Optimization of the ultrasound-assisted synthesis of lutein disuccinate using uniform design

Article abstract of DOI:10.1016/j.ultsonch.2013.06.004

The ultrasound-assisted synthesis of lutein disuccinate from all-trans lutein (AL) and succinic anhydride (SA) was investigated in this study. Triethylamine was used as the catalyst. Based on the single-factor experiments, a 7-level-3-factor uniform desig

Full text of DOI:10.1016/j.ultsonch.2013.06.004

Ultrasonics Sonochemistry 21 (2014) 98–103
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Optimization of the ultrasound-assisted synthesis of lutein disuccinate
using uniform design
a,b,
b
a
Da-Jing Li a,c, , Jiang-Feng Song
, Ai-Qin Xu , Chun-Quan Liu
⇑
⇑
a Institute of Farm Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
b College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
c College of Forestry, Northeast Forestry University, Harbin 150040, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The ultrasound-assisted synthesis of lutein disuccinate from all-trans lutein (AL) and succinic anhydride
(SA) was investigated in this study. Triethylamine was used as the catalyst. Based on the single-factor
experiments, a 7-level-3-factor uniform design and response surface analysis were further employed
to evaluate the effects of the selected variables including molar ratio of SA/AL, reaction time and ultra-
sonic power on the yield of lutein disuccinate. The results indicated that the data were adequately fitted
into a second-order polynomial model; the molar ratio of SA/AL significantly affected the synthesis of
lutein disuccinate, whereas reaction time and ultrasonic power did not. Based on ridge max analysis,
the optimum condition for lutein disuccinate synthesis was predicted to be the molar ratio of SA/AL
265.3:1, ultrasonic power 300 W and reaction time 131.6 min with the lutein disuccinate yield of
80.53 0.18%, which give a 43.8% increase compared with the traditional method, and also significantly
shorten the reaction time.
Received 22 April 2013
Received in revised form 7 June 2013
Accepted 8 June 2013
Available online 15 June 2013
Keywords:
Lutein disuccinate
Ultrasound-assisted synthesis
Uniform design
LC–MS analysis
NMR spectroscopy
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
and succinic acid, respectively [4]. In general, their preparation
by purely chemical means requires vigorous conditions, high
Many studies have demonstrated the utility of lutein-based
supplementation for the clinical improvement of vision, reduction
of ultraviolet (UV)-based inflammation, and potentially the inhibi-
tion and/or amelioration of age-related macular degeneration
(AMD) [1,2]. Although xanthophylls of the C40 series such as
lutein, zeaxanthin, and astaxanthin extracted from plant materials
have been approved for use as aqueous-phase singlet oxygen
quenchers, direct radical scavengers, and lipid-peroxidation
chain-breakers, and complicates parenteral delivery of these com-
pounds, their low aqueous solubility and low stability in the native
state have limited their uses in the food industry [3]. One way to
increase the solubility of lutein in water-based formulas and
dispersions is to esterify the compounds with aliphatic acids.
In the recent years, some C40-xanthophylls have been success-
fully modified. Hawaii Biotech, Inc. (HBI) synthesized a novel
carotenoid derivative, the disodium disuccinate derivative of syn-
thetic astaxanthin [3]. This novel derivative exhibits good water
dispersibility. Nadolski had reported that two novel lutein deriva-
tives were synthesized by esterification with inorganic phosphate
temperatures with incomplete conversions (below 60%), very long
stirring times (up to 18 h) can lead to the formation of colored
by-products and to the destruction of reaction products.
Nowadays, ultrasound-assisted synthesis as an effective tech-
nique is widely used in chemical reactions, which exhibits many
advantages including higher yield, shorter reaction time and
milder reaction condition when compared with conventional
methods [5–9]. Ultrasound irradiation is well known to accelerate
chemical reactions [10]. This is due to the phenomenon of acoustic
cavitation, that is, the formation, growth and collapse of micromet-
rical bubbles, formed by the propagation of a pressure wave
through a liquid. The collapses are quasiadiabatic processes, result-
ing in the generation of high temperatures and pressures in the
nanosecond time scale, accompanied by sonoluminescence and
mechanical effects. These effects can be used to accelerate chemi-
cal reactions, reducing the reaction time and optimizing the
benefit-cost relation. Up to our best knowledge, usage of ultra-
sound-assisted synthesis has not been previously reported in
lutein derivatives.
The experimental technique of uniform design is a new method
established together by Fang et al. [11]. It applies the experiments
with many factors and many levels and is based on orthogonal test.
Uniform design allows the largest possible amount of levels for
each factor, and the number of levels can be equal to the number
⇑
Corresponding authors at: Institute of Farm Product Processing, Jiangsu
Academy of Agricultural Sciences, Nanjing 210014, China. Tel.: +86 25 8439
1255; fax: +86 25 8439 1570.
E-mail addresses: lidajing@163.com (D.-J. Li), songjiangfeng102@163.com
(J.-F. Song).
1350-4177/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ultsonch.2013.06.004

D.-J. Li et al. / Ultrasonics Sonochemistry 21 (2014) 98–103
99
of experiment runs, which has been successfully used for develop-
ing, improving and optimizing processes [12,13]. In general, Uni-
form design is preferred since it reduces the number of
experiments significantly to evaluate multiple parameters and
their interactions. Therefore, it is less laborious and time-consum-
ing than other approaches required to optimize a process.
In order to study the optimal conditions to obtain the best pos-
sible yield in the succinic anhydride esterification of lutein under
ultrasonic conditions, this work aims to optimize this reaction
using a uniform design.
performed. Elution was carried out using solvent A and B (50:50,
V/V) at a flow rate of 1.0 mL/min, and the eluents were examined
by UV light at a wave-length of 450 nm. The binary mobile phase
consisted of (A) acetonitrile:acetic acid (99.95:0.05, V/V) and (B)
methanol:acetic acid (99.95:0.05, V/V).
2.4. MS and NMR confirmation
For MS, experiments were carried out on an Agilent 1290 Infin-
ity LC/Agilent Technologies 6460 MS. The positive ion mode (APCI)
was used to detect lutein and its esters, with total ion current (TIC)
2. Materials and methods
scanning range 50–1200 m/z, corona current 4 lA, capillary voltage
4500 V and nitrogen as nebulizer gas (purity 99.9% and flow rate
2.1. Materials
4 L/min) and vaporizer temperature at 350 °C.
For NMR, 20 mg lutein disuccinate purified by preparative HPLC
(Amersham Biosciences AKTA Purifier with Frac-900) was dis-
solved in CDCl3. NMR experiments were acquired on an NMR spec-
trometer (BRUKER 300 MHz/52 mm, Milton, Ontario, Canada) at
298 K. The proton chemical shifts were referenced to the TMS sig-
nal at 0 ppm (25 °C).
All-trans lutein (ꢀ90.42%) was prepared from marigold flowers
and purified in our laboratory.
Chemicals: Analytical grade triethylamine, methylene chloride
and acetic acid were all from Sinopharm Chemical Reagent Co.,
Ltd. HPLC-grade acetonitrile and methanol were purchased from
TEDIA Company Inc. (Tedia Company, Inc., Fairfield, OH, USA).
Deionized water was prepared with a Milli-Q system (Millipore,
Bedford, MA, USA).
2.5. Experimental design
Apparatus: Desktop triple-frequency constant temperature
numerical control ultrasonic cleaner from Kunshan Ultrasonic
Instruments Co. Ltd. (KQ-300GVDV, Shanghai, China).
At first, the effect of changing a single factor on the yield of lu-
tein disuccinate was studied. Namely, we studied the variable con-
dition of a factor when the others were invariable. Uniform design
then was applied to determine the optimum condition of the ultra-
sound-assisted synthesis of lutein disuccinate. The investigated
levels of each factor were selected depending on the above exper-
iment results of the single factor. The combination affects of inde-
pendent variables X1 (molar ratio of SA/AL), X2 (ultrasonic power,
W) and X3 (reaction time, min) at seven variation levels in the syn-
thesis process, is shown in Table 1.
2.2. Synthetic procedure
The ultrasonic experiments were performed on a Kunshan KQ-
300GVDV ultrasonic cleaner (Kunshan Ultrasonic Instruments Ltd.
Co., China) with frequencies of 45 kHz, 80 kHz and 100 kHz. The
flask mentioned below was located in the cleaning bath and the
surface of reactants was slightly lower than the level of water in
the cleaning bath. The temperature of the water bath was kept at
25 °C by the addition or removal of water. A reflux condenser
was attached to the flask. The flask was sealed and purged with
nitrogen to ensure an inert atmosphere for the reaction vessel.
Reaction scheme is depicted in Fig. 1. Appropriate quantities of
all-trans lutein (AL), and succinic anhydride (SA) were added to a
flame-dried flask in 10 mL of methylene chloride. After dissolution
under manual agitation, the appropriate quantity of triethylamine
was added. The mixture was submitted to ultrasonic irradiation
under nitrogen atmosphere for 12 h, and thereafter, the solvent
was evaporated. The residue was taken-up in 5 mL acetonitrile,
2.6. Statistical analysis
All the trials were performed in triplicate. For single-factor test,
each data was average value of three parallel experiments. For uni-
form design and subsequent analysis, the software named as Data
Processing System (DPS Version7.05, Refine Information Tech. Co.,
China) was used to generate statistical analysis and regression
model. A total of seven combinations were chosen in random order
according to DPS software configuration for three factors [14]. The
coded and actual values are also shown in Table 1. The significance
of each coefficient was determined using the Student’s t-value and
p-value, and the result is shown in Table 2.
the test solution was filtered through a 0.45 lm microporous
membrane, then for HPLC analysis. All operations were carried un-
der dark conditions.
3. Results and discussion
2.3. Determination of lutein disuccinate by analytical HPLC
3.1. Single factor results
YMC Carotenoid C30 column (4.6 mm ꢁ 250 mm i.d., 5
lm,
3.1.1. The effect of molar ratio of SA/AL on the yield of lutein
disuccinate
YMC, Wilmington, NC) and HPLC (Agilent 1200 series, USA) was
This experiment adopted 50:1 M, 100:1 M, 150:1 M, 200:1 M,
250:1 M and 300:1 M ratio of succinic anhydride (SA) to all-trans
lutein (AL) to study the effect of different molar ratio of SA/AL on
lutein disuccinate yields in ultrasound-assisted synthesis. In these
synthesis reactions, other experimental conditions were as fol-
lows: reaction temperature, 25 °C; ultrasonic power, 300 W; ultra-
sonic frequency, 45 kHz; catalyst concentration, 0.6% (percent by
weight of AL).
The result shows that the yield of lutein disuccinate increased
with elevating molar ratio of SA/AL, and the yield reached the high-
est when molar ratio of SA/AL increased to 250:1 (Fig. 2a). An
enhancement in the concentration of succinic anhydride can
Fig. 1. Synthesis of lutein disuccinate.

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D.-J. Li et al. / Ultrasonics Sonochemistry 21 (2014) 98–103
Table 1
Independent variables of the process and their corresponding levels.
Independent variables
Levels
1
2
3
4
5
6
7
X1: molar ratio of SA/AL
X2: ultrasonic power (W)
X3: reaction time (min)
200:1
120
25
220:1
150
50
240:1
180
75
260:1
210
100
280:1
240
125
300:1
270
150
320:1
300
175
Table 2
Uniform design with the observed responses and predicted values.
value of succinic anhydride higher than three, reduction in produc-
tion of -tocpheryl succinate was observed.
a
No.
Variable levels
Y (%)
Ye-Y
X1
X2
X3
Experimental
Predicted
3.1.2. The effect of ultrasonic power on the yield of lutein disuccinate
The effect of ultrasonic power on the lutein disuccinate yields
had been studied in this work when different ultrasonic power
(180 W, 210 W, 240 W, 270 W and 300 W) was set under the reac-
tion conditions as follows: molar ratio of SA/AL, 250:1; reaction
temperature 25 °C; ultrasonic frequency, 45 kHz; catalyst concen-
tration, 0.6% (percent by weight of AL).
1
2
3
4
5
6
7
1
2
3
4
5
6
7
2
4
6
1
3
5
7
3
6
2
5
1
4
7
0.1030
29.91
45.83
57.43
64.63
24.05
52.21
60.85
29.0863
48.7317
55.8081
62.4838
23.5587
56.5525
58.6889
ꢂ0.0313
ꢂ0.0606
ꢂ0.0828
ꢂ0.1159
0.2610
ꢂ0.0734
The result implied the yield of lutein disuccinate was always
enhanced before the ultrasonic power 270 W, and then it reached
the highest and was not changed when the ultrasonic power was
increased (Fig. 2b). It appears that higher molar conversion was ob-
tained with higher ultrasonic power. Xiao et al. [16] also demon-
strated the ultrasound-accelerated synthesis of sugar esters. They
suggested that the acceleration was likely due to an increase in col-
lisions between the two substrates and the catalyst by ultrasound.
displace the chemical equilibrium to products formation, resulting
in higher conversions. On the other hand, excess succinic anhy-
dride concentrations may reduce the reaction rate due to the inhi-
bition effect. Similar results were observed by Zhen and Mo [15],
where higher conversions (about 84%) in
a-tocpheryl succinate
were obtained at a molar ratio of 3:1. However, for a molar ratio
70
70
180W
210W
240W
270W
300W
(b)
(a)
50:1
100:1
150:1
200:1
250:1
300:1
60
60
50
40
30
20
10
50
40
30
20
10
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Reaction time (h)
Reaction time (h)
70
60
50
40
30
20
10
70
60
50
40
30
20
10
(d)
45KHz
80KHz
100KHz
0.2%
0.4%
0.6%
0.8%
1.0%
(c)
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Reaction time (h)
Reaction time (h)
Fig. 2. Effect of the molar ratio of SA/AL (a), ultrasonic power (b), ultrasonic frequency (c) and catalyst concentration (d) on the reaction process curve.

D.-J. Li et al. / Ultrasonics Sonochemistry 21 (2014) 98–103
101
Table 3
However, the reaction yields didn’t show a continuous increase
Significance of regression coefficient for the yield of lutein disuccinate.
with ultrasonic power more than 270 W might due to the forma-
tion of large number of cavitation bubbles in the liquid [17,18].
The combination of these bubbles forming larger and more stable
bubbles could create a barrier to the acoustic energy transmission
throughout the reaction mixture leading to poor mixing effects be-
tween the two immiscible layers [19].
Variables
Partial correlation
Computed
Significance
t-value
level p-value
r(y, X1)
rðy; X21Þ
rðy; X22Þ
0.9776
ꢂ0.9791
0.9159
ꢂ0.9601
0.9766
4.6408
4.8181
0.0434
0.0405
2.2823
3.4316
4.5426
0.1500
0.0754
0.0452
rðy; X23Þ
r(y, X1X3)
3.1.3. The effect of ultrasonic frequency on the yield of lutein
disuccinate
This experiment adopted 45 kHz, 80 kHz, and 100 kHz ultra-
sound-assisted synthesis to investigate the effect of ultrasonic fre-
quency on yields. Other experimental conditions were as follows:
reaction temperature 25 °C; molar ratio of SA/AL, 250:1; ultrasonic
power, 270 W; catalyst concentration, 0.6% (percent by weight of
AL).
From Fig. 2c, it could be clearly seen that the lutein disuccinate
yield gradually decreased with changed ultrasonic frequency, and
the yield reached the highest (65.23%) when ultrasonic frequency
was 45 kHz, and the reaction time was 2 h. Generally, higher fre-
quencies are favorable from the point of view of energy efficiency
of the sonochemical processes, at lower frequencies, the cavity
grows to a larger size and the collapse is less violent [20]. Never-
theless, as the ultrasound frequency increases, the range of ambi-
ent radius for an active bubble becomes less wideness and the
optimal ambient radius becomes smallest. Moreover, higher fre-
quency cause the swelling time shorter, cavitation bubble has no
time to collapse, so at the same operating intensity of irradiation,
higher frequency will reduce cumulative effects of cavitation.
each coefficient was determined using the Student t-test and p-va-
lue in Table 3. The corresponding variables will be more significant
if the absolute t-value becomes larger and the p-value becomes
smaller [22]. It can be seen that the variable with the largest effect
was the quadratic terms ðX21Þ, the linear terms of the molar ratio
(X1), followed by interaction effects of the molar ratio and reaction
time (X1X3).
Then the prediction was obtained by DPS software. An optimum
condition for the synthesis of lutein disuccinate which determined
by ridge max analysis was found as follow: molar ratio of SA/AL
with 265.3:1, ultrasonic power of 300 W, reaction time of
131.6 min. The adequacy of the predicted model (Eq. (1)) was
examined by carrying out the lutein disuccinate synthesis experi-
ment under the optimal condition afore-mentioned. The results
showed lutein disuccinate yield of 79.78 1.18% under the optimal
condition. This observed value did not significantly differ from the
predicted value of 80.53 0.42%. Thus, the model developed, as
shown in Eq. (1), adequately predicts the yield in the lutein disuc-
cinate synthesis reaction.
3.1.4. The effect of amounts of catalysts on the yield of lutein
disuccinate
3.3. Comparison of ultrasound and conventional synthesis methods
The effect of catalysts on the yields had been studied in this
work when different amounts of catalysts (0.2%, 0.4%, 0.6%, 0.8%
and 1.0%, percent by weight of AL) was set under the reaction con-
ditions as follows: reaction temperature 25 °C; molar ratio of SA/
AL, 250:1; ultrasonic power, 270 W; ultrasonic frequency, 45 kHz.
The effect of catalyst concentration on the rate of reaction has
been shown in Fig. 2d. It can be seen from the figure that increase
in rate of reaction is significant for increase in the catalyst concen-
tration from 0.2% to 0.8%. But an increase in the catalyst concentra-
tion beyond 0.8% does not result in any further increase in rate of
reaction and equilibrium conversion. Santos et al. [21] have re-
ported similar effects of catalyst concentration on the ultrasound
assisted esterification reactions.
The conventional synthesis method was carried out at ambient
temperature by stirring magnetically at the highest possible speed
of the stirrer to completely mix the two phases, other conditions
were kept same with optimal ultrasound synthesis. Fig. 3 shows
the effect of the ultrasound and conventional synthesis on lutein
disuccinate formation. It has been observed that use of ultrasound
enhances the limiting equilibrium conversion from about 56% in
12 h with conventional synthesis method to about 80% in 2 h of
reaction time. Thus, the use of ultrasonic irradiations is in both
enhancing the rate of reaction as well as in shifting the equilibrium
and resulting in higher product yields. Ultrasound generated cavi-
tation results in conditions of intense turbulence and micro-scale
liquid circulation currents which help in uniform mixing at
micro-level and hence in the elimination of the mass transfer
3.2. Obtaining optimum synthesis condition
The uniform design method was used for more efficient optimi-
zation of the various operation variables in the ultrasound-assisted
synthesis of lutein disuccinate. Based on the above results, three
main factors were chosen, i.e., molar ratio of SA/AL, reaction time
and ultrasonic power. A regression analysis was carried out to fit
the mathematical model to the experimental data aiming at an
optimal region for the studied. The following regression equation,
which is an empirical relationship between the yield and the test
variable in coded unit as given in Eq. (1), can describe the predicted
model:
80
ultrasound assisted synthesis
70
conventional esterification
60
50
40
30
20
10
0
Y ¼ ꢂ498:16 þ 4:21X1 ꢂ 8:72 ꢁ 10ꢂ3X12 þ 2:30 ꢁ 10ꢂ4X22
ꢂ 3:22 ꢁ 10ꢂ3X32 þ 3:22 ꢁ 10ꢂ3X1 ꢁ X3
ð1Þ
0
100
200
300
400
500
600
700
800
The multiple coefficient of determination (R2) of the predicted
model was 0.9796, suggesting a good fit, and the predicted model
seemed to reasonably represent the observed values. Thus, the re-
sponse was sufficiently explained by the model. The significance of
Reaction time(min)
Fig. 3. Comparison between conventional and ultrasound esterification process
curve.

102
D.-J. Li et al. / Ultrasonics Sonochemistry 21 (2014) 98–103
Fig. 4. LC–MS product ions.
Fig. 5. 1H NMR spectrum.
resistances [23]. Moreover, because of the simultaneous nucleation
and homogeneous heating, uniformly small particles can be
synthesized.
d170 = 0.92, d180 = 1.67, d190 = 1.98, d200 = 2.11, d220 = 2.65, d220 =
2.63, d24 Exchangeable.
4. Conclusions
3.4. MS and NMR confirmation
After the experimental observations, it is possible conclude the
ultrasound irradiation can improve the esterization of lutein,
decreasing the time reaction and improving the yield of lutein disuc-
cinate. The uniform design techniques helped us to understand the
influence of the reagents in the yield, and the data provided by these
findings are useful to optimize the synthesis of lutein disuccinate.
Moreover, the obtained statistical model is considered well fitted
and valid at the 95% confidence level. Through MS and NMR confir-
mation, lutein disuccinate was well synthesized and purified.
To confirm the structure of the target compound, a further puri-
fication was investigated by preparative HPLC; the purified com-
pound was introduced by direct infusion and analyzed by APCI in
the positive mode with m/z scan from 50 to 1200. The mass spec-
trum was shown in Fig. 4. Lutein disuccinate was identified based
on the fragmentations at m/z 651.1 [M+Hꢂ118], 559.1
[M+Hꢂ118ꢂ92], 533.1 [M+Hꢂ118+Hꢂ118ꢂH], due to the loss of
one H2O and one succinic anhydride, one H2O and one succinic
anhydride and one toluene, two succinic anhydride from the
molecular ions at m/z 668.8.
Acknowledgments
Structure elucidation of isolated lutein disuccinate was further
performed by NMR. Based on the 1H NMR data (Fig. 5), the location
of the hydrogen atom in the organic molecules, the relative number
of hydrogen atoms in the mother nucleus skeleton and various func-
tional groups, the spatial structure can be identified. 1H NMR:
d2h00i = 1.62, d2h00i = 1.62, d3 = 5.11, d4h00i = 2.37, d4h0i = 2.37, d7a =
6.14, d8a = 6.36, d10a = 6.14, d11a = 6.64, d14a = 6.27, d15a = 6.64,
d16 = 1.09, d17 = 1.12, d18 = 1.74, d19 = 1.98, d20 = 2.11, d22 = 2.7,
d23 = 2.69, d24 Exchangeable, d20h00i = 1.62, d20h0i = 1.62, d30 = 5.5,
d40 = 5.37, d60a Exchangeable, d150a = 6.64, d140a = 6.27, d120a =
6.36, d110a = 6.64, d100a = 6.14, d80a = 6.14, d70a = 5.44, d160 = 0.90,
This work was supported by grants from the National Natural
Science Foundation (31101385) and the Fundamental Research
Funds for the Central Universities (Grant No. DL10BA12).
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