Article

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

Equilibrium Solubility Determination and Modeling of

Fenbendazole in Cosolvent Mixtures at (283.15−328.15) K
Jianqiang Zhang,† Chunjuan Huang,‡ Juan Chen,‡ and Renjie Xu*,‡
†
Henan Provincial Key Laboratory of Surface & Interface Science, Zhengzhou University of Light Industry, Zhengzhou, Henan
450001, People’s Republic of China
‡
Guangling College, Yangzhou University, Yangzhou, Jiangsu 225000, People’s Republic of China
*
S Supporting Information
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ABSTRACT: Four liquid mixtures formed by mixing water and four organic
solvents (methanol, ethanol, ethylene glycol, and N,N-dimethylformamide
Downloaded via NOTTINGHAM TRENT UNIV on August 17, 2019 at 01:58:43 (UTC).

(DMF)) in different ratios were used as solvents, and fenbendazole was used as
a solute. The concentration of the solute within T = 283.15−328.15 K and in
different mixed solvents was determined by static techniques at p = 101.1 kPa.
The experimental solubility of fenbendazole was obviously affected by the solution
system temperature and organic solvent concentration. High temperature and
high concentration were beneficial to the dissolution of solutes. Conversely, low
temperature and low concentration hinder dissolution. In all mixture systems
studied, the control of temperature and organic solvent concentration remained
unchanged, and the DMF + water system was most beneficial for the dissolution
of solutes. Solid powder at the bottom of the vessel when the fenbendazole
dispersion process achieved dynamic equilibrium was tested by XPRD. Several
thermodynamic cosolvency models Jouyban−Acree model, van’t Hoff−Jouyban−
Acree model, and Apelblat−Jouyban−Acree model were employed to calculate the solubility data of fenbendazole. The
calculation result has a very little error with the experimental value and the relative average deviation value of ≤2.90% and the
root-mean-square deviation value of ≤1.440 × 10−3. The purpose of this work is to provide basic information and extend the
library of solubility of bioactive drug fenbendazole in aqueous solutions, relevant for pharmaceutical separation, purification, and
further application.

■ INTRODUCTION
Aqueous solubility of a drug is an indispensable process for the
study of biological activity and drug mechanism of many liquid
dosage form and formulation of soft gelatin capsules drugs.1−7
Due to the low concentration of some drugs in water, it may
obviously have an influence on the biopharmaceutical and
pharmacokinetic properties of the drugs.8 For common’s point,
it would be efficient to employ classical methods, that is,
cosolvents, surfactants, and cosolvents containing hydrotropy
to promote solute to dissolve in water more easily.1,7 In some
degrees, cosolvency is the most effective solubilization strategy
to improve the solubility of which aqueous cosolvent mixtures
are essential for pharmaceutical fields in that it acted as a
reaction medium during the synthesis of the drug and also
removes impurities in the drug to purify the drug.3,4,9 Solvent
crystallization is a crucial step to refine the drug fenbendazole
products for commercial market. Fenbendazole is almost
insoluble in water resulting in the low bioavailability of oral
drugs; meanwhile, drug solubility in aqueous mixtures is also
required in some further pharmaceutical applications.8,10,11
Fenbendazole (C15H13N3O2S; CAS Registry No. 43210-67-
9; molar mass 299.35 g·mol−1; chemical name, methyl N-(6-
phenylsulfanyl-1H-benzoimidazol-2-yl) carbamate, molecule
structure shown in Figure S1 of the Supporting Information),
a veterinary drug with white crystalline powder, belongs to a
member of the series of benzimidazoles that is substituted by
(methoxycarbonyl)amino and phenylsulfanediyl groups at 2-
and 5-positons possessing 5-thiophenyl.12−14 Scientific reports
indicated that fenbendazole is extensively efficacious broad-
spectrum insecticides applied to human and animals,
particularly as veterinary medicine for the treatment of
nematode infections, internal worm parasites, tapeworm
infections, and pinworm populations in animals.13−21 Not
only that but also fenbendazole has excellent negligible damage
to the body, has an excellent curative effect on the lesion, does
not produce side effects, and is therefore the first choice for the
treatment of rodent inflammation.13−15,18,19 It also has a role as
an antinematodal drug when combined with various kinds of
supplementary vitamins.19 So far, literature surveys have been
reported concerning the synthesis of fenbendazole.22−25 In
regard to the process of fenbendazole preparation, it often
appears low purity, poor quality, and unsatisfactory color of the
product. To date, fenbendazole remains the preferred
insecticide in modern animal husbandry, hence, which leads
Received: May 27, 2019
Accepted: August 5, 2019

© XXXX American Chemical Society A DOI: 10.1021/acs.jced.9b00471

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

the increasing demand for it year by year. Considering the

analytical
abundant biological activity and medicinal value of the

conductivity
method
fenbendazole product, it is necessary to satisfy product’s

HPLCa

meter
criteria including the high purity, good quality and color, and

GCb

GC

GC

GC
strong stability, thus meeting downstream industrial needs.
What is more, drug’s solubility in aqueous mixtures is a key

purification

distillation
basis for separating and refining the fenbendazole product

method
significantly. To obtain as much as possible of higher purity
fenbendazole, some available solvents such as methanol,
ethanol, isopropanol, dimethylsulfoxide (DMSO), poly-
(ethylene glycol)s, etc. were purified by means of the

conductivity, <2 μS·cm−1

final massfraction purity
cosolvency.3,4 The study’s help for process improvement and
industrial production lies in studying on the dispersion of
fenbendazole in aqueous solutions of several groups of organic
solvents at T = 283.15−328.15 K with p = 101.1 kPa.

0.995

0.998

0.996

0.996

0.998
EXPERIMENTAL SECTION
Drug, Reagents, and Methods. Fenbendazole (mass
fraction ≥0.995) was purchased from Adamas-Beta Reagent

fraction purity
initial mass
Co., Ltd., China without further purification. The organic

0.995

0.998

0.996

0.996

0.998
reagents (methanol, etc.) used in this experiment were all
produced by Merck Reagent Co., Ltd., China, and the ratio of
the quality of impurities to the total mass of the drug did not
exceed 0.005, which was checked by gas chromatography (GC,

Adamas Reagent Co. Ltd.,

Merck Reagent Co., Ltd.,

Merck Reagent Co., Ltd.,

Merck Reagent Co., Ltd.,

Merck Reagent Co., Ltd.,

FULI 9790, China). The water required for this research work
was distilled water (conductivity <2 μS·cm−1) obtained by two
distillations in the laboratory. The specific details of other solid
source

drugs involved and the abovementioned liquid reagents are

detailed in Table 1. The dissolution experiment of
China

China

China

China

China
our lab
fenbendazole was carried out on a set of equipment with
constant temperature and agitation. A simple illustration of the
working principle is shown in Figure S2 of the Supporting
CAS reg. no.
43210-67-9

7732-18-5
Information. The working principle was almost the same as the
107-21-1
67-56-1

64-17-5

equipment involved before.26 The first step was to briefly 68-12-2

introduce the composition of the stirring function zone.
Table 1. Detailed Information of Fenbnedazole and the Selected Solvents

Glassware containing solvents and solutes was placed within

methyl N-(6-phenylsulfanyl-1H-benzoimidazol-2-yl)carbamate

the effective distance of the magnetic stirrer, and the magnetic

rotor was then placed in a glass container to adjust the
rotational speed of the magnetic rotor for the purpose of
agitating the solution. The second step described the working
principle of the constant temperature function zone. It had
High-performance liquid chromatography. bGas chromatography.

three modules: water bath, circulating fluid system, and device

for maintaining system temperature. The circulating fluid was
IUPAC names

charged into the thermostatic bath (model: QYHX-1030;

standard uncertainty: 0.05 K; Shanghai Joyn Electronic Co.,
Ltd., China), and the circulating water pump was turned on to
circulate the circulating liquid (water + isopropanol) between
the tank containing the circulating fluid and the intermediate
sandwich of the glass container; the temperature of the water
bath was set to be constant so that the entire solution system
was in a relatively stable temperature environment. Since the
temperature control error of the constant temperature water
bath was relatively large, to ensure the scientificity of the
experiment, the use of mercury glass micro thermometer
(standard uncertainty: 0.02 K) made the measurement of the
N,N-dimethylformamide

system temperature more scientific and accurate. Organic

solvents were often more volatile than water, so it was
chemicals

necessary to add a sealing device to the top of the glass

ethylene glycol
fenbendazole

container. The quality of all the chemicals involved in this

methanol

study was obtained from the analytical balance (model:

ethanol

water

BSA224S; standard uncertainty: 0.0001 g; Satorius Scientific

Instrument, Beijing).
a

B DOI: 10.1021/acs.jced.9b00471
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

Table 2. Experimental Mole Fraction Solubility (xeT,w × 103) of Fenbendazole in Methanol (w) + Water (1 − w) within T =
283.15−328.15 K at p = 101.1 kPaa
w
T (K) 1 0.9008 0.7998 0.7012 0.5986 0.5005 0.3990 0.2989 0.2002 0.1006 0
283.15 0.2479 0.2229 0.1919 0.1732 0.1384 0.1260 0.1039 0.08386 0.05281 0.02062 0.003692
288.15 0.2997 0.2730 0.2420 0.2172 0.1861 0.1551 0.1228 0.09888 0.06239 0.02460 0.004511
293.15 0.3823 0.3579 0.3021 0.2649 0.2234 0.1861 0.1517 0.1216 0.07671 0.03049 0.005709
298.15 0.4893 0.4486 0.3742 0.3183 0.2697 0.2200 0.1880 0.1501 0.09469 0.03793 0.007246
303.15 0.6014 0.5584 0.4529 0.3971 0.3412 0.2792 0.2271 0.1809 0.1144 0.04625 0.009030
308.15 0.7476 0.6873 0.5570 0.4763 0.3999 0.3317 0.2747 0.2181 0.1380 0.05622 0.01119
313.15 0.8985 0.8376 0.6701 0.5708 0.4777 0.3909 0.3277 0.2602 0.1651 0.06798 0.01383
318.15 1.066 0.9793 0.7870 0.6753 0.5660 0.4606 0.3875 0.3078 0.1961 0.08162 0.01697
323.15 1.276 1.160 0.9369 0.8066 0.6825 0.5460 0.4586 0.3638 0.2324 0.09761 0.02070
328.15 1.518 1.392 1.156 0.9884 0.8309 0.6634 0.5399 0.4280 0.2741 0.1162 0.02511
a
Standard uncertainties u are u(T) = 0.02 K and u(p) = 0.45 kPa; relative standard uncertainties ur are ur(x) = 0.025 and ur(w) = 0.0002; w
represents the mass fraction of methanol in mixed solvents of methanol + water.

Preparation of Binary Solvent Mixtures. The most
important equipment used to configure mixed solvents with
different water contents in the experiment was the analytical
balance. The mass of the mixed solvent is about 50 g (standard
uncertainty: 0.0001 g) per time. The proportion of water mass
in mixed solvents was distributed within a range of 0−1.0, and
the interval of water mass fraction in each mixed solvent was
0.1. The dissolution device designed in this study was relatively
sealed; there was almost no evaporation and leakage of the
solvent, and the experimental pressure environment was
maintained at around 101.1 kPa.
Solubility Determination. The fenbendazole was dis-
persed in several groups of mixed solvents ({methanol (1) +
water (2)} and so on). When the dissolution reached
equilibrium conditions, the mole ratio of fenbendazole to the
whole solution in the sample was acquired by the isothermal
static technique,20−23 and the most important instrument
required to analyze the content of fenbendazole under the
premise that the composition in the upper clear liquid no
longer changes was high-performance liquid chromatography
(HPLC, Shimadzu-6A). A saturated solution of fenbendazole
was required before the analysis experiment. A brief
description of its preparation process was carried out by
mixing about 50 g of the mixed solvent with an excess of the
solute to obtain a saturated solution of fenbendazole. The mass
fractions of water in the binary solvent mixtures varied from 0
to 1.0. The density of the solute was larger than that of the
solvent. Under normal conditions, the solute sinks to the
bottom of the container, so it is necessary to continuously
dissolve the fenbendazole by continuous stirring with a
relatively stable temperature environment. The jacket of the
glass container was used to achieve a constant temperature of
the dissolution system with the help of circulating fluid. How
to determine whether the dissolution is in equilibrium was a
very important step in this experiment. The solution was
stirred for a while, and 1 mL of the solution was taken with a
pretreated syringe (2 mL) equipped with a pore syringe filter
(PTFE 0.2 μm) and diluted; HPLC was still used to determine
the solute concentration. The above operation was repeated
every interval until the obtained result was relatively stable, and
the dissolution could be considered to be saturated. What is
more, two different experimental procedures were performed,
one of which was to make the amount of fenbendazole dissolve
in excess of equilibrium and then precipitated a portion of the
solute to saturate it, and the other was to slowly reduce the
C DOI: 10.1021/acs.jced.9b00471
amount of solvent to bring it to saturation. The results
obtained by the two operations consistently indicate that the
dissolution time of the solute reaches the saturation state was
20 h. Then, the stirring operation was terminated to facilitate
the natural sedimentation of the solute. The natural settling
took approximately 1 h, and the clear liquid phase was sucked
into a 50 mL preweighed volumetric flask using a pretreated
syringe attached with a filter (PTFE 0.2 μm), and the sample
was weighed again after entering the volumetric flask. Next,
methanol was injected into the volumetric flask so that the
liquid herein reached a volume of 50 mL, and after mixing was
continued, the diluted solute concentration was continued via
HPLC.
The mole ratio of fenbendazole to the entire mixed solution
can be calculated by eq 1, and the ratio of the mass of the
organic solvent and water to the total mass of the mixed
solvent can be calculated by eqs 2 and 3
m1/M1
x w,T =
m1/M1 + m2 /M 2 + m3 /M3 (1)
m2
w1 =
m 2 + m3 (2)
m3
w2 =
m 2 + m3 (3)
where m1, m2, and m3 are the mass of solute fenbendazole, the
mass of organic solvent in the mixed solvent, and the mass of
water, respectively. M1, M2 and M3 are the corresponding mole
masses.
Analysis Method. In the operation of characterizing the
equilibrium concentration of fenbendazole dispersed in mixed
solvents, the most important device was the HPLC. The type
of column it was equipped with was called the reverse phase
column (LP-C18, 250 mm × 4.6 mm). In this exploration
experiment, the working temperature of the column was
adjusted to 303 K. The maximum ultraviolet absorption
wavelength of the detector of the HPLC was selected to be 240
nm, which was obtained by scanning fenbendazole dissolved in
methanol via ultraviolet with a flow rate of 0.8 mL·min−1. The
above characterization operation was performed at least three
times for each experiment, and the values obtained by adding
all the obtained results and dividing by the number of
repetitions were the final results (relative standard uncertainty:
0.050).
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

Table 3. Experimental Mole Fraction Solubility (xeT,w × 103) of Fenbendazole in Ethanol (w) + Water (1 − w) within T =
283.15−328.15 K at p = 101.1 kPaa
w
T (K) 1 0.8969 0.8001 0.6999 0.6003 0.5001 0.3994 0.2999 0.1986 0.1006 0
283.15 0.1646 0.1453 0.1268 0.1102 0.09448 0.07840 0.06087 0.04221 0.02463 0.01125 0.003692
288.15 0.2187 0.1906 0.1643 0.1467 0.1194 0.09790 0.07521 0.05171 0.03001 0.01369 0.004511
293.15 0.2913 0.2515 0.2269 0.1913 0.1557 0.1247 0.09508 0.06502 0.03764 0.01720 0.005709
298.15 0.3777 0.3240 0.2952 0.2412 0.2012 0.1570 0.1192 0.08133 0.04710 0.02162 0.007246
303.15 0.4780 0.4231 0.3684 0.2982 0.2475 0.1936 0.1465 0.09978 0.05784 0.02667 0.009030
308.15 0.5979 0.5230 0.4509 0.3687 0.3023 0.2368 0.1787 0.1216 0.07058 0.03272 0.01119
313.15 0.7340 0.6570 0.5448 0.4490 0.3654 0.2868 0.2162 0.1471 0.08568 0.03997 0.01383
318.15 0.9183 0.8088 0.6605 0.5493 0.4459 0.3495 0.2625 0.1783 0.1038 0.04863 0.01697
323.15 1.115 0.9612 0.7858 0.6552 0.5314 0.4187 0.3140 0.2133 0.1246 0.05870 0.02070
328.15 1.369 1.144 0.9463 0.7796 0.6353 0.5031 0.3763 0.2552 0.1492 0.07060 0.02511
a
Standard uncertainties u are u(T) = 0.02 K and u(p) = 0.45 kPa; relative standard uncertainties ur are ur(x) = 0.025 and ur(w) = 0.0002; w
represents the mass fraction of ethanol in mixed solvents of ethanol + water.

Table 4. Experimental Mole Fraction Solubility (xeT,w × 103) of Fenbendazole in EG (w) + Water (1 − w) within T = 283.15−
328.15 K at p = 101.1 kPaa
w
T (K) 1 0.8996 0.8008 0.6979 0.6006 0.4989 0.4000 0.3003 0.2012 0.09980 0
283.15 0.1274 0.1112 0.1010 0.08529 0.07507 0.06996 0.06038 0.05046 0.03429 0.01540 0.003692
288.15 0.1715 0.1482 0.1277 0.1073 0.09197 0.08686 0.07487 0.06179 0.04161 0.01865 0.004511
293.15 0.2316 0.2052 0.1796 0.1592 0.1336 0.1132 0.09503 0.07769 0.05202 0.02333 0.005709
298.15 0.3048 0.2696 0.2287 0.2067 0.1659 0.1454 0.1197 0.09721 0.06489 0.02920 0.007246
303.15 0.3996 0.3526 0.2964 0.2555 0.2095 0.1737 0.1489 0.1250 0.07978 0.03596 0.009030
308.15 0.5128 0.4445 0.3781 0.3243 0.2681 0.2170 0.1833 0.1521 0.09730 0.04400 0.01119
313.15 0.6485 0.5620 0.4752 0.4088 0.3321 0.2708 0.2241 0.1887 0.1182 0.05365 0.01383
318.15 0.8121 0.7035 0.5911 0.4933 0.4013 0.3246 0.2718 0.2311 0.1425 0.06497 0.01697
323.15 1.012 0.8635 0.7255 0.6029 0.5058 0.4036 0.3281 0.2747 0.1709 0.07825 0.02070
328.15 1.258 1.092 0.9028 0.7621 0.6395 0.5015 0.3946 0.3254 0.2042 0.09380 0.02511
a
Standard uncertainties u are u(T) = 0.02 K and u(p) = 0.45 kPa; relative standard uncertainties ur are ur(x) = 0.025 and ur(w) = 0.0002; w
represents the mass fraction of EG in mixed solvents of EG + water.

Table 5. Experimental Mole Fraction Solubility (xeT,w × 103) of Fenbendazole in DMF (w) + Water (1 − w) within T = 283.15
to 328.15 K at p = 101.1 kPaa
w
T (K) 1 0.9006 0.8021 0.7022 0.6003 0.5001 0.3976 0.2996 0.1992 0.1026 0
283.15 39.71 29.83 17.84 10.65 7.131 5.375 4.098 2.540 0.9199 0.1253 0.003692
288.15 55.93 40.96 23.97 14.01 9.166 6.992 5.005 3.078 1.085 0.1484 0.004511
293.15 73.08 55.34 30.58 17.69 11.44 8.796 6.070 3.772 1.300 0.1804 0.005709
298.15 99.65 75.84 40.40 23.06 14.67 11.08 7.516 4.530 1.577 0.2212 0.007246
303.15 134.4 100.1 52.76 31.07 18.58 13.63 9.181 5.434 1.886 0.2667 0.009030
308.15 175.5 126.9 67.09 39.40 23.05 16.52 11.05 6.490 2.234 0.3194 0.01119
313.15 227.3 159.0 84.76 48.72 28.45 19.96 13.26 7.675 2.641 0.3818 0.01383
318.15 291.5 199.8 106.1 60.23 34.85 23.73 15.80 9.025 3.104 0.4535 0.01697
323.15 374.5 253.0 133.0 73.39 42.66 28.44 18.80 10.55 3.637 0.5366 0.02070
328.15 469.8 305.7 163.4 87.25 51.42 33.56 22.12 12.20 4.230 0.6308 0.02511
a
Standard uncertainties u are u(T) = 0.02 K and u(p) = 0.45 kPa; relative standard uncertainties ur are ur(x) = 0.025 and ur(w) = 0.0002; w
represents the mass fraction of DMF in mixed solvents of DMF + water.

XPRD Characteristic. The X-ray powder diffraction
(XPRD, Bruker AXS D8 Advance, Germany) had an
irreplaceable role in the operation of detecting the crystal
structure of the solid drug. This fenbendazole dissolution study
had no doubt that it needed its assistance. In the detection
process, the Cu Kα radiation (λ = 1.54184 nm) played a major
role, and the detection conditions were often adjusted to a
tube voltage of 40 kV and tube current of 30 mA. The effective
value was obtained at a scan speed of 5°·min−1 started at a
D DOI: 10.1021/acs.jced.9b00471
diffraction angle of 5° and stopped at a diffraction angle of 80°
(2θ) with the temperature environment at room temperature
and pressure environment at atmospheric pressure.
■ RESULTS AND DISCUSSION
XPRD Test. The XPRD was the most common equipment
for detecting whether the solute changes in the crystal
structure during the dissolution process and determining
whether the solute was chemically reacted with the solvent.
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data
Figure 1. Mole fraction solubility (x) of fenbendazole in methanol
(w) + water (1 − w) mixed solutions with various mass fractions at
different temperatures: w, mass fraction of methanol; black star open,
w = 1; red triangle up open, w = 0.9008; blue circle open, w = 0.7998;
light green box, w = 0.7012; purple star solid, w = 0.5986; dark yellow-
green diamond, w = 0.5005; dark blue diamond solid, w = 0.3990;
maroon triangle down solid, w = 0.2989; purple triangle up solid, w =
0.2002; green circle solid, w = 0.1006; pink, w = 0; solid line,
calculated curves by the Jouyban−Acree model.
Figure 2. Mole fraction solubility (x) of fenbendazole in ethanol (w)
+ water (1 − w) mixed solutions with various mass fractions at
different temperatures: w, mass fraction of ethanol; black box solid, w
= 1; red triangle up open, w = 0.9969; light green triangle up solid, w
= 0.8001; blue triangle down solid, w = 0.6999; cyan diamond solid, w
= 0.6003; purple star solid, w = 0.5001; dark yellow-green star solid, w
= 0.3994; dark blue box, w = 0.2999; dark purple circle open, w =
0.1986; maroon circle open, w = 0.1006; green star open, w = 0; solid
line, calculated curves by the Jouyban−Acree model.
Ten groups of samples contain the fenbendazole solid
remaining during the dissolution process, and the solids of
the fenbendazole drug raw material and fenbendazole
recrystallized in pure solvent were all characterized by
XPRD. The patterns obtained areplotted in Figure S3 of the
Supporting Information. The details contained in it were that
the characteristic peaks of all the patterns were almost
negligible from the characteristic peaks of the raw materials.
Then, the statement that the solute did not react with the
solvent before and after the fenbendazole dispersion process
was convincing enough.
Experimental Solubility. The solute fenbendazole was
dispersed in mixed liquids of organic solvent and water, and
the fenbendazole concentration data when the thus formed
mixtures reach the equilibrium are recorded in detail in Tables
2−5. More vividly, the dissolution temperature and the
proportion of water in the mixed solvent as a function of
E DOI: 10.1021/acs.jced.9b00471
Article
Figure 3. Mole fraction solubility (x) of fenbendazole in EG (w) +
water (1 − w) mixed solutions with various mass fractions at different
temperatures: w, mass fraction of EG; blue star open, w = 1; maroon
triangle up open, w = 0.8996; green circle open, w = 0.8008; red box,
w = 0.6979; violet star solid, w = 0.6006; orange diamond solid, w =
0.4989; gray diamond solid, w = 0.4000; maroon triangle down solid,
w = 0.3003; pink triangle up solid, w = 0.2012; blue circle solid, w =
0.0998; teal box solid, w = 0; solid line, calculated curves by the
Jouyban−Acree model.
Figure 4. Mole fraction solubility (x) of fenbendazole in DMF (w) +
water (1 − w) mixed solutions with various mass fractions at different
temperatures: w, mass fraction of DMF; black box solid, w = 1; red
circle solid, w = 0.9006; light green triangle up solid, w = 0.8021; blue
triangle down solid, w = 0.7022; cyan diamond solid, w = 0.6003; pink
diamond open, w = 0.5001; dark yellow-green star solid, w = 0.3976;
dark blue box open, w = 0.2996; purple circle open, w = 0.1992;
maroon triangle up open, w = 0.1026; green star open, w = 0; solid
line, calculated curves by the Jouyban−Acree model.
fenbendazole content are shown in Figures 1−4. The hidden
details in Tables 2−5 are that the high temperature favors the
dissolution of fenbendazole and conversely hinders its
dissolution. The lower proportion of water in the binary
mixed solvent favors the dispersion of fenbendazole, and
conversely, it was not conducive to its dispersion. In the
aqueous solution of the organic solvent studied, a larger
amount of fenbendazole solid was desirable to be dispersed in
the system formed by DMF + water under the same conditions
of the external environment.
Thermodynamic Modeling. The use of thermodynamic
models to calculate solid−liquid phase equilibrium data is a
common approach, and the three thermodynamic models
involved in the fenbendazole dissolution system have been
described in detail in previously published publications.3,4,26−28
They are the Jouyban−Acree model,3,4,29,30 van’t Hoff−
Jouyban−Acree model,3,4,31 and modified Apelblat−Jouy-
ban−Acree model.3,4,31
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data Article

Table 6. Data of Parameters Obtained Using Thermodynamic Models

Jouyban−Acree van’t Hoff−Jouyban−Acree Apelblat−Jouyban−Acree
solvents, RAD, and RMSD parameter value parameter value parameter value
methanol + water J0 1603.15 A1 4.843 A1 86.53429
J1 −1716.98 B1 −3717.56 B1 −7489.35111
J2 1550.25 A2 1.760 C1 −12.11788
B2 −4053.94 A2 −31.77654
J0 1601.22 B2 −2503.09058
J1 −1728.29 C2 4.97333
J2 1545.44 J0 1603.63245
J1 −1717.81005
J2 1551.46530
RAD·102 2.53 2.77 2.66
RMSD·104 0.14 0.14 0.14
ethanol + water J0 1316.73 A1 6.335 A1 57.55099
J1 −895.28 B1 −4242.48 B1 −6612.97570
J2 443.23 A2 1.760 C1 −7.59403
B2 −4053.94 A2 −31.77654
J0 1314.40 B2 −2503.09058
J1 −907.33 C2 4.97333
J2 437.40 J0 1315.61795
J1 −899.02061
J2 440.44994
RAD·102 0.72 1.40 1.17
RMSD·104 0.06 0.07 0.06
EG + water J0 1330.62 A1 7.379 A1 78.33350
J1 −1490.17 B1 −4612.22 B1 −7902.41975
J2 1251.62 A2 1.760 C1 −10.51743
B2 −4053.94 A2 −31.77654
J0 1327.10 B2 −2503.09058
J1 −1504.40 C2 4.97333
J2 1242.82 J0 1330.06353
J1 −1492.89273
J2 1250.23196
RAD·102 2.38 2.90 2.56
RMSD·104 0.11 0.12 0.12
DMF + water J0 3006.11 A1 14.582 A1 73.17110
J1 −3824.28 B1 −5031.66 B1 −7754.05801
J2 3300.15 A2 1.760 C1 −8.68146
B2 −4053.94 A2 −31.77654
J0 3004.38 B2 −2503.09058
J1 −3835.22 C2 4.97333
J2 3295.86 J0 3006.96517
J1 −3824.40731
J2 3302.34249
RAD·102 1.18 1.50 1.33
RMSD·104 11.74 14.40 12.48

Jouyban−Acree Model. The mathematical expression of
Jouyban−Acree model can be written as eq 4. The variable in
the left part of the equation is the logarithm of the solute mole
fraction, and the variable in the right part is the reciprocal of
the temperature3,4,29,30
2
w1w2
ln x w,T = w1 ln x1,T + w2 ln x 2,T + ∑ J (w1 − w2)i
T (K) i = 0 i
(4)
where xw,T, x1,T, and x2,T are the ratios of the moles
fenbendazole to the moles of the miscible system
temperature T, the molar concentration of fenbendazole
pure organic solvents, and the molar concentration
fenbendazole in pure water, respectively. w1 and w2 represent
the mass ratio of organic solvent to mixed solvent and the mass
ratio of water to mixed solvent, respectively, and Ji is the
Jouyban−Acree model parameters.
van’t Hoff−Jouyban−Acree Model. The mathematical
expression of the van’t Hoff equation can be written as eq 5.
The logarithm of the mole concentration of fenbendazole in
the equation is proportional to the reciprocal of temperature.
B
ln x T = A +
T (K) (5)
of
at The logarithm of the solute mole fraction in the pure solvent
in in eq 4 is replaced with the right part of eq 5 to obtain eq
of 6.3,4,31
F DOI: 10.1021/acs.jced.9b00471
J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data

■
Article

i B1 yzz ij B2 yzz
ln x w,T = w1jjjjA1 + zz + w2jjjA 2 + z
T(K) z{
CONCLUSIONS
k T (K) { k Four liquid mixtures formed by mixing water and four organic
2 solvents (methanol, ethanol, ethylene glycol (EG), and N,N-
ww dimethylformamide (DMF)) in different ratios were used as
+ 1 2 ∑ Ji (w1 − w2)i
T (K) i = 0 (6) solvents, and fenbendazole was used as a solute. The
concentration of the solute at T = 283.15−328.15 K and in
A1, B1, A2, B2, and Ji are the equation parameters. different mixed solvents was determined by static techniques at
Modified Apelblat−Jouyban−Acree Model. Compared an atmospheric pressure of p = 101.1 kPa. A common feature
with the van’t Hoff equation, the right part of the modified in all systems studied is that the decrease in temperature had a
Apelblat equation has one more variable logarithm of negative effect on the dispersion of fenbendazole. The higher
temperature that can be written as eq 732,33 the water content in the mixed solvent, the more difficult it was
to dissolve fenbendazole. The three models also played an
B irreplaceable role. The values of RAD (×10−2) and RMSD
ln x T = A + + C ln(T (K))
T (K) (7) (×10−3) were not more than 2.90 and 1.440, respectively. The
results of this study not only helped to improve the production
where A, B, and C are the equation parameters. process of fenbendazole but also laid the data foundation and
The logarithm of the solute mole fraction in the pure solvent materialized information for the purification of darazole drugs.

■
in eq 4 is replaced with the right part of eq 7 to obtain eq

ÄÅ ÉÑ
8.3,4,31
ÅÅ ÑÑ
ASSOCIATED CONTENT
Å
ln x w,T = w1ÅÅÅA1 + + C1 ln(T (K))ÑÑÑÑ
*
ÅÅÇ ÑÑÖ
S Supporting Information
B1

ÄÅ É
The Supporting Information is available free of charge on the

ÅÅi yzÑÑÑÑ
T (K)

Å j
j z
ACS Publications website at DOI: 10.1021/acs.jced.9b00471.
+ w2ÅÅÅjjA 2 + + C2 ln(T (K))zzÑÑÑ
ÅÅÇÅk {ÑÑÖÑ
B2 Chemical structure of fenbendazole, experimental
T (K) apparatus, and XPRD patterns (PDF)

■
2
ww
+ 1 2 ∑ Ji (w1 − w2)i AUTHOR INFORMATION
T (K) i = 0 (8)
Corresponding Author
The above three models are based on experimentally *E-mail: xurenjie126@163.com. Phone: +86 514 87993918.
measured data to obtain model parameters by nonlinear Fax: +86 514 87994009.
regression. The objective function is defined as ORCID
Renjie Xu: 0000-0001-5541-1622
F= ∑ (lnxie − lnxic)2 Funding
i=1 (9)
This work was supported by National Natural Science
Whether the selection of the model is appropriate that Foundation of China, Grant/Award no. 21506058.
requires the necessary means to verify, the mathematical Notes
expression of the relative average deviation (RAD) and root- The authors declare no competing financial interest.

■
mean-square deviation (RMSD) are written as eqs 10 and 11
ij |x w,T | yzz
j
j zz
REFERENCES
∑ jj z
c e
1 − x w,T

k {
RAD =
e
N x w,T (10)
N c e
∑i = 1 (x w,T − x w,T)2
RMSD =
N (11)
where N is the number of experimental data points, xew,T is the
data obtained through research experiments, and xcw,T is the
data calculated through reliable models.
The calculation of model equations and the regression of
model parameters require some computer software assistance.
The software used in this research experiment is Mathcad
software, and the obtained data together with the RAD and the
RMSD values are detailed in Table 6. In the three models, the
results calculated by the Jouyban−Acree model are drawn as
curves and vividly drawn in Figures 1−4. Careful study of the
values recorded in Table 6 is not difficult to find that the value
of RAD is less than 2.90% (van’t Hoff−Jouyban−Acree model
for ethanol + water). Besides, the RMSD is not greater than
1.440 × 10−3. Overall, the calculated value is the closest to the
experimental value.
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H DOI: 10.1021/acs.jced.9b00471
J. Chem. Eng. Data XXXX, XXX, XXX−XXX