Modified Method for Measuring the Solubility of Pharmaceutical Compounds in Organic Solvents by Visual Camera

Article abstract of DOI:10.1021/acs.jced.5b00122

A modified synthetic method with a high definition visual camera technique for measuring the solubility of solutes in solvents or mixed solvents was proposed. To verify the reliability of the experimental apparatus, the solubility of NH₄Cl in water was determined at different temperatures. The relative standard errors were less than 1%, compared to the literature data. The solubilities of betulonic acid in six organic solvents from (278.15 to 313.15) K were measured and correlated with the Apelblat equation and universal quasichemical equation, respectively. The modified method was quite concise and user-friendly, and made the process of dissolution to become visualized and automatic.

Full text of DOI:10.1021/acs.jced.5b00122

Article
pubs.acs.org/jced
Modified Method for Measuring the Solubility of Pharmaceutical
Compounds in Organic Solvents by Visual Camera
Ning Tang, Wei Shi, and Weidong Yan*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
*
S Supporting Information
ABSTRACT: A modified synthetic method with a high definition visual camera technique for measuring the solubility of solutes
in solvents or mixed solvents was proposed. To verify the reliability of the experimental apparatus, the solubility of NH Cl in
4
water was determined at different temperatures. The relative standard errors were less than 1%, compared to the literature data.
The solubilities of betulonic acid in six organic solvents from (278.15 to 313.15) K were measured and correlated with the
Apelblat equation and universal quasichemical equation, respectively. The modified method was quite concise and user-friendly,
and made the process of dissolution to become visualized and automatic.
INTRODUCTION
After the measurement, the video record was replayed to find
the phase equilibrium point. This method is proven to obtain
reliable and precise data of solubility, compared with literature
data. Since the whole dissolving process can be recorded
clearly, this method will have potential in the study of
recrystallization kinetics or supersaturated phenomenon in a
solid−liquid system.
■
Methods of measuring solubility of a solute in a pure solvent or
mixed solvent can be classified as an analytical method and a
synthetic method. The analytical method can be used to
determine the concentration of a saturated solution by chemical
analytical methods, for example, the HPLC method and the UV
1
method, but it is usually tedious and time-consuming.
Betulonic acid (C H O , CAS: 4481-62-3, MW: 454.69,
30
46
3
Alternately, synthetic methods obtain the composition of a
saturated solution by weighing or measuring the individual
components, and the solubility can be determined by the state
in which the solid phase just disappears. Disappearance of the
solid phase can be achieved either by a change of temperature
or by the addition of a known amount of solvent. Nowadays,
the solubility is usually measured by a synthetic method via a
laser monitoring observation technique. The laser technique is
used to obtain the experimental data of solubility immediately,
but it is not easy to check whether the solid−liquid equilibrium
is reached, especially for systems that can be easily emulsified or
that some residual crystal is too big so that it remained in the
bottom of cell.
On the basis of a synthetic method, a laser monitor or naked-
eye observation was replaced by a high definition visual camera
to monitor the disappearance or formation of the solid phase in
solution at a given temperature. The connection of the visual
camera with a syringe pump through a PC implements
visualization and automation for the whole measuring process.
Figure 1) is derived from betulin by an oxidation reaction. Until
the 2000s, the interest to betulonic acid was primarily due to its
role as the precursor for the synthesis of betulinic acid.
Betulinic acid is an effective drug as an anticancer and anti-HIV
4
5,6
2
activities and against human melanoma. It is also currently
undergoing clinical trials as an anticancer compound at the US
7
3
National Institute of Health. But now, betulonic acid has a
highly specific antiprostate cancer activity in vitro cell cultures as
8
,9
well.
To effectively separate and purify the betulin, betulonic acid,
and betulinic acid from reactive mixtures by recrystallization, it
is essential to know the solubilities of them in different solvents
for selecting suitable solvents of recrystallization. The
solubilities of betulin have been measured in the 14 pure
Received: February 9, 2015
Accepted: December 21, 2015
Published: December 31, 2015
©
2015 American Chemical Society
35
DOI: 10.1021/acs.jced.5b00122
J. Chem. Eng. Data 2016, 61, 35−40

Journal of Chemical & Engineering Data
Article
spectrum of betulonic acid are shown in Figures S1 and S2 of
Supporting Information. The purity of betulonic acid was more
than 0.99 mass fractions, determined by HPLC.
Apparatus and Procedure. The experimental apparatus
Figure 2) for the measurement of solubility was approximately
(
Figure 1. Molecular structure of betulonic acid.
1
10
solvents and CHCl3 + CH OH mixed solvent. The
3
solubilities of betulinic acid have also been measured in the
11
12
different pure solvents and THF + water mixed solvent.
However, the solubility of betulonic acid in solvents has not
been found in the literature. The solubilities of betulonic acid in
six organic solvents from (278.15 to 313.15) K were measured
by the method proposed in this work. The temperature-
dependent solubility data of betulonic acid were correlated with
the Apelblat equation and the universal quasichemical
Figure 2. Schematic diagram of experimental device. 1, syringe pump;
, high precision glass injector; 3, syringe needle; 4, Pt1000
thermometer; 5, high definition camera with LED; 6, 10 mL cell; 7,
double-jacketed cylindrical vessel; 8, water inlet; 9, water outlet; 10,
IKA magnetic stirrer; 11, computer.
2
(UNIQUAC) model, respectively.
EXPERIMENTAL SECTION
Materials. The betulin (white powder, 0.95 mass fractions)
■
the same as those devices using laser monitor technique. The
modification was replaced the laser monitor with a high
definition visual camera. A double-jacketed cylindrical glass
equilibrium cell with a volume of 10 mL and a magnetic stirrer
(COLOR SQUID, IKA, Sweden) was used for the solubility
measurements, and a rubber plug was put on the vessel to
prevent the evaporation of the solvent, through which a high
precision platinum resistance thermometer (JM 6200, Tianjin
Jinming Instrument CO., LTD, China) with an uncertainty of
u(T) = 0.01 K and a syringe needle for solvent injection were
inserted into the cell below the surface of liquid phase. The
needle was linked by a precision glass injector (5000 μL,
Shanghai Bolige Industry & Trade Co., Ltd., China), which was
driven by a single channel syringe pump (LSP01−1A, Baoding
Longer Precision Pump Co., Ltd., China). A circulating water
bath with a thermostat (THD-2006, Ningbo Tianheng
was supplied by Skyherb Ingredients Co., Ltd. The source and
purity of betulonic acid, methanol, ethanol, 1-propanol, 2-
propanol, 2-methoxyethanol, and 2-propoxyethanol are de-
scribed in Table 1. The densities of materials at 298.15 K were
measured by density meter (DMA 5000M, Anton Paar), and
they were compared with the data from the literature.
Preparation of Betulonic Acid. Betulonic acid was
13
synthesized by a method similar to the one in the literature.
Because betulin is the most commonly available triterpenoid
from the outer bark of the white birch, straight oxidation of
betulin into betulonic acid with the Jones reagent (CrO3/
H SO /acetone) was used, and the overall yield was likely up to
2
4
7
5%. Betulonic acid was separated from the raw product by
means of silica gel column chromatography and purified by
recrystallization with methanol. The H NMR and C NMR
1
13
Table 1. Source, Mass Fraction Purity and Density of the Chemicals Used in This work at Temperature T = 298.15 K and
a
Pressure p = 0.1 MPa
mass fraction
purity
purification
analysis
method
density measured
density literature value
3
b
3
chemicals
methanol
source
method
(25 °C/(g/cm ))
(g/cm )
0.786531
Sinopharm
Chemicals
≥ 0.995
distillation
GC
0.788
ethanol
Sinopharm Chemicas
≥ 0.995
≥ 0.990
distillation
distillation
GC
GC
0.788
0.801
0.78499
0.80061
1-propanol
Sinopharm
Chemicals
2-propanol
Sinopharm
Chemicals
≥ 0.997
distillation
GC
0.781
0.78139
2
2
-methoxyethanol Aladdin
≥ 0.990
≥ 0.994
≥ 0.99
distillation
GC
0.961
0.908
0.960978
-propoxyethanol
Aladdin
distillation
GC
0.9112 (20 °C)
betulonic acid
Synthesis
recystallization
HPLC
a
b
Standard uncertainties u are u(T) = 0.01 K, u (p) = 5Kpa, u (ρ) = 0.001 Zafarani-Moattar, Mohammed Taghi; J. Chem. Thermodyn. 2006, 38(11):
r
1
377−1384. Wankhede, D. S.; Indian. J.Pure. Ap.Phy. 2006, 44(12): 909. Hwang, In-Chan; J. Chem. Eng. Data. 2009, 54(3): 1041−1045. Kim,
Hyeon-Deok; J. Chem. Eng. Data. 2010, 55(7): 2474−2481. Dubey, Gyan Prakash; J. Chem. Eng. Data. 2010, 55(4): 1700−1703. Lide, D. R.; CRC
Handbook of Chemistry and Physics, 75th ed.; CRC Press Inc.: Boca Raton, FL, 1994−1995; p 3−160.
3
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Article
Instrument Works Co., Ltd., China) was applied to maintain
the temperature within ±0.01 K. The mass of solute and
solvent that were put into the cell were measured with a
precision analytical balance (CP225D, Sartorius, Germany)
with an uncertainty of u(m) = 0.01 mg. And then, a high
definition visual camera with LED connected with computer
was put in front of the glass equilibrium cell to record the entire
dissolution process.
single crystal diffractometer (Gemimi A Ultra, Agilent) with the
detector of Atlas CCD.
RESULTS AND DISCUSSION
■
Physical Properties of Betulonic Acids. The results of
TGA, DSC, and XRD measurements of betulonic acid were
shown in Figure 3, Figure 4, and Figure 5. It can be seen that
Solubility was determined by observing disappearance or
formation of crystal. This method was based on the sequential
addition of the known amount of solvent required to
completely dissolve the solute at a given temperature. The
initial mass of solute and solvent were weighed precisely and
put into the cell to be stirred at a speed of about (500 to 1000)
rpm. Such a small volume of glass equilibrium cell was designed
to make the samples to be used as less as possible. And it
should make sure that the saturated solutions with excess solid
solute in the cell were obtained before determination. The
addition of solvent was continued until the solid phase
disappeared and the solution became clear. To make the
system close to the solid−liquid equilibrium, it was necessary to
add the rate of solvent as slowly as possible, so the injected rate
−1
of solvent was set at about 10−20 μL·min . The visual camera
was adjusted to a best definition and started to record a video at
the same time as the syringe pump began to inject the solvent
into cell. Therefore, the mass of solvent injected into the cell
can be calculated through the injected rate of the solvent, the
time the last of the solid disappeared by playback of the video
recorded, and the density of solvent at a given temperature.
The whole process of experiment usually took at least 60 min.
Consequently, the solubility (x) of solute can be calculated by
eq 1:
Figure 3. TGA thermograms of betulonic acid under N2.
mA/MA
x =
m /M + m /M
(1)
A
A
B
B
where m and m refer to the masses of the solute and solvent,
A
B
respectively, while M and M represent the molecule weights
A
B
of solute and solvent.
To verify the reliability of experimental apparatus, the
solubility of NH Cl in water was determined at 283.2 K, 293.2
4
K, and 303.2 K. The experimental data are listed in Table S1.
The solubility experiments were repeated three times. The
relative standard deviation was less than 3%. The relative
standard errors were less than 1%, compared to the literature
data. The results show this apparatus is producing good quality
data.
Figure 4. Experimental heat flow from DSC measurement of betulonic
acid.
Thermogravimetric analysis (TGA) was performed on a
thermogravimetric analyzer (SDT Q600, TA Instruments,
the decomposition temperature of betulonic acid is 348.61 °C.
The melting point (T ) and enthalpy of fusion (Δ H) of
−1
USA) at a heating rate of 10 K·min under a nitrogen
atmosphere. The melting point and enthalpy of fusion data
were determined by DSC Q100 differential scanning
calorimeter (DSC instruments) in a nitrogen atmosphere and
m
fus
−1
betulonic acid were found to be 257.34 °C and 26.3 kJ·mol ,
u (T ) = 0.002 and u (Δ H) = 0.02, respectively. Compared
r
m
r
fus
14
to the literature 257−258 °C, the melting value of betulonic
−1
at a heating rate of 10 K·min as well.
acid is credible.
A single-solvent crystallization technique was used to prepare
the single crystal of betulonic acid for the XRD experiment. A
Solubility Data of Betulonic Acid. The solubilities (mass
fraction and mole fraction) of betulonic acid in six solvents
from (278.15 to 318.15) K at atmospheric pressure are
presented in Table 2 and plotted in Figure 6. From Table 2 and
Figure 5, it can be seen that the solubility of betulonic acid in a
given solvent increases with the rising temperature. Moreover,
the solubility order is 2-propoxyethanol >1-propanol >2-
methoxyethanol >2-propanol > ethanol > methanol at a low
temperature. However, the order is 2-propoxyethanol >1-
0
.1 g portion of white powder sample was dissolved in the
smallest amount of selected solvent methanol at 60 °C. The
solution was allowed to cool and was placed in a dry and
ventilated place. As the temperature of the solution was cooled
down and the solvent was evaporated slowly, the crystals were
formed. Finally, the solid crystals were collected by filtration
and dried. The XRD experiment was carried out using an X-ray
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Figure 6. Solubilities of betulonic acid in selected solvents: □,
methanol; ■, ethanol; △, 2-propanol; ▲, 1-propanol; ○, 2-
methoxyethanol; ●, 2-propoxyethanol.
Figure 5. Molecule and numbering scheme of betulonic acid without
H atom.
affected not only by the polarities of the solvent but also by the
intermolecular interactions and the ability of solvent to form
hydrogen bonds with betulonic acid. The structure of betulonic
acid contains proton acceptors, a carbonyl group, and a
carboxyl group that cause a large difference of the solubility in
organic solvents with betulin and betulinic acid. This might
be attributed to the polarity and structure of betulonic acid.
Calculation of the Solubility Parameter of BoA with
Apelblat Equation Model. The relationship between mole
Table 2. Solubilities (g/100g of Solvent) and Mole Fraction
3
1
0 x of Betulonic Acid in Different Solvents from
Temperature T = 278.15b K to 313.15 K at Pressure p = 0.1
MPa
a
1
11
103x
103x
T/K
S/(g/100g)
T/K
S/(g/100g)
Methanol
1.83
Ethanol
3.71
2
78.15
83.15
88.15
93.15
98.15
03.15
08.15
13.15
18.15
1.29
1.36
1.46
1.57
1.71
1.92
2.11
2.34
2.70
278.15
283.15
288.15
293.15
298.15
303.15
308.15
313.15
318.15
3.76
3.99
4.54
5.03
5.66
6.17
6.93
7.57
8.48
2
2
2
2
3
3
3
3
1.93
3.94
fraction solubility and temperature is described by the Apelblat
2.07
4.48
15−17
equation,
which has been widely used in the correlation of
2.23
4.96
solubility data and temperature of massive substances.
According to the equation, the mole fraction solubility of
betulonic acid can be calculated through eq 2:
2.43
5.59
2.72
6.09
2.99
6.84
B
T/K
3.32
7.47
ln x = A +
+ C ln T/K
3.84
8.37
(2)
1
-Propanol
2-Propanol
4.02
where x and T denote the calculated mole fraction solubility of
the solute and absolute temperature (K), respectively. A, B, and
C are the empirical model parameters. The values of parameters
A, B, and C and the root-mean-square deviations (rmsd’s) are
listed in Table 3. The rmsd is defined as eq 3:
2
2
2
2
2
3
3
3
3
78.15
83.15
88.15
93.15
98.15
03.15
08.15
13.15
18.15
5.51
7.28
7.62
278.15
283.15
288.15
293.15
298.15
303.15
308.15
313.15
318.15
5.31
5.64
5.77
4.27
6.26
8.27
4.93
6.51
6.92
9.14
5.72
7.50
7.86
10.39
11.63
13.07
14.43
16.33
6.60
8.65
1
/2
8.80
7.323
8.603
10.405
11.942
2-Propoxyethanol
10.43
10.81
11.19
11.54
11.97
12.57
13.11
13.74
14.480
9.68
N
i=1
⎡
⎢
2 ⎤
∑
(xi,cal − xi,exp
)
9.89
11.37
13.75
15.78
⎥
rmsd =
10.91
12.35
-Methoxyethanol
5.16
⎢
⎣
N
⎥
⎦
(3)
2
Table 3. Parameters and rmsd of the Apelblat Equation
2
2
2
2
2
3
3
3
3
78.15
83.15
88.15
93.15
98.15
03.15
08.15
13.15
18.15
8.63
9.23
278.15
283.15
288.15
293.15
298.15
303.15
308.15
313.15
318.15
23.88
24.75
25.00
26.41
27.40
28.78
30.01
31.44
33.15
5.52
4
solvent
methanol
ethanol
a
b/K
c
10 rmsd
5.79
9.69
−313.617
−93.343
−245.191
−254.775
−178.471
−97.310
12267.397
2353.304
9108.417
9005.187
6713.584
3558.095
46.705
14.087
36.868
38.581
26.579
14.354
0.16
0.59
0.16
2.23
1.02
6.98
6.17
10.33
10.76
11.74
12.70
13.66
14.95
6.50
1
2
2
2
-propanol
7.02
-propanol
7.59
-methoxyethanol
-propoxyethanol
8.16
8.94
a
Standard uncertainties u are u(T) = 0.01 K, u(p) = 5 Kpa, u (S) =
r
0
.03, u (x) = 0.03.
r
where N is the number of experimental points, xi,cal and xi,exp
represent the solubilities calculated from eq 2 and the
experimental solubility values, respectively. From the data
listed in Table 3, it can be seen that the calculated solubilities
were in good agreement with the experimental values.
propanol > 2-propanol > 2-methoxyethanol > ethanol >
methanol at a high temperature, and all the data showed that
betulonic acid has good solubility in organic solvents. Normally,
the solubility ability of betulonic acid in different solvents is
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Journal of Chemical & Engineering Data
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Calculation of the Solubility Parameter of BoA with
UNIQUAC Equation Model. According to the solid−liquid
equilibrium theory, the experimental data of betulonic acid can
be expressed as eq 4:
interaction parameters obtained in this work are given in Table
4 together with the root-mean-square deviations (rmsd). As can
Table 4. Parameters and rmsd of the UNIQUAC Equation
⎛
⎝
⎞
1 ⎠
4
Δ H ⎛T
⎞
⎟
⎠
solvent
methanol
a12
a21
10 rmsd
1
fus
t
ln⎜
⎟ =
⎜
− 1
⎜
⎟
8594.97
4592.203
3461.058
3132.422
4270.003
3916.292
−883.687
−1218.301
−1332.494
−1092.212
−1571.675
−1896.863
0.75
0.67
3.07
3.84
2.50
2.67
γx
RT ⎝ T
1
t
ethanol
ΔC ⎛
⎞
⎟
⎠
ΔCp
p T
R ⎝ T
Tt
T
1-propanol
t
−
⎜
− 1
+
ln
2
2
-propanol
R
(4)
-methoxyethanol
where γ and x refer to the activity coefficients and mole
fractions of betulonic acid in the solution, respectively; Δ H
refers to the enthalpy of fusion of the solute at melting
1
1
2-propoxyethanol
fus
temperature; T and T are the solid−liquid equilibrium
be seen from Tables 3 and 4, the results correlated with the
Apelblat equation and UNIQUAC model are both satisfactory.
However, the results of the UNIQUAC model were better than
those of the Apelblat equation. It means those parameters listed
in Table 4 could be used to predict the solubilities of betolonic
acid at different temperatures.
t
temperature and triple-point temperature of the solute,
respectively; ΔC is the distinction of the heat capacities for
p
the solid and the liquid phases and R is the gas constant.
Since the distinctions of the heat capacities for the solid and
the liquid phases of the solute were negligible, and the triple-
point temperature (T ) is similar to the normal melting
t
temperature (T ), eq 4 could be simplified to eq 5:
CONCLUSIONS
m
■
A modified method with a synchronized visual camera instead
of laser or naked-eye observation was proposed to measure the
solubility of betulonic acid, and this method was verified to be
reliable through comparing results with literature and repeated
experiments. The betulonic acid was synthesized from betulin
using Jone’s reagent in our work, and DSC, TGA, and XRD
were carried out to determine the melting point, enthalpy of
fusion, the decomposition point, and the structure of betulonic
acid. The mole fraction solubility of betulonic acid was
measured in six different organic solvents from 278.15 K to
318.15 K with the modified apparatus that made the
experiments visualized and automatic. The solubility of
betulonic acid was found to increase exponentially with an
increase of temperature. Experimental data of the solubility of
betulonic acid were correlated with the Apelblat equation and
UNIQUAC equation. The results showed that the calculated
solubilities have satisfactory agreement with the experimental
data by the two equations.
⎛
⎝
⎞
1 ⎠
1
Δ H ⎛T
⎞
⎟
fus
m
ln⎜
⎟ =
⎜
− 1
⎜
⎟
⎠
γx
RT ⎝ T
1
m
(5)
with the experimental x , Δ H, T , and T values known, the
activity coefficients of betulonic acid in the selected solvents
can be obtained from eq 5.
1
fus
m
The activity coefficient of betulonic acid in eq 5 can be
18
calculated by the UNIQUAC eq 6:
ϕ
xi
θi
z
2
i
ln γ = ln
+
qi ln
+ li
i
ϕ
i
⎡
⎤
⎥
ϕ
xi
θτ
j ji
i
⎢
−
∑ xl + q 1 − ln(∑ θτ ) − ∑
i j
j ij
i
⎢
∑ θ τ ⎥
j
⎣
j
j
k
k kj ⎦
(6)
where
q x
rx
∑j r x
i
i i
i
ϕi =
,
θi =
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jced.5b00122.
∑ q x
■
j j
j
j
j
*
S
li = z (r − q ) − (r − 1)
i
i
i
2
1
H NMR spectrum of betulonic acid; 13C NMR
The coordination number z is set equal to 10. r and q are the
i
i
spectrum of betulonic acid; comparison of lit. and exp.
structural parameters of pure solvent i. The structural
values for solubility and relative error of NH Cl (PDF)
parameters of betulonic acid were calculated by the functional
4
1
9
group approach.
AUTHOR INFORMATION
Corresponding Author
Tel: +86-571-87951430. Fax: +86-571-87951895. E-mail:
yanweidong@zju.edu.cn.
Notes
m
m
■
*
r = ∑ n R , q = ∑ n Q
i
i
i
i
i
i
i=1
i=1
(7)
where m is is the number of functional groups in the molecule
and n is the repeating number of each function group. The
structural parameters, R and Q of function group i, were taken
The authors declare no competing financial interest.
i
i
from Dortmund Data Bank (DDBST GmbH, Germany). Two
REFERENCES
■
adjustable parameters τ and τ are expressed by
ij
ji
(
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aij
aji
⎛
⎞
⎟
⎛
⎞
⎟
τij = exp⎜⎝
−
⎠
,
τji = exp⎜⎝
−
⎠
52, 1366−1368.
RT
RT
(8)
(
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ji
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3
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Journal of Chemical & Engineering Data
Article
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DOI: 10.1021/acs.jced.5b00122
J. Chem. Eng. Data 2016, 61, 35−40