Analytica Chimica Acta 597 (2007) 179186

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. Brandao 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 Qumica, Campus Universita rio de Ondina, Salvador, Bahia 40170-290, Brazil
b Universidade Estadual de Campinas, Instituto de Qumica, Campinas, S
a o 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

Abstr act
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.

2.

3.

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

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

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S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179186

1. Intr oduction
1.1. Application of multivariate techniques in analytical
chemistry
In recent years, chemometric tools have been frequently
applied to the optimization of analytical methods, considering 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. Furthermore these methods allow the development of mathematical
models that permit assessment of the relevance as well as statistical signicance of the factor effects being studied as well
as evaluate the interaction effects between the factors. If there
signicant interaction effects between factors the optimal conditions 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 optimization. That is why multivariate optimization schemes involve
designs for which the levels of all the variables are changed
simultaneously. The rst step of multivariate optimization is
accomplished screening the factors studied (full factorial or fractional factorial design) in order to obtain the signicant effects of
the analytical system. After determining the signicant 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) [13].
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 [410] cloud point
extraction [1113], liquidliquid extraction [14,15] and coprecipitation [16]; procedures for sample digestion [1720];
sampling systems [21]; chromatographic methods [2228];
capillary electrophoresis [29] methods employing ow injection analysis [30,31] and sequential injection analysis [3235];
electroanalytical methods [3639] 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 coupled 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 classied as qualitative or quantitative. In an optimization of a digestion process of lubricating

oil samples using focused-microwave assistance for determination of several metals employing ICP OES, the factors could be:
type of acid mixture (qualitative factor), amount of acid mixture, 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 considering the inconvenience of using very acidic solutions for
quantication using ICP OES); (b) residual carbon (this parameter reects directly the efciency of the mineralization process
of the organic matrix); (c) quantication of the metals using
ICP OES (this response can be evaluated by recoveries for each
metal and shows the efciency of the digestion process, without 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 performed in two ways. Response surfaces can be determined for
each response and these surfaces can be analyzed simultaneously. Or a model for a single composite function that takes into
account all three responses can be determined to obtain a single 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 factor levels. During the optimization of an analytical procedure
involving a multielement technique (ICP OES, ICP-MS and
chromatography) generally the composite response will be resultant of several single responses with similar effects. However,
the digestion process described for quantication of metals in
oil samples clearly exemplies a situation where the individual
responses have different effects. This aspect should be considered 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 dimensionless 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 values 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 employing gas chromatography with mass spectrometry detection. A
desirability function was proposed for simultaneously optimizing the resolution and the peak width of the separation process
[49]. Another paper used a desirability function involving the
responses, size and coefcient of variation of the analytical signal, during the optimization of a ow injection system
with electrochemical detection for the determination of hydroquinone 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) 179186

pharmaceutical preparations employing capillary electrophoresis. They used a desirability function to simultaneously optimize
ve responses: the three resolutions, the analysis time and the
capillary current [51]. Ortiz et al. reported the use of a desirability function to optimize instrumental responses obtained
in analysis involving electroanalytical methods. Two applications were discussed: (1) the simultaneous maximization of
the peak current and minimization of its standard deviation
for the determination of copper(II) by differential pulse anodic
stripping voltammetry; and (2) the simultaneous maximization
of the peak current and minimization of the blank signal for
the determinations of nickel(II) and indomethacin by adsorptive stripping voltammetry. In all these cases, the experimental
conditions for which the optima are found for each individual
response are quite different so one is required to look for a compromise solution, that can be achieved using the desirability
function [52]. A method was developed for the determination
of pesticide multiresidues by matrix solid-phase dispersion and
gas chromatography. The authors employed a desirability function to optimize simultaneously pesticide recoveries and matrix
cleanup [53]. Concha-Herrera et al. [54] performed a chromatographic separation procedure for the determination of proteic
primary amino acids. They used a desirability function involving resolution(s) between peaks (and) analysis time during the
optimization step of method. Simultaneous optimization of the
resolution and analysis time was achieved using Derringers
desirability function for a method proposed for the determination 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 DerringerSuich desirability function
[48]. These were established considering mainly the objective
of the analytical system being optimized. Then, during the optimization step of an on-line pre-concentration system for the
determination of copper by ame atomic absorption spectrometry, Ferreira et al. proposed a multi-response function, involving
analytical signal (absorbance) and pre-concentration time. This
multi-response function was called sensitivity efciency and
it has been dened as the analytical signal obtained for an online enrichment system for a pre-concentration time of 1 min
[56]. This multi-response function was also used for the optimization 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 catechol in water samples, using a polymeric sorbent based on
molecular imprinting technology with subsequent determination by differential pulse voltammetry. The sensitivity efciency
was determined considering the electrochemical signal and the
pre-concentration time [37]. During the optimization of a preconcentration procedure using cloud point extraction for the
determination of six metal ions (cadmium, chromium, copper, manganese, nickel and lead) employing ICP OES, another
multiple response function was found for obtaining of a simultaneous pre-concentration condition [58]. The behaviors of ve
of these ions as a function of varying experimental conditions are highly correlated and can all adequately be described
by a rst principal component whereas the nickel ion behav-

181

ior is quite different and is described by a second principal

component.
1.3. The robustness of analytical methods
In validation studies multivariate optimization techniques are
also used for determination of robustness, which is dened as
the capacity of an analytical method to reproduce results when
the procedure is performed under small changes in the nominal
values of the experimental factors established in the optimization
step [59,60,45,6163].
1.4. Box-Behnken design as a tool for multivariate
optimization
Box-Behnken designs (BBD) [64] are a class of rotatable
or nearly rotatable second-order designs based on three-level
incomplete factorial designs. For three factors its graphical representation can be seen in two forms:
1a. A cube that consists of the central point and the middle
points of the edges, as can be observed in Fig. 1a.

Fig. 1. (a) the cube for BBD and three interlocking 22 factorial design (b).

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S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179186

Table 1
Coded factor levels for a Box-Behnken design of a three-variable system
Experiment

x1

x2

x3

1
2
3
4
5
6
7
8
9
10
11
12
C
C
C

1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0

1
1
1
1
0
0
0
0
1
1
1
1
0
0
0
0

0
0
0
0
1
1
1
1
1
1
1
1
0
0
0
0

1b. A gure of three interlocking 22 factorial designs and a

central point, as shown in Fig. 1b.
The number of experiments (N) required for the development
of BBD is dened as N = 2k(k 1) + C0 , (where k is number of
factors and Co is the number of central points). For comparison,
the number of experiments for a central composite design is
N = 2k + 2k + C0 . Tables 1 and 2 contain the coded values of the
factor levels for BBD on three, four and ve factors, respectively.
A comparison between the BBD and other response surface
designs (central composite, Doehlert matrix and three-level full
factorial design) has demonstrated that the BBD and Doehlert
matrix are slightly more efcient than the central composite
design but much more efcient than the three-level full factorial designs where the efciency of one experimental design

is dened as the number of coefcients in the estimated model

divided by the number of experiments. Table 3 establishes a comparison among the efciencies of the BBD and other response
surface designs for the quadratic model. This Table demonstrates
also that the three-level full factorial designs are costly when the
factor number is higher than 2.
Another advantage of the BBD is that it does not contain
combinations for which all factors are simultaneously at their
highest or lowest levels. So these designs are useful in avoiding experiments performed under extreme conditions, for which
unsatisfactory results might occur. Conversely, they are not indicated for situations in which we would like to know the responses
at the extremes, that is, at the vertices of the cube.
BBD for four and ve factors can be arranged in orthogonal
blocks, as shown in Table 2. In this table, each ( 1, 1) combination within a row represents a full 22 design. Dashed lines
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
themselves are orthogonal to the block effects. This orthogonal
blocking is a desirable property when the experiments have to
be arranged in blocks and the block effects are likely to be large.
2. Application of Box-Behnken designs (BBD) for
optimization of analytical systems
2.1. Application of BBD for the optimization of the
spectroanalytical method
Korn and de Oliveira used BBD during the optimization of
a sequential injection analysis method proposed for the determination of sulphate in ethanol automotive fuel employing
molecular absorption spectrophotometry (MAS) [65]. Araucaria angustifolia (named pinhao) wastes were tested as solid

Table 2
Coded factor levels for Box-Behnken designs for optimizations involving four and ve
factors

S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179186

183

Table 3
Comparison of efciency of central composite design (CCD), Box-Behnken design (BBD) and Doehlert design (DM)
Factors (k)

2
3
4
5
6
7
8

Number of coefcients (p)

6
10
15
21
28
36
45

Number of experiments (f)

Efciency (p/f)

CCD

DM

BBD

CCD

DM

BBD

9
15
25
43
77
143
273

7
13
21
31
43
57
73

13
25
41
61
85
113

0.67
0.67
0.60
0.49
0.36
0.25
0.16

0.86
0.77
0.71
0.68
0.65
0.63
0.62

0.77
0.60
0.61
0.46
0.42
0.40

phase for extraction of chromium VI. BBD was used for optimization of the experimental factors [66]. Chemical factors of
a method proposed for the quantication of amikacin in pharmaceutical formulations were optimized also using BBD [67].
Otero-Rey et al. used BBD for optimization of several experimental parameters on arsenic and selenium leaching from coal
y ash samples and their determination using hydride generation
coupled with atomic uorescence 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)-2naphthol (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]. BosqueSendra et al. [72] described the advantages of the BBD as
response surface methodology for obtaining second order models 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 sensitivity 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 quantication of the copper signal. An evaluation of the performance of the equipment

using the optimized conditions was performed for six other elements [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 process 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 GCMS
[77]. McKenon and coworkers used BBD for optimization of
method involving supercritical uid extraction for the determination 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 CGMS
method for the determination of aminoglycoside antibiotics.
BBD was used for the optimization of the derivatization reaction [80]. Walters and Qiu employed BBD for the optimization
of the separation process of hydroxamates (arginine, leucine,
threonine, histidine and Tryptophan) using paper chromatography [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
Chromium VI
Amikacin
Arsenic and selenium
Cadmium
Lead
Lead
Formaldehyde

Ethanol automotive fuel

Water
Pharmaceutical formulations
Coal y ash
Drinking water
Drinking water
Water

SIA/MAS
MAS
Chemiluminescence
HG AFS
KR-FAAS
KR-FAAS
SPE-ICP OES
MAS

Instrumental factors
Chemical factors
Chemical factors
Chemical factors
Chemical factors
Chemical factors
Chemical factors
Chemical factors

[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]

Sequential injection analysis (SIA); molecular absorption spectrophotometry (MAS); knotted reactor (KR); hydride generation coupled with atomic uorescence
spectrometry (HG AFS); solid phase extraction (SPE); inductively coupled plasma optical emission spectrometry (ICP OES).

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S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179186

Table 5
Application of BBD for the optimization of chromatographic methods
Analyte

Sample

Chromatographic technique

Optimized process

References

2-4-6 TCA, 2-4-6 TBA

Aliphatic aldehydes
Organochlorine pesticides
Fatty acid composition
Captopril
Aminoglycoside antibiotics
Aminoacids hydroxamates

Wine

Sediments
Castor oil
Pharmaceutical tablets

GC-ECD
HPLC
GCMS
GC-FID
HPLC
GCMS
PC

Extraction step
Derivatization reaction
Extraction step
Extraction step
Separation step
Derivatization reaction
Separation step

[75]
[76]
[77]
[78]
[79]
[80]
[81]

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 chromatographymass spectrometry (GCMS); gas chromatography with ame ionisation detection GC-FID; paper chromatography
(PC).

2.3. Application of BBD for the optimization of capillary

electrophoresis

the optimization of the sorption process of verox red using a

biopolymer [92].

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 ascorbic acid and isoascorbic acid [83]. These authors concluded
that the optimizations using the three designs furnished similar
and efcient 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 determination of sulphonamides, dihydrofolate reductase inhibitors and
beta-lactam antibiotics also employing CE. The experimental
factors were optimized using BBD [86].

2.6. Other applications of BBD

2.4. Application of BBD for the optimization of

electroanalytical methods
BBD has not been used for the optimization of electroanalytical 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

Matthews et al. used BBD for the optimization of an enzymatic 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 oxidation 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 electrochemical process using reticulated vitreous carbon-supported-onpolyaniline 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

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 immobilized 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

The Box-Behnken is a good design for response surface

methodology because it permits: (i) estimation of the parameters of the quadratic model; (ii) building of sequential designs;
(iii) detection of lack of t 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 efcient than the central composite design but much more efcient
than the three-level full factorial designs.

S.L.C. Ferreira et al. / Analytica Chimica Acta 597 (2007) 179186

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 Desenvolvimento Cientco e Tecnologico (CNPq), Coordenaca o de
Aperfeicoamento de Pessoal do Ensino Superior (CAPES), and
Fundaca o de Amparo a` Pesquisa do Estado da Bahia (FAPESB)
for nancial support.
References
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