Journal of Environmental Treatment Techniques  
2020, Volume 8, Issue 3, Pages: 1112-1117  
J. Environ. Treat. Tech.  
ISSN: 2309-1185  
Journal web link: http://www.jett.dormaj.com  
Application of Response Surface Methodology for  
Optimization of Cefixime Removal from Aqueous  
Solutions by Granular Ferric Hydroxide  
1
2
2
1
Roqiyeh Mostafaloo , Mahdi Asadi-Ghalhari *, Rahim Aali , Fatemeh sadat Tabatabaei ,  
1
1
Elaheh Sadat , Amin Kishipour  
1
Student Research Committee, Qom University of Medical Sciences, Qom, Iran  
2
Research Center for Environmental pollutants, Department of Environmental Health Engineering, Faculty of Health, Qom University of Medical  
Sciences, Qom, Iran  
Received: 15/04/2020  
Accepted: 05/06/2020  
Published: 20/09/2020  
Abstract  
In general, very limited information is available on the adsorption of antibiotics by granular ferric hydroxide (GFH) in an aqueous  
solution. In order to gain an understanding of the adsorption process of cefixime by GFH, this study was conducted in a controlled batch  
system and using central composite design by response surface methodology (RSM). The effects of pH, initial Cefixime concentration,  
adsorbent dose and contact time on the adsorption rates of cefixime were investigated. The results of optimization of the variables derived  
–
1
–1  
in the initial pH = 6, cefixime concentration were 8 mg L , adsorbent dosage = 1 g L and contact time = 50 min, and maximum removal  
2
efficiency of 99.63%. According to RSM, this study follows the Quadratic model (R = 0.970). Considering the good quality, economic  
and feasibility aspects, adsorption of CFX with GFH is recommended as a successful method of CFX removal from various aqueous  
solutions.  
Keywords: Adsorption, Cefixime, Granular ferric hydroxide, Aqueous solution  
Introduction1  
Antibiotics are  
media, throat inflammation, bronchitis, and urinary tract  
1
infections [16; 17]. After consume of CFX, about 40-50% can  
be absorbed by gastrointestinal tract and around 50% is  
excreted in the aquatic environment by urine [1]. Due to the  
harmful effects of these compounds as well as their cumulative  
and non-biodegradable properties, their removal from the  
sewage is necessary [18]. However, conventional biological  
treatment methods can eliminate less than 20% of these  
pollutants. Therefore, researchers are looking for suitable  
alternative methods for the treatment of pharmaceutical  
wastewater. Biological removal methods are a cost-effective  
method but have little effect on resistant organic compounds.  
Chemical and physical treatment can produce high efficiency  
and produce high quality wastewater but its treatment costs are  
relatively high [19]. However, the adsorption method, which is  
a physical method, is one of the most widely used methods for  
removal of aquatic pollutant [20; 21]. Studies show that iron  
and aluminum oxides have an important role in the absorption  
of pollutants. The University of Berlin (Germany) has  
introduced a new adsorbent called granular iron hydroxide  
a
large and diverse group of  
Pharmaceuticals compounds, which are widely used in  
medicine, veterinary medicine and agriculture. These  
compounds are not fully metabolized in the body after use [1]  
And they enter aquatic environments from various point and  
non-point sources such as sewage, waste and agricultural runoff  
[2]. These compounds play an important role in infectious  
disease treatment [3; 4]. But, Because of the widespread  
diversity and use and antibiotic resistance, they are recognized  
as the most important emerging pollutants in the aquatic  
environment [5-8]. Although their detected value is trace levels  
(ng/L to low µg/L), [9] But even that, low concentration levels  
can cause irreversible effects such as carcinogenesis,  
mutagenesis, disruption of endocrine and emergence of  
antibiotic-resistant genes and damage to DNA and lymphocytes  
[10-12]. Therefore, the presence of these compounds in water,  
especially drinking water sources, poses a serious threat to  
human health and the environment. Therefore, investigation,  
monitoring and removal of these compounds from aquatic  
environments are important requirements that can have a  
significant impact on water quality [2]. CFX is one of the third  
generation antibiotics of cephalosporin [13; 14]. This  
compound can be used against pathogens such as anaerobic  
bacteria, Enterobacteriaceae, gram-negative strains such as  
Escherichia coli, Klebsiella, Hemophilus influenza, Serratia  
and etc. [15]. Therefore, this drug used to treat a wide range of  
infections such as respiratory infections, gonorrhea, otitis  
(GFH) [22]. GFH is among excellent adsorbents for impurities  
in water, which having a high porosity and suitable sites smaller  
than 4.5 microns [23]. The adsorbent of GFH had favorable  
results in the removal of arsenic [24], fluoride [23], bromate  
[25], phosphate [26], perchlorate [27] and other natural organic  
matter [25]. According to searches, it seems that GFH has not  
yet been used to absorb pharmacological compounds from  
aquatic environments. On the other hand, in a report published  
Corresponding author: Mahdi Asadi-Ghalhari, Research Center for Environmental pollutants, Department of Environmental Health  
Engineering, Faculty of Health, Qom University of Medical Sciences, Qom, Iran. E mail: mehdi.asady@gmail.com.  
1
112  
Journal of Environmental Treatment Techniques  
2020, Volume 8, Issue 3, Pages: 1112-1117  
by the World Health Organization in 2019 on the rate of  
antibiotic consumption, CFX was introduced as one of the most  
widely used antibiotics [28]. Therefore, the researchers decided  
to investigate the efficacy of GFH in the absorption of cefixime  
antibiotics. In this study, effective parameters in the adsorption  
process, including pH, initial CFX concentration, adsorbent  
dose and contact time were first investigated using response  
surface methodology (RSM).  
by Eq. 1.  
(퐶0 − 퐶푡)  
R% =  
× 1ꢀꢀ  
(1)  
퐶0  
where C  
0
t
and C are the initial and final concentration of CFX  
in solution (mg/l), respectively.  
Table 2: Coded and actual values of numeric factors  
level  
2
Materials and Methods  
2
.1 Chemicals  
Factor (unit)  
Code  
-
훼
-1  
0
6
+1  
+훼  
In this study, All the employed chemical compounds were  
of laboratory grade. CFX 98% with molecular formula  
Solution pH  
X
X
1
2
(A)  
(B)  
3
1
4.5  
7.5  
9
⁠ ⁠ ⁠  
16 15 5 7 2  
C⁠ H⁠ N O S ;453.45 mol.wt were purchased from sigma  
Initial CFX  
concentration  
Aldrich Co.(USA). Hydrochloric acid, Sodium hydroxide and  
methanol, were purchased from Merck Company.  
4.5  
0.5  
8
1
11.5 15  
1.5  
(
mg/l)  
2
.2 Preparation of GFH  
GFH dose (g/l)  
X
X
3
4
(C)  
(D)  
0
5
2
GFH was purchased from Wasserchemie GmbH & Co.  
Reaction time  
min)  
Table 1 demonstrates the characteristics physical and chemical  
of GFH. In order to remove moisture, GFH granules was placed  
in the oven at 105°C for 90 min and also, placed in the  
desiccator for cooling [29].  
27.5 50 72.5 95  
(
2 Results and Discussion  
.1 Statistical analysis  
The CCD was used to determine the correlation of four  
3
Table 1: The characteristics of GFH  
Character  
Value  
280  
0.32 - 2  
43 - 48  
7.5 – 8.2  
1250  
independent factors (pH (A), CFX concentration (B), GFH  
dosage (C), and contact time (D)) in removal of CFX by GFH.  
The CCD selected the Quadratic model as the best fitted model  
for this study. This model is presented in Eq. 2.  
2
Specific surface area (m /g)  
Particle size (mm)  
Water content  
pHpzc  
Bulk density (kg/m )  
3
R (CFX reduction efficiency (%)) =+93.14 -2.71 *A -1.16 *B  
+16.04 *C +7.41 *D +2.28 *A B +3.69 *A C -8.04 *C D -  
Porosity of grains (%)  
72 - 77  
2
2
1
0.12 * C -5.31* D (2)  
2
.3 Experimental design  
RSM is a combines of efficient mathematical approaches  
As shown in Table 4, analysis of variance (ANOVA)  
and statistical powerful technique that are used to the modeling  
and analysis of design parameters on the desired value of the  
response function [30]. also, it is used to minimize the number  
of experiments for optimization studies in chemical and  
biochemical processes [31]. In this study, a central composite  
design (CCD) used for optimization and statistical analysis of  
four factors solution pH (A), initial CFX concentration (B),  
GFH dose (C) and Reaction time (D). Each factor was  
examined at five levels i.e. (-α, -1, 0, +1 and +α) (Table 2) and  
the model was designed with 30 runs along the levels as given  
in Table 3. In this work, Analysis of variance (ANOVA test)  
was used to the multiple regression analysis of the model and  
response surface graphs were done by using Design- Expert,  
version 7.1.6.  
indicate that there is a significant relationship between  
independent variables and the removal efficiency of CFX. Also,  
The Model F-value of 72.15 implies the model is significant  
and there is only a 0.01% chance that a "Model F-Value" this  
large could occur due to noise. Values of "Prob > F" less than  
0.0500 indicate model terms are significant. According to Table  
4, In this case A, C, D, AC, CD, C , D are significant model  
terms. Values greater than 0.1000 indicate the model terms are  
not significant. Also, the F-value for Lack of Fit is 3.46 which  
indicate the relationship between Lack of Fit and pure error is  
not significant. Additionally, determination coefficient "R-  
Squared" of 0.639, "Pred R-Squared" of 0.9134 and "Adj R-  
Squared" of 0.9567 is in reasonable agreement which determine  
the quality of polynomial model. "Adeq Precision" measures  
the signal to noise ratio of the study. A ratio greater than 4 is  
desirable and indicate this model can be used to navigate the  
design space which in this work, ratio of 30.839 indicates an  
adequate signal.  
The coefficient of variation (CV) indicates the degree of  
precision and credibility of the result. It is the ratio of the  
standard deviation to the average of data (sd/mean) and is a  
good measure of relative variability of the experiments. [33] In  
general, a lower the value of the CV % (<10%) means the  
smaller level of dispersion around the mean [34]. In this study,  
a small value of CV (5.42) and standard deviation (4.38)  
indicates greater reliability of the model.  
2
2
2
.4 Adsorption experiment  
After preparation of the GFH, desired concentrations were  
prepared based on 1 mg/L CFX stock solution and the  
adsorption experiments were carried out according to the RSM  
matrix (Table 3). Each run of experiment, a volume of 10 mL  
CFX solution in Erlenmeyer flasks was prepared. The pH of the  
samples was adjusted using 1 N solutions of HCl or NaOH and  
measured by pH7110 (WTW). In the following, Samples were  
placed in a shaker incubator at 200 rpm to be mixed. After  
elapse of contact time, samples were Centrifuge 5804  
(
Eppendorf) for 20min at 4000 rpm to separate the adsorbent.  
The CFX concentration was determined by spectrophotometer  
T80 UV/VIS, PG Instruments Ltd) within the wavelength of  
88.5 nm [32] and removal efficiency of CFX was calculated  
(
2
1
113  
Journal of Environmental Treatment Techniques  
2020, Volume 8, Issue 3, Pages: 1112-1117  
Table 3: Central composite designed experiments and obtained and predicted responses  
Removal Efficiency (%)  
CFX Concentration  
Run Order pH  
GFH dose (g/L)  
Time (min)  
(mg/l)  
Obtained  
Predicted  
Residual  
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
6
8
1
50  
94.92  
43.53  
97.40  
86.63  
96.53  
68.14  
88.81  
91.86  
94.30  
94.36  
90.48  
93.81  
15.65  
52.45  
96.39  
85.27  
69.56  
93.49  
60.78  
94.08  
85.63  
93.70  
44.96  
89.82  
89.92  
95.02  
82.22  
45.11  
89.16  
99.63  
93.14  
40.93  
95.57  
86.96  
96.47  
71.83  
84.73  
93.13  
89.95  
93.13  
86.70  
93.13  
20.57  
57.06  
98.55  
80.07  
69.60  
96.84  
56.06  
93.13  
87.71  
94.24  
49.17  
95.46  
92.97  
95.20  
88.68  
38.69  
90.81  
93.13  
1.78  
7.5  
4.5  
4.5  
7.5  
7.5  
6
11.5  
4.5  
4.5  
11.5  
11.5  
8
0.5  
1.5  
0.5  
1.5  
0.5  
2
27.5  
72.5  
72.5  
27.5  
72.5  
50  
2.61  
1.83  
-0.33  
0.06  
-3.69  
4.08  
6
8
1
50  
-1.27  
4.35  
4.5  
6
11.5  
8
1.5  
1
27.5  
50  
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.23  
6
8
1
95  
3.77  
6
8
1
50  
0.67  
6
8
0
50  
-4.92  
-4.61  
-2.16  
5.20  
6
8
1
5
3
8
1
50  
4.5  
7.5  
4.5  
4.5  
6
11.5  
4.5  
4.5  
4.5  
8
0.5  
0.5  
1.5  
0.5  
1
72.5  
72.5  
27.5  
27.5  
50  
-0.03  
-3.35  
4.72  
0.95  
9
8
1
50  
-2.08  
-0.53  
-4.21  
-5.64  
-3.05  
-0.18  
-6.46  
6.42  
7.5  
4.5  
6
4.5  
11.5  
1
1.5  
0.5  
1
27.5  
27.5  
50  
7.5  
7.5  
4.5  
7.5  
6
4.5  
11.5  
11.5  
4.5  
15  
8
1.5  
1.5  
1.5  
0.5  
1
72.5  
72.5  
72.5  
27.5  
50  
-1.65  
6.50  
6
1
50  
3
.2 The Influence of variables and their interactions on  
from 0.5 to 1.5 g/l and increasing the reaction time from 27.57  
to 72.5 min increased CFX adsorption efficiency. The fast  
removal efficiency of the early stages can be attributed to the  
presence of more active sites on the GFH surface which an  
increase in GFH dosage can increase active surface places and  
provided a wider contact area between CFX and GFH  
Nevertheless, these sites become saturated over time and, on  
the other hand, the removal efficiency decreases due to the  
repulsive force between the ions adsorbed on GFH and the  
soluble phase ions [35, 36]. Amarai obtained similar results  
with the interaction of time and dosage parameters on the  
removal of ciprofloxacin and amoxicillin, which is consistent  
with the present study [37].  
pollutant level  
3
D contours and perturbation plots were used to evaluate  
the effect of variables on the efficiency of cefixime removal  
process by GFH. As shown in Fig 1, the perturbation plot was  
used for compares the effect of dependent factors at a particular  
point in the design space. In this graph, the slope of each line  
indicates the sensitivity of that factor in adsorption process.  
According fig 1 the factors C (GFH dose) and D (reaction time)  
had the greatest impact. In Eq 2, dose of GFH, with coefficients  
of 16.04 have the most effects on the removal of CFX (%).3D  
contours in Fig. 2-a and 2-b show the interaction between of  
GFH dosage with reaction time and pH on CFX removal  
efficiency. As shown in Fig 2-a, increasing the GFH dosage  
1
114  
Journal of Environmental Treatment Techniques  
2020, Volume 8, Issue 3, Pages: 1112-1117  
Table 4: The analysis of variance (ANOVA) for adsorption of CFX on GFH  
Mean  
Square  
Source  
Sum of Squares  
df  
F-Value  
p-value  
Model  
12454.49  
176.34  
32.57  
9
1383.83  
176.34  
32.57  
72.15  
9.19  
< 0.0001  
0.0066  
Significant  
A-pH  
1
B-CFX(mg/l)  
C-GFH Dos(g/l)  
D-time(min)  
AB  
1
1.70  
0.2074  
6173.00  
1317.46  
83.20  
1
6173.00  
1317.46  
83.20  
321.83  
68.69  
4.34  
< 0.0001  
< 0.0001  
0.0503  
1
1
AC  
217.97  
1053.29  
2913.51  
802.81  
383.62  
349.92  
33.70  
1
217.97  
1035.29  
2913.51  
802.81  
19.18  
11.36  
53.97  
151.90  
41.85  
0.0030  
CD  
1
< 0.0001  
< 0.0001  
< 0.0001  
C2  
1
D2  
1
Residual  
20  
15  
5
Lack of Fit  
Pure Error  
Cor Total  
13.33  
3.46  
0.0882  
Not significant  
6.74  
12838.11  
29  
R-Squared  
Adj R-Squared  
Pred R-Squared  
Adeq Precision  
Coefficient of variation (%)  
standard deviation  
0.9701  
0.9567  
0.9134  
30.839  
5.42  
4.38  
the isoelectric point (pHpzc) is an important factor for surface  
charge, when the pH is lower than pHpzc, the surface charge of  
GFH is usually positive and the higher than pHpzc is negative  
charge. Therefore, in pH below 7.5, the GFH surface charge  
was positive and CFX charge was mostly in the form of a  
negative charge. Thus, by electrostatic interactions, CFX  
negative ions are adsorbed on the positive surface of GFH.  
The interaction between pH and initial CFX concentration  
is shown in Fig 2-c. According to the fig 2-c, the removal  
efficiency decreased with increasing initial concentration from  
1
00  
C
D
A
B
B
A
9
0
D
8
0
4
.5 to 11.5 mg/L and increasing pH from 4.5 to 7.5. This  
70  
C
decrease in removal efficiency at concentrations higher than  
CFX can be attributed to the saturation and reduction of active  
sites present on the GFH surface [36; 39]. Similar results were  
obtained in the study of Omrane et al [40].  
60  
-
1.000  
-0.500  
0.000  
0.500  
1.000  
4
Conclusions  
In this study, the adsorption of CFX on GFH from aqueous  
Deviation from Reference Point (Coded Units)  
solutions was investigated. The RSM method based on CCD  
was employed to investigate the interactive effects of  
independent factors and get to the more reliable results. The  
results of study showed that increasing the contact time and  
GFH dosage improved CFX removal, while increasing initial  
CFX concentration and pH the had a negative effect on its  
elimination. The F-value for Lack of Fit and determination  
Figure 1: Perturbation plots for CFX reduction efficiency (A) pH, (B)  
Initial concentration, (C) GFH dose and (D) contact time  
Diagram 2-b also shows the interaction between pH and  
GFH dosage. With increasing adsorbent dose and decreasing  
pH from 7.5 to 4.5 the adsorption efficiency increased from  
about 60% to <99%. The surface properties of CFX ions is pH  
dependent. The CFX ionizing molecule has two carboxyl  
groups (pKa is 3.73 and 1/2).[38] The surface properties of  
CFX ions is pH dependent. The CFX ionizing molecule has two  
carboxyl groups (pKa is 3.73 and 1/2). At higher pH < 3.37 it  
is mainly CFX in the form of negative ions. On the other hand,  
2
coefficient (R ) were 3.46, 0.0882 and 0.9701, respectively.  
Also, the CCD selected Quadratic model as the best fitted  
model for this study. Due to the high removal efficiency of CFX  
antibiotic with GFH, it is recommended to use this adsorbent  
for removal of CFX from aqueous solutions.  
1
115  
Journal of Environmental Treatment Techniques  
2020, Volume 8, Issue 3, Pages: 1112-1117  
(
a)  
(b)  
100  
101  
86.5  
90.75  
73  
80.5  
59.5  
70.25  
46  
60  
1.50  
27.50  
1.50  
1.25  
38.75  
7.50  
1.25  
1
.00  
6.75  
6.00  
1.00  
50.00  
C: GFH(g/l)  
0.75  
5.25  
0.75  
61.25  
D: time (min)  
0.50 4.50  
C: GFH (g/l)  
A: pH  
0.50 72.50  
100  
(c)  
97.25  
94.5  
91.75  
89  
4.50  
6.25  
4.50  
8.00  
B: CFX(mg/l)  
5.25  
9.75  
6.00  
6.75  
11.50 7.50  
A: pH  
Figure 2: Response surfaces plots for CFX removal as a function of (a) GFH dosage and time (b) GFH dosage and contact time, (c) pH and initial  
concentration of CFX  
photocatalysis. Journal of environmental management.  
Aknowledgment  
2
012;98:168-74.  
Authors would like to thank of Qom University of Medical  
Sciences for supporting the current study.  
3
4
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Derakhsheshpoor R, Homayoonfal M, Akbari A, Mehrnia MR.  
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Analytical and Bioanalytical Electrochemistry. 2020;12(1):36-47.  
Ethical issue  
Authors are aware of, and comply with, best practice in  
publication ethics specifically with regard to authorship  
(avoidance of guest authorship), dual submission, manipulation  
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antibiotics from aqueous matrices–a review. Journal of  
environmental management. 2011;92(10):2304-47.  
of figures, competing interests and compliance with policies on  
research ethics. Authors adhere to publication requirements  
that submitted work is original and has not been published  
elsewhere in any language.  
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Magureanu M, Piroi D, Mandache NB, David V, Medvedovici A,  
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Competing interests  
The authors declare that there is no conflict of interest that  
would prejudice the impartiality of this scientific work.  
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