Article

Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX pubs.acs.org/jced

Solubility and Modeling of Hesperidin in Cosolvent Mixtures of

Ethanol, Isopropanol, Propylene Glycol, and n‑Propanol + Water
Renjie Xu,*,† Yang Cong,‡ Min Zheng,‡ Gaoquan Chen,‡ Jiao Chen,‡ and Hongkun Zhao‡
†
Guangling College, Yangzhou University, YangZhou, Jiangsu 225009, People’s Republic of China
‡
College of Chemistry & Chemical Engineering, Yangzhou University, YangZhou, Jiangsu 225002, People’s Republic of China
*
S Supporting Information

ABSTRACT: Equilibrium solubility of hesperidin in aqueous solutions of

ethanol, isopropanol, propylene glycol, and n-propanol was determined by static
technique at temperatures ranging from 293.15 to 333.15 K under p = 101.1 kPa.
The hesperidin solubility increased monotonously with the increase in mass
fraction of ethanol isopropanol, propylene glycol, and n-propanol and
temperature. At the same composition of alcohol and temperature, the mole
fraction solubility of hesperidin was largest in propylene glycol + water among
the four cosolvent mixtures. The solubilities of hesperidin were correlated with
Jouyban−Acree model, Apelblat−Jouyban−Acree model, and van’t Hoff−
Jouyban−Acree model. The obtained average relative deviations were less than
2.38%.

■ INTRODUCTION
Hesperidin is a flavanone glycoside (CAS Registry no. 520-26-3,
molecular structure shown in Figure 1) found abundantly in
Figure 1. Chemical structure of hesperidin.
citrus fruits. It has been widely used in anticancer, antioxidant,
antimicrobial, and anti-inflammatory activities.1−6 Nevertheless,
its aqueous solubility is very small, which is a key drawback in
formulation development,7,8 and it is poorly absorbed in the
small intestine, which significantly decreases the drug bioavail-
ability.2,3,9,10 Some toxic or unsafe solvents, e.g., chloroform, meth-
anol, and ether, are often employed in the extraction of bioactive
materials.11,12 The above solvents are not appropriate for the
formulation progress. Nontoxic/safe solvents, including ethanol,
isopropanol, PEG-400, and propylene glycol, have been applied
in the formulation process and in the drugs’ solubilization.13−16
Improvement of solubility and bioavailability of hesperidin have
been studied by numerous methods, including microparticles,
complexation, and nanocrystals.7,17,18 In the previous works, only
the solubilities of hesperidin in ethanol, water, isopropanol,
1-butanol, propylene glycol, and PEG-400 are available.19
From practical viewpoints, the drug’s solubility in cosolvent
solutions is very essential in the purification of material, design of
dosage form, and knowing the mechanism regarding the chem-
ical and physical stability of pharmaceutical solutions. So, it is of
great importance to determine the drug solubility in mixed
solvents.20−22
Although several semiempirical and theoretical equations may
be used to forecast the drug solubility in mixed solvents, the
experimental data are needed for pharmaceutical researchers.23
Due to the low solubility of hesperidin in water, the solvent
mixtures can be used to improve the drug solubility. It is generally
known that ethanol is a safe and common cosolvent employed in
the pharmaceutical industry, owing to its high solubilization
capacity. Moreover, ethanol may influence the drug’s absorption,
metabolism, excretion, and distribution.24 Isopropanol is a color-
less and flammable chemical compound with a strong odor. It is
miscible with water, ether, ethanol, and chloroform, and it dissolves
a wide range of nonpolar solvents. Compared to alternative
solvents, it is relatively nontoxic. Isopropanol is employed indi-
vidually or in mixtures with other solvents for different aims25,26
comprising in penetration-enhancing pharmaceutical composi-
tions for topical transepidermal and percutaneous uses.
Propylene glycol is a common cosolvent in pharmacy.27 In con-
trast, n-propanol is not a common cosolvent in the pharma-
ceutical industry, however it is usually employed as a solvent for
cellulose esters and resins.28 Under the considerations indicated
above, the key purpose of the present work is to report the
solubility of hesperidin (component 3) in ethanol (1) + water (2),
isopropanol (1) + water (2), propylene glycol (1) + water (2), and
n-propanol (1) + water (2) mixtures at different temperatures.
Received: November 1, 2017
Accepted: January 26, 2018

© XXXX American Chemical Society A DOI: 10.1021/acs.jced.7b00948

J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

Table 1. Detailed Information of Hesperidin and the Selected Solvents

CAS registry initial mass purification analytical
chemicals number molar mass g·mol−1 source fraction purity final mass fraction purity method method
hesperidin 520-26-3 610.56 Adamas Reagent Co. Ltd., 0.981 0.997 recrystallization HPLCa
China
ethanol 64-17-5 46.06 Sinopharm Chemical 0.995 0.995 GCb
Reagent Co., Ltd., China
isopropanol 67-63-0 60.10 0.994 0.994 GC
propylene 57-55-6 76.09 0.994 0.994 GC
glycol
n-propanol 71-23-8 60.10 0.995 0.995 GC
water 7732-18-5 18.01 our lab conductivity <2 μS·cm−1 distillation conductivity
meter
a
High-performance liquid chromatography. bGas chromatography.

■ EXPERIMENTAL SECTION
Materials and Apparatus. Hesperidin with a purity of
0.981 (mass fraction) was purchased from Adamas Reagent
Co., Ltd., China. The crude material was purified three times
by using crystallization in ethanol. Its final composition was
0.997 (mass fraction), which was confirmed by HPLC (high-
performance liquid chromatography, Agilent 1260). Ethanol,
isopropanol, propylene glycol, and n-propanol were provided
by Sinopharm Chemical Reagent Co., Ltd., China, with purities
greater than 0.993, which were determined using gas
chromatography (Smart (GC-2018)). The water was twice-
distilled water with conductivity below 2 μS·cm−1. The com-
prehensive information on these materials is tabulated
in Table 1.
The experimental apparatus was similar to those used in our
previous publications.29−34 It is illustrated briefly here. The
experimental apparatus comprised a 100 mL jacketed glass vessel
with a circulating mixture of isopropanol + water and an electro-
magnetic agitator. The temperature of the isopropanol + water
mixture was retained at a desired value with a thermostatic bath,
with a model of QYHX-1030 (standard uncertainty, 0.05 K),
purchased from Shanghai Joyn Electronic Co., Ltd., China. A
condenser was employed to stop the solvent from escaping.
Before determination, the reliability of the experimental
apparatus was tested by measuring the benzoic acid solubility
in toluene.29,30
Preparation of Mixed Solvents. In the solubility measure-
ment, an analytical balance with a model of BSA224S was used to
prepare the mixed solvents. Every solvent mixture in a vessel was
around 60 mL with a relative standard uncertainty of 0.0002. The
composition of organic solvent in the solutions changed from
0 to 1 for the n-propanol + water system and from 0.1 to 0.9 for
the other three systems. The local atmospheric pressure was
about 101.1 kPa in our experiment process.
Solubility Determination. In the present work, the equilib-
rium for the binary solutions of ethanol + water, isopropanol +
water, propylene glycol + water, and (n-propanol + water was
built by a static technique,29−34 and HPLC was used to analyze
the hesperidin solubility in equilibrium liquor.
An excess amount of hesperidin and about 60 mL of mixed
solvents were added into the vessel. The temperature of the
mixtures was kept at a certain value via circulating isopropanol +
water solution. In order to acquire the equilibrium time of the
solutions, 0.5 mL of equilibrium liquor was taken out every 2 h
with a 2 mL syringe that was preheated before being used, and
the liquor was analyzed by HPLC. The analytical results showed
that 13 h was enough for all the solutions to arrive at equilibrium.
Once the system was in equilibrium, stirring was stopped.
B DOI: 10.1021/acs.jced.7b00948
An hour later, the clear liquor was withdrawn with a 2 mL syringe
that was precooled or preheated in advance, and then the liquor
was transferred rapidly to a volumetric flask that was preweighed.
The sample was diluted with methanol, and 1 μL was taken out to
be tested with HPLC.
The solubility of hesperidin (xw,T) in mole fraction in the four
mixed solvents was acquired using eq 1, and the initial
composition of mixed solvents (w) was computed via eqs 2
and 3.
m1/M1
x w,T =
m1/M1 + m2 /M 2 + m3 /M3 (1)
m2
w1 = w =
m 2 + m3 (2)
m3
w2 =
m 2 + m3 (3)
Here m1 is the mass of hesperidin; m2 is the mass of isopropanol,
ethanol, propylene glycol, or n-propanol; and m3 is the mass of
water. M1, M2, and M3 denote the molar masses of the corre-
sponding solvents. The relative standard uncertainty for mole
fraction solubility was evaluated to be 3.43%.
Analysis. The composition of hesperidin was tested by using
HPLC (Agilent-1260)19,35 equipped with a reverse phase col-
umn of LP-C18 (250 mm × 4.6 mm). The temperature of the
column was about 303 K, and the wavelength of the detector was
346 nm, which was confirmed via UV-scanning. The mobile
phase included two components, which were methanol and
water. The volume ratio of methanol to water was 45:55. The
final data are the average value of the three tests.
X-ray Powder Diffraction. The hesperidin was charac-
terized by X-ray powder diffraction (XRD) performed on a
HaoYuan DX-2700B instrument. The hesperidin was tested by
Cu Kα radiation (λ = 1.54184 nm). The tube current and voltage
were 30 mA and 40 kV, respectively. The data were gathered
within the range from 5 to 80° at room temperature.
■ RESULTS AND DISCUSSION
XRD Analysis. For the sake of validating the existence of the
polymorph transformation or solvate formation of hesperidin,
the solid equilibrating with liquor is tested by X-ray powder
diffraction. The patterns of all solids in equilibrium with the
mixed solvents are shown in Figure 2. The XRD patterns of all
solids equilibrating with their equilibrium liquor show identical
characteristic peaks with hesperidin (raw material). So, no solvate
formation or polymorph transformation is observed during the
whole process of solubility determination.
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

temperature and content of ethanol, isopropanol, propylene

Figure 2. XRD patterns of hesperidin: (a) raw material; (b) crystallized
in ethanol + water mixture; (c) crystallized in isopropanol + water
mixture; (d) crystallized in propylene glycol + water mixture; and
(e) crystallized in n-propanol + water mixture.
Solubility Data. The solubility of hesperidin in mixed solvents
of ethanol + water, isopropanol + water, propylene glycol + water,
and n-propanol + water together with those in neat solvent19 are
presented in Tables 2, 3, 4, and 5, respectively. Moreover, the
relation between solubility and solvent composition and
temperature are plotted in Figures S1−S4 of the Supporting
Information. It can be observed that the hesperidin solubility is a
function of temperature and solvent composition. The sol-
ubilities of hesperidin increase monotonously with increasing
glycol, and n-propanol for the binary solutions investigated.
The highest solubility value of hesperidin is observed in neat
solvents at T = 333.15 K, for example, 0.0841 × 10−3 in ethanol,
0.0586 × 10−3 in isopropanol, 1.58 × 10−3 in propylene glycol,
and 0.425 × 10−3 in n-propanol.19 Nevertheless, the lowest
solubility of hesperidin is found in neat water (0.000142 × 10−3 at
T = 293.15 K).19 At the same temperature and content of ethanol,
isopropanol, propylene glycol, or n-propanol, the mole fraction
solubility of hesperidin was the largest in propylene glycol
(1) + water (2) solutions, and it was the smallest in isopropanol
(1) + water (2) mixtures. Mole fraction solubility may depend
upon factors such as solvent polarity and chemical structure. The
highest solubility value of hesperidin in neat organic solvents may
be due to lower polarity of ethanol, isopropanol, propylene glycol,
and n-propanol in comparison with higher polarity of water.36
Compared with the other three organic solvents, the hesperidin
solubility values are considerably increased from water to pure
propylene glycol. Addition of a little amount of propylene glycol
in water results in remarkable enhancement in hesperidin solubility.
On the other hand, the solubililies of hesperidin in the four solvent
mixtures are all smaller than that in PEG-40019 at the correspond-
ing temperature. Unfortunately, no data on solubility for hesperidin
in neat n-propanol and aqueous mixtures of n-propanol have been
reported so far in the previous publications for comparison.
Solubility Modeling. The cosolvency models given from
1960 to 2007 for correlating the solid solubility in cosolvent

Table 2. Experimental Mole Fraction Solubility (xeW,T·103) of Hesperidin in Mixed Solvent of Ethanol (w) + Water (1-w) with
Various Mass Fractions within the Temperature Range of T/K = 293.15−333.15 under p = 101.1 kPaa
w
T/K 0b 0.1006 0.2001 0.3003 0.4005 0.4988 0.5994 0.7011 0.8001 0.8997 1b
293.15 0.000142 0.000280 0.000671 0.00168 0.00391 0.00767 0.0129 0.0181 0.0226 0.0260 0.0308
298.15 0.000147 0.000290 0.000701 0.00176 0.00410 0.00809 0.0138 0.0197 0.0245 0.0288 0.0345
303.15 0.000152 0.000301 0.000734 0.00185 0.00432 0.00861 0.0148 0.0215 0.0271 0.0324 0.0395
308.15 0.000156 0.000313 0.000770 0.00195 0.00458 0.00926 0.0160 0.0235 0.0301 0.0369 0.0472
313.15 0.000161 0.000325 0.000803 0.00204 0.00482 0.00983 0.0172 0.0256 0.0334 0.0410 0.0527
318.15 0.000165 0.000339 0.000835 0.00214 0.00508 0.0105 0.0186 0.0280 0.0369 0.0462 0.0612
323.15 0.000170 0.000351 0.000868 0.00222 0.00532 0.0110 0.0198 0.0301 0.0403 0.0520 0.0656
328.15 0.000175 0.000367 0.000903 0.00234 0.00565 0.0118 0.0211 0.0324 0.0438 0.0588 0.0779
333.15 0.000180 0.000382 0.000938 0.00245 0.00593 0.0125 0.0226 0.0347 0.0473 0.0651 0.0845
a
Standard uncertainties, u, are u(T) = 0.05 K and u(p) = 0.45 kPa. Relative standard uncertainty. ur. is ur (xeW,T) = 0.0343. Solvent mixtures were
prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of ethanol in
mixed solvents of ethanol (w) + water (1-w). bTaken from ref 19.

Table 3. Experimental Mole Fraction Solubility (xeW,T·103) of Hesperidin in Mixed Solvent of Isopropanol (w) + Water (1-w) with
Various Mass Fractions within the Temperature Range of T/K = 293.15−333.15 under p = 101.1 kPaa
w
T/K 0b 0.1008 0.1991 0.3007 0.4001 0.5012 0.5997 0.7004 0.8002 0.9009 1b
293.15 0.000142 0.000967 0.00288 0.00531 0.00693 0.00779 0.00832 0.00947 0.0113 0.0122 0.0129
298.15 0.000147 0.000987 0.00295 0.00551 0.00730 0.00837 0.00912 0.0106 0.0129 0.0143 0.0153
303.15 0.000152 0.00101 0.00302 0.00574 0.00774 0.00902 0.0102 0.0120 0.0149 0.0167 0.0187
308.15 0.000156 0.00103 0.00310 0.00595 0.00820 0.00964 0.0109 0.0132 0.0170 0.0202 0.0214
313.15 0.000161 0.00106 0.00319 0.00622 0.00867 0.0105 0.0122 0.0151 0.0194 0.0241 0.0261
318.15 0.000165 0.00108 0.00328 0.00644 0.00918 0.0113 0.0134 0.0169 0.0222 0.0276 0.0310
323.15 0.000170 0.00111 0.00338 0.00676 0.00982 0.0124 0.0151 0.0194 0.0261 0.0331 0.0382
328.15 0.000175 0.00114 0.00352 0.00708 0.0105 0.0135 0.0168 0.0220 0.0302 0.0392 0.0462
333.15 0.000180 0.00118 0.00366 0.00752 0.0112 0.0151 0.0193 0.0259 0.0364 0.0485 0.0586
a
Standard uncertainties, u, are u(T) = 0.05 K and u(p) = 0.45 kPa. Relative standard uncertainty, ur, is ur (xeW,T) = 0.0343. Solvent mixtures were
prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of isopropanol
in mixed solvents of isopropanol (w) + water (1-w). bTaken from ref 19.

C DOI: 10.1021/acs.jced.7b00948
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

Table 4. Experimental Mole Fraction Solubility (xeW,T·103) of Hesperidin in Mixed Solvents of Propylene Glycol (w) + Water (1-w)
with Various Mass Fractions within the Temperature Range of T/K = 293.15−333.15 under p = 101.1 kPaa
w
T/K 0b 0.1004 0.1997 0.3009 0.4005 0.5001 0.5998 0.7005 0.8011 0.9002 1b
293.15 0.000142 0.00126 0.00668 0.0243 0.0611 0.118 0.187 0.256 0.318 0.376 0.443
298.15 0.000147 0.00129 0.00682 0.0249 0.0634 0.125 0.202 0.286 0.365 0.443 0.535
303.15 0.000152 0.00131 0.00695 0.0255 0.0654 0.131 0.214 0.310 0.405 0.511 0.647
308.15 0.000156 0.00134 0.00707 0.0261 0.0679 0.138 0.231 0.336 0.453 0.574 0.725
313.15 0.000161 0.00137 0.00723 0.0268 0.0705 0.146 0.248 0.370 0.509 0.656 0.886
318.15 0.000165 0.00140 0.00737 0.0275 0.0736 0.153 0.267 0.405 0.563 0.745 0.984
323.15 0.000170 0.00143 0.00753 0.0283 0.0763 0.161 0.284 0.441 0.625 0.846 1.14
328.15 0.000175 0.00146 0.00772 0.0290 0.0789 0.170 0.303 0.478 0.691 0.953 1.31
333.15 0.000180 0.00150 0.00795 0.0301 0.0827 0.181 0.328 0.532 0.779 1.10 1.58
a
Standard uncertainties, u, are u(T) = 0.05 K and u(p) = 0.45 kPa. Relative standard uncertainty, ur, is ur (xeW,T) = 0.0343. Solvent mixtures were
prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of propylene
glycol in mixed solvents of propylene glycol (w) + water (1-w). bTaken from ref 19.

Table 5. Experimental Mole Fraction Solubility ((xeW,T·103)) of Hesperidin in Mixed Solvents of n-Propanol (w) + Water (1-w) with
Various Mass Fractions within the Temperature Range of T/K = 293.15−333.15 under p = 101.1 kPaa
w
b
T/K 0 0.1007 0.1997 0.3001 0.4003 0.5011 0.5988 0.7002 0.8007 0.9005 1
293.15 0.000142 0.00200 0.00942 0.0225 0.0345 0.0429 0.0498 0.0602 0.0801 0.111 0.142
298.15 0.000147 0.00202 0.00950 0.0229 0.0356 0.0446 0.0539 0.0654 0.0894 0.122 0.166
303.15 0.000152 0.00204 0.00958 0.0232 0.0368 0.0476 0.0571 0.0724 0.0967 0.138 0.190
308.15 0.000156 0.00206 0.00966 0.0236 0.0381 0.0492 0.0617 0.0788 0.109 0.156 0.218
313.15 0.000161 0.00208 0.00974 0.0240 0.0391 0.0527 0.0656 0.0875 0.120 0.180 0.252
318.15 0.000165 0.00211 0.00982 0.0244 0.0405 0.0546 0.0704 0.0931 0.136 0.199 0.289
323.15 0.000170 0.00213 0.00990 0.0248 0.0415 0.0579 0.0746 0.102 0.146 0.227 0.329
328.15 0.000175 0.00216 0.0100 0.0253 0.0429 0.0602 0.0800 0.111 0.165 0.249 0.375
333.15 0.000180 0.00219 0.0101 0.0257 0.0444 0.0636 0.0855 0.120 0.181 0.282 0.425
a
Standard uncertainties, u, are u(T) = 0.05 K and u(p) = 0.45 kPa. Relative standard uncertainty, ur, is ur (xeW,T) = 0.0343. Solvent mixtures were
prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of n-propanol in
mixed solvents of n-propanol (w) + water (1-w). bTaken from ref 19.

mixtures have been reviewed by Jouyban and co-workers.23 In ⎛ B1 ⎞ ⎛ B2 ⎞

the present work, three models are applied in correlating the ln x w,T = w1⎜A1 + ⎟ + w2⎜A 2 + ⎟
⎝ T /K ⎠ ⎝ T /K ⎠
hesperidin solubility in mixed solvents of ethanol + water, 2
isopropanol + water, propylene glycol + water, and n-propanol + w1w2
water, which are the Jouyban−Acree model,23,30,37 the van’t
+ ∑ Ji (w1 − w2)i
T /K i=0 (6)
Hoff−Jouyban−Acree model,30,37 and the modified Apelblat−
Jouyban−Acree model.30,37 A1, B1 and A2, B2 are model parameters.
The Jouyban−Acree model, expressed as eq 4, gives a precise The modified Apelblat equation is expressed as
description for solute solubility in solvent mixtures.23,30,37 B
ln x T = A + + C ln(T /K)
2 T /K (7)
w1w2
ln x w,T = w1ln x1,T + w2 ln x 2,T + ∑ Ji (w1 − w2)i here A, B, and C are parameters.
T /K i=0
By introducing eqs 4−7, the modified Apelblat−Jouyban−
(4)
Acree model is derived and described as eq 8.30,37
where xw,T stands for the solubility of solute in mole fraction in ⎡ B1 ⎤
mixed solutions at T/K; w1 and w2 represent the content of ln x w,T = w1⎢A1 + + C1ln(T /K )⎥
⎣ T /K ⎦
solvents 1 (ethanol, isopropanol, propylene glycol, or n-propanol) ⎡⎛ ⎤ 2
B2 ww
and 2 (water) free of the solute (hesperidin), respectively; and + w2⎢⎜A 2 + + C2 ln(T /K )⎥ + 1 2 ∑ Ji (w1 − w2)i
⎢⎣⎝ T /K ⎦ T /K i=0
x1,T and x2,T denote the solute solubility in mole fraction in neat
solvent. Ji are model parameters. (8)
The van’t Hoff equation is expressed as The determined solubility of hesperidin in ethanol + water,
isopropanol + water, propylene glycol + water, and n-propanol +
B water solutions is correlated using eqs 4, 6, and 8. The objective
ln x T = A +
T /K (5) function is defined as
e c
The van’t Hoff−Jouyban−Acree model30,37 may be acquired by F= ∑ (lnx w,T − lnx w,T)2
combining eqs 4 and 5, and it is expressed as eq 6. i=1 (9)

D DOI: 10.1021/acs.jced.7b00948
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

Table 6. Values of Parameters Obtained Using Solubility Models

Jouyban−Acree van’t Hoff− Jouyban−Acree Apelblat− Jouyban−Acree
parameter value parameter value parameter value
ethanol + water
J0 1535.85 A1 −1.822 A1 17.11
J1 420.36 B1 −2515.38 B1 −3414.89
J2 −1136.47 A2 −13.82 C1 −2.79
B2 −571.41 A2 −14.77
J0 1537.83 B2 −525.82
J1 418.90 C2 0.139
J2 −1131.53 J0 1525.35
J1 396.69
J2 −1162.58
RAD·102 0.82 0.83 0.81
RMSD·105 0.05 0.05 0.06
isopropanol + water
J0 2044.26 A1 1.99 A1 −336.5
J1 −2099.04 B1 −3920.56 B1 12014.31
J2 1632.80 A2 −13.82 C1 50.04
B2 −571.41 A2 −14.77
J0 2055.38 B2 −525.82
J1 −2083.73 C2 0.14
J2 1660.72 J0 2052.07
J1 −2089.26
J2 1652.41
RAD·102 1.02 2.38 1.22
RMSD·105 0.02 0.06 0.03
propylene glycol + water
J0 3156.06 A1 2.64 A1 −16.33
J1 −1488.75 B1 −3038.07 B1 −2122.53
J2 156.39 A2 −13.82 C1 2.79
B2 −571.41 A2 −14.77
J0 3161.27 B2 −525.82
J1 −1484.31 C2 0.14
J2 169.41 J0 3166.97
J1 −1473.35
J2 183.63
RAD·102 0.74 0.74 0.64
RMSD·105 0.41 0.77 0.91
n-propanol + water
J0 2635.52 A1 0.32 A1 −36.51
J1 −3098.64 B1 −2695.34 B1 −972.85
J2 1858.14 A2 −13.82 C1 5.45
B2 −571.41 A2 −22.24
J0 2639.98 B2 −180.65
J1 −3095.57 C2 1.248
J2 1869.28 J0 2642.5
J1 −3089.34
J2 1875.61
RAD·102 0.42 0.58 0.53
RMSD·105 0.08 0.10 0.12

With the intention of demonstrating the deviations and evaluating here N denotes the number of data points; xew,T refers to the
the selected models, RMSD (root-mean-square deviation) and determined solubility in the present work; and xcw,T is the solubility
RAD (the relative average deviation) are employed. computed by using models.
N
According to the determined solubility data, the equation
c e
∑i = 1 (x w,T − x w,T)2 parameters are attained with Mathcad software. The obtained
RMSD =
N (10) data of equation parameters along with the RAD and RMSD
values are tabulated in Table 6. The solubility of hesperidin in the
1 ⎛ |x w,T
c e
− x w,T|⎞ four solvent mixtures of ethanol + water, isopropanol + water,
RAD = ⎜
∑⎜ e
⎟⎟ propylene glycol + water, and n-propanol + water is calculated,
N ⎝ x w,T ⎠ (11) and the calculated values using the Jouyban−Acree model are
E DOI: 10.1021/acs.jced.7b00948
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data
plotted in Figures S1−S4 of the Supporting Information. It can
be seen from Table 6 that the largest RAD value is 2.38%, which
was acquired via the van’t Hoff−Jouyban−Acree model for
isopropanol + water mixtures. In addition, the RMSD values are
all less than 0.91 × 10−5. The RAD and RMSD values acquired by
using the Jouyban−Acree model are relatively small. On the
whole, the three models may all be used to correlate the hesper-
idin solubility in ethanol + water, isopropanol + water, propylene
glycol + water, and n-propanol + water solutions.
■
CONCLUSION
The hesperidin solubility in four mixed solvents of ethanol (1) +
water (2), isopropanol (1) + water (2), propylene glycol (1) +
water (2), and n-propanol (1) + water (2) at temperatures ranging
from 293.15 to 333.15 K was determined. The solubilities of
hesperidin increased monotonously with the increasing mass
fractions of ethanol, isopropanol, propylene glycol, and n-propanol
and temperature for the studied binary solutions. The maximum
solubility value of hesperidin was observed in neat solvents at T =
333.15 K (0.0841 × 10−3 in ethanol, 0.0586 × 10−3 in isopropanol,
1.58 × 10−3 in propylene glycol, and 0.425 × 10−3 in n-propanol).
However, the lowest solubility value of hesperidin was found in
neat water (0.000142 × 10−3 at T = 293.15 K). At the same
solvent composition and temperature, the hesperidin solubility
in propylene glycol + water was greater than those in n-propanol
+ water, isopropanol + water, and ethanol + water mixtures. The
higher solubility of hesperidin in neat organic solvents might be
contributed to the lower polarity of ethanol, isopropanol, pro-
pylene glycol, and n-propanol in comparison with the higher
polarity of water. Furthermore, the hesperidin solubility was well
correlated, it acquired RAD lower than 2.38% and RMSD lower
than 0.91 × 10−5.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jced.7b00948.
Solubility (x) of hesperidin in four cosolvent mixtures with
various mass fractions at different temperatures (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*Tel: + 86 514 87993918; Fax: + 86 514 87994009; E-mail:
279483919@qq.com.
ORCID
Renjie Xu: 0000-0003-1888-8864
Hongkun Zhao: 0000-0001-5972-8352
Notes
The authors declare no competing financial interest.
■
REFERENCES
(1) Garg, A.; Garg, S.; Zaneveld, L. J. D.; Singla, A. K. Chemistry and
Pharmacology of the Citrus Bioflavonoid Hesperidin. Phytother. Res.
2001, 15, 655−669.
(2) Salas, M. P.; Céliz, G.; Geronazzo, H.; Daz, M.; Resnik, S. L.
Antifungal Activity of Natural and Enzymatically-Modified Flavonoids
Isolated from Citrus Species. Food Chem. 2011, 124, 1411−1415.
(3) Cao, R. G.; Yang, X.; Strappe, P.; Blanchard, C.; Zhou, Z. K. Natural
Products Derived from Tea on the Solubility of Hesperidin by LC-
TOF/MS and NMR. Int. J. Food Prop. 2017, 20, S270.
(4) Chiba, H.; Uehara, M.; Wu, J.; Wang, X.; Masuyama, R.; Suzuki, K.;
Kanazawa, K.; Ishimi, Y. Hesperidin, a Citrus Flavonoid, Inhibits Bone
F DOI: 10.1021/acs.jced.7b00948
Article
Loss and Decreases Serum and Hepatic Lipids in Ovariectomized Mice.
J. Nutr. 2003, 133, 1892−1897.
(5) Kanno, S.; Shouji, A.; Asou, K.; Ishikawa, M. Effects of Naringin on
Hydrogen Peroxide-Induced Cytotoxicity and Apoptosis in P388 Cells.
J. Pharmacol. Sci. 2003, 92, 166−170.
(6) Benavente-Garcia, O.; Castillo, J. Update on Uses and Properties of
Citrus Flavonoids: New Findings in Anticancer, Cardiovascular, and
Anti-Inflammatory Activity. J. Agric. Food Chem. 2008, 56, 6185−6205.
(7) Freag, M. S.; Elnaggar, Y. S. R.; Abdallah, O. Y. Development of
Novel Polymer-Stabilized Diosmin Nanosuspensions: In Vitro Apprais-
al and Ex Vivo Permeation. Int. J. Pharm. 2013, 454, 462−471.
(8) Freag, M. S.; Elnaggar, Y. S. R.; Abdallah, O. Y. Lyophilized
Selfphytosomal Nanocarriers (Lspns) as Platforms for Enhanced
Diosmin Delivery: Optimization and Ex-Vivo Permeation. Int. J.
Nanomed. 2013, 8, 2385−2397.
(9) Mauludin, R.; Müller, R. H. Physicochemical Properties of
Hesperidin Nanocrystal. Int. J. Pharm. Pharm. Sci. 2013, 5, 954−960.
(10) Manach, C. L.; Morand, C.; Gil-Izquierdo, A.; Bouteloup-
Demange, C.; Rémésy, C. Bioavailability in Humans of the Flavanones
Hesperidin and Narirutin after the Ingestion of Two Doses of Orange
Juice. Eur. J. Clin. Nutr. 2003, 57, 235−242.
(11) Jassbi, A. R.; Miri, R.; Asadollahi, M.; Javanmardi, N.; Firuzi, O.
Cytotoxic, Antioxidant and Antimicrobial Effects of Nine Species of
Woundwort (Stachys) Plants. Pharm. Biol. 2014, 52, 62−67.
(12) Yadav, U. C. S.; Baquer, N. Z. Pharmacological Effects of
Trigonella Foenumgraecum L. in Health and Disease. Pharm. Biol. 2014,
52, 243−254.
(13) Jimenez, J. A.; Martinez, F. Thermodynamic Study of the
Solubility of Acetaminophen in Propylene Glycol + Water Cosolvent
Mixtures. J. Braz. Chem. Soc. 2006, 17, 125−134.
(14) Shakeel, F.; Alanazi, F. K.; Alsarra, I. A.; Haq, N. Solubility
Prediction of Indomethacin in PEG 400 + Water Mixtures at Various
Temperatures. J. Mol. Liq. 2013, 188, 28−32.
(15) Shakeel, F.; Alanazi, F. K.; Alsarra, I. A.; Haq, N.
Thermodynamics-Based Mathematical Model for Solubility Prediction
of Glibenclamide in Ethanol-Water Mixtures. Pharm. Dev. Technol.
2014, 19, 702−707.
(16) Shakeel, F.; Anwer, M. K.; Shazly, G. A.; Jamil, S. Measurement
and Correlation of Solubility of Bioactive Compound Silymarin in Five
Different Green Solvents at 298.15 to 333.15 K. J. Mol. Liq. 2014, 195,
255−258.
(17) Sansone, F.; Rossi, A.; Del Gaudio, P.; De Simone, F.; Aquino, R.
P.; Lauro, M. R. Hesperidin Gastroresistant Microparticles by
Spraydrying: Preparation, Characterization, and Dissolution Profiles.
AAPS PharmSciTech 2009, 10, 391−401.
(18) Ficarra, R.; Tommasini, S.; Raneri, D.; Calabrò, M. L.; Di Bella, M.
R.; Rustichelli, C.; Gamberini, M. C.; Ficarra, P. Study of Flavonoids/
Beta-Cyclodextrins Inclusion Complexes by NMR, FT-IR, DSC, X-ray
Investigation. J. Pharm. Biomed. Anal. 2002, 29, 1005−1014.
(19) Anwer, M. K.; Al-Shdefat, R.; Jamil, S.; Alam, P.; Abdel-Kader, M.
S.; Shakeel, F. Solubility of Bioactive Compound Hesperidin in Six Pure
Solvents at (298.15 to 333.15) K. J. Chem. Eng. Data 2014, 59, 2065−
2069.
(20) Jouyban, A. Handbook of Solubility Data for Pharmaceuticals; CRC
Press: Boca Raton, FL, 2010.
(21) Rubino, J. T. Cosolvents and Cosolvency. In Encyclopedia of
Pharmaceutical Technology; Swarbrick, J., Boylan, J. C., Eds.; Marcel
Dekker, Inc.: New York, 1988; Vol. 3, pp 375−398.
(22) Yalkowsky, S. H. Solubility and Solubilization in Aqueous Media;
American Chemical Society and Oxford University Press: New York,
1999; pp 180−235.
(23) Jouyban, A. Review of the Cosolvency Models for Predicting
Solubility of Drugs in Water-cosolvent Mixtures. J. Pharm. Pharm. Sci.
2008, 11, 32−58.
(24) Jouyban, A.; Shokri, J.; Barzegar-Jalali, M.; Hassanzadeh, D.;
Acree, W. E., Jr.; Ghafourian, T.; Nokhodchi, A. Solubility of
Chlordiazepoxide, Diazepam, and Lorazepam in Ethanol + Water
Mixtures at 303.2 K. J. Chem. Eng. Data 2009, 54, 2142−2145.
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

(25) Breon, T. L.; Paruta, A. N. Solubility Profiles for Several

Barbiturates in Hydroalcoholic Mixtures. J. Pharm. Sci. 1970, 59, 1306−
1313.
(26) Herkenne, C.; Naik, A.; Kalia, Y. N.; Hadgraft, J.; Guy, R. H. Effect
of Propylene Glycol on Ibuprofen Absorption into Human Skin in Vivo.
J. Pharm. Sci. 2008, 97, 185−197.
(27) Avdeef, A. Solubility of Sparingly-Soluble Ionizable Drugs. Adv.
Drug Delivery Rev. 2007, 59, 568−590.
(28) Delgado, D. R.; Martínez, F. Solubility and Solution
Thermodynamics of Some Sulfonamides in 1-Propanol + Water
Mixtures. J. Solution Chem. 2014, 43, 836−852.
(29) Han, S.; Meng, L.; Du, C. B.; Xu, J.; Cheng, C.; Wang, J.; Zhao, H.
K. Solubility Measurement and Thermodynamic Modeling of 4-
Nitrophthalimide in Twelve Pure Solvents at Elevated Temperatures
Ranging from (273.15 to 323.15) K. J. Chem. Eng. Data 2016, 61, 2525−
2535.
(30) Cheng, C.; Cong, Y.; Du, C. B.; Wang, J.; Yao, G. B.; Zhao, H. K.
Solubility Determination and Thermodynamic Models for Dehydroe-
piandrosterone Acetate in Mixed Solvents of (Ethyl Acetate +
Methanol), (Ethyl Acetate + Ethanol) and (Ethyl Acetate +
Isopropanol). J. Chem. Thermodyn. 2016, 101, 372−379.
(31) Wang, J.; Xu, R. J.; Xu, A. L. Solubility Determination and
Thermodynamic Functions of 2-Chlorophenothiazine in Nine Organic
Solvents from T = 283.15 K to T = 318.15 K and Mixing Properties of
Solutions. J. Chem. Thermodyn. 2017, 106, 132−144.
(32) Xu, A. L.; Xu, R. J.; Wang, J. Solubility Determination and
Thermodynamic Modelling of Terephthaldialdehyde in ten Organic
Solvents from T = (273.15 to 318.15) K and Mixing Properties of
Solutions. J. Chem. Thermodyn. 2016, 102, 188−198.
(33) Yao, G. B.; Li, Z. H.; Xia, Z. X.; Yao, Q. C. Solubility of N-
Phenylanthranilic Acid in Nine Organic Solvents from T = (283.15 to
318.15) K: Determination and Modeling. J. Chem. Thermodyn. 2016,
103, 218−227.
(34) Wang, J.; Xu, A. L.; Xu, R. J. Solubility of 2-Nitro-p-
phenylenediamine in Nine Pure Solvents and Mixture of (Methanol +
N-Methyl-2-pyrrolidone) from T = (283.15 to 318.15) K: Determi-
nation and Modeling. J. Chem. Thermodyn. 2017, 108, 45−58.
(35) Joubert, E.; Otto, F.; Grüner, S.; Weinreich, B. Reversed-phase
HPLC Determination of Mangiferin, Isomangiferin and Hesperidin in
Cyclopia and the Effect of Harvesting Date on the Phenolic
Composition of C. Genistoides. Eur. Food Res. Technol. 2003, 216,
270−273.
(36) Smallwood, I. M. Handbook of Organic Solvent Properties; Amold:
London, 1996.
(37) Jouyban, A.; Fakhree, M. A. A.; Acree, W. E. Comment on
“Measurement and Correlation of Solubilities of (z)-2-(2-Aminothiazol-
4-yl)-2-methoxyiminoacetic Acid in Different Pure Solvents and Binary
Mixtures of Water + (Ethanol, Methanol, or Glycol). J. Chem. Eng. Data
2012, 57, 1344−1346.

G DOI: 10.1021/acs.jced.7b00948
J. Chem. Eng. Data XXXX, XXX, XXX−XXX