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Box-Behnken design: An alternative for the optimization of analytical

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 Analytica Chimica Acta 597 (2007) 179–186

Review

Box-Behnken design: An alternative for the optimization

of analytical methods
S.L.C. Ferreira a,∗ , R.E. Bruns b , H.S. Ferreira a , G.D. Matos a , J.M. David a ,
G.C. Brandão a , E.G.P. da Silva a , L.A. Portugal a , P.S. dos Reis c,a ,
A.S. Souza a , W.N.L. dos Santos c
a Universidade Federal da Bahia, Instituto de Quı́mica, Campus Universitário de Ondina, Salvador, Bahia 40170-290, Brazil
b Universidade Estadual de Campinas, Instituto de Quı́mica, Campinas, São Paulo 13084-971, Brazil
c Universidade Do Estado da Bahia, Rua Silveira Martins, 2555, Cabula, Salvador-Bahia 41.195.001, Brazil

Received 15 May 2007; received in revised form 1 July 2007; accepted 3 July 2007
Available online 23 July 2007

Abstract
The present paper describes fundamentals, advantages and limitations of the Box-Behnken design (BBD) for the optimization of analytical
methods. It establishes also a comparison between this design and composite central, three-level full factorial and Doehlert designs. A detailed
study on factors and responses involved during the optimization of analytical systems is also presented. Functions developed for calculation of
multiple responses are discussed, including the desirability function, which was proposed by Derringer and Suich in 1980. Concept and evaluation
of robustness of analytical methods are also discussed. Finally, descriptions of applications of this technique for optimization of analytical methods
are presented.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Box-Behnken design; Multivariate optimization; Experimental design; Analytical methods; Desirability function; Robustness

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
1.1. Application of multivariate techniques in analytical chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
1.2. Factors and responses in multivariate optimization techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
1.3. The robustness of analytical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
1.4. Box-Behnken design as a tool for multivariate optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2. Application of Box-Behnken designs (BBD) for optimization of analytical systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
2.1. Application of BBD for the optimization of the spectroanalytical method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
2.2. Application of BBD for the optimization of chromatographic methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
2.3. Application of BBD for the optimization of capillary electrophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
2.4. Application of BBD for the optimization of electroanalytical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
2.5. Application of BBD for the optimization of sorption process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
2.6. Other applications of BBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

∗ Corresponding author. Fax: +55 71 32355166.

E-mail address: slcf@ufba.br (S.L.C. Ferreira).

0003-2670/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.aca.2007.07.011
180 S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179–186
1. Introduction
1.1. Application of multivariate techniques in analytical
chemistry
In recent years, chemometric tools have been frequently
applied to the optimization of analytical methods, consider-
ing their advantages such as a reduction in the number of
experiments that need be executed resulting in lower reagent
consumption and considerably less laboratory work. Further-
more these methods allow the development of mathematical
models that permit assessment of the relevance as well as sta-
tistical significance of the factor effects being studied as well
as evaluate the interaction effects between the factors. If there
significant interaction effects between factors the optimal con-
ditions indicated by the univariate studies will be different from
the correct results of the multivariate optimization. The larger the
interaction effects the greater the difference that will be found
using univariate and multivariate optimization strategies. So the
univariate procedure may fail since the effect of one variable
can be dependent on the level of the others involved in the opti-
mization. That is why multivariate optimization schemes involve
designs for which the levels of all the variables are changed
simultaneously. The first step of multivariate optimization is
accomplished screening the factors studied (full factorial or frac-
tional factorial design) in order to obtain the significant effects of
the analytical system. After determining the significant factors,
the optimum operation conditions are attained by using more
complex experimental designs such as Doehlert matrix (DM),
central composite designs (CCD) and three-level designs such
as the Box-Behnken design (BBD) [1–3].
In analytical chemistry, multivariate techniques have been
applied to the optimization of chemical factors during the
development of analytical strategies involving pre-concentration
systems using solid phase extraction [4–10] cloud point
extraction [11–13], liquid–liquid extraction [14,15] and co-
precipitation [16]; procedures for sample digestion [17–20];
sampling systems [21]; chromatographic methods [22–28];
capillary electrophoresis [29] methods employing flow injec-
tion analysis [30,31] and sequential injection analysis [32–35];
electroanalytical methods [36–39] and thermogravimetry [40].
Other applications include the optimization of instrumental
parameters of equipment for analysis by graphite furnace atomic
absorption spectrometry (GF AAS) [41,42], inductively cou-
pled plasma optical emission spectrometry (ICP OES) [43,44]
and inductively coupled plasma mass spectrometry (ICP-MS)
[45]. Several review papers have been published on this subject
[46,47].
1.2. Factors and responses in multivariate optimization
techniques
During the multivariate optimization procedure, there are two
types of variables: the responses and the factors. The responses
are the dependent variables. Their values depend on the levels
of the factors, which can be classified as qualitative or quanti-
tative. In an optimization of a digestion process of lubricating
oil samples using focused-microwave assistance for determina-
tion of several metals employing ICP OES, the factors could be:
type of acid mixture (qualitative factor), amount of acid mix-
ture, power applied and digestion time (quantitative factors).
In the same study, several responses could be evaluated: (a)
residual acidity after digestion (this response is important con-
sidering the inconvenience of using very acidic solutions for
quantification using ICP OES); (b) residual carbon (this param-
eter reflects directly the efficiency of the mineralization process
of the organic matrix); (c) quantification of the metals using
ICP OES (this response can be evaluated by recoveries for each
metal and shows the efficiency of the digestion process, with-
out considering the residual acidity and residual carbon). If one
knows the natures of the relationships between the responses
and the factors, i.e. the response surfaces, the optimal values
of the factors can be determined. The optimization can be per-
formed in two ways. Response surfaces can be determined for
each response and these surfaces can be analyzed simultane-
ously. Or a model for a single composite function that takes into
account all three responses can be determined to obtain a sin-
gle response surface. The advantages of each approach are still
being investigated.
Another question that should be addressed is whether the
different responses suffer similar effects on changing the fac-
tor levels. During the optimization of an analytical procedure
involving a multielement technique (ICP OES, ICP-MS and
chromatography) generally the composite response will be resul-
tant of several single responses with similar effects. However,
the digestion process described for quantification of metals in
oil samples clearly exemplifies a situation where the individual
responses have different effects. This aspect should be consid-
ered during the establishment of an appropriate optimization
strategy.
An increasingly popular form for treating multiple responses
makes use of a desirability function D, which was proposed by
Derringer and Suich in 1980 [48]. Individual response surfaces
are determined for each response. Predicted values obtained
from each response surface are transformed to a dimension-
less scale di . The scale of the desirability function ranges
between d = 0 (for an unacceptable response value) and d = 1
(for a completely desirable one). D is calculated combining
the individual desirability values by applying the geometric
mean: D = (d1 × d2 × . . . dm )1/m . An algorithm is then applied
to the D function in order to determine the set of variable val-
ues that maximize it. This function has been frequently used
during the optimization of analytical systems, which involve
several responses. Garcia et al. optimized the chromatographic
conditions for the determination of eight hormones employ-
ing gas chromatography with mass spectrometry detection. A
desirability function was proposed for simultaneously optimiz-
ing the resolution and the peak width of the separation process
[49]. Another paper used a desirability function involving the
responses, size and coefficient of variation of the analyti-
cal signal, during the optimization of a flow injection system
with electrochemical detection for the determination of hydro-
quinone in cosmetics [50]. Candioti et al. proposed a method
for separation and determination of four active ingredients in
 S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179–186 181

pharmaceutical preparations employing capillary electrophore- ior is quite different and is described by a second principal
sis. They used a desirability function to simultaneously optimize component.
five responses: the three resolutions, the analysis time and the
capillary current [51]. Ortiz et al. reported the use of a desir- 1.3. The robustness of analytical methods
ability function to optimize instrumental responses obtained
in analysis involving electroanalytical methods. Two applica- In validation studies multivariate optimization techniques are
tions were discussed: (1) the simultaneous maximization of also used for determination of robustness, which is defined as
the peak current and minimization of its standard deviation the capacity of an analytical method to reproduce results when
for the determination of copper(II) by differential pulse anodic the procedure is performed under small changes in the nominal
stripping voltammetry; and (2) the simultaneous maximization values of the experimental factors established in the optimization
of the peak current and minimization of the blank signal for step [59,60,45,61–63].
the determinations of nickel(II) and indomethacin by adsorp-
tive stripping voltammetry. In all these cases, the experimental
1.4. Box-Behnken design as a tool for multivariate
conditions for which the optima are found for each individual
optimization
response are quite different so one is required to look for a com-
promise solution, that can be achieved using the desirability
Box-Behnken designs (BBD) [64] are a class of rotatable
function [52]. A method was developed for the determination
or nearly rotatable second-order designs based on three-level
of pesticide multiresidues by matrix solid-phase dispersion and
incomplete factorial designs. For three factors its graphical rep-
gas chromatography. The authors employed a desirability func-
resentation can be seen in two forms:
tion to optimize simultaneously pesticide recoveries and matrix
cleanup [53]. Concha-Herrera et al. [54] performed a chromato-
graphic separation procedure for the determination of proteic 1a. A cube that consists of the central point and the middle
primary amino acids. They used a desirability function involv- points of the edges, as can be observed in Fig. 1a.
ing resolution(s) between peaks (and) analysis time during the
optimization step of method. Simultaneous optimization of the
resolution and analysis time was achieved using Derringer’s
desirability function for a method proposed for the determina-
tion of of phenyl thiohydantoin amino acids employing micellar
liquid chromatography [55].
Other multi-response functions have been also proposed but
these are not based on the Derringer–Suich desirability function
[48]. These were established considering mainly the objective
of the analytical system being optimized. Then, during the opti-
mization step of an on-line pre-concentration system for the
determination of copper by flame atomic absorption spectrome-
try, Ferreira et al. proposed a multi-response function, involving
analytical signal (absorbance) and pre-concentration time. This
multi-response function was called “sensitivity efficiency” and
it has been defined as the analytical signal obtained for an on-
line enrichment system for a pre-concentration time of 1 min
[56]. This multi-response function was also used for the opti-
mization of an on-line pre-concentration system proposed for the
determination of lead using FAAS [57] and in another method
performed for selective extraction and determination of cat-
echol in water samples, using a polymeric sorbent based on
molecular imprinting technology with subsequent determina-
tion by differential pulse voltammetry. The sensitivity efficiency
was determined considering the electrochemical signal and the
pre-concentration time [37]. During the optimization of a pre-
concentration procedure using cloud point extraction for the
determination of six metal ions (cadmium, chromium, cop-
per, manganese, nickel and lead) employing ICP OES, another
multiple response function was found for obtaining of a simul-
taneous pre-concentration condition [58]. The behaviors of five
of these ions as a function of varying experimental condi-
tions are highly correlated and can all adequately be described
by a first principal component whereas the nickel ion behav- Fig. 1. (a) the cube for BBD and three interlocking 22 factorial design (b).
182 S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179–186

Table 1 is defined as the number of coefficients in the estimated model

Coded factor levels for a Box-Behnken design of a three-variable system divided by the number of experiments. Table 3 establishes a com-
Experiment x1 x2 x3 parison among the efficiencies of the BBD and other response
1 −1 −1 0
surface designs for the quadratic model. This Table demonstrates
2 1 −1 0 also that the three-level full factorial designs are costly when the
3 −1 1 0 factor number is higher than 2.
4 1 1 0 Another advantage of the BBD is that it does not contain
5 −1 0 −1 combinations for which all factors are simultaneously at their
6 1 0 −1
7 −1 0 1
highest or lowest levels. So these designs are useful in avoid-
8 1 0 1 ing experiments performed under extreme conditions, for which
9 0 −1 −1 unsatisfactory results might occur. Conversely, they are not indi-
10 0 1 −1 cated for situations in which we would like to know the responses
11 0 −1 1 at the extremes, that is, at the vertices of the cube.
12 0 1 1
C 0 0 0
BBD for four and five factors can be arranged in orthogonal
C 0 0 0 blocks, as shown in Table 2. In this table, each (±1, ±1) com-
C 0 0 0 bination within a row represents a full 22 design. Dashed lines
0 0 0 separate the different blocks. Because of block orthogonality, the
second-order model can be augmented to include block effects
without affecting the parameter estimates, that is, the effects
1b. A figure of three interlocking 22 factorial designs and a themselves are orthogonal to the block effects. This orthogonal
central point, as shown in Fig. 1b. blocking is a desirable property when the experiments have to
be arranged in blocks and the block effects are likely to be large.
The number of experiments (N) required for the development
of BBD is defined as N = 2k(k − 1) + C0 , (where k is number of 2. Application of Box-Behnken designs (BBD) for
factors and Co is the number of central points). For comparison, optimization of analytical systems
the number of experiments for a central composite design is
N = 2k + 2k + C0 . Tables 1 and 2 contain the coded values of the 2.1. Application of BBD for the optimization of the
factor levels for BBD on three, four and five factors, respectively. spectroanalytical method
A comparison between the BBD and other response surface
designs (central composite, Doehlert matrix and three-level full Korn and de Oliveira used BBD during the optimization of
factorial design) has demonstrated that the BBD and Doehlert a sequential injection analysis method proposed for the deter-
matrix are slightly more efficient than the central composite mination of sulphate in ethanol automotive fuel employing
design but much more efficient than the three-level full fac- molecular absorption spectrophotometry (MAS) [65]. Arau-
torial designs where the efficiency of one experimental design caria angustifolia (named pinhão) wastes were tested as solid

Table 2
Coded factor levels for Box-Behnken designs for optimizations involving four and five
factors
 S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179–186 183

Table 3
Comparison of efficiency of central composite design (CCD), Box-Behnken design (BBD) and Doehlert design (DM)
Factors (k) Number of coefficients (p) Number of experiments (f) Efficiency (p/f)

CCD DM BBD CCD DM BBD

2 6 9 7 – 0.67 0.86 –
3 10 15 13 13 0.67 0.77 0.77
4 15 25 21 25 0.60 0.71 0.60
5 21 43 31 41 0.49 0.68 0.61
6 28 77 43 61 0.36 0.65 0.46
7 36 143 57 85 0.25 0.63 0.42
8 45 273 73 113 0.16 0.62 0.40

phase for extraction of chromium VI. BBD was used for opti-
mization of the experimental factors [66]. Chemical factors of
a method proposed for the quantification of amikacin in phar-
maceutical formulations were optimized also using BBD [67].
Otero-Rey et al. used BBD for optimization of several experi-
mental parameters on arsenic and selenium leaching from coal
fly ash samples and their determination using hydride generation
coupled with atomic fluorescence spectrometry (HG AFS) [68].
Ferreira et al. proposed two on-line pre-concentration systems
for the determination of cadmium and lead in drinking water
by FAAS employing knotted reactor and 1-(2-pyridylazo)-2-
naphthol (PAN) as complexing reagent. In both methods, the
optimization step was performed using BBD [69,70]. Zougagh
et al. developed an on-line system for the pre-concentration and
determination of lead in water using ICP OES. The solid phase
extraction process was optimized using BBD [71]. Bosque-
Sendra et al. [72] described the advantages of the BBD as
response surface methodology for obtaining second order mod-
els in full detail. They used this design for re-optimization of
the pararosaniline classical method for the determination of
formaldehyde employing MAS. A comparison with the classical
method [73], which was optimized using a univariate strategy,
revealed that the re-optimized procedure using BBD has a sensi-
tivity almost twice as large as the univariate result. BBD was used
also for the optimization of the factors of a direct-current plasma
system. The factors involved were horizontal position, vertical
position, nebulizer pressure and electrode sleeve pressure. Three
responses (precision, drift and sensitivity) were evaluated. All
the optimization was carried out by quantification of the cop-
per signal. An evaluation of the performance of the equipment
using the optimized conditions was performed for six other ele-
ments [74]. Table 4 summarizes applications of BBD for the
optimization of chemical systems involving spectroanalytical
techniques.
2.2. Application of BBD for the optimization of
chromatographic methods
Carasek and coworkers optimized a microextraction pro-
cess for the determination of 2,4,6-trichloroanisole and
2,4,6-tribromoanisole in wine samples employing BBD [75].
Pyrzynska and coworkers used BBD for optimization of the
derivatization reaction established during the development of a
method proposed for the determination of aliphatic aldehydes by
HPLC [76]. BBD was used for optimization of a procedure using
microwave-assisted extraction proposed for the determination of
persistent organochlorine pesticides in sediment using GC–MS
[77]. McKenon and coworkers used BBD for optimization of
method involving supercritical fluid extraction for the determi-
nation of fatty acid composition of castor seeds using GC-FID
[78]. The separation process performed for the determination of
captopril in pharmaceutical tablets using HPLC was optimized
also using BBD [79]. Petz and coworkers proposed a CG–MS
method for the determination of aminoglycoside antibiotics.
BBD was used for the optimization of the derivatization reac-
tion [80]. Walters and Qiu employed BBD for the optimization
of the separation process of hydroxamates (arginine, leucine,
threonine, histidine and Tryptophan) using paper chromatogra-
phy [81]. Table 5 presents applications of BBD for optimization
of chromatographic methods.

Table 4
Application of BBD for the optimization of spectroanalytical methods
Analyte Sample Analytical technique Optimized parameters References

Sulphate Ethanol automotive fuel SIA/MAS Instrumental factors [65]

Chromium VI Water MAS Chemical factors [66]
Amikacin Pharmaceutical formulations Chemiluminescence Chemical factors [67]
Arsenic and selenium Coal fly ash HG AFS Chemical factors [68]
Cadmium Drinking water KR-FAAS Chemical factors [69]
Lead Drinking water KR-FAAS Chemical factors [70]
Lead Water SPE-ICP OES Chemical factors [71]
Formaldehyde – MAS Chemical factors [72]

Sequential injection analysis (SIA); molecular absorption spectrophotometry (MAS); knotted reactor (KR); hydride generation coupled with atomic fluorescence
spectrometry (HG AFS); solid phase extraction (SPE); inductively coupled plasma optical emission spectrometry (ICP OES).
184 S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179–186
Table 5
Application of BBD for the optimization of chromatographic methods
Analyte Sample Chromatographic technique
2-4-6 TCA, 2-4-6 TBA Wine GC-ECD
Aliphatic aldehydes – HPLC
Organochlorine pesticides Sediments GC–MS
Fatty acid composition Castor oil GC-FID
Captopril Pharmaceutical tablets HPLC
Aminoglycoside antibiotics – GC–MS
Aminoacids hydroxamates PC
2,4,6-trichloroanisole (2-4-6TCA); 2,4,6-tribromoanisole (2-4-6TBA); gas chromatography and electron-capture detection (GC-ECD); high performance liquid
chromatography (HPLC); gas chromatography–mass spectrometry (GC–MS); gas chromatography with flame ionisation detection GC-FID; paper chromatography
(PC).
2.3. Application of BBD for the optimization of capillary
electrophoresis
Gong and coworkers compared response surfaces based on
complementary three-level Box-Behnken, face-centered central
composite and full factorial designs during the optimization of
procedures employing capillary electrophoresis (CE) for the
determination of tamsulosin enantiomers [82] and also ascor-
bic acid and isoascorbic acid [83]. These authors concluded
that the optimizations using the three designs furnished similar
and efficient results. A procedure for neuropeptide separation
employing CE was optimized using BBD [84]. Ragonese et
al. performed a separation procedure for the determination of
ethambutol hydrochloride in pharmaceutical formulations using
CE. The optimization step was carried out using BBD [85].
Hows et al. proposed a method for separation and determina-
tion of sulphonamides, dihydrofolate reductase inhibitors and
beta-lactam antibiotics also employing CE. The experimental
factors were optimized using BBD [86].
2.4. Application of BBD for the optimization of
electroanalytical methods
BBD has not been used for the optimization of electro-
analytical methods. Only a procedure employing adsorption
stripping voltammetry for the determination of nalidxic acid and
7-hydroximethylanalidxic acid in urine samples was established
using this design [87].
2.5. Application of BBD for the optimization of sorption
process
Kannan et al. proposed the use of straw carbon for the
adsorption of the copper(II), cadmium(II) and nickel(II) metal
ions. The optimization step was carried out using BBD [88].
Madaria et al. applied carbon aerogel for electrolytic removal
of mercury from aqueous solutions. Experimental factors were
optimized employing BBD [89]. Activated carbon immobi-
lized with Pseudomonas putida was evaluated as solid phase
for extraction of phenol. The optimization step was performed
using BBD [90]. The optimization of the adsorption process of
Rhodamine 6G from water using both chitosan and activated
carbon was performed also using BBD [91]. BBD was used for
Optimized process References
Extraction step [75]
Derivatization reaction [76]
Extraction step [77]
Extraction step [78]
Separation step [79]
Derivatization reaction [80]
Separation step [81]
the optimization of the sorption process of verofix red using a
biopolymer [92].
2.6. Other applications of BBD
Matthews et al. used BBD for the optimization of an enzy-
matic procedure for the determination of arsenic in aqueous
solutions [93].
Silva and coworkers developed a study in order to detect
the most important factors that effect the formation of the four
trihalomethanes (THM) (chloroform, bromodichloromethane,
chlorodibromomethane and bromoform) in water disinfection
processes using chlorine. BBD was used during the optimization
step [94].
Petz and Lamar developed a receptor protein microplate
assay for the detection and determination of penicillins and
cephalosporins with intact beta-lactam in milk, bovine and
porcine muscle juice, honey and egg samples. The optimization
step was performed using BBD [95].
Wu and coworkers developed a photoelectrocatalytic oxida-
tion system using a Ti/TiO2 electrode for the degradation of
fulvic acid (FA). The optimization step was carried out using
BBD [96].
BBD was employed for the optimization of an electrochem-
ical process using reticulated vitreous carbon-supported-on-
polyaniline cathodes for the reduction of hexavalent chromium
of industrial wastewater samples [97].
Rajkumar et al. investigated the electrochemical oxidation
process of phenol using a Ti/TiO2 –RuO2 –IrO2 anode. The
experimental factors were optimized using BBD [98].
3. Conclusions
The Box-Behnken is a good design for response surface
methodology because it permits: (i) estimation of the param-
eters of the quadratic model; (ii) building of sequential designs;
(iii) detection of lack of fit of the model; and (iv) use of blocks.
A comparison between the Box-Behnken design and other
response surface designs (central composite, Doehlert matrix
and three-level full factorial design) has demonstrated that the
Box-Behnken design and Doehlert matrix are slightly more effi-
cient than the central composite design but much more efficient
than the three-level full factorial designs.
 S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179–186
The application of Box-Behnken designs for optimization of
analytical methods still is limited, but different applications of
these designs in the optimization of procedures involving several
analytical techniques are presented in this paper.
Acknowledgements
The authors are grateful for Conselho Nacional de Desen-
volvimento Cientı́fico e Tecnológico (CNPq), Coordenação de
Aperfeiçoamento de Pessoal do Ensino Superior (CAPES), and
Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB)
for financial support.
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