Enhancement of Curcumin Solubility by Phase

Change from Crystalline to Amorphous

in Cur-TPGS Nanosuspension
Gye Hwa Shin, Jinglei Li, Jin Hun Cho, Jun Tae Kim, and Hyun Jin Park

Abstract: Nanosuspensions (NSs) were fabricated to enhance water solubility, dissolution rate, and oral adsorption of
water insoluble curcumin using sonoprecipitation method. As a good stabilizer, d-α-Tocopherol polyethylene glycol 1000
succinate (TPGS) was used to improve the stability of curcumin-TPGS NSs (Cur-TPGS NSs). Ultrasonic homogenization
(UH) could effectively enhance the solubility of curcumin and to produce homogeneous NSs with small particle sizes.
Water solubility of curcumin was significantly improved from 0.6 µg/mL in pure water to 260 µg/mL in the mixture of
curcumin and TPGS (1:10) with UH treatment. The mean particle size of Cur-TPGS NSs was decreased significantly
after UH and maintained between 208 and 246 nm. Lyophilized powder of Cur-TPGS NSs was dissolved about 91.08%
whereas the pristine curcumin powder was dissolved only 6.5% at pH 7.4. This study showed a great potential of
Cur-TPGS NSs as a good nano-formulation of curcumin with enhanced solubility and improved oral adsorption.

Keywords: curcumin, nanosuspensions, TPGS, ultrasonic homogenization, solubility

Introduction
As a natural phenolic compound, curcumin has shown vari-
ous health benefits such as antioxidant, anti-inflammatory, antimi-
crobial, anticancer, anti-Alzheimer activities, and wound-healing
properties (Pulla Reddy and Lokesh 1992; Lantz and others 2005;
Nagarajan and others 2010; Zhang and others 2013). Although
curcumin has showed wide range of therapeutic effects, the phar-
macological application of curcumin has been quite limited be-
cause of its extremely low solubility in both acidic and neutral
pHs, poor adsorption in the gastrointestinal environment, and
very low oral bioavailability. It has been reported that curcumin
can be solubilized only less than 0.6 µg/mL in pure water and 1
mg/mL in ethanol (Kurien and others 2007). In order to overcome
these limitations, many encapsulation technologies have been de-
veloped. In particular, nanocarrier systems have been more at-
tracted to improve the water solubility, adsorption rate, and oral
bioavailability of curcumin. Recently, various nanocarrier systems
were developed such as solid lipid nanoparticles (SLNs), nanos-
tructured lipid carriers (NLCs), nanoemulsions, nanohydrogels,
N: Nanoscale Food
but the maximum solubility of curcumin was still 4.2 µg/mL in
pure water (Donsi and others 2010).
Nanosuspensions (NSs), known as nanocrystals, are highly sta-
ble colloidal system containing nanosized cores surrounded by
surfactant molecules. It has been reported that NSs have a lot of
advantages such as high stability, very high drug loading, cost ef-
fective, and enhanced oral bioavailability of poorly water soluble
drugs (Wang and others 2013; Danhier and others 2014). NSs also
could encapsulate nonsoluble compounds because they are not
necessary to dissolve the nonsoluble core compounds in solvents
such as water, oil, and/or organic solvents. But, their solubility
can be improved by surrounding the core compounds with water
soluble surfactant molecules. Due to these advantages, NSs have
been more attracted attention as novel delivery carriers for poorly
water soluble functional materials such as curcumin. In the previ-
ous literatures, many NSs have been prepared in organic solvents
by evaporative precipitation or supercritical antisolvent processes
while some NSs prepared by mechanical process such as high pres-
sure homogenization and media milling (Hecq and others 2005;

polymeric nanoparticles, polymeric micelles, and nanoliposomes Kakran and others 2010; Zhao and others 2010; Ghosh and others
(McClements and others 2007; Helgason and others 2009; Xie 2012; Liu and others 2012). Compared to these techniques, ultra-
Science

and others 2011; Pan and others 2013; Salminen and others 2013;
Li and others 2015). Traditional delivery systems have used organic
solvents to improve the curcumin solubility. Recently, however,
many studies have focused on the improving the solubility without
organic solvent because it could not be applied to the food system
when it use any toxic organic solvent in whole processing. One
research group used only mechanical techniques such as high pres-
sure homogenization (HPH) to improve the curcumin solubility
MS 20151233 Submitted 7/22/2015, Accepted 12/9/2015. Authors Shin, Li,
and Park are with College of Life Sciences & Biotechnology, Korea Univ., Anam-dong,
Seongbuk-gu, Seoul 136–701, Korea. Author Cho is with Woongjin Co., Ltd.
Changgyeonggung-ro, Jongro-gu, Seoul 03130, Korea. Author Kim is with Dept.
of Food Science and Technology, Keimyung Univ., Daegu 704-701, Korea. Direct
inquiries to authors Kim & Park (E-mail: jtkim92@kmu.ac.kr, hjpark@korea.ac.kr).
sonic homogenization is more effective to make food grade NSs
because it is easy and fast process to make smaller solid dispersion
by breaking the intermolecular interactions as well as it does not
need any organic solvents (Matteucci and others 2006; Patel and
Chakraborty 2014). In addition, proper stabilizer is necessary to
prepare highly stable NSs because only proper stabilizer could ef-
ficiently interact and surround with the specific core compounds.
d-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) has
been used as a stabilizer, adsorption enhancer, and emulsifier in
many delivery system (Zhang and others 2012). TPGS is a wa-
ter soluble stabilizer formed by the esterification of vitamin E
succinate with polyethylene glycol 1000 and approved as GRAS
(generally recognized as safe) in 2006. TPGS has a hydrophilic
polar head group and a lipophilic alkyl tail within its amphiphilic
structure and shows hydrophile–lipophile balance (HLB) value of
13 (Mu and Feng 2002). Because it has the advantages of both
PEG 1000 and vitamin E, TPGS could be used to develop many

Journal of Food Science ! Vol. 81, Nr. 2, 2016

C 2016 Institute of Food Technologists⃝
⃝ R

N494 doi: 10.1111/1750-3841.13208

Further reproduction without permission is prohibited
Enhancement of curcumin solubility . . .

drugs delivery systems as a good stabilizer or surfactant. Besides Tocopherol polyethylene glycol 1000 succinate (TPGS) was pur-
working as a stabilizer, TPGS can extend the half-life of a drug chased from Sigma-Aldrich (St. Louis, Mo., U.S.A.). Aqueous so-
in plasma, increase the cellular uptake of the drug as an effective lutions (Milli-Q system, 18.3 M") were used for all experiments.
P-glycoprotein inhibitor, and overcome multidrug resistance in
cancer cells (Dintaman and Silverman 1999; Collnot and others Preparation of Cur-TPGS NSs
2010). Therefore, TPGS could enhance the oral bioavailability of NSs were prepared using ultrasonic homogenization (UH) with
anticancer drugs and has been used for various nanocarrier formu- a model VCX 750 apparatus (Sonics & Materials, Newtown,
lations of highly hydrophobic anticancer drugs to enhance their Conn., U.S.A.). The ultrasonic probe can produce the maximum
therapeutic effect (Cao and Feng 2008). power input of 750 W and frequency of 20 kHz. Figure 1(A)
In this study, curcumin-TPGS (Cur-TPGS) NSs were fabricated shows the schematic of the preparation process of Cur-TPGS NSs
using ultrasonic homogenization (UH) to improve the water sol- using UH. In Cur-TGPS NSs, water insoluble curcumin crystals
ubility, dissolution behavior, and oral adsorption of Cur-TPGS could be surrounded by TPGS molecules and formed like micelle
NSs. The effects of UH and the ratio of curcumin to TPGS on structure. Briefly, curcumin powder was added to an aqueous so-
the NSs were investigated by measuring the solubility, particle lution containing TPGS. The ratios of curcumin to TPGS were
size, polydispersity index (PDI), and zeta potential. The physico- varied into 2:1, 1:1, 1:2, 1:5, and 1:10 (w/w). The mixture of
chemical properties of Cur-TPGS NSs were characterized by dif- curcumin and TPGS was magnetically stirred overnight to reach
ferential scanning calorimetry (DSC), X-ray diffraction (XRD), the equilibrium solubility at room temperature. Fully dissolved
and Fourier transform infrared spectroscopy (FT-IR). The mor- Cur-TPGS NSs were successfully fabricated by UH for 30 min
phologies of Cur-TPGS NSs and the freeze-dried Cur-TPGS NS with 30% vibration amplitude in an ice bath to maintain a constant
powder were observed by field emission scanning electron micro- temperature. The prepared Cur-TPGS NSs were centrifuged at
scope (FE-SEM) and transmission electron microscope (TEM). 5000 rpm for 10 min to remove both impurity and not dissolved
Finally, the dissolution behavior of the Cur-TPGS NS powders curcumin. To extend their storage stability and study the physical
was also tested. characteristics, Cur-TPGS NSs were prefrozen using liquid nitro-
gen and kept in an ultralow temperature refrigerator, then they
were freeze-dried under vacuum for 24 h.
Materials and Methods
Materials Solubility test
Curcumin (mixture of demethoxycurcumin and bisdemethoxy- The solubility of Cur-TPGS NSs was measured using a spec-
curcumin, !98%) was purchased from Acros (N.J., U.S.A.). D-α- trophotometric method. 30 mL of Cur-TPGS NSs was magnetic

Figure 1–Schematic representation of (A) preparation procedure of

Cur-TPGS NSs and (B) photographic pictures of curcumin in pure
water and Cur-TPGS NSs.

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 Enhancement of curcumin solubility . . .

stirred for 24 h then, centrifuged at 5000 rpm for 10 min. Nondis- pristine curcumin. In vitro dissolution experiments were performed
solved curcumin crystalline was precipitated and the supernatant according to the USP Apparatus type II (paddle) method (Soluble
was analyzed to measure the absorbance at 425 nm using UV- extraction bath, Wooju Scientific Co., Korea) which could test
Vis spectrophotometer (Optizen POP, Mecasys Co. Ltd, Daejeon, both tablet and powder form. USP 5 mg of freeze-dried Cur-
Korea) with 1 cm optical path length. TPGS NS powder was used for the dissolution test with 500
mL of PBS buffer (0.01M, pH 7.4) at 37 °C under 100 rpm.
Measurements of mean particle size, PDI, and zeta Aliquots of solution (5 mL) were collected at time intervals (5,
potential 10, 20, 30, 45, 60, 90, and 120 min) and then filtered through a
The mean particle size, PDI (polydispersity index), and zeta 0.45 µm syringe filter, and an equal volume of blank buffer (5 mL)
potential of Cur-TPGS NSs were measured using dynamic light was added to maintain the same volume of dissolution medium.
scattering with a nano-ZS nanosize analyzer (Malvern, Worces- The dissolved Cur-TPGS NSs powder in the buffer solutions was
tershire, U.K.). Three milliliters of NSs were added to polystyrene determined to measure the absorbance at 425 nm using UV-Vis
latex cells, and the mean particle size, PDI, and zeta potential werespectrometer.
measured at 25 °C with a detector angle of 90° and wavelength
of 633 nm. Each sample was measured at least 3 times and the Morphology analysis
average values were used. The morphology of Cur-TPGS NSs was characterized using
a transmission electron microscopy (TECNAI G2 F30 TEM,
Characterization of Cur-TPGS NSs Philips-FEI, Eindhoven, Holland). To prepare the TEM samples,
Structural characterization of Cur-TPGS NSs was performed Cur-TPGS NSs were dropped onto a carbon-coated grid and kept
by Fourier transform infrared (FT-IR) spectroscopy using a model for 1 min, and the excess was removed with filter paper. This step
V430 apparatus (Jasco, Tokyo, Japan) at 20 °C. The FT-IR spectra was repeated 3 times. Finally, the grid was stained with uranyl
of curcumin, TPGS, and Cur-TPGS NSs were obtained to ver- acetate for 3 min and dried overnight and imaged. The mor-
ify the interactions between curcumin and TPGS. Each sample phology of the freeze-dried Cur-TPGS NS powder was observed
was mixed with KBr at a ratio of 1:10 and prepared as a 1 mm under field emission scanning electron microscopy (FE-SEM S
semitransparent pellet by compression under a force of 5 tons in a 4300, Hitachi, Tokyo, Japan) after coating by platinum sputtering
hydraulic press. Each spectrum was obtained from the average of equipment.
64 scans at a resolution of 2 cm−1 in the wavelength range 4000
to 800 cm−1 . Statistical analysis
The thermal characteristics of curcumin, TPGS, and the freeze- The data of the solubility and particle size of Cur-TPGS NSs
dried Cur-TPGS NS powder were analyzed using a differen- were statistically analyzed using analysis of variance (ANOVA).
tial scanning calorimetry (DSC) (Perkin-Elmer Pyris 1 DSC, The Statistical Package for the Social Science (SPSS, Version 20.0,
Waltham, Mass., U.S.A.). Approximately 10 mg of sample was SPSS Inc., Chicago, Ill., U.S.A.) was used for the analysis. Dun-
heated in an open aluminum pan from 20 to 300 °C at a scanning can’s multiple range tests were used to determine any significant
rate of 10 °C/min. difference (P < 0.05) in each group.
The crystalline state of Cur-TPGS NSs was estimated using a
X-ray diffractometer (ATX-G, Rigaku Co., Tokyo, Japan) with Results and Discussion
Cu Kα radiation at a wavelength of 0.154 nm, generated at
300 mA and 60 kV. The scanning speed was 1°/min over a 2θ Effect of TPGS and UH on the solubility
range of 5° to 40°. Figure 1(B) shows the picture of pure curcumin powder in
water and Cur-TPGS NSs after centrifugation at 5000 rpm for
In vitro dissolution test 10 min. Pure curcumin was shown being nearly insoluble in water
In vitro dissolution test carried out to show how fast Cur-TPGS and most curcumin powders were precipitated and adhered to the
NSs powder can re-disperse into aqueous medium compared to glass vial wall surface. However, Cur-TPGS NSs by UH treat-
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Figure 2–Solubility of Cur-TPGS NSs at various

ratios of curcumin and TPGS before and after
ultrasonic homogenization (UH) treatment.
∗ Different superscript letters indicate a
significant difference at P < 0.05 by Duncan’s
multiple range test.

N496 Journal of Food Science ! Vol. 81, Nr. 2, 2016

Enhancement of curcumin solubility . . .
ment were homogeneously dispersed in water phase and showed
a yellowish suspension without any phase separation or precip-
itation of free curcumin powder after they were centrifuged at
5000 rpm for 10 min. Figure 2 shows the curcumin solubility at
various ratios (2:1, 1:1, 1:2, 1:5, and 1:10 (w/w)) of curcumin to
TPGS before and after UH. Curcumin solubility was 32 µg/mL
when curcumin concentration was equal or higher than TPGS
concentration. This solubility was about 5 times higher than that
in pure water (0.6 µg/mL). However, curcumin solubility was
significantly (P < 0.05) increased, when TPGS concentration was
higher than curcumin concentration. With 10 times TPGS con-
centration, curcumin solubility was around 189 µg/mL which is
about 315 times higher than that in pure water and about 6 times
higher than the lowest one (32 µg/mL) in this experiment. UH
treatment was not significantly (P > 0.05) affected on the cur-
cumin solubility when the ratio of curcumin to TPGS was 2:1
and 1:1. However, UH treatment was significantly (P < 0.05)
increased curcumin solubility when TPGS was added more than
twice the curcumin concentration. When the ratio of curcumin
to TPGS was 1:2, curcumin solubility was improved about 134%
from 38 to 89 µg/mL. The maximum solubility of 262 µg/mL
was obtained with curcumin to TPGS ratio of 1:10 after UH
treatment. The solubility was not increased anymore with further
increase the TPGS concentration.
In preliminary experiment, high pressure homogenization
(HPH) technique was applied for Cur-TPGS NSs preparation
instead of UH. However, it formed lots of bubbles by TPGS and
made loss of curcumin suspension during HPH process. Finally,
UH process was selected and applied to produce Cur-TPGS NSs,
because it showed more efficient and higher solubility than HPH
technique. UH process destructed solid curcumin particles in a
colloidal dispersion and provided physical stability due to prevent-
ing sedimentation by enough power input and UH treatment time
(Patel and others 2014). Also, stabilizer is critical excipient to form
NS. Selection of an appropriate stabilizer can prevent agglomera-
tion or aggregation of curcumin nanocrystals by reduction of the
high surface energy of them (Patravale and others 2004) TPGS
could thoroughly wet curcumin in water phase and reduce ag-
glomeration of NSs by prevent Ostwald’s ripening. Finally, TPGS
could offer physical stability of Cur-TPGS NSs. (Gao and others
2010). Therefore, TPGS concentration and UH treatment were
pivotal to improve the curcumin solubility in Cur-TPGS NSs.
Particle size, PDI, and zeta potential of Cur-TPGS NSs
Figure 3(A) shows the mean particle size and PDI (polydispersity
index) of Cur-TPGS NSs before and after UH. The mean particle
size and PDI value of Cur-TPGS NSs before UH were increased
from 240 to 479 nm and 0.298 to 0.565, respectively, with TPGS
concentration. The higher PDI value indicates that the NSs are
more heterogeneous whereas smaller PDI value indicates that the
NSs are more homogeneous. After UH treatment, however, the
mean particle sizes were ranged between 208 and 246 nm and not
Figure 3–The effect of the TPGS concentration on (A)
the mean particle size and PDI value and (B) zeta
potential of Cur-TPGS NSs before and after UH
treatment. ∗ Different superscript letters indicate a
significant difference at P < 0.05 by Duncan’s
multiple range test.
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Vol. 81, Nr. 2, 2016 ! Journal of Food Science N497
 Enhancement of curcumin solubility . . .
significantly different (P > 0.05) with TPGS concentration. It has
been also reported that sonication process was very effective to de-
crease particle size and produce homogeneous colloidal system by
reducing agglomeration through management of nucleus growth
condition and population (Luque de Castro and Priego-Capote
2007; Vasconcelos and others 2007; Abbas and others 2015). Re-
duced particle size may improve water solubility and dissolution
rate of the water insoluble compounds which can correlate with
substantial enhancement of oral bioavailability (Tran and others
2015). PDI values were also significantly decreased after UH and
maintained less than 0.3 which means that Cur-TPGS NSs were
maintained in high homogeneity after UH. This result suggested
that UH could effectively decrease the particle size of Cur-TPGS
NSs and ensure more homogeneous size distribution. Figure 3(B)
shows zeta potential (ZP) of Cur-TPGS NSs before and after
UH. ZP values of Cur-TPGS NSs were ranged from –16.4 to
–23.3 mV before UH. Although the ZP of Cur-TPGS NSs in
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Figure 4–(A) FT-IR spectra, (B) DSC thermograms, and (C) XRD patterns peaks of pure curcumin appeared at 2θ = 8.94°, 12.21°, 14.53°,
of curcumin, Cur-TPGS NSs, and TPGS.
N498 Journal of Food Science ! Vol. 81, Nr. 2, 2016
ratio of 2:1 decreased by UH, the ZP of other samples was not
significantly (P > 0.05) different before and after UH. It has been
known that higher ZP value above ±30 mV is usually related
to the good stability of nanoparticles. But it is usually suitable
for nanoparticles with low molecular weight stabilizers and pure
electric stabilization. Theoretically, ZP is deemed to be the elec-
tric potential at shear plane. The electric double layer is formed
by the stern layer and part of the diffusion layer, which plays a
critical role in the stability of the system. However, the adsorbed
layers of large molecules could shift the plane of shear to further
distance from the particle surface (Gao and others 2010). This
results in a reduction of the measured ZP values. Even though
ZP values decreased, Cur-TPGS NSs were relatively stable due to
their steric stabilization (Gao and others 2010; Rachmawati and
others 2013). Therefore, the reduced ZP values are not definitely
correlated with lower stability of Cur-TPGS NSs. On the other
hand, TPGS could prevent the aggregation of small particles be-
cause of its amphiphilic feature of hydrophobic portion of PEG
and hydrophilic portion of tocopherol succinate then NSs could
maintain the long term stability (Yue and others 2013).
Characterization of Cur-TPGS NSs before and after UH
treatment
FT-IR spectra were investigated to observe the chemical in-
teraction between curcumin and TPGS. Figure 4(A) shows the
FT-IR spectra of pure curcumin, Cur-TPGS NS (ratio of 1:1),
and TPGS. In the range of 600 to 4000 cm−1 , the IR spectrum
of Cur-TPGS NS (1:1) was similar to that of pure TPGS. The
typical IR peaks of curcumin were observed at 1512, 1627, and
3507 cm−1 which are assigned to the C=O vibration, the C=C
vibration, and the C=O vibration, and the O–H stretching vibra-
tion, respectively (Mohan and others 2012).Two peaks at 1512 and
1627 cm−1 and were also observed on the spectrum of Cur-TPGS
NS but their intensity was decreased. In particular, the peak at 3507
cm−1 for pure curcumin by O–H stretching vibration was disap-
peared in Cur-TPGS NS as shown in Figure 4(A). It suggested
that the intermolecular hydrogen bonding might be occurred be-
tween curcumin and TPGS due to disappearing. This interaction
led to alter crystalline structure of curcumin to amorphous state
(Suresh and others 2013).
Figure 4(B) shows the DSC thermograms of curcumin, TPGS,
and lyophilized Cur-TPGS NS powders in the ratio of 1:1 and
1:10. A melting endothermic peak of the curcumin powder was
observed at 180 °C. However, the melting peaks of lyophilized
Cur-TPGS NS powders in the ratio of 1:1 and 1:10 and TPGS
were observed at 32.6, 37.6, and 40.2 °C, respectively. Endother-
mic peak of curcumin at 180 °C was disappeared and only the
melting peak near the TPGS peak was observed in lyophilized
Cur-TPGS NS powders (1:1 and 1:10 ratio). The DSC spectrum
of Cur-TPGS NSs was very similar to that of curcumin amor-
phous solid dispersion (Chuah and others 2014). Disappearance of
curcumin endothermic peak might be related to the phase change
of crystalline to amorphous of curcumin by the interactions be-
tween curcumin and TPGS, thus the solubility and dissolution rate
of curcumin could be improved (Suresh and others 2013). There-
fore, an amorphous or disordered crystalline phase of curcumin
might exist in Cur-TPGS NS system.
The crystalline state of Cur-TPGS NSs was investigated us-
ing XRD. Figure 4(C) shows the XRD patterns of curcumin,
Cur-TPGS NSs before and after UH, and TPGS. Characteristic
17.35°, 18.19°, 21.27°, 23.41°, 24.57°, 25.59°, and 27.39°, which
Enhancement of curcumin solubility . . .
indicate that pure curcumin was present as a highly crystalline form
(Donsi and others 2010). The typical characteristic TPGS peaks
were observed at 2θ = 19.10° and 23.29° and these peaks were
also clearly observed in both Cur-TPGS NSs before and after UH.
Two peaks at 2θ = 12.21° and 14.53° for curcumin were disap-
peared for Cur-TPGS NS before UH and 2 peaks at 2θ = 8.94°
and 17.35° were greatly decreased their intensities. In addition,
these 2 peaks at 2θ = 8.94° and 17.35° were disappeared after
UH treatment. These results suggested that UH could be used to
efficiently prepare the amorphous state of Cur-TPGS NSs. XRD
results seem to be consistence with DSC analysis. Based on FT-
IR, DSC, and XRD studies, TPGS may be mainly distributed on
the surface of curcumin and cover the curcumin molecules due to
A B
C D
the appearance of the crystalline structure of TPGS and the dis-
appearance of the characteristic curcumin peaks. The crystalline
structure of curcumin may obstruct its solubility in pure water.
But the amorphous state formed by TPGS and UH can improve
significantly curcumin solubility (Liu and others 2012). These re-
sults inferred that solubility of Cur-TPGS NSs can be improved
due to changing crystalline state to amorphous state as well as small
particles size.
Dissolution test
Figure 5 shows the dissolution behaviors of pure curcumin
and the lyophilized Cur-TPGS NS powder. A semi-sponge-like
powder of Cur-TPGS NSs (ratio of 1:10) was prepared by
Figure 5–Dissolution test of curcumin and the
freeze-dried Cur-TPGS NSs at pH 7.4.
Figure 6–(A) Photographic picture of the freeze-dried
Cur-TPGS NS powder, (B) FE-SEM image of the
freeze-dried Cur-TPGS NSs, and TEM images of Cur-TPGS
NSs with (C) a scale bar of 0.5µm and (D) a scale bar of
100 nm.
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 Enhancement of curcumin solubility . . .
lyophilization, which provided a more stable NS by avoiding Ost-
wald ripening (Gao and others 2010). The freeze-dried powder
exists as yellowish porous fibers, which appear ready for dissolving
in aqueous solution. Approximately 91% of the lyophilized
Cur-TPGS NS powder was homogeneously dissolved within 5
min at pH 7.4, while only 6.5% of the pristine curcumin powder
was dissolved within 120 min as shown in Figure 5. Based on the
previous reports, the freeze-dried curcumin powder obtained by
high-pressure homogenization treatment (without TPGS) showed
a slow dissolution rate and did not fully dissolve until 60 min, while
the freeze-dried Cur-TPGS NSs showed a rapid dissolution rate
and high solubility (about 91%) (Donsi and others 2010). Dissolu-
tion rate of Cur-TPGS NSs was remarkably improved compared
to that of pristine curcumin powder. The major factors to improve
dissolution rate are known as high surface area, wettability, porosity,
amorphous state, and absence of aggregation and agglomeration
(Vasconcelos and others 2007; Suresh and others 2013). Thus, the
dissolution rate of Cur-TPGS NSs could be significantly improved
due to high surface areas by reduction of particles size, amorphous
state, and high porosity based on results of DSC, XRD, and disso-
lution test. This could support that TPGS is very efficient stabilizer
to improve the water solubility and dissolution rate of curcumin.
Morphology of Cur-TPGS NS
Figure 6(A) shows the picture of the freeze-dried Cur-TPGS
NSs. The freeze-dried sample shows a highly porous, sponge-
like morphology with yellow color. The porous structure the
freeze-dried Cur-TPGS NSs was also observed in the FE-SEM
images as shown in Figure 6(B). Based on these photographs, it
can be concluded that the highly porous structure could be mainly
attributed to the good solubility and rapid dissolution rate of the
freeze-dried Cur-TPGS NSs. Many spherical particles were also
observed in the freeze-dried Cur-TPGS NSs as shown in SEM
image. This means that TPGS could homogeneously cover the
surface of the curcumin molecules and form micelle-like round
shape particles. Figure 6(C) and (D) were TEM images of Cur-
TPGS NSs (ratio 1:1) with scale bar of 0.5 µm and 100 nm,
respectively. Cur-TPGS NSs contained a lot of spherical shape
particles like micelles. Based on the previous reports, it is possible
to form TPGS micelles. As shown in the TEM images, the mean
size of the micelles was ranged from 208 to 246 nm, which was
coincided to those measured by zeta size analyzer in the previous
section. These morphology results demonstrated that stable Cur-
N: Nanoscale Food
TPGS NSs were successfully formed by using TPGS as an efficient
stabilizer.
Science
Conclusions
UH process could make Cur-TPGS NSs smaller and more ho-
mogeneous. The mean particle size of Cur-TPGS NSs was signif-
icantly (P < 0.05) decreased after UH treatment. PDI values were
also greatly decreased which means that more homogeneous Cur-
TPGS NSs were produced after UH treatment. Curcumin solubil-
ity was depend to the TPGS concentration and UH treatment. UH
treatment was not significantly (P > 0.05) changed the solubility
when TPGS concentration was equal or less than curcumin con-
centration. However, UH treatment could increase the solubility
when TPGS concentration was more than 1.5 time of curcumin.
Study of thermal characterization proved that TPGS could well
surround and stabilize curcumin molecules in NS system. The
phase change of curcumin from crystalline to amorphous phase
might be the primary reason to improve the water solubility of
curcumin in Cur-TPGS NSs. Lyophilized powder of Cur-TPGS
N500 Journal of Food Science ! Vol. 81, Nr. 2, 2016
NSs showed very fast dissolution rate while pure curcumin powder
could not dissolved in buffer solution. Cur-TPGS NSs prepared
by UH treatment showed a great potential as a good curcumin
delivery carrier with high water solubility and dissolution rate.
Acknowledgments
This research was supported by the International Research
& Development Program of the National Research Founda-
tion of Korea (NRF) funded by the Ministry of Education, Sci-
ence and Technology (MEST) of Korea (Grant number: NRF-
2012K1A3A1A20031356) and Basic Science Research Program
through NRF funded by the Ministry of Education (Grant num-
ber: NRF-2015R1D1A4A01019211).
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N: Nanoscale Food
Science
Vol. 81, Nr. 2, 2016 ! Journal of Food Science N501