promising for future full-scale applications in water pu-
rification.
Being working with the aim of environmental and health pro-
tection, it is vital to evaluate the agreement of the entire pro-
tocol used in this study with the main concepts of green ana-
lytical chemistry. In this evaluation, we adopted the most recent
and updated metric and software: analytical greenness (AGREE)
[28] that applies twelve assessment criteria to measure the green-
ness of analytical techniques including sample treatment, sam-
ple amount, device positioning, sample preparation stages, au-
tomation/miniaturization, derivatization, waste, analysis through-
put, energy consumption, source of reagents, toxicity, and opera-
tor’s safety. The output of this metric is a pictogram with a score
from 0–1, where the ideally green analytical method has a score
equals to 1. In the present study, we assumed equal weights for
the twelve assessment principles, thus supposing equal importance
for all criteria. Then, we conducted a comparison between the de-
veloped protocol and different techniques devoted to the elimina-
tion of these NSAIDs from water [55–61]. It is understandable from

13
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
Fig. 9. Removal of the targeted pharmaceutical compounds from different water samples, where 10 mL of the water samples were treated with 100 mg MWCNTs for 30 min.
Fig. 10. Results of the AGREE analysis of the proposed and reported analytical techniques for NSAIDs in water (Methods 1–7 are referring to reference [55–61], respectively).
Fig. 10 that the developed protocol is the greenest among the pub-
lished methods since it has the highest score of 0.53, while the re-
ported methods [55–61] have scores ranging from 0.18 to 0.41. For
confirmation of this outcome, a further evaluation of the method
greenness was conducted using the analytical eco-scale score met-
ric [29] that assumes a score of 100 on the eco-scale for the ideal
green analytical method. For each parameter that decreases the
method greenness, such as the quantity of reagents, dangers, en-
ergy, and waste, penalty points are allocated and deducted from
the perfect score of 100 to calculate the analytical eco-scale score.
As distinguished from Table 9 and Table S1 (Supplementary Ma-
terial), the proposed method possesses the highest analytical eco-
scale score among the reported literature. With a score of 78, the
proposed method belongs to the “excellent green analysis” cate-
gory, while all of the reported methods have scores < 75 that clas-
sifies them as “acceptable green analysis” [29].
14
Journal of Chromatography A 1639 (2021) 461891
The main reasons behind the greenness of the developed pro-
tocol compared to reported methods as concluded from the two
greenness measurement metrics [28,29] are:
1. The fewer steps needed for removal of the analytes by the
MWCNTs compared to the reported methods [55–61] that adopt
solid-phase extraction which requires repetitive steps of car-
tridge conditioning, repetitive elution, drying, and reconstitu-
tion.
2. No need for derivatization prior analysis in contrary to some of
the reported methods [56,60].
3. Lower total energy consumption relative to GC–MS or LC-MS
methods [56,57,59–61].
4. Minimal use of organic solvents and toxic reagents.
5. Generation of smaller volume of waste than most of the re-
ported literature.
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al. Journal of Chromatography A 1639 (2021) 461891

Table 9
Comparison of the performance of the developed method and reported literature for removal of the four NSAIDs from water.

Run Adsorption
time Linear detection LOD on column capacity Eco-scale
Analytical Method (min) Extraction method range (mg/L) (ng) (%) score Remarks Ref No.

HPLC-UV 22 SPE using ethyl 0.1 to 50 0.12–0.71 81–102 66 – [55]

acetate as eluent
GC–MS 31 SPE using methanol as 20–250 0.02–0.06 84 72 Derivatization with MSTFA for [56]
eluent 12 hr is required
HPLC-DAD and 12 SPE using methanol as 0.02 – 3 (UV) 0.06–14 (UV) 96–109 60 Preconcentration and analysis [57]
LC-MS eluent 0.001–0.2 (MS) 0.01–1 (MS) program needs up to 80 min
HPLC-UV 6 SPE using methanol, 1–10 0.16–0.52 76 to 98 71 detection wavelength program [58]
formic acid, and acetic is needed
acid as eluents
HPLC-DAD and 12 SPE using methanol as 0.1–20 (UV) 0.12–1.96 80–103 60 Gradient elution and detection [59]
LC-MS eluent 0.01–5 (MS) wavelength program are needed
GC–MS 22 SPE using ethyl 0.05–4.0 0.01–0.02 98.5–107 60 Derivatization with [60]
acetate as eluent bis(trimethylsilyl)
trifluoroacetamide and 1%
trimethyl chlorosilane in the
presence of pyridine is needed
UHPLC-TOF/MS 5 Rotating-disk sorptive 0.01–1 0.001–0.05 74–110 70 – [61]
extraction
HTLC-UV 16 MWCNTs 0.05–100 0.11–1.8 76.4 - 97.6 78 – This method

6. Safety to the user by avoiding corrosive solvents or toxic
reagents.
7. Low occupational hazards.
3.14. Comparison of the performance of developed protocol and
reported literature for removal of the cited NSAIDs from wastewater
A further comparison of the performance of the developed
protocol and literature methods for removal of the four NSAIDs
from the water concerning the linearity, LOD, adsorption capac-
ity (%), the time needed, and availability and accessibility of the
used instruments, has been conducted and the obtained results are
shown in Table 9. As apparent from the represented data, most of
the reported literature applied mass spectrometry-based analysis
[56,57,59–61] that is not available in all laboratories and requires
skilled operators which puts some restrictions on the wide appli-
cation of these methods. Another factor that gives the proposed
method a privilege is the speed of analysis relative to most of
the reported methods [55,56,60]. In addition, the reported methods
adopt solid-phase extraction that inherently needs repetitive steps
in contrast to the developed method that uses MWCNTs as adsor-
bent which requires minimal steps. It is also important to highlight
that most of the reported methods need some additional steps
such as detection wavelength programming [58,59], gradient elu-
tion [59], and lengthy derivatization [56,60] which consume more
time, effort, and energy. The adsorption capacities of the developed
method and the reported methods are comparable where 76.4-
97.6% adsorptions are achieved by the developed method while the
adsorptions % of the reported methods ranged from 74–110%. Al-
though mass spectrometry is a more sensitive detection method,
the developed method showed comparable sensitivity to that of
some of the reported mass spectrometry-based methods [57,59].
4. Conclusions
In this study, a thermodynamic description of the retention of
KET, NAP, DIC, and IBU on the ZORBAX 300SB-C18 column is re-
ported. The dependence of the retention on hydrophobicity is ev-
idenced. Furthermore, the optimized and validated isocratic HTLC
technique was used to investigate the elimination of the four drugs
from an aqueous solution using MWCNTs. The NSAIDs uptake by
the MWCNTs depends on the temperature, pH, mass of MWCNTs,
and the contact time. The kinetic study evidenced that the ad-
sorption of the four compounds on MWCNTs achieved equilibrium
within 30 min. In all cases, the adsorption kinetics is satisfacto-
rily fitted by the pseudo-second-order kinetic model and the rate-
determining step of the adsorption process is the intraparticle dif-
fusion. Further, the thermodynamic study shows that the adsorp-
tion is exothermic and driven by the enthalpy. As well, the results
show that the adsorption is better at a lower temperature. Efficient
elimination of 83.8%, 94.8%, 97.6%, and 76.4%, of KET, NAP, DIC, and
IBU, respectively, from water samples at the optimum conditions
demonstrates the great potential of the MWCNTs as an efficient ad-
sorbent for water purification. The results of the binding capacity
and adsorption affinity of the four studied compounds on MWCNTs
are promising for further studies to scale-up the procedure to ful-
fill real-world water purification applications. At last, due to their
good extraction performance, optimization of the enrichment fac-
tor of MWCNTs in solid-phase extraction cartridges is the subject
of an ongoing study.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.chroma.2021.461891.
CRediT authorship contribution statement
Lateefa A. Al-Khateeb: Conceptualization, Methodology, Data
curation, Formal analysis, Investigation, Resources, Writing - review
& editing. Mona A. Al-zahrani: Methodology, Data curation, For-
mal analysis, Investigation. Mohamed A. El Hamd: Data curation,
Validation, Investigation, Writing - review & editing. Mahmoud
El-Maghrabey: Conceptualization, Data curation, Formal analysis,
Methodology, Validation, Investigation, Writing - review & edit-
ing. Fatimah A. Dahas: Resources, Investigation, Writing - review
& editing. Rania El-Shaheny: Conceptualization, Data curation, For-
mal analysis, Methodology, Validation, Investigation, Writing - orig-
inal draft.

15
L.A. Al-Khateeb, M.A. Al-zahrani, M.A. El Hamd et al.
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