Food Chemistry 289 (2019) 384–395

Contents lists available at ScienceDirect

Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem

Review

Experimental design in pesticide extraction methods: A review T

a,⁎ a b
S.T. Narenderan , S.N. Meyyanathan , Veera Venkata Satyanarayana Reddy Karri
a
Department of Pharmaceutical Analysis, JSS College of Pharmacy, Udhagamandalam, JSS Academy of Higher Education & Research, Tamil Nadu, India
b
Department of Pharmaceutics, JSS College of Pharmacy, Udhagamandalam, JSS Academy of Higher Education & Research, Tamil Nadu, India

A R T I C LE I N FO A B S T R A C T

Keywords: The sample extraction process is considered as the essential step in the pesticide residue analysis, as it provides
Extraction methods the base for the detection of the pesticides in trace level. Various factors need to be optimized during the
Pesticide residue extraction of pesticides due to the complexity of the matrix which is time-consuming and tedious. Therefore, the
Design of experiment use of experimental design in the optimization process proves to be effective with minimum experiments and
Screening designs
cost. This paper is aimed to overview the experimental designs that are frequently used for screening (full
Response surface methodology
factorial, fractional factorial, Plackett-Burman Design) and optimizing (central composite design, Box-Behnken design,
Optimization
Taguchi design, Doehlert design, D-optimal design) the most influential factors to provide a sequential under-
standing of the linear and complex interactions in the pesticide extraction methods. Further, a systematic ap-
proach has been discussed about the use of experimental designs in pesticide extraction and also the softwares
used for application-oriented readers.

1. Introduction
In recent years, there has been an emerging concern about the in-
creased occurrences of contaminants such as pesticides in food com-
modities (FAO, 2014). The presence of these detrimental substances in
food commodities has proven to be toxic to humans (Boobis et al., 2008;
Ntzani, Ntritsos, Chondrogiorgi, Evangelou, & Tzoulaki, 2013). There-
fore, several techniques are developed for the detection of pesticide
residue such as liquid-liquid extraction (LLE), solid-phase extraction
(SPE), solid phase microextraction (SPME), liquid-liquid microextrac-
tion (LLME), matrix solid-phase dispersion (MSPD) and QuEChERS
(quick, easy, cheap, effective, rugged and safe) extraction method
(Narenderan & Meyyanathan, 2018). Despite of the extraction method
followed, various factors need to be optimized to produce an efficient
method. However, the major drawbacks in the residual analysis is (i)
the optimization of the extraction method for complex matrices and (ii)
the low analyte levels to be quantified (Hajšlová & Zrostlıkova, 2003).
Further, the conventional strategies for optimizing extraction method
through univariate approach have some drawbacks such as provide
inefficient results as it gives only superficial system optimum. The
traditional method also ignores the interaction between various factors
during the extraction process and requires multiple runs unnecessarily
(Fernandes et al., 2012).
A multivariate technique is routinely applied to optimize the dif-
ferent working conditions in various extraction processes to improve
their performance. Experimental designs are found to be the most ef-
ficient method in identify and optimizing the significant factors to
achieve a competent result due to its advantages such as providing
precise information with a minimum number of experimental runs,
identifying the factor interactions and allowing multiple response

Abbreviations: ANOVA, analysis of variance; ASE, accelerated solvent extraction; BBD, Box-Behnken design; CCD, central composite design; DLLME, dispersive
liquid-liquid microextraction; DNSUAME, dispersive nano solid material-ultrasound assisted microextraction; DSLLME, dispersive solidification liquid-liquid mi-
croextraction; F-value, Fisher ratio; FrFD, fractional factorial design; FFD, full factorial design; GCB, graphitized carbon black; HS-SPME, headspace-solid phase
microextraction; IL, ionic liquid; LLE, liquid-liquid extraction; LLE-dSPE, liquid-liquid extraction-dispersive solid phase extraction; LLME, liquid-liquid micro-
extraction; MgSO4, magnesium sulphate; MIP-NPs, molecular imprinted polymer nano particle; MISPE, molecular imprinted solid-phase extraction; MSB, magnetic
solvent bar; MSPD, matrix solid-phase dispersion; NaCl, sodium chloride; OA, orthogonal array; OCPs, organochlorine pesticides; OPPs, organophosphate pesticides;
p-value, probability value; P-B design, Plackett-Burman design; PLE, pressurized liquid extraction; PSA, primary secondary amine; QuEChERS, quick easy cheap
effective rugged and safe; rpm, rotation per minute; RSD, relative standard deviation; RSM, response surface methodology; SBSE, stir bar sorptive extraction; SC-CO2,
supercritical-carbon dioxide; SDME, single-drop microextraction; SFE, super critical fluid extraction; SPE, solid-phase extraction; SPME, solid phase microextraction;
USA-TFME, ultrasound assisted-thin film microextraction; USL-SPE, ultrasound leaching-solid phase extraction; +, high level; −, low level; α, star point or axial
point
⁎
Corresponding author.
E-mail address: mail2narenderan@gmail.com (S.T. Narenderan).

https://doi.org/10.1016/j.foodchem.2019.03.045
Received 26 November 2018; Received in revised form 9 March 2019; Accepted 10 March 2019
Available online 12 March 2019
0308-8146/ © 2019 Elsevier Ltd. All rights reserved.
S.T. Narenderan, et al.
Fig. 1. Experimental design classification chart.
optimizations (Amirat, Ziani, & Messadi, 2016; dos Anjos & de Andrade,
2014). The significance of the multivariate technique has been show-
cased over the decade by numerous book chapters, reviews and
countless number of research papers describing their applications and
emphasizing its growth in the field of analytical chemistry. Recently,
Sahu et al. (2018) have overviewed the various strategies and its ap-
plication in the chromatographic separation. Similarly, Hibbert (2012)
has also demonstrated the performance of the experimental design in
the chromatographic techniques. Application of experimental design in
the context of environmental contaminant has been reviewed by Callao
(2014) and Mas, de Juan, Tauler, Olivieri, and Escandar (2010). Few
reviews have been studied towards the application of extraction method
such as super critical fluid extraction (SFE) (Sharif et al., 2014) and
microextraction (Abdulra'uf, Sirhan, & Tan, 2015) for the analysis of
bioactive compounds and pesticides, respectively. However, with an
increase in the importance of extraction methods in the field of pesti-
cide residue analysis, it becomes necessary to review the screening and
optimization designs on various methods of pesticide residue analysis.
Usually, the optimization of the extraction processes is done by a
two-step process (screening followed by optimization) (Fig. 1). Pri-
marily, the screening designs such as full factorial, fractional factorial
and Plackett-Burman design are used to identify the potential variables
form a small number of experiments. Central composite, Box-Behnken
and Taguchi designs are secondary approaches to identify the critical
levels of the most important factor obtained from a screening design.
Finally, the design to be chosen depends on the type and number of
variables to be studied, depending on the on the purpose of their use
and on the preferences of the analyst in the extraction process.
The objective of the present review is to summarize the applications
of experimental designs during screening and optimization of the ex-
traction process for pesticide residue analysis. Further, a systemic ap-
proach in employing an experimental design in the extraction of pes-
ticide residue is also been discussed.
2. System design
An experimental design is a trial set-up which evaluates several
factors (pH, temperature, time etc.) at a given number of levels in a
predefined number of experiments for the optimization of the extrac-
tion process. In the 1920s to 1930s Ronald A. Fisher invented design of
experiment to draw results from experiments with natural fluctuations
(temperature, rainfall and soil condition) to prevent systemic bias (Box,
1980). After the successful initiation in the agriculture sector, since the
1940′s the experimental design has been applied in military and in
385
Food Chemistry 289 (2019) 384–395
industries due to its emphasis on quality improvement.
Over an decade, experimental design has played a major role in the
application of analytical chemistry due its advantages to classical single
variable optimization, as it generates large amount of information from
a minimum number of experimental runs and the possibility to evaluate
the interaction effect between the variables on the response (Ebrahimi-
Najafabadi, Leardi, & Jalali-Heravi, 2014). In the experimental opti-
mization, the experimental design must be selected to suit an adequate
mathematical function. The quality and precision of fitted models
should be evaluated in order to accurately reflect the results obtained
from experiments.
2.1. Screening designs
A number of factors usually influence the extraction of the pesticide
residue from the matrices. Screening design is used to select the factor
which has the most significant effect for the optimization of the ex-
traction technique. Designs such as full factorial, fractional factorial
and Plackett-Burman are commonly employed were a large number of
variables are examined with a minimum number of experiments. These
screening methods are employed to improve the extraction of pesticide
residues from the complex matrices.
2.1.1. Full factorial design (FFD)
A two-level FFD (Fig. S1) (Supplementary file) is one of the com-
monly employed screenings for the investigation of the significant
parameters (de Souza Pinheiro & de Andrade, 2009). FFD can be de-
noted by 2 k where k is the number of factors studied. The factors are
studied in two levels high (+1) and low (−1), respectively (example
shown in Table 1). Geometrically with the increase in the number of
factors, there is an increase in the number of experiments.
Duodu, Goonetilleke, and Ayoko (2016) have optimized an extrac-
tion technique using accelerated solvent extraction (ASE) to extract
organochlorine pesticides (OCPs) from river sediments. The important
factors (number of cycles, adsorbent mass, temperature and solvent
ratio) were screened by a 24 factorial design before optimization of the
selected factors by response surface methodology. The screening data
obtained was evaluated using analysis of variance (ANOVA) at 95%
confidence level (assumptions: normality, constant variance and in-
dependence). The experimental results concluded that number of cycles
significantly increased recoveries of pesticides but increase in tem-
perature impacted on the recovery due to the degradation of pesticide
at high temperature. Further, solvent ratio and adsorbent mass were
much influenced in the recovery of the OCPs. El Atrache et al. (2013)
S.T. Narenderan, et al. Food Chemistry 289 (2019) 384–395

Table 1 vortexing and no significant effect (p = 0.05) was seen using salts or
A three factor comparison between factorial design (FD), central composite deep freezing in the partition step to improve migration of analytes
design (CCD) and Box-Behnken design (BBD). ‘+, −, 0 and α’ represents factors from aqueous to the organic phase. Further, C18 was significantly more
at different levels. effective than PSA in the clean-up step because the wheat samples
Runs FD CCD BBD consist of low-fat content and PSA is effective in removing fatty acids.
The authors could conclude that the most favourable condition for
Factors Factors Factors pesticide extraction at an agitation time of 9 min by ultrasound at 375
A B C A B C A B C
Watts, partitioning with salts {2 g sodium chloride (NaCl) and 4 g
magnesium sulphate (MgSO4)} and clean-up with 0.25 g C18 with 0.3 g
1 + + + + + + − − 0 MgSO4 with the model being significant (p < 0.05) for the factors and
2 + + − + + − + − 0 the interactions between them.
3 + − − + − − − + 0
4 − − + − − + + + 0
A study by Goulart et al. (2010) involves the use of a complete 23
5 − + + − + + − 0 − factorial design for the simultaneous evaluation of three factors: ex-
6 − + − − + − + 0 − traction time in the ultrasonic bath, salt concentration and the ratio
7 + − + + − + − 0 + between the water and solvent extractor volume were studied at two
8 − − − − − − + 0 +
levels. The results were evaluated using the extraction recovery per-
9 0 0 0 0 − −
10 0 0 0 0 + − centage. The developed method had a percentage recovery of the car-
11 0 0 0 0 − + bamate aldicarb, carbofuran and carbaryl at 90%, 95% and 96%, re-
12 0 0 0 0 + + spectively. The detection limit was from 5.0 to 10.0 µg/L. The model
13 0 0 0 0 0 0 was evaluated for t-test at 95% significance level with 8 repetitions
14 0 0 0 0 0 0
(n = 8) and the results showed a significant increase in the extraction
15 −α 0 0 0 0 0
16 +α 0 0 0 0 0 efficiency with increased ultrasonic bath time (5.3%) and salt con-
17 0 −α 0 0 0 0 centration (4.6%). The positive effect of salt concentration is due to the
18 0 +α 0 solvation of ions by water molecules which facilitate migration of
19 0 0 −α
analytes to the organic phase. Hence the factors, ultrasonic bath time of
20 0 0 +α
10 min, NaCl concentration of 1.5% (w/v) and sample: acetonitrile
ratio (1:2, v/v) were chosen as optimized parameters. A new single-
applied an FFD for the quantitative determination of carbamate pesti- drop microextraction (SDME) technique was used to determine the
cide in surface water by SPE technique. A two-level (24) full factorial organophosphate and pyrethroid pesticide. A 22 FFD was used to select
design was used for screening the factors which affected the extraction the important variable (pH and salt addition) (de Souza Pinheiro, da
procedure. Four factors (eluent volume, sample volume, adsorbent mass Rocha, & de Andrade, 2011). The results obtained from the Pareto chart
and adsorbent type) were studied in this experiment. The Pareto gra- (p = 0.05) conclude that the pH and salt effects were not significant at
phic analysis results showed that the efficiency of carbamate pesticides the 95% confidence level. Hence, the pH was maintained at 5.0 and no
from water sample was improved with the increase in the eluent vo- salts were added. The developed extraction method had a recovery
lume and sample volume, about 87.63% of the response is bridged by between 76.2 and 107 % in different water samples. The method
these two factors at a probability value 0.05 (p = 0.05). To increase the showed the detection limit ranging from 0.05 and 0.38 µg/L and
recovery of pesticides, it is worth working with high eluent volume and quantification limit ranging from 0.15 and 1.1 µg/L. Though the FFD
sample volume which has a significant effect on the extraction effi- has some advantage such as identifying the main interaction factors, the
ciency of pesticides. major drawback involves in the increase in the number of trials with
Another study by Facco et al. (2015) involves the use of FFD to increment in the number of factors geometrically.
optimized a multi-residue QuEChERS extraction method to determine
eight carbamate pesticides in maize. Agitation time, type of sorbent, 2.1.2. Fractional factorial design (FrFD)
freezing time and temperature rage were considered as the input vari- FrFD is another screening design which evaluates the effect of cer-
able, which were studied at two levels low and high. Factors were tain factors in minimum runs and relatively advantageous compared to
studied for the response of the compounds with extraction efficiency in the full factorial design as it requires a large number of runs (Rodrigues
the range of 70–120%. The results from the Pareto chart concluded that et al., 2011; Silva, Simão, Dias, Carletto, & Carasek, 2015). A graphical
the factors: agitation time, cooling time and temperature had no sig- representation of FrFD is shown in Fig. S2 (Supplementary file). To
nificant effect (p = 0.05) on acceptable recovery. Despite, the interac- obtain the significant parameters for the extraction of pesticide from
tions between factors such as sorbent type and temperature had a sig- soil samples by ultrasound leaching-solid phase extraction (USL-SPE)
nificant negative effect. Similarly, the change from C18 (sorbent) to followed by dispersive solidification liquid-liquid microextraction
primary secondary amine (PSA) has a strong negative effect which was (DSLLME), Ahmadi et al. (2015) applied FrFD (26-2) before employing
due to the ability of C18 (to remove long chained fatty compounds and response surface methodology (RSM) based on central composite design
polar interferences) and PSA (to remove organic acid, lipids and fatty (CCD). Six factors: volume of extracting solvent, the volume of dis-
acids) in the extraction of compounds from maize. Finally, the most persant/eluting solvent, extraction time, salt concentration, the flow
favourable conditions adopted were: agitation time (1 h) and freezing rate of the sample, the volume of sample solution were considered in
time (12 h) at a temperature ranging from −10 to −20 °C. The method this study to determine the most significant factors. The results ob-
efficiency was improved in the clean-up step using the sorbents PSA tained were evaluated by ANOVA at 5% significance level and it was
(50 mg) and C18 (50 mg). observed that the factors, volume of dispersant/eluent solvent, volume
Similarly, Friedrich, Martins, Prestes, and Zanella (2016) used a of extraction solvent and flow rate of the sample showed statistical
factorial design in the development of multi-residue method for the significance (p = 0.05) which was further investigated using CCD. The
determination of forty-two multiclass pesticides in wheat involving other factors (extraction time, salt effect and breakthrough volume in
QuEChERS extraction methodology. The most influential factors such SPE) were not found to be significant (p > 0.05). Bordagaray, Garcia-
as agitation (ultrasound and vortexing), partitioning (deep freezing and Arrona, and Millán (2011) tried to find out the effects of various factors
salts) and cleanup (C18 and PSA) were evaluated. The results on the on SPME technique in triazole fungicide determination from juice
factor analysis described that ultrasound was much more effective than samples. The effect of six factors, namely extraction time, extraction
temperature, desorption time, desorption temperature, agitation and

386
S.T. Narenderan, et al.
fibre type were studied to determine the most influential factor by
fractional factorial design (26-2). The obtained data were evaluated by
ANOVA (Fisher ratio, F-test) and the major effect was evaluated by
Pareto chart at 95% significant level (p = 0.05). It was observed that
fibre type, extraction time and temperature were found significant from
Pareto chart analysis (p = 0.05).
Cavaliere, Monteleone, Naccarato, Sindona, and Tagarelli (2012)
performed a screening design using half-fractional factorial design (25-
1
) with sixteen runs to determine the influential factors for the recovery
of carbamate pesticides in water samples by SPME. Desorption tem-
perature (220–270 °C), extraction temperature (25–60 °C), extraction
time (15–45 min), pH (2–7) and NaCl addition (0–15%) were the stu-
died factors. The influence of each variable and the possible effects on
the response were studies by Pareto chart and the three factors, NaCl
addition, pH and extraction time were found to have a statistically
significant effect on the recovery efficiency (p = 0.05) and a CCD was
used to optimize the most significant factors. It was observed that,
extraction efficiency was much affected by the concentration of NaCl,
due to its ability to reduce the polar interferences. Similarly, Passeport
et al. (2010) investigated the influence of seven factors of SPME for
extracting sixteen pesticides from water samples by employing frac-
tional factorial screening design (27-3). Two levels were determined
(+1 and −1) for each factor: extraction temperature (25–65 °C), ex-
traction time (30–80 min), desorption time (5–15 min), desorption
temperature (200–270 °C), stirring speed 250–750 rotation per minute
(rpm), sample pH (acid-basic) and ionic strength through NaCl addi-
tion. ANOVA was used to determine the significance and interactions of
the factors. Student t-test and associated probability value (p-value)
were processed at 5% significance level (p < 0.05). The results con-
cluded that NaCl addition and extraction time had a significant effect
on the pesticide extraction efficiency. Despite the hydrophobic nature
of the pesticides, their affinity for the fibre was higher which may be
resulted due to the reduced movement of the least polar molecules
towards fibre. The increase in the ionic strength and the extraction time
had a significant positive effect which may be due to the molecules
diffusion into the solid phase.
Rodriguez, Villoslada, Moreno-Bondi, and Marazuela (2010) opti-
mized a pressurized liquid extraction (PLE) for the determination of
fluoroquinolone in infant foods. An FrFD was used to screen the sig-
nificance of four extraction parameters: solvent composition, tem-
perature, pressure and number of cycles. The most significant factors
identified by ANOVA analysis at 5% significant level were solvent
composition (acetonitrile-50 mM orthophosphoric acid, temperature
(°C) and pressure (psi). The solvent composition had a significant effect
on the extraction recovery of fluoroquinolone compared to the other
two significant factors as it may be due to the behaviour of fluor-
oquinolone as zwitterions at neutral pH. Hence, a higher level of or-
thophosphoric acid is required to enhance the solubility in cationic
form. Further, extraction temperature and pressure facilitates disrupt of
analyte-matrix interaction to increase the extraction efficiency. Though,
the FrFD requires fewer runs, the major drawback is the lack of factor
interactions, where no measurement of errors is possible in this design.
2.1.3. Plackett-Burman (P-B) design
In 1946, a screening design was developed by statistician R.L.
Planket and J.P. Burman that gives information on the single factor and
not on the interactions (Plackett & Burman, 1946). A P-B design is a
two-level fractional factorial design for examining N−1 factors, where
N is a multiple of 4. Despite its drawback, such as not considering any
two-factor interaction effect, Plackett-Burman design is most popular
because it is both economical and efficient (Abdulra'uf & Tan, 2015).
Abdulra'uf and Tan (2014) employed P-B design (27-4) to determine
the significance of the factors affecting the SPME of the pesticides. The
effect of seven factors was screened namely, extraction temperature,
extraction time, desorption temperature, desorption time, salt addition,
pH and stirring rate. The CCD was used for the optimization of the
387
Food Chemistry 289 (2019) 384–395
selected variables. The data obtained were analyzed by ANOVA and the
main significant factors were evaluated by F-test and Pareto chart
analysis (graphical). The significant factors (pH, extraction time and
temperature) were selected based on the significance value (p = 0.05)
with a confidence level of 95%. Extraction temperature and time were
observed to show a positive effect due to the disruption of analyte-
matrix interaction, while the pH showed a negative effect. Another
study by Fang et al. (2017) involves the optimization of liquid-liquid
extraction combined with dispersive solid phase extraction (LLE-dSPE)
involving P-B design for the determination of twelve pesticides in the
blended oil sample. P-B design was used to confirm the critical factors
by less experimental frequency. PSA addition, vortexing time, solvent
type, extraction centrifugal temperature, extraction centrifugal time,
extraction centrifugal rate, purification centrifugal temperature, pur-
ification centrifugal rate, purification centrifugal time, C18 addition
and graphitized carbon black (GCB) addition were screened for se-
lecting the significant parameters. The average recovery rate was con-
sidered to select the significant factor for optimization. It was observed
from the Pareto chart (p = 0.05), that the type of solvent used had the
most significant impact on extraction efficiency. The use of acetonitrile
had better extraction efficiency than acidified (1% acetic acid) acet-
onitrile. Though, higher vortexing time would result in abstraction of
impurities in the matrix and decreased recovery, increased vortexing
time had a secondary effect with increased extraction efficiency. Fur-
ther, the next most significant factor PSA and GCB were optimized by
CCD.
Khodadoust, Ghaedi, and Hadjmohammadi (2013) applied a P-B
design (27-4) to investigate the screening of dispersive nano solid ma-
terial-ultrasound assisted microextraction (DNSUAME) of bendiocarb
and promecarb from different water samples. The factors such as ad-
sorbent (NiZnS-AC), pH of the sample, ionic strength, vortexing time,
ultrasonic time, ultrasonic temperature, desorption volume were stu-
died in eight runs with two central points. The obtained polynomial
equation was determined for its significance by F-test at 95% sig-
nificance and a p-value less than 0.05 were considered. The results
concluded that extraction efficiency increased with increased ad-
sorbent, vortexing and extraction time. Finally, the obtained significant
variable (adsorbent amount, vortexing time and ultrasonic time) on the
efficiency of extraction procedure were optimized by CCD.
S. Li, Liu, Dong, Xu, Xu, Hu, et al. (2016) reported the determination
of thiacloprid, spirotetramat and spirotetramats four metabolites using
the QuEChERS method to quantify the pesticides in pepper. A P-B de-
sign was operated on fifteen experimental runs (12 + 3 centre points)
to eliminate the effect of extraneous variables. In this case, five factors:
ratio of extraction solution, sodium chloride amount, PSA amount, C18
amount, GCB amount was studied. The obtained results were studied by
ANOVA (t-test at 95% confidence level) and represented in Pareto chart
(p = 0.05) in which the factors: the ratio of extracting solvent (formic
acid %), amount of PSA and NaCl showed a significant effect on the
extraction efficiency. Finally, a CCD was used to optimize the screened
significant factors. Rai et al. (2016) investigated the QuEChERS pro-
cedure combined with dispersive liquid-liquid microextraction
(DLLME) for the quantitative determination of thirty-six multiclass
pesticides in different fruits and vegetables. P-B design evaluated the
main factors which had a significant effect on the extraction efficiency
with less number of experiments. Seven factors were studied namely,
the quantity of anhydrous MgSO4, NaCl, pH, the volume of extraction
solvent, disperser solvent, disperser medium and sonication time were
studied. ANOVA with 95% confidence level was used to evaluate the
results and the effect of variables in the screening effect was expressed
in Pareto chart (p = 0.05). The design was carried out prior to CCD in
which the significant factors (salt addition, volume of disperser solvent
and medium) were optimized. The design requires eight runs with three
replicates in order to reduce the experimental error.
Another study by Yang et al. (2016) involves the use of P-B design to
screen the factors affecting the extraction efficiency in DLLME
S.T. Narenderan, et al.
procedure and further optimized by CCD in the extraction of fungicide
from the water. The experimental design includes twelve runs with
three replicates to nullify the effect of nuisance variables. Initially, the
volume of ionic liquid (IL), amount of sorbent, desorption time, volume
of elution and extraction time were screened and factors like extraction
solvent, amount of sorbent and desorption time were optimized as they
produced a positive effect on recoveries. The extraction solvent and
amount of sorbent had the significant effect on extraction recoveries
which may be because, the pesticide extraction takes place only with an
adequate volume of IL and a suitable amount of adsorbent, as it can
make complete contact with the extraction solvent. The analytes se-
parated from the magnetic nanoparticle exerts a strong effect on the
extraction, which is due to the surface-area dependent procedure,
where sufficient desorption time is advantageous. The model was stu-
died based on the bar length in Pareto chart (p = 0.05) at 95% con-
fidence level.
Similarly, Zhang et al. (2012) applied P-B design to identify the
factors having a significant effect on the extraction efficiency using
DLLME method. Five factors namely, amount of (C6MIM)Cl, ultrasound
time, centrifugation time, molar ratio of (C6MIM)Cl and LiNf2 and ionic
strength were studied. To determine the main effects, ANOVA (t-test)
was used at 95% significance and the Pareto chart was used to stan-
dardize the P-B design where 5% significant level (p < 0.05) were
considered to have a greater effect on recoveries. The quantity of
[C6MIM]Cl, ultrasound time and centrifugation time provided the best
extraction results. It was observed that the quantity of [C6MIM]Cl was
found to be the most significant factor but high quantities of
[C6MIM]Cl affected the extraction efficiency, which might be due to
the formation of [C6MIM]NTf2 after the in-situ metathesis reaction
(settlement at the bottom of the tube). Further, sufficient ultrasound
time increased the extraction efficiency through the formation of the
fine dispersive mixture and also with increased centrifugation time the
sedimentation phase was achieved by breaking of the cloudy solution in
turn to achieve high recovery.
2.2. Response surface designs
Optimization is a secondary practice in experimental design that
establishes the optimal conditions or settings of an experiment. The
significant factors identified by the screening design will be further
subjected for optimization in the extraction process based on its ex-
traction efficiency (Fig. 2). The response surface design is further ca-
tegorized into two type’s symmetrical design and asymmetrical design.
The symmetrical design covers the domain in centre point to estimate
experimental errors {central composite design (CCD), Box-Behnken
Fig. 2. Common factors optimized in extraction process through experimental
design.
388
Food Chemistry 289 (2019) 384–395
design (BBD), Doehlert design and Taguchi design}, whereas D-optimal
design forms an asymmetrical shape when the asymmetrical experi-
mental domain is examined. Table 1 describes the three-factor com-
parison between factorial design, central composite design and Box-
Behnken design with three levels designated as ‘+’, ‘−’, ‘0’ and the star
point ‘α’ in CCD. The use of these optimization designs in the extraction
of pesticide residue is summarized in Table 2.
2.2.1. Central composite design (CCD)
Central composite design (CCD) was developed by Box and Wilson
which combines a two-level factorial design with a star design and
centre points (G. Box & Wilson, 1951). The major advantage of CCD
over factorial design is that it provides similar results with a short
number of experiments. The experimental number of CCD is as per
k2 + 2 k + Cp where Cp is the replicate number of centre points and k is
the factor number. An example of CCD is shown in Fig. S3
(Supplementary file). CCD has been connected broadly within the op-
timization process of an extraction step in pesticide determination to
decide the ideal condition of the experimental parameters (Asensio-
Ramos, Hernández-Borges, Borges-Miquel, & Rodríguez-Delgado, 2011;
Fang, Lau, Law, & Li, 2012; Farajzadeh, Bahram, Jafary, & Bamorowat,
2011; Frenich, Romero-González, Vidal, Ocaña, & Feria, 2011; Garbi,
Sakkas, Fiamegos, Stalikas, & Albanis, 2010; Georgakopoulos et al.,
2011; Heidari & Razmi, 2012; Hosseini et al., 2013; Jovanov et al.,
2013; Kujawski, Pinteaux, & Namieśnik, 2012; Li et al., 2017; Li et al.,
2016; Martins, Donato, Prestes, Adaime, & Zanella, 2013; Melo, Aguiar,
Mansilha, Pinho, & Ferreira, 2012).
Bazrafshan, Ghaedi, Rafiee, Hajati, and Ostovan (2017) reported a
selective ultrasound-assisted microextraction method to determine
carbaryl from water samples in different conditions. A screening (P-B)
design was applied to screen the significance of six variables (adsorbent
amount, ultrasonic time, eluent volume, pH of the sample, ultrasonic
temperature and vortexing time). Adsorbent dosage and ultra-sonica-
tion time were found to be the significant factors which were optimized
using CCD. As the amount of sorbent increases the number of active
sites of nano-sized molecular-imprinted polymer (MIP-NPs) for selec-
tive adsorption of carbaryl increases. The increase in the ultrasonication
time enhances the dispersion of MIP-NPs in solvent and in turn, facil-
itates the accessibility of carbaryl to active sites of the adsorbent which
subsequently causes in the increased extraction efficiency. Further, the
F value of 21.05 (95% confidence level) and p-value of 0.0146 (< 0.05)
implies the significance of the model and the desirability procedure was
applied to optimize the factors, sorbent mass (9.42 mg), pH (3.56) and
sonication time (6.75 min) which produced a maximum response of
97.5%.
In 2017, Farina, Abdullah, Bibi, and Khalik (2017) used CCD to
determine the optimum conditions for the extraction of pesticide re-
sidue from leafy vegetables. Four parameters namely, sample amount,
solvent volume, NaCl and MgSO4 amount were evaluate based on the
significance of extraction efficiency. ANOVA was used to obtain the
optimum extraction condition by evaluating the relation between re-
sponse and the significant variables (95% confidence level). Sample
amount and NaCl amount were used at five levels to identify the op-
timal values. The sample amount (10 g) and NaCl amount (12 g) had a
significant effect (p < 0.05) on the peak area during the extraction
process due to the NaCl amount which enhanced the efficiency of ex-
traction in phase separation by acetonitrile and it is necessary to
monitor the addition of salts to control water in the organic phase
(Anastassiades, Lehotay, Štajnbaher, & Schenck, 2003).
Recently, Heravizadeh, Khadem, Nabizadeh, and Shahtaheri (2018)
tried to find out the effects of various parameters on molecular im-
printed solid-phase extraction (MISPE) of pesticide residue from urine
samples. MISPE adsorption phase (sample pH, sorbent mass and sample
flow rate) and desorption phase (elution solvent volume, amount of
acid in elusion solvent and elution flow rate) were optimized with CCD
with nine central and six axial points. Finally, based on the regression
 S.T. Narenderan, et al.

Table 2
Summarization of optimization designs used in the extraction of pesticide residue.
Design Analyte(s)a Factors optimized Extraction method LODs Reference
usedb

CCD Multiclass pesticide (05) Four factors: Sample pH (5.20); NaCl percentage (30%); volume of methanol (418 µL); amount of ionic Liquid IL-DLLME 0.02–27.07 ng/g Asensio-Ramos et al. (2011)
(117.5 mg)
CCD Multiclass pesticide (08) Five factors: Temperature (102 °C); time (20 min); extraction solvent (4.56 mL); pH (12); organic solvent (0.1%) MAE/SPE 0.12–2.53 µg/kg Fang et al. (2012)
CCD Triazole pesticides (06) Six factors: Extraction time (20–30 min); chloroform volume (20 µL); methanol volume (1–1.5 µL); DLLME 0.11–1.04 µg/L Farajzadeh et al. (2011)
centrifugation time (5 min); centrifugation rate (5000–6000 rpm); salt amount (30%, w/v)
CCD Multiclass pesticide (77) Two factors: Extracting time (60 min); extracting temperature (70 °C) SPME 0.1–47.1 ng/L Frenich et al. (2011)
CCD Multiclass pesticide (06) Two factors: Extraction time (11.5 min); drop depth (0.65 cm) SDME 0.003–0.045 µg/L Garbi et al. (2010)
CCD OPPs (04) Two factors: Fortification level (0.04 mg/kg); C18 sorbent amount (271 mg) QuEChERS Not stated Georgakopoulos et al. (2011)
CCD OPPs (04) Four factors: Solution pH (9.16); ionic strength (10 mmol/L); adsorbent (97.4 mg); equilibrium time (0 min) MSPE 4.3–47.4 pg/mL Heidari and Razmi (2012)
CCD OCPs (06) Four factors: Time (5 min); salt concentration (1.55 mol/L); ethanol volume (2.5 mL); 1-decanol volume LLME 1.4–7.0 µg/L Hosseini et al. (2013
(150 µL)
CCD Neonicotinoid insecticide Two factors: Extraction solvent (2.0 mL); dispersive solvent acetonitrile (0.5 mL) DLLME 0.5–1.0 µg/kg Jovanov et al. (2013)

389
(07)
CCD OCPs (11) Two factors: Extracting solvent (100 µL) DLLME Not stated Kujawski et al. (2012)
CCD Multiclass pesticide (72) Two factors: pH of sample (3.0); eluent methanol/methylene chloride (10:90, v/v) SPE 0.01–0.25 µg/L Martins et al. (2013)
CCD Multiclass pesticide (10) Three factors: pH (8.0), NaCl percentage (17.6%); extraction time (30 min) SPME 0.37–1.54 mg/kg Melo et al. (2012)
BBD OCPs (16) Three factors: Solvent composition (1:1, v/v); dispersant ratio (4:1, w/w); dispersant composition (10% silica) MSPD 0.1–1.8 ng/g Salemi et al. (2012)
BBD Benzimidazole fungicides Three factors: Solvent pH (4.0); sample pH (7.0); solvent volume (2 mL) SA-LLE 0.14–0.38 ng/mL Wen et al. (2013)
(04)
Taguchi design diazinon Five factors: Temperature (55 °C) LLE Not stated Rasoulifard et al. (2015)
Doehlert matrix Carbamates (08) Three factors: Eluent volume (5.5 mL); sample volume (143.5 mL); adsorbent mass (200 mg) SPE 0.1–0.5 µg/L El Atrache et al. (2013)
D-optimal Dichlobenil Seven factors: First vortex mixing (2 min); first centrifugation time (10 min); first rotational speed (3000 rpm); QuEChERS 1.55–5.0 µg/kg Herrero et al. (2014)
second vortex mixing (30 s); second centrifugation time (1 min); evaporation temperature (50 °C); evaporation
time (10 min);

a
OCPs, organochlorine pesticides; OPPs, organophosphorus pesticides.
b
QuEChERS, quick, easy, cheap, effective, rugged and safe; LLE, liquid-liquid extraction; MSPE, matrix solid phase extraction; LLME, liquid-liquid microextraction; MSPD, matrix solid-phase dispersion; SA, salting-out
assisted.
Food Chemistry 289 (2019) 384–395
S.T. Narenderan, et al.
model (p < 0.05) the optimum conditions were determined as follows:
sorbent mass (25 mg), sample pH (6.19), flow rate (2.15 mL/min),
solvent volume (methanol-acetic acid {92.7: 7: 3, v/v}) and flow rate of
2.1 mL/min. Jia, Chu, Ling, Huang, and Chang (2014) used QuEChERS
in different conditions for the extraction of pesticide residue in baby
food. CCD was used for the optimization of the experimental para-
meters (volume of extraction solvent, amount of sodium acetate, acet-
onitrile content in the mixture solvent). The obtained model was well
fitted and the regression was statistically significant at the 99% con-
fidence level (p < 0.05). The author concludes that the amount of
water content was crucial in order to achieve an acceptable recovery
rate without losing the analytes that are unstable in water and it was
observed that sodium acetate has a dissolving effect which could in-
terfere in the extraction efficiency. Hence, the best condition was using
10 mL acetonitrile-water (84:16, v/v) mixture with 1.45 g of sodium
acetate. The recoveries obtained were in the range from 79.8 to
110.7%.
In continuation, Jia, Chu, and Zhang (2015) in 2015 applied CCD as
an optimization procedure for the extraction of pesticides from nu-
traceuticals products obtained from green tea. In preliminary, an FrFD
was performed with the variables namely, extraction time, water con-
tent in the mixture solvent, extraction solvent volume, ionic strength
and pH. Based on the individual recoveries of the analytes three sig-
nificant factors were considered (extraction solvent volume, pH and
water content) for optimization using CCD. Hence, the ideal extraction
condition was 5 mL volume of acetonitrile-water solution (84:16, v/v)
mixture with 1% acetic acid and 0.30 g of sodium acetate anhydrous at
pH 5.0. The regression model was found to be statistically significant at
99.24% confidence level (p < 0.05). Kemmerich et al. (2015) used
CCD to optimize the different influential factors in buffered QuEChERS
extraction method. Four factors (NaCl, Chromosorb W-HP amount, PSA
amount and Oasis amount) were selected and studied under twenty-
seven experimental runs based on the cost analysis, the range of sorp-
tion and efficient results. Further, the amount of NaCl and PSA were
studied using CCD considering the compounds with recovery ranging
from 70 to 120% and relative standard deviation (RSD) below 20%. The
authors conclude that the optimal conditions (p = 0.05) were obtained
with a maximum amount of PSA due to the removal of major lipid and
fatty acid content and intermediate quantity of NaCl was used to avoid
a decrease in the recovery of the analyte of interest, by preventing
excessive extraction of polar co-extractives. S. Li, Liu, Zhu, Dong, Xu, Li
et al. (2014) applied QuEChERS for the extraction of fluxapyroxad and
its three metabolites in soils. A P-B design was used to screen the sig-
nificant factors (acetic acid percentage, water volume, extraction time,
PSA amount, C18 amount and GCB amount). ANOVA was performed to
study the main effects by t-test at 95% significance. After which the
significant (p < 0.05) three factors (acetic acid percentage, water vo-
lume and PSA amount) were studied using the CCD to evaluate the
optimal working condition for the QuEChERS procedure. The obtained
data were accessed by ANOVA and the results indicate the significance
with p < 0.05 and the lack of fit being not significant (p > 0.05) in-
dicating the model fitted the response. The results for the optimum
working condition were (1.2% acetic acid, 4.2 mL water and 0 mg PSA)
reported with the use of Derringers desirability function.
Similarly, a CCD response surface methodology was used for the
optimization of the QuEChERS method for the estimation of five dif-
ferent post-harvest pesticides in fruits and vegetables. Initially, a P-B
design was used to screen the significant factor in which the PSA
amount and C18 amount had no significant effect on the extraction
efficiency and were eliminated from further studies. Three factors (GCB
amount, the percentage of toluene, and hydrochloric acid) had the most
significant on extraction yield at about 95% confidence level
(p < 0.05), which was optimized by CCD. The regression analysis in-
dicated that the quadratic model was statistically significant with
p < 0.05 and the lack of fit being non-significant (p > 0.05). It was
observed that the analytes detected had a major effect on the extraction
390
Food Chemistry 289 (2019) 384–395
efficiency with respect to pH and solubility. As the compounds were
highly acidic it was important to maintain the pH of the extraction
solvent to increase the extraction efficiency and further addition of
toluene enhanced the recovery of the analytes, both polar and non-
polar. The maximum recoveries of the analyte were obtained at the
following conditions: 0 mg GCB and extraction solvent of 1:1 acetoni-
trile-toluene (v/v) containing 0.25% hydrochloric acid (M. Li, Dai,
Wang, Kong, He, Huang, et al., 2017). Souza-Silva and Pawliszyn
(2015) employed CCD to determine the optimal conditions of SPME of
multi-residue pesticide from the grape. A screening design (P-B design)
was employed to select the most influential factor among the eight
factors (extraction time, sample temperature, incubation time, sodium
sulphate addition, isopropyl alcohol addition, sample dilution, stirring
rate and pH). ANOVA was used to evaluate the result and the results
were statistically significant with 95% confidence level (p < 0.05). The
four significant factors: dilution ratio, extraction temperature, extrac-
tion time and salt addition were optimized using CCD. The selected
factors had a direct impact on extraction efficiency with increase in
extraction time the recovery increased until a maximum was reached,
whereas increased in extraction temperature decreased the sample
viscosity and thereby caused increased analyte diffusion into the
medium. In addition, the use of salts modifies the ionic strength of the
medium and improves the recovery of polar analytes and pre-
dominantly the use of diluent (water) minimizes the effect of the matrix
and elevates the release of analytes from its matrix causing increased
extraction efficiency. The effect of these factors on the extraction of
pesticide residue was evaluated and a total of twenty-seven runs was
performed in this study. The extraction efficiency was improved when
the sample temperature was set at 55 °C with an addition of 1.2 g of
sodium sulphate and 4 mL of water as it improves the mass transfer. The
extraction time of 30 min represents good extraction efficiency and
improves the method sensitivity with a quantification limit of ≤ 10 ng/
g.
Zohrabi, Shamsipur, Hashemi, and Hashemi (2016) optimized the
parameters of liquid-phase microextraction that were affecting the ex-
traction yield of organophosphate pesticides (OPPs) from water samples
using CCD. Three independent factors (extraction solvent, extraction
time and amount of salt) were studied at five levels with four replicates.
The total peak area was considered as the dependent variable to opti-
mize the model. The significance of each factor was evaluated by
ANOVA and the regression coefficient p-value was lower was lower
than 0.0001 and Fisher ratio (F-value) of 251.70. The following con-
ditions were selected based on the CCD result: extraction solvent vo-
lume was maintained at 30 µL as the increase in solvent causes sample
dilution and a decrease in solvent cause sample manipulation. The
extraction time and salt addition were set at 5 min and 4 g, respectively.
The extraction time had played a crucial role in the pesticide recovery
as it influences the partition of the target analytes (donor and acceptor
phase) and similarly, the addition of salt has influenced the extraction
process by decreasing the solubility of analytes in the aqueous phase.
2.2.2. Box-Behnken design (BBD)
The Box-Behnken design was developed by Box and Behnken (G. E.
Box & Behnken, 1960). It has three levels and can be applied to issues
having three or more factors. This design requires 2 k (k−1) + Cp, here
k is factor numbers and Cp is the central point number (Fig. S4)
(Supplementary file). BBD was found to be an economical alternative as
CCD required more factor levels than BBD. BBD is employed to de-
termine the critical parameters for the optimization of the extraction
process in pesticide residue determination (Salemi, Shafiei, & Vosough,
2012; Wen et al., 2013). The efficiency of the experimental model is
determined by the number of coefficients in the estimated model di-
vided by the number of experiments (Ferreira et al., 2007). A com-
parison between BBD, CCD and Doehlert design in terms of coefficient
number and experimental number are shown in Table 3.
Assoumani, Margoum, Guillemain, and Coquery (2014) optimized
S.T. Narenderan, et al. Food Chemistry 289 (2019) 384–395

Table 3 extractant volume and extraction time for the extraction of multiple
Comparison between BBD, CCD and Doehlert design in terms of coefficient pesticides in celery at three levels by BBD. The designed was screened
number and experimental number {adapted from Ferreira, Bruns, Ferreira, for three levels low, medium and high and the results obtained were
Matos, David, Brandao, et al. (2007)}. found to be statistically significant (p = 0.05). It was observed that high
Factors (k) Number of Number of experiments (f) Efficiency (p/f) extraction solvent volume, long extraction time and moderate disperser
coefficient volume provided high recovery. The authors concluded that high ex-
(p) CCD Doehlert BBD CCD Doehlert BBD traction recovery was obtained with the optimized parameters of
design design
899.50 µL, extraction time of 1.62 min and with moderate disperser
2 6 9 7 – 0.67 0.86 – volume 101.78 µL.
3 10 15 13 13 0.67 0.77 0.77 A three-factor, three-level BBD design was optimized using in-
4 15 25 21 25 0.60 0.71 0.60 dependent variables namely, a number of the magnetic solvent bar
5 21 43 31 41 0.49 0.68 0.61
(MSB), extraction temperature and extraction time. The maximum ef-
6 28 77 43 61 0.36 0.65 0.46
7 36 143 57 85 0.25 0.63 0.42 fects of unexplained variability were observed due to the extraneous
8 45 273 73 113 0.16 0.62 0.40 factors. Accordingly, low, middle and high levels of each variable were
designated. The summary of the ANOVA results demonstrates that the
obtained results were highly significant (p < 0.05). Finally, the au-
the factors affecting the extraction efficiency of stir bar sorptive ex- thors conclude that with the number of MSB increased the response first
traction (SBSE) in freshwater samples. In this study, the authors used and then decreases which may be due to the increase in bars (does not
three experimental designs for the optimization of thermal desorption influence desorption rate). Extraction time is another important factor
of selected pesticides. Initially, an FrFD was employed for screening the where an increase in extraction time would achieve high extraction
factors (injection temperature, desorption flow, desorption temperature efficiency. However, too long extraction time causes loss of extraction
and desorption time) at two levels. Then the influential factors namely, solvent and decrease in extraction yield. Similarly, low extraction
desorption temperature, desorption flow and injector temperature were temperature causes less diffusion rate and high temperature causes the
optimized in order to reach maximum desorption of the analytes. The volatilization of extraction solvent. Hence, the optimal conditions were
study was carried out in three levels low (−1), medium (0) and high generated with an extraction time of 25 min using 6 number of MSB and
(+1) in twelve experiments. The first vector explained 77% of the total maintain the extraction temperature at 30 °C (Wu et al., 2015).
variance of the experimental results. Further, a third experimental de-
sign (BBD) was used to determine the best condition (concentration, 2.2.3. Taguchi design
decontamination temperature and decontamination time) for the Taguchi design was developed by Genichi Taguchi for studying
thermal decontamination of the SBSE stir bars after the desorption step. multiple factors with various factor levels based on the orthogonal
Finally, the following conditions were optimized for thermal deso- array (OA) (Fig. S5a) (Supplementary file). This design proposed three
rption: 300 °C during 10 min under helium flow of 75 mL/min, while steps (concept design, parameter design and tolerance design) to
maintaining the temperature of 60 °C in the injector and the optimized achieve a rugged optimization design (Taguchi, 1986). This design
condition for thermal decontamination were 300 °C for 50 min. proposes two different orthogonal designs (controlled and noise vari-
Bazhdanzadeh, Talebpour, Adib, and Aboul-Enein (2011) used SBSE able) to provide a list of samples proposed by Taguchi method (Fig.
for the extraction of chlorpromazine and trifluoerazine from human S5b) (Supplementary file).
serum. A screening design was used to screen the influential factors in Rasoulifard, Akrami, and Eskandarian (2015) determined the op-
the extraction method (sample volume, extraction time, temperature, timum condition on the diazinon removal by assessing the influential
stirring rate and pH) followed by a response surface methodology. The parameters (temperature, time, diazinon concentration persulfate con-
significance of the effects was evaluated by ANOVA at 95% confidence centration and UV irradiation intensity) using an L16 array. Based on
level (p = 0.05). Then, the significant parameters affecting the extrac- the ANOVA analysis the authors concluded that among the screened
tion (sample volume, time, temperature and pH) were evaluated at parameters, temperature (55 °C) was found to be the most influential
thirty-six runs including twelve replicates. In desorption step the factors factor as it contributes about 82.99% since increase in temperature
namely, solvent volume, time and temperature were studied. The re- lowers the activation energy and causes conversion of persulfate oxi-
sults conclude that the optimal procedure for extraction was found to be dant ions to sulfate radicals with higher degradation abilities for more
of 1 mL sample volume, extraction time of 24 min at 31 °C with a pH of effective removal. Bagheri et al. (2016) employed a Taguchi orthogonal
8.1. The best condition for desorption step includes 150 µL mobile array (OA16) design to optimize the significant factors affecting the
phase for 20 min at 50 °C. supercritical fluid extraction. The effect of five factors (temperature,
García-Rodríguez, Cela-Torrijos, Lorenzo-Ferreira, and Carro-Diaz pressure, static time, dynamic time, and modifier volume) at four-level
(2012) analyzed seventeen pesticide residues in seaweeds using MSPD. factorial design using sixteen experiments was studied. A statistical
The values were assigned at two levels to find the effect of dispersant- ANOVA was performed to determine the most significant factors by F-
sample (1.0–2.0; using 0.2 g of sample), florisil-GCB ratio (2.0–9.0; test and it was found to be significant at 95% confidence level
using 0.4 g of GCB), ethyl acetate percentage (20–50%) and elution (p = 0.05). The results specify that the recovery was much influenced
volume (5–15 mL) were evaluated using a BBD. The design involves by pressure which is probably due to the increased supercritical carbon
twenty-seven experiments (including three centre points) which were dioxide (SC-CO2) density at high pressure and the recovery dropped
found to be statistically significant (p = 0.05). The authors conclude with high pressure as it reduced diffusion rate of the extraction material
that the optimum condition where high efficiency in extraction was and hence, the pressure was maintained at 280 bars. It was observed
obtained with dispersant-sample ratio of 4:1 and florisil-GCB ratio of that temperature and extraction time had an influence on the extraction
9:1 using 0.4 g of GCB as it improves the removal of interferences efficiency of the analytes by decreasing the density at constant pressure.
(pigments and polyphenols) along with the use of sodium sulphate for Further, to increase the extraction recovery a primary (static mode) and
its ability to remove traces of water molecule which might interfere secondary (dynamic mode) extraction steps were performed where
with the organic solvent during the extraction. A medium-high polarity static mode (10 min) enabled the penetration of fluid into the matrix
elution solvent (14 mL) hexane: ethyl acetate mixture containing a 40% and in dynamic mode (10 min) SC-CO2 was continuously passed to
ethyl acetate was used as it provided high extraction efficiency of the boost the analytes solubility. However, SC-CO2 solubility was major
analytes. depend on the modifier volume (methanol) as increased use of modifier
Wang et al. (2016) observed the influence of chloroform volume, volume attributes to new interactions of the solute with a modifier

391
S.T. Narenderan, et al.
which diminishes solute supercritical CO2 interaction. Hence, 100 µL of
modifier was used to increase the extraction efficiency.
Similarly, a Taguchi OA design was used for the optimization of the
accelerated solvent extraction (ASE) method for the estimation of
thirty-three OCPs and nine pyrethroid pesticides in Morinda officinalis.
L9 (34) OA was selected to study the three factors at three levels tem-
perature (50 °C, 80 °C, 100 °C), ratio of acetone to n-hexane (1:1, 1:4,
1:9) and amount of florisil (5 g, 8 g, 12 g). The factors selected were
found to be significant as the temperature limits the loss of volatile
compounds in ASE and the use of florisil preferentially removes the
matrix interferences and retains the polar analytes of Morinda officinalis
(Richter et al., 1996). The study was carried out by spiking the analytes
to be detected in negative Morinda officinalis and the output variable
was selected based on the influence associated with each factor. Finally,
the results conclude that the changes in the florisil and ratio of acetone
and n-hexane were more significant (12.21) than temperature (8.83).
The authors concluded that the optimum working conditions were
namely, ratio of acetone and n-hexane 1:1, amount of florisil 8 g and
temperature of 50 °C was selected as the minor factor from the ground
analysis (Liu et al., 2015).
Recently, Ayazi, Esfahlan, and Khoshhesab (2018) used OA design
to optimize the factors influencing the extraction efficiency of ultra-
sound-assisted thin film microextraction (USA-TFME) for the detection
of OPPs in aqueous samples. Five factors which affect the extraction of
USA-TFME were investigated namely, pH, salt content, extraction time,
volume of elusion solvent and desorption time. A four-level L16 (45) was
employed to study the five factors using sixteen experiments con-
sidering the peak area as a response. The experimental data were
evaluated using ANOVA in which the extraction time and pH value had
the highest F-value at a confidence level of 95%. It was observed that
pH can change the surface charge of sorbent and the charge of target
analytes, it would be preferable to use a sorbent in a neutral state which
would establish efficient interaction between analytes and nano-
composite surface. Further, based on the results from Taguchi design
the authors concluded the optimum conditions for the USA-TFME in-
volves the following parameters; pH (5.0), salt content (20% w/v),
extraction time (35 min), desorption time (20 min) and elusion solvent
(300 µL).
2.2.4. Other optimization designs
An alternative for the second-order models is the use of Doehlert
design (Doehlert, 1970) (Fig. S6) (Supplementary file). Doehlert design
requires fewer experiments, which is more efficient and offer ad-
vantages in relation to CCD and BBD (Table 3). Carro et al. (2012)
optimized the DLLME parameters for the extraction of multiclass pes-
ticides from water. The effect of three factors (extraction solvent vo-
lume, disperser volume and shaking time) was studied. The design in-
volves sixteen runs which were performed to prevent against the
lurking effect of variables and ANOVA of the quadratic regression
model indicated a high significance at 95% confidence level
(p < 0.05). The dispersant and extractant solvent had the most influ-
ence on the efficiency of extraction. The results obtained from the re-
sponse surface design revealed that an increase in the efficiency of
DLLME when medium to high levels of the three factors was used. Fi-
nally, the optimized condition involves the use of 178 µL of tri-
chloroethane (extraction solvent) and 1.9 mL of acetonitrile (dispersion
solvent) with manual shanking for 3 min. García-Chao et al. (2010)
applied Doehlert design to identify the effects of various parameters on
the SPE of insecticide residue in honey and pollen samples. The opti-
mization was carried out by optimizing two factors (methanol-water
ratio and dilution factor). The matrix dimension includes five-levels for
factor one and three-level for factor two. In total seven experiments
were carried out with two experiments additionally for the central
point. The results obtained were significant at a 99% confidence level
(p < 0.05) and the correlation coefficient was at higher than 0.99. The
dilution factor was not much influential than the methanol-water ratio
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Food Chemistry 289 (2019) 384–395
factor. The recoveries were higher for all the analytes with the fol-
lowing optimized parameters: methanol-water ratio (10:90, v/v) and
the dilution factor at 4.
García-Rodríguez, Carro-Díaz, Lorenzo-Ferreira, and Cela-Torrijos
(2010) investigated the influence of florisil and GCB adsorbents effect
in clean-up using the Doehlert design for the detection of pesticide
residue in edible seaweed. In order to completely remove all co-ex-
tracted pigments in a single step, GCB was evaluated as an in-cell clean-
up adsorbent. The studies were conducted at five-levels (florisil) and
three-levels (GCB), respectively. The authors concluded that the PLE
efficiency was increased with medium levels of GCB and low amount of
florisil in which the amount of florisil was the significant factor. To find
the best conditions a multi-criteria optimization approach, based on
desirability function was followed and the final condition resulted in
0.4 g of GCB and 1.6 g of florisil were the extracts were found to be
colourless with significant reduction on the background noise. Further,
a factorial design was opted to optimize the PLE conditions to achieve
better efficient extraction. Five factors were selected namely tempera-
ture, static extraction time, number of cycles, percentage solvent flush
and percent of n-hexane with ethyl acetate mixture were studied. The
results (percent recovery) were studied using ANOVA and all the ana-
lytes showed statistical significance at 95% confidence level. Based on
the delta weight plots the authors optimized a flush of 70 °C with one
cycle at a temperature of 100 °C for 2 min. The percentage of n-hexane
was optimized at 80% to have a clear extract as the polarity of the
solvent would affect the pigments and impurities. Merib, Nardini, and
Carasek (2014) used headspace-solid phase microextraction (HS-SPME)
in different conditions for the extraction of organochlorine pesticides
from bovine milk samples. To improve the extraction efficiency, opti-
mization was carried out using Doehlert design. The two most im-
portant factors in SPME methodology are extraction temperature and
time as increase in temperature the analytes can effectively dissociate
from the matrix and move into the head-space for rapid extraction but
as the temperature increases sample distribution decreases. Similarly,
suitable extraction time allows sufficient analytes to reach the extrac-
tion phase. Hence, these two factors: extraction temperature (40, 60
and 80 °C) and extraction time (10, 37, 65, 92 and 120 min) were
evaluated. The factor extraction time was studied at five levels due to
its wider interval than the extraction temperature (80 °C). The results
obtained from the response surface design optimized the extraction
temperature at 80 °C with an extraction time of 90 min due to the
samples total fat content, higher extraction time and temperature are
required to improve the HS-SPME sensitivity.
Another design which has gained attention over the years is the use
of D-optimal design. The D-optimal design is useful when the number of
experiment chosen is too large (Fig. S7) (Supplementary file). This
design requires a low number of experiments with the same precision of
the full design. Herrero, Reguera, Ortiz, and Sarabia (2014) applied a D-
optimal design for the optimization of the extraction of dichlobenil and
its metabolite from onions. Seven factors namely, time of first vor-
texing, time and the rotational speed of the first centrifugation, time of
the second vortexing, time of second centrifugation step, temperature
and time of evaporation were evaluated in this study. The results were
statistically evaluated using ANOVA which depicted the model fitted
significantly at 5% experimental response (p < 0.05) and the lack of fit
being non-significant (p > 0.05). The authors conclude that the fol-
lowing optimum conditions for the extraction and cleanup procedure as
they were significant: first vortex mixing (2 min), first centrifugation
time (10 min), first rotational speed (3000 rpm), second vortex mixing
(30 s), second centrifugation time (1 min), evaporation temperature
(50 °C) and evaporation time (10 min). El-Osmani et al. (2014) applied
a D-optimal design with the aim to optimize the parameters without
bias for the SPE method in the analysis of pesticide in water samples.
Five factors which has the possible effect on the extraction efficiency
were studied (sample flow rate, sample pH, elusion flow rate, ionic
strength, and nature of eluent) at thirty-four experimental runs. The
S.T. Narenderan, et al.
Table 4
Commonly employed software packages in experimental design {adapted from
Hibbert (2012)}.
Software Company and web link
Software specialized in experimental design
Design-Expert Stat-Ease Inc., www.statease.com/dx11.html
Fusion Pro S-Matrix Corporation, www.smatrix.com/fusion_pro.html
Modde Umetrics, https://umetrics.com/product/modde-pro
Unscrambler Camo AS, www.camo.com/p2_tuf.htm
DOE++ Reliasoft Corporation, https://www.reliasoft.com
DOE wisdom Launsby Consulting, www.launsby.com/BookIM.html
DOEpack Productivity-Quality Systems, Inc., www.pqsystems.com
Statistical software with experimental design compatibility
SPSS IBM, www.ibm.com
JMP SAS Institute Inc., sas.com/en_us/home.html
Minitab Minitab Inc., www.minitab.com/
STATISTICA StatSoft, www.statsoft.com/
Matlab The Mathworks Inc., www.mathworks.com/
Origin Microcal Software, www.originlab.com
Statgraphics Startpoint Technologies, www.statgraphics.com/
obtained results were accessed for ANOVA, squared and interaction
terms to test the significance of the method (p < 0.05). It was observed
that the maximum effect was seen with increase in the ionic strength
and elusion flow rate because as the ionic strength increases aqueous
samples leads to weakening of the interactions between un-dissociated
molecules in water (Font, Manes, Molto, & Pico, 1993) and with in-
creased flow rate desorption of target analytes was greater. Hence, the
authors finally concluded that the optimal parameters with increased
extraction efficiency were obtained with the following parameters:
sample flow rate (2–4 mL), pH (6.0), elusion flow rate (0.5 mL/min),
ionic strength (100 g/L), ethyl acetate-methanol (1:1, v/v).
3. Systematic approach of experimental designs in pesticide
extraction
Step i: Selection of appropriate experimental design for pesticide extraction
The process of experimental design is categorized into two phases
based on its use in pesticide extraction. Initially, the factors (selected
based on the extraction method) are screened to identify the influen-
cing factors on the extraction efficiency of pesticide and further opti-
mization of the significant factors in phase two. In the process of ex-
perimental design, it is essential to screening the factors prior to
optimization as it saves money and time. Usually, an FFD is opted when
the factor size is small but when the factor size increases (> 5) P-B
design or FrFD is used as it provides limited experimental runs equal to
the number of factors. The factors which provide the best results in the
extraction efficiency are taken for further optimization studies. In the
optimization, designs such as CCD, BBD, Taguchi, Doehlert and D-op-
timal are used. It is noted that CCD is among the popular design used
though, BBD, Doehlert (greater efficiency) and D-optimal (accessibility
of factor spacing) are quite better.
Step ii: Design matrix preparation (software) and data analysis
The second step in the study is the preparation of a design matrix
through experimental design software. A number of softwares are
commercially available in the market as summarized in Table 4. The
factors to be studied are loaded into the software where experimental
runs are obtained (design matrix) based on the number of factors and
responses required. It is essential to know the influence of the selected
factors such as extraction time, solvent pH, extraction temperature,
flow rate, salt addition, dispersant volume and sorbent addition in the
extraction efficiency prior to the analysis to have the easy processing of
data. After experimentation and providing the response values, the
393
Food Chemistry 289 (2019) 384–395
design matrix will provide the significance, lack of fit, coefficient, p-
value for the better understanding of results. If the investigators con-
sider the obtained model insufficient, a higher model can be used and
the model fitting for experimental design in the pesticide extraction
study can be processed through ANOVA. The model is acceptable with
significant regression and lack of fit being non-significant.
4. Conclusion
Monitoring of the pesticide residue in the food commodities has
increased due to its detrimental effect on humans. However, the de-
tection of these substances is highly tedious due to its matrix inter-
ferences and its low detection limit. Hence, the use of experimental
design and statistics has grown massively in the recent years as it
provides precise results in the extraction of pesticides residue with the
ability to estimate the effect of multiple parameters with few runs. The
various factors optimized during the extraction process are extraction
time, extraction solvent, pH, solvent volume, salt addition and type of
solvent, etc. Over the last decade, several experimental designs were
used in the extraction of pesticide, which was selected based on the
number of factors to be optimized. Among the screening and optimi-
zation designs, Plackett-Burman design and central composite design
was employed frequently in the optimization process. The results ob-
tained from the various experimental designs were studied on the basis
of extraction efficiency of the analyte of interest.
Experimental design can accurately assess all the factors in an ex-
traction process to that of traditional method (one-factor-at-a-time)
since it is economical and less tedious. Further, the implementation of
the experimental design in the chromatography, with the extension of
the extraction process will be additional valuable development in the
optimization of multi-residue detection methods. Nevertheless, in near
future, the experimental design will play a brilliant perspective in the
discipline of analytical chemistry.
Declaration of interests
None.
Acknowledgements
The author Mr. Narenderan.S.T would like to dedicate this work to
his parents and sister for their continuous encouragement and support.
The author thanks Drs. Y. Karthik & L. Navya for their support on the
revision of the article.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.foodchem.2019.03.045.
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