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Optimization of parameters for the fabrication of gelatin nanoparticles by

Taguchi robust design method

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Optimization of parameters for the fabrication of gelatin nanoparticles by the

Taguchi robust design method
M. Jahanshahi a; M. H. Sanati b; Z. Babaei a
a
Nanobiotech. Research Lab, School of Chemical Engineering, Babol University of Technology, Babol, Iran b
The National Research Center for Genetic Engineering and Biotechnology, Tehran, Iran

Online Publication Date: 01 January 2008

To cite this Article Jahanshahi, M., Sanati, M. H. and Babaei, Z.(2008)'Optimization of parameters for the fabrication of gelatin
nanoparticles by the Taguchi robust design method',Journal of Applied Statistics,35:12,1345 — 1353
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 Journal of Applied Statistics
Vol. 35, No. 12, December 2008, 1345–1353

Optimization of parameters for the

fabrication of gelatin nanoparticles by the
Taguchi robust design method

M. Jahanshahia∗ , M.H. Sanatib and Z. Babaeia

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a Nanobiotech. Research Lab, School of Chemical Engineering, Babol University of Technology, Babol,
Iran; b The National Research Center for Genetic Engineering and Biotechnology, Tehran, Iran

(Received 15 December 2007; final version received 1 July 2008)

The Taguchi method is a statistical approach to overcome the limitation of the factorial and fractional
factorial experiments by simplifying and standardizing the fractional factorial design. The objective of
this study was to optimize the fabrication of gelatin nanoparticles by applying the Taguchi design method.
Gelatin nanoparticles have been extensively studied in our previous works as an appropriate carrier for drug
delivery, since they are biodegradable, non-toxic, are not usually contaminated with pyrogens and possess
relatively low antigenicity. Taguchi method with L16 orthogonal array robust design was implemented
to optimize experimental conditions of the purpose. Four key process parameters – temperature, gelatin
concentration, agitation speed and the amount of acetone – were considered for the optimization of gelatin
nanoparticles. As a result of Taguchi analysis in this study, temperature and amount of acetone were
the most influencing parameters of the particle size. For characterizing the nanoparticle sample, atomic
force microscope and scanning electron microscope were employed. In this study, a minimum size of
gelatin nanoparticles was obtained at 50 ◦ C temperature, 45 mg/ml gelatin concentration, 80 ml acetone
and 700 rpm agitation speed. The nanoparticle size at the determined condition was less than 174 nm.

Keywords: gelatin; drug carrier; nanoparticles; optimization; Taguchi method; statistical experimental
design

Introduction
Over the past three decades, there has been a considerable increase of interest in research world-
wide regarding the development of new colloidal drug delivery systems. The ideal colloidal
delivery system would transport the associated drug to its desired site of action and would then
release it at an optimum rate. The carrier itself should be non-toxic and degradable in vivo, so
that it does not accumulate indefinitely in the tissues [16]. Nanoparticulate colloidal drug carriers
can be used to improve the therapeutic index of both established and new drugs by modifying

∗ Corresponding author. Emails: mmohse@yahoo.com; mjahan@nit.ac.ir

ISSN 0266-4763 print/ISSN 1360-0532 online

© 2008 Taylor & Francis
DOI: 10.1080/02664760802382426
http://www.informaworld.com
 1346 M. Jahanshahi et al.

their distribution and thus increasing their efficacy and reducing their toxicity [8]. Although vari-
ous biodegradable nanoparticles of natural polymers such as starch, chitosan, liposomes [14] are
largely in use as drug carriers in controlled drug-delivery technology, gelatin nanoparticles repre-
sent a promising carrier system for controlled drug delivery [6]. Gelatin, a natural macromolecule,
is widely used in biotechnological and biomedical applications. It has a number of advantages
in comparison with the other synthetic polymers, which make it suitable for drug-carrying: for
example, it is biodegradable, non-toxic and easy to crosslink. Moreover, it is inexpensive, can be
sterilized, is not usually contaminated with pyrogens and possesses relatively low antigenicity [5].
It has been used for decades in parental formulations and is an approved plasma expander. Thus,
it is a good contender for the preparation of nanoparticles for the purpose of controlled release
applications of drugs [1]. Gelatin nanoparticles have been used for delivery of different drugs [23],
gene delivery [10], as carriers to deliver drug to lungs, and recently antibody, modified gelatin
nanoparticles were used to target lymphocytes, leukemic cells and primary T-lymphocytes [3,7].
It has been shown that particle size is an important factor for the tissue and organ distribution of
bionanoparticles [19]. For example, body distribution studies have shown that nanoparticles larger
than 230 nm accumulate in the spleen due to the size of the capillaries in this organ [13]. Different
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in vitro studies indicate that the particle size also influences the cellular uptake of nanoparticles.
Therefore size optimization of the nanoparticles is one of the important purposes in the fabrication
of gelatin nanoparticles.
Efficient analyses of this complex system have been performed recently, using statistical exper-
imental design [21] and the Taguchi method [15,17]. The statistical experimental design can
determine the effect of the factors on characteristic properties and the optimal conditions of the
factors. It uses the tables of orthogonal arrays and analysis of variance (ANOVA), which can esti-
mate the effect of a factor on the characteristic properties. Conventional statistical experimental
design can determine the optimum condition on the basis of the measured values of the character-
istic properties, while Taguchi’s experimental design (also known as a robust parameter design)
does this on the basis of the variability of characteristic properties. In other words, the Taguchi
method can determine the experimental condition having the least variability as the optimum
condition [12].
In this work, simple coacervation method is used for manufacturing gelatin nanoparticles as a
drug-delivery system, and the essential parameters are considered. The objective of the present
study is the optimization of the preparation of gelatin nanoparticles by the Taguchi design method
which shows a controllable particle diameter and a narrow size distribution. In addition, atomic
force microscope (AFM) and scanning electron microscope (SEM) characterize the shape and
morphology of the products. This study is intended to establish a rational basis for the controlled
production and application of protein-based nanoparticles as a drug carrier system.

Materials and methods

Material
Gelatin type-A (from porcine skin), glutaraldehyde grade 1.25% aqueous solution, HCl and
acetone were obtained from Sigma, Poole, UK. Trypsin-EDTA was purchased from Gibco
(New York, NY, USA). Double distilled water was used for all the experiments. All chemicals
were of analytical grade and were used as received.

Fabrication and purification of gelatin nanoparticles

Gelatin nanoparticles were prepared using a desolvation technique. Gelatin type-A (1.25 g) was
dissolved in distilled water (25 ml) under constant heating temperature range. Acetone (25 ml)
 Journal of Applied Statistics 1347

was added to the gelatin solution as a desolvating agent to precipitate the high molecular weight
(HMW) gelatin. The supernatant was discarded and the HMW gelatin was re-dissolved by adding
25 ml distilled water and stirring at 600 rpm under constant heating. The pH of the gelatin solution
was adjusted at 2.5 by the addition of 100 μl HCl (0.1 N). Acetone (75 ml) was added drop-wise
to form nanoparticles. At the end of the process, glutaraldehyde solution (250 μl) was used for
preparing nanoparticles as a cross-linking agent, and stirred for 12 h at 600 rpm. The particles were
purified by threefold centrifugation and redispersion in acetone (30%) in milliQ water. After the
last redispersion, the acetone was evaporated using concentrator (speed vacuum). The resultant
nanoparticles were stored at 2–8 ◦ C. Subsequently, the following parameters were changed to study
their effect on the characteristics of the nanoparticles: temperature, rate of agitation, concentration
of gelatin, concentration of acetone and cross-linker. As for temperature, it was found that the
preparation of nanoparticles at ambient temperature (25 ◦ C) was not possible since the gelatin
formed a highly viscous gel in this circumstance and there was a possibility of denaturation
of gelatin at high temperatures; thus the temperatures were adjusted between 40 and 60 ◦ C. The
agitation speed was set at 500–800 rpm, concentration of gelatin was in the range of 45–60 mg/ml
and acetone concentration was maintained between 60 and 80 ml according to literature as well
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as our previous publication [6,8].

Figure 1. The procedure of the Taguchi method.

 1348 M. Jahanshahi et al.

Taguchi method
There are many ways to design a test, but the most frequently used approach is a full factorial
experiment. However, for full factorial experiments, there are 2f possible combinations that must
be tested (f = the number of factors, each at two levels). Therefore, it is highly time-consuming
when there are many factors [20].
In order to minimize the number of tests required, fractional factorial experiments (FFEs) were
developed. FFEs use only a portion of the total possible combinations to estimate the effects
of main factors and the effects of some of the interactions. Taguchi developed a family of FFE
matrices that could be utilized in various situations. These matrices reduce the experimental
number but still obtain reasonably rich information [4].
The fundamental principle of the Taguchi method is to improve the quality of a product by mini-
mizing the effect of the causes of variation without eliminating the causes. In this methodology, the
desired design is finalized by selecting the best performance under conditions that produce con-
sistent performance [9]. The conclusions drawn from the small set of experiments are valid over
the entire experimental region spanned by the factors and their setting levels. Taguchi approach
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provides systematic, simple and efficient methodology for the optimization of the near-optimum
design parameters with only a few well-defined experimental sets.
Two major tools used in the Taguchi method are the orthogonal arrays and ANOVA and the
signal-to-noise ratio (S/N ). ANOVA is a matrix of numbers arranged in rows and columns. Each
row represents the level of factors in each run and each column represents a specific level for a
factor that can be changed for each run. S/N is indicative of quality, and the purpose of the Taguchi
experiment is to find the best level for each operating parameter so as to minimize (or maximize)
S/N [11].
Taguchi method for optimization has been represented in the form of a flowchart as shown in
Figure 1.

Experimental
Details of experiments
The first step is to determine the various factors/parameters and their level that influences the
performance characteristic(s). Factors that have significant effect on the performance should be
chosen. One of the main features of the Taguchi method is its ability to point out our insignificant
variables, even if they had been considered to be significant at the beginning of the optimization
process.
The DESIGN EXPERT 6.07 (Stat-Ease Inc., Minneapolis, MN, USA) software was used for
regression and graphical analysis of the obtained data. For our experiments, we considered four
parameters (temperature, gelatin concentration, agitation speed and the amount of acetone). These
four strategy parameters or factors, for convenience, are represented by the letters A−D. The
factors (A−D) and the corresponding parameters are listed. The levels of each operating parameter
are listed in Table 1. Here, L16 (44 ) ANOVA was selected, which represents 16 experiments with
four 4-level factors. On the other hand, the full factorial design, which represents the traditional
or classical approach, considers all possible combinations of input parameters and, for the given
situation, would require 256 (44 ) experiments to be performed.
To select an appropriate orthogonal array, total degrees of freedom need to be computed.
The degrees of freedom are the number of comparisons to be made between design parameters.
For example, a 4-level design parameter counts for 3 degrees of freedom. Therefore, in the
present work, total degrees of freedom are 15 (see [2]). Basically, degrees of freedom for an
orthogonal array should be greater than or at least equal to the number of design parameters. Each
parameter is assigned to each column of the orthogonal array, so 16 parameter combinations are
 Journal of Applied Statistics 1349
Table 1. Levels of different parameters.

Level
Factor 1 2 3 4

A: Temperature (◦ C) 40 50 55 60
B: Gelatin concentration (mg/ml) 45 50 55 60
Acetone (ml) 60 65 75 80
D: Agitation speed (rpm) 500 600 700 800

available. Therefore, only 16 experiments are required to study the entire parameter space using
L16 orthogonal array.

Discussion
Analysis of experimental data
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Experimental data were analyzed by using S/N ratio and ANOVA. Based on the results of the
S/N ratio and ANOVA, optimal parameter settings for better accuracy are obtained and verified
experimentally. Regression models are developed to obtain the compensation factor for any set
of process parameters.

Analysis using S/N ratio

In the Taguchi method, S/N ratio is a measure of quality characteristics and deviation from the
desired value. The term ‘signal’ represents the desirable value (mean) and ‘noise’ represents the
undesirable value (standard deviation from mean) for the output characteristic [22]. The S/N ratio
(η) is defined as
η = −10 log(MSD),
where MSD is the mean-square deviation for the output characteristic. Parts can be built with
better accuracy if the shrinkage effect is reduced. So, ‘the smaller-the-better’ type of S/N ratio is
used in the analysis for better accuracy. For the smaller-the-better case, the S/N ratio is obtained
by the following equation [22]:
1 2
n
MSD = y ,
n i=1 i
where n is the total number of the experiments in the orthogonal array and Yi is the mean percentage
shrinkage for the ith experiment.
In the present study, L16 (4ˆ 4) orthogonal array [2] with 4 columns and 16 rows was used,
which is presented in Table 2. In addition, S/N ratio was calculated for each experiment.
The data generated are analyzed for identifying the optimum level of parameters [18]. The
average S/N ratio of each control factor at each level and the range of S/N ratio of each factor (D =
delta = S/Nmax_S/N min) are determined. The greatest variation of S/N ratio in the temperature
reveals that it has the most important influence on the particle diameter. The amount of acetone
addition has the second most important effect on the nanoparticle size.
Table 3 shows the main effects of the factors on the gelatin nanoparticle size. The Model F -value
of 9.12 shows that the model is significant. There is only a 4.72% chance that such a large Model
F -Value could occur due to noise. Values of Prob > F less than 0.0500 indicate that model terms
are significant. Therefore, A and C (temperature and amount of acetone) are significant model
terms and R-squared is equal to 0.9733.
 1350 M. Jahanshahi et al.

Table 2. Experimental measured values for gelatin nanoparticles size and S/N ratio (Taguchi
orthogonal array table of L-16).

Experimental conditions Diametera

Experiment Actual Predicted S/N ratio
number A B C D value value (dB)

1 1 1 1 1 301.1 309.54 −49.5

2 1 2 2 2 286.3 283.49 −49.1
3 1 3 3 3 286.4 276.11 −49.1
4 1 4 4 4 240.0 244.66 −47.5
5 2 1 2 3 194.0 198.66 −45.7
6 2 2 1 4 248.0 237.71 −47.6
7 2 3 4 1 209.1 206.29 −46.5
8 2 4 3 2 198.4 206.84 −46.5
9 3 1 3 4 230.3 227.49 −47.1
10 3 2 4 3 199.0 207.44 −45.7
11 3 3 1 2 336.8 341.46 −50.5
12 3 4 2 1 292.0 281.71 −49.2
−47.8
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13 4 1 4 2 245.2 234.91
14 4 2 3 1 241.0 245.66 −48.1
15 4 3 2 4 298.2 306.64 −49.4
16 4 4 1 3 316.0 313.19 −49.9
a Average diameter of gelatin nanoparticles.

Table 3. The ANOVA table of gelatin nanoparticles size.

p-value
Factors Degrees of freedom Sum of squares F -Value prob > F

A 3 11336.91 13.71 0.0295

B 3 4249.81 5.14 0.1059
C 3 13834.29 16.73 0.0223
D 3 724.93 0.88 0.5417
Model 12 30145.95 9.12 0.0472

Figure 2. Response graph of S/N ratio for the smaller-the-better analysis of nanoparticle size.
 Journal of Applied Statistics 1351

Figure 3. The SEM image of gelatin nanoparticles.

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Figure 4. Topography of gelatin nanoparticles using AFM: (a) Two-dimensional, (b) Three-dimensional.
 1352 M. Jahanshahi et al.

The response graphs corresponding to the different factors are presented in Figure 2. Due to the
large difference in the maximum and minimum values of S/N , these values have been converted
into dB for drawing the response graphs.
From Table 3 and Figure 2, it can be found that the temperature and amount of acetone are the
significant parameters that affect the size. Therefore, based on the S/N and ANOVA analyses, the
optimal parameters for nanoparticle size are the temperature at level 2, the gelatin concentration
at level 1, amount of acetone at level 4 and agitation speed at level 3. The best parameters for
the production of nanobioparticles were obtained at: temperature, 50 ◦ C; gelatin concentration,
45 mg/ml; rate of acetone adding, 80 ml and 700 rpm, agitating. Under these conditions the
program-estimated gelatin nanoparticle diameter was 168.7 nm, while based on the experiment
the nanoparticle diameter achieved was 174 nm. There is a good agreement between the predicted
and experimental values of particle size. Consequently, particle size in the fabrication of gelatin
nanoparticle can be decreased using the Taguchi method.

Nanoparticle characteristics and size-distribution determination

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Average particle size based on size distribution was calculated by photon correlation spectroscopy.
An SEM picture of gelatin nanoparticles is shown in Figure 3, which clearly indicates the smooth
and spherical nanoparticles with an average diameter of about 100–300 nm. The AFM photograph
(Figure 4) clearly presents that no hair cracks or heterogeneity appears on the nanoparticle surface.
These pictures obviously present a morphological evidence for solid and smooth nanoparticles
which are suitable for drug delivery (see refs [7,19] for more details).

Conclusion
Our systematic investigation of the synthesis parameters shows that it is possible to prepare
nanoparticles with different particle sizes and a relatively narrow size distribution. Due to the
SEM and AFM analyses, the protein nanoparticle, as it has been assembled here, not only mimics
the size and surface chemistry of nanoparticles such as viruses and plasmid, but also can be
used as a drug-delivery vehicle in its own right. The size of gelatin nanoparticles fabricated here
was influenced by several process variables including agitation speed, temperature and gelatin
concentration. The Taguchi method was adopted for the design of experiments, and analysis
of experimental data was carried out successfully by maximizing S/N ratio and ANOVA. The
best result (minimum size of the gelatin nanoparticles) was attained at 50 ◦ C, 45 mg/ml gelatin
concentration, 80 ml acetone with 700 rpm agitating and, based on these conditions, the gelatin
nanoparticle diameter achieved was 174 nm. This result in comparison with the literature is more
favorable in terms of minimum size which is suitable for drug delivery systems (e.g. see ref.
[5]). The result shows that the data analyzed by the Taguchi method are in good agreement with
the experimental findings. To the best of our knowledge the current study is to of the first one
have demonstrated optimized fabrication of protein nanoparticles. Loading the drug on these
nanoparticles will be the next step of the work and the subject of our further publication.

Acknowledgements
The authors would like to thank Babol University of Technology for supporting this research. Also, special thanks go to
The National Research Center for Genetic Engineering and Biotechnology, Iran.

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 Journal of Applied Statistics 1353

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