International Journal of Technology (2015) 7: 1211-1220

ISSN 2086-9614 © IJTech 2015

SELECTED NATURAL DEEP EUTECTIC SOLVENTS FOR THE EXTRACTION OF

-MANGOSTIN FROM MANGOSTEEN (Garcinia mangostana L.) PERICARP

Kamarza Mulia1*, Elsa Krisanti1, Felita Terahadi1, Sylvania Putri1

1
Department of Chemical Engineering, Faculty of Engineering, Universitas Indonesia, Kampus UI
Depok, Depok 16424, Indonesia

(Received: June 2015 / Revised: September 2015 / Accepted: September 2015)

ABSTRACT
This research considers the application of Natural Deep Eutectic Solvents (NADES) as green
solvents for the extraction of bioactive compounds, mainly -mangostin, from the pericarp of
mangosteen (Garcinia mangostana L.). Extractions were carried out using NADES consisting
of choline chloride, a quarternary ammonium salt, and four hydrogen bond donors: 1,2-
propanediol, citric acid, glycerol, and glucose. -mangostin extraction yield of 2.6
% (w/w) in dried pericarp was obtained using a mixture of choline chloride and 1,2-propanediol
in 1:3 mole ratio. The presence of hydrogen bonding was indicated by the broadening of the OH
peak in the infra-red spectra of the NADES used. The polarity and viscosity data of NADES
were determined to describe the solubility of -mangostin. The decomposition and glass
transition temperatures were determined in order to study their thermal behavior and stability.
The results of this study suggest that NADES made of choline chloride and diol-based
hydrogen bond donors are effective for the extraction of bioactive compounds from the
mangosteen pericarp.

Keywords: -mangostin; Deep eutectic solvent; Extraction; Garcinia mangostana L.; NADES

1. INTRODUCTION
The large-scale usage of conventional organic solvents has been associated with a negative
impact on environment with related health and safety issues. Although organic solvents are able
to extract bioactive substances with high yields, these solvents have high volatility factor or a
tendency to vaporize and some of them have toxicity properties that leave excess residue in the
extracts (Dai et al., 2013a; Azmir et al., 2013). Green solvents are required urgently to replace
hazardous organic solvents (Bi et al., 2013), resulting in what is known as green extraction
processes (Chemat et al., 2012). Initially, ionic liquids (ILs) appeared to be green solvents that
are non-hazardous and reduce waste because they have negligible vapor pressures (Earle &
Seddon, 2000; Earle et al., 2006). Even though ILs are commonly used in various fields,
synthetic ionic liquids are not yet used as solvents in the pharmaceutical industry. This is due to
issues related to high toxicities and irritating properties of some ILs, and also to high synthesis
costs of ILs in general (Dai et al., 2013b; Choi et al., 2011; Angell et al., 2012).
Deep eutectic solvents (DES) are a new type of solvent that have similar physical characteristics
as ionic liquids. DES is a mixture of two or more compounds that consists of a hydrogen bond
acceptor (HBA) and hydrogen bond donors (HBD) that form intermolecular hydrogen bonds
with each other, having a lower melting point than those of the individual components. Most of

* kmulia@che.ui.ac.id, Tel.+62-21-7863516, Fax. +62-21-7863515

Permalink/DOI: http://dx.doi.org/10.14716/ijtech.v6i7.1984
1212 Selected Natural Deep Eutectic Solvents for the Extraction of -Mangostin
from Mangosteen (Garcinia mangostana L.) Pericarp

these solvents will be in liquid form at room temperature (Pena-

Abbott et al. (2004) first reported that DES can be formed between quaternary ammonium salts,
such as choline chloride with a range of amides, carboxylic acids and alcohols. Bi et al. (2013)
reported that DES could be used to extract flavonoid compounds, such as myricetin and
amentoflavone, from Chamaecyparis obtuse. As a solvent for extraction, DES can be reused
after extraction due to its negligible volatility, so it is more environmentally friendly and this
can reduce operating costs (Maugeri et al., 2012; Hayyan et al., 2013). The existence of Natural
Deep Eutectic Solvent (NADES) was reported as being a mixture of various cellular
constituents (primary metabolites) from all kinds of organisms. Therefore, NADES is DES that
contain natural components that are abundant, having diverse chemical properties,
biodegradability and low toxicity (Dai et al., 2013a; Dai et al., 2013b).
Mangosteen (Garcinia mangostana L.) is a tropical tree originating from Indonesia that is
widely used in traditional medicine. Phytochemical studies have shown that mangosteen
pericarp contain secondary metabolites, such as oxygenated and prenylated xanthones. These
xanthones are reported to have antioxidant, antitumoral, anti-inflammatory, antiallergy,
antibacterial, antifungal and antiviral activities (Akao et al., 2008; Yu et al., 2007; Kondo et al.,
-mangostin shown in
Figure 1 being the most abundant. Other xanthones isolated from mangosteen pericarp in
- -mangostin, gartanin and 8-deoxygartanin (Pedraza-
Chaverri et al., 2008). It is reported that a potent anti- -
mangos - - -mangostin) from the pericarp of
mangosteen is effective against human leukemia HL 60 cells, and colon cancer DLD-1 cells
(Akao et al., 2008; Aisha et al., 2012a; Aisha et al., 2012b). The efficacy of mangostin could be
improved when the active compound is administered in the form of a controlled release
formulation, in which the bioactive compounds are released only in the targeted areas within the
human body (Ahmad et al., 2012; Ahmad et al., 2013).

Figure 1 Molecular structure of -mangostin

In this study, NADES is used for the extraction of the mangostins from the pericarp of
mangosteen. The NADES used were mixtures of choline chloride (ChCl) and an organic acid
(citric acid), a sugar (glucose), and two polyalcohols (glycerol and 1,2-propanediol). The
extracts were obtained using a shaking method and analyzed using High Performance Liquid
Chromatography (HPLC) following the procedure reported by Pothitirat (2009). In addition,
ultrasonic-assisted extraction was also carried out for comparison. The physicochemical
properties of NADES obtained in this study were polarity using Nile Red as the solvatochromic
probe, viscosity using a Brookfield viscometer, infrared spectra using Fourier Transform
Infrared (FT-IR) spectroscopy, and thermal behavior using Differential Scanning Calorimetry
(DSC)
Mulia et al. 1213

2. EXPERIMENTAL
2.1. Chemicals
Analytical grade choline chloride (> 98 %), 1,2-propanediol (> 99 %), glycerol (> 99 %), citric
acid, d-(+)-glucose (> 99.5 %), and Nile Red were purchased from Sigma Aldrich. HPLC grade
-mangostin was
purchased from Aktin Chemical Inc. (China).
2.2. Preparation of Raw Material
Mangosteen pericarp was separated and cleaned from its edible parts; the tough outer skin was
peeled; and its inner part was cut and dried at room temperature. After drying, the dried
material was ground using an electric grinder and the powder obtained was dried using an oven
(65oC, 40 min) to reduce the water content. The dried powder that passed through a 20 mesh
sieve was stored in a sealed container to avoid contact with air and exposure to direct sunlight.
2.3. Preparation of NADES
NADES used in this study are mixtures of choline chloride and a HBD having a certain mole
ratio as listed in Table . These NADES were prepared by heating mixtures that consists of
solid-liquid and solid-solid compounds at 50 and 80oC under constant stirring, respectively.
Stirring was continued for a period from 30 90 min until a clear solution was formed (Dai et
al., 2013b).

Table 1 NADES used in this study

HBA:HBD
Code HBA HBD
Mole Ratio
DES-1 1,2-propanediol 1:1
DES-2 1,2-propanediol 1:2
DES-3 1,2-propanediol 1:3
DES-4 choline chloride citric acid 1:1
DES-5 (ChCl) citric acid 2:1
DES-6 glycerol 1:1
DES-7 glycerol 3:2
DES-8 glucose 1:1
DES-9 glucose 5:2

2.4. FT-IR Analysis

FT-IR spectroscopy analysis was performed to analyze the presence of molecular interactions
between choline chloride and HBD. Perkin Elmer Spectrum 1000 FT-IR Spectrophotometer
was used in this study. Aliquots of 0.5 mL liquid samples were scanned in the wavelength range
of 4000-400 cm-1.
2.5. NADES Physicochemical Properties Tests
Physicochemical properties of NADES were studied by performing polarity, viscosity and
calorimetry tests. The polarity of NADES were determined following the procedure reported by
Reichardt (1994) and Ogihara et al. (2004). Nile Red dye was used as the solvatochromic probe
and the change of color was detected by a UV-Vis Spectrometer in the wavelength range of
400 max in nm. The solvent polarity ENR was calculated using the
formula shown in Equation 1:
1214 Selected Natural Deep Eutectic Solvents for the Extraction of -Mangostin
from Mangosteen (Garcinia mangostana L.) Pericarp

(1)

The viscosity test was performed using a Brookfield viscometer at room temperature with LV
spindle no.1 at 6, 12, and 30 rpm. DSC analysis was performed at the National Nuclear Energy
Agency of Indonesia and recorded at temperature range of 50 to 400 C at a rate of 20 C/min.
2.6 -mangostin with NADES
-mangostin using NADES was carried out by mixing aliquots of 0.2 g
mangosteen pericarp powder and 2 g NADES in a sealed extraction tube. The extraction was
carried out at room temperature by shaking the tubes at 65 shake/min. The suspension was then
centrifuged for 15 min at 3000 rpm and filtrated through a filter paper to obtain the supernatant.
The percentage of -mangostin extracted was determined using HPLC several times in 24 h to
find the optimum extraction time. This extraction procedure was repeated for the NADES tested
in triplicate.
2.7 HPLC Analysis
HPLC analysis was performed using the HPLC Shimadzu Prominence UFLC system equipped
with LC-20AD pump, SPD-20A 230 V UV-
and a C-18 column (250 mm long and 4.6 mm diameter). The sample injection volume was 8

mobile phase consisted of 0.1 % (v/v) orthophosphoric acid and acetonitrile. The mobile phase
was filtered -vis
detector wavelength was set at 244 and 320 nm. Prior to injection, the sample was first diluted
with methanol with uniform dilution factor for all samples, and then filtered th
membrane (Sartorius filter syringe, NY).

3. RESULTS AND DISCUSSION

3.1. NADES Structure Analysis with FT-IR
In order to detect conformational changes that occur due to the presence of hydrogen bonds
formed between the anion of choline chloride with the hydroxyl groups of the HBD depicted in
Figure 2, the FT-IR spectra of pure compounds as well as NADES were obtained and analyzed.
Figure 3 shows the IR spectrum of ChCl showing a strong and wide hydroxyl (OH) peak in
3650 3200 cm-1 range. In addition, there are also peaks indicating the presence of a specific
group of quaternary ammonium compounds, in the range of 900 980 cm-1. The absorption peak
which shown at the wavelength of 953.7 cm-1 is suspected to be the peak of the C-N group of
choline chloride. Generally, changes in the structure can be seen from the widening or
narrowing of the peaks involving OH groups, the shift of C-H and C=O peak of acids, or loss of
the representative group peak of pure substances.

Figure 2 Hydrogen bonding between the anion of choline chloride and the hydroxyl group of an HBD

Figure 3 also shows that the absorption peak of the hydroxyl groups of the two NADES consists
of choline chloride and 1,2-propanediol in a molar ratio of 1:2 and 1:3. Further examination of
the three spectra revealed that the peak of the OH group in 1,2-propanediol at 3357 cm-1 is
shifting and widening. This is due to the formation of hydrogen bonds in NADES. At a molar
Mulia et al. 1215

ratio of 1:3, the alcohol group peaks became stronger and wider due to the increasing number of
hydrogen bonds formed. Similar phenomena were found in ChCl: citric acid (1:1) NADES and
ChCl: glycerol (1:1) NADES. The OH group peak of choline chloride was present, but shifted
in NADES. In the 1,2-propanediol IR spectrum, the absorption of the carbon-hydrogen (CH)
sp3 group can also be seen in the 2960 to 2850 cm-1 range. In the ChCl:1,2-propanediol
NADES, this CH peak is more clearly visible for the 1:3 molar ratio mixture. This change is
also due to the effect of the formation of hydrogen bonding that occurs in NADES.

Figure 3 FT-IR spectra of choline chloride, ChCl:1,2-propanediol (1:2), and ChCl:1,2-propanediol (1:3)

3.2. Physical Properties of NADES

Physical properties of NADES were determined to see their effect on the NADES preparation
and on the extraction yields. Polarity and viscosity are common parameters used to describe the
effect of solvents on the solubility of the solute, while the glass transition temperature (Tg) and
decomposition temperature (Td) were determined to study thermal behavior and the stability of
NADES within a certain temperature range. The test results are summarized in Table 2.
The formation of the colored Nile Red - NADES complex took some time, because of the
viscous nature of NADES. Higher solvent polarity parameter (ENR) values indicate a less polar
compound. It is noted that the NADES used in this study have slightly different polarities, in
the range of the polarity of water and methanol having ENR values of 48.21 and 51.89
kcal/mole, respectively (Dai et al., 2013b). In ENR scale, the order of polarity is water DES-
1216 Selected Natural Deep Eutectic Solvents for the Extraction of -Mangostin
from Mangosteen (Garcinia mangostana L.) Pericarp

4/5 DES-8/9 > ethanol > DES-6/7 > DES-1/2/3. NADES with 1,2- propanediol and glycerol
as HBD are found to be less polar than ethanol. NADES having citric acid and glucose as HBD
are more polar than ethanol, having similar ENR to water.

Table 2 Physical properties of NADES and ethanol

Code Viscosity (cP) Tg (oC) Td (oC) ENR* (kcal/mole)
DES-1 37.10 152 322.85 56.50
DES-2 35.20 56.73
DES-3 31.60 56.62
DES-4 82.60 110 287.36 48.05
DES-5 77.50 47.65
DES-6 46.80 290 - 55.62
DES-7 38.80 55.52
DES-8 42.17 175 285.85 47.49
DES-9 27.83 48.71
Ethanol 1.07 51.61
*
ENR was calculated using Equation 1.

Table 2 also shows that the viscosities of NADES with polyalcohols (1,2-propanediol and
glycerol) as HBD are lower than the viscosities of other HBD. Moreover, NADES that contains
HBD with more OH- groups are more viscous, which might be due to the formation of
hydrogen bonds with choline chloride as indicated by their ENR values. The DSC analysis
shows that NADES with citric acid and glucose as HBD have lower decomposition
temperatures than those of NADES with 1,2-propanediol. The higher decomposition
temperature of NADES with propanediol as HBD indicates that this NADES has higher thermal
stability. The decomposition temperature of NADES in the range of 285-322 C, is affected by
the stability of its HBD (Abbas, 2010). The DSC analysis also shows that choline chloride
NADES with different HBD compounds have different glass temperatures.
3.3. -mangostin with Shaking Method
Extraction was carried out by shaking NADES at frequency of 65 shakes/min and at room
temperature (~27oC). Figure 4 shows the extraction yields obtained in 24 hours using NADES
ChCl-1,2-propanediol (1:2) and ethanol as the reference solvent. After two hours, extraction
-mangostin concentration
obtained from extraction began to stabilize. Based on this result, subsequent shaking time was
set to 6 h.
The long extraction time is due to the viscous nature of NADES that make it difficult to break
its intermolecular bonding to form new bonds with mangostin compounds. As a comparison,
ethanol can extract mangostin faster than NADES ChCl-1,2- propanediol (1:2). This is because
ethanol has a lower viscosity than those of NADES, therefore, with the kinetic energy resulted
from the shaking, intermolecular bonding within ethanol active groups were more easily broken
to form new bonds with mangostin active groups. Low viscosity solvents have higher diffusion
coefficients so that the rate of extraction increases. The influence of viscosity ( ) on the
diffusion coefficient (D) is expressed by the Stokes-Einstein equation as shown in Equation 2:

(2)
Mulia et al. 1217

Figure 4 Effect of time on mangostin yield using ChCl-1,2-propanediol (1:2 mole ratio) as
NADES and ethanol as reference solvent

where is inversely proportional to D, k is the Boltzmann constant, and r is the radius of the
solvent molecule. It can be inferred that NADES with a higher viscosity and a larger molecule
than ethanol will have lower diffusivity values, and therefore, need more time to penetrate the
plant matrix. The mangostin might be absorbed on the NADES by physical adsorption and
nd electrostatic
interaction. Polarity might also play a role in extraction efficiency of mangostin.
3.4. Effects of Types and Compositions of NADES on Extraction Yields
Extraction using NADES listed in Table 2 was carried out by shaking at room temperature for 6
h and the results are shown in Figure 5. The data obtained clearly shows that mixtures of
choline chloride in combination with 1,2- -mangostin in much
higher quantities (up to 2.6 %) compared to the other DES containing citric acid, glycerol, and
-mangostin extraction yield was obtained using a mixture of
ChCl salt and 1,2-propanediol with a molar ratio of 1:3 (DES-3). One of the factors that
influence the extraction yield is the polarity of the solvent used. In the polarity scale, DES-1 to
DES-3 have the highest ENR value or the least polar among the HBD tested, and therefore, most
suitable for the extraction of the non-polar compounds such as mangostins. This is consistent
with the theory of "like dissolves like", where a compound will be more easily dissolved by
solvents with similar polarity as it has a similar intermolecular force.
Figure 5 also shows -mangostin extracted as the 1,2-propanediol to
ChCl ratios decreases from 3 to 1 in DES-3 to DES-1, respectively. This is because the addition
of charge carried by ChCl in NADES mixture makes the cohesive energy between molecules in
NADES become stronger due to the increasing number of Cl- ions from ChCl. The
intermolecular interactions in NADES molecules that have more ChCl than the amount of HBD
tend to be stronger than in NADES with a balanced ratio between ChCl and HBD, so the solute
experiences a higher degree of difficulty to break in the intermolecular bond between NADES
molecules.
1218 Selected Natural Deep Eutectic Solvents for the Extraction of -Mangostin
from Mangosteen (Garcinia mangostana L.) Pericarp

Figure 5 Effects of types and compositions of NADES on extraction result

Although polarity is usually the main factor affecting the extraction ability of a solvent, in this
case, it is difficult to observe the extraction trend only in terms of polarity. The polarity results
using the Nile Red test showed that almost all NADES tested have a molar transition energy
value (ENR) similar to each other. There is no direct relationship between polarity and extraction
yield of mangostin. Thus, it can be assumed that in this case, polarity is not the only factor that
influences the interaction between the NADES -mangostin from the mangosteen pericarp.
The effect of viscosity might play an important role in influencing the extraction results. This is
because the energy received by the matrix plant and NADES in the shaking method is too
small, so it is not enough to help the active compounds in the samples to diffuse into the
solvent. NADES with low viscosity tends to give better results either because the flow of active
compounds through solvent system is not blocked or better solvent penetration occurs into the
matrix plant. This could explain the high extraction results using NADES with 1,2-propanediol
HBD.
Other factors to be considered are branches present in the alcohol hydrogen bond donors used.
The alcohol HBD with more branches exerts more steric hindrance, affecting the interaction of
mangostin with chloride ions of ChCl. Steric hindrance caused by the formation of a rigid
conformation of NADES means it has a high surface tension so that a higher energy input is
required for the active compound to interact with the chloride ions in NADES (Bi et al. 2013).
This explains why NADES with glycerol (DES-6 and 7) whose viscosity and polarity are
similar to NADES with 1,2-propanediol (DES-1 to DES- -
mangostin. Glycerol itself as a pure compound has a simple structure, but its OH groups are
adjacent to each other which results in a compact structure. Thus, there is a barrier for chloride
ions to be able to bind freely with all OH groups contained in glycerol, so NADES formed
using glycerol also has a dense and rigid conformation which makes difficult to interact with -
mangostin. For NADES with 1,2-propanediol as HBD, the OH group in 1,2-propanediol might
be locked in a certain position, but the alkane chain might rotate freely. This explains why
extraction with NADES of ChCl-1,2-propanediol gave the highest yield of -mangostin.

4. CONCLUSION
NADES can be used to extract mangostin from the pericarp of the mangosteen fruit with yields
similar to that obtained using ethanol as the reference organic solvent. NADES consisting of
choline chloride and 1,2- -mangostin extraction yields up to 2.6 % (w/w),
much higher than those of NADES containing other hydrogen bonding donors (citric acid,
glycerol, and glucose). This is due to the favorable physicochemical properties of this NADES:
Mulia et al. 1219

slightly polar, less viscous, and low steric hindrance of 1,2-propanediol having only a short
branch. NADES application for mangostin extraction showed the potential of this green solvent
for the extraction and isolation of bioactive compounds from natural materials.

5. ACKNOWLEDGEMENT
The authors are grateful for the financial support from Indonesia Biological Sciences Research
Grant Program contract number CRDF Global USA, IDB 1-80760-DE-14.

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