LWT - Food Science and Technology 64 (2015) 1278e1282

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LWT - Food Science and Technology

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Solubility and thermodynamics of vanillin in Carbitol-water mixtures

at different temperatures
Faiyaz Shakeel a, b, *, Nazrul Haq a, b, Nasir A. Siddiqui c, Fars K. Alanazi b,
Ibrahim A. Alsarra a, b
a
Center of Excellence in Biotechnology Research, College of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
b
Kayyali Chair for Pharmaceutical Industry, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451,
Saudi Arabia
c
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia

a r t i c l e i n f o a b s t r a c t

Article history: The solubilities of crystalline vanillin were measured in various Carbitol-water mixtures at different
Received 10 May 2015 temperatures and atmospheric pressure by an isothermal method. The measured solubilities were
Received in revised form compared with calculated ones. The root mean square deviations in the range of 0.18e5.62 % showed
12 July 2015
good correlation between experimental and calculated solubilities of vanillin. The mole fraction solu-
Accepted 15 July 2015
bility of vanillin was found to be highest in pure Carbitol (2.37
101 at 298.15 K) and lowest in pure
Available online 17 July 2015
water (1.23
103 at 298.15 K) at each temperature investigated. The solubility data of vanillin was also
treated thermodynamically and results indicated an endothermic, spontaneous and an entropy-driven
Keywords:
Carbitol
dissolution of vanillin in all Carbitol-water mixtures. Based on these results, vanillin has been consid-
Cosolvent mixture ered as freely soluble in Carbitol and soluble in water.
Solubility 2015 Elsevier Ltd. All rights reserved.
Thermodynamics
Vanillin

1. Introduction compound in water (mole fraction solubility: 1.23
103) at tem-

Vanillin is a commonly used avoring agent in food, beverage
and pharmaceutical industries which is obtained from the bean or
pod of Vanilla orchid (Kumar, Sharma, & Mishra, 2012). It is a
phenolic compound and its molecular structure is presented in
Fig. 1 (molecular formula: C8H8O3; molar mass: 152.15 g mol1)
(Noubigh, Cherif, Provost, & Abderrabba, 2008; Shakeel, Haq, &
Siddiqui, 2015). It has been reported in literature that vanillin and
its analogs have various benecial effects from health point of view
(Al-Naqeb, Ismail, Bagalkotkar, & Adamu, 2010). These benecial
effects include antioxidant, cholesterol lowering, antibacterial,
cytotoxic, antimicrobial and antimutagenic effects. These effects are
mainly due to the presence of phenolic compounds (Al-Naqeb et al.,
2010; Kayaci & Uyar, 2012; Kumar et al., 2012; Peng et al., 2010;
Rupasinghe, Boulter-Bitzer, Ahn, & Odumeru, 2006). Vanillin has
been investigated as a freely soluble bioactive compound in Car-
bitol (mole fraction solubility: 2.38
101) and soluble bioactive
* Corresponding author. Center of Excellence in Biotechnology Research, College
of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia.
E-mail address: faiyazs@fastmail.fm (F. Shakeel).
perature T 298.15 K (Noubigh et al., 2008; Shakeel, Haq, &
Siddiqui, 2015). The solubility and thermodynamic data of bioac-
tive compounds such as vanillin in water-cosolvent mixtures are
extremely useful in extraction of these bioactive compounds from
their respective plant source, purication/isolation, crystallization
and preformulation studies/formulation development of these
compounds (Chen et al., 2014; Shakeel & Anwer, 2015; Shakeel,
Haq, & Salem-Bekhit, 2015, Shakeel, Haq, Siddiqui, Alanazi, &
Alsarra, 2015). Recently, Carbitol has been investigated as a po-
tential cosolvent in solubility enhancement of bioactive com-
pounds such as isatin and reserpine in literature (Shakeel, Haq,
et al., 2015; Shakeel, Haq, Iqbal, Alanazi, & Alsarra, 2015; Shakeel,
Haq, Siddiqui, et al., 2015). Various semiempirical solubility
models are used to validate experimental solubilities of bioactive
compounds and to correlate these data with calculated solubilities.
Nevertheless, Van't Hoff, the modied Apelblat and Yalkow-
skyeRoseman models are generally applied semiempirical models
for this purpose (Apelblat & Manzurola, 1999; Shakeel, Haq, &
Siddiqui, 2015; Yalkowsky & Roseman, 1981). The solubility and
thermodynamic data of vanillin in various Carbitol-water mixtures
have not been reported in literature. Hence, in the current

http://dx.doi.org/10.1016/j.lwt.2015.07.043
0023-6438/ 2015 Elsevier Ltd. All rights reserved.
 F. Shakeel et al. / LWT - Food Science and Technology 64 (2015) 1278e1282 1279

3. Results and discussion

3.1. Measured solubilities of vanillin

The measured solubilities of vanillin in various Carbitol-water

mixtures at T 298.15e318.15 K and p 0.1 MPa are listed in
Table 2. The solubility data of vanillin in Carbitol-water mixtures are
Fig. 1. Structure of vanillin. not yet available in literature. Nevertheless, it has been reported as
soluble in water and freely soluble in Carbitol (Shakeel, Haq, &
investigation, the solubilities of vanillin in various Carbitol-water Siddiqui, 2015). In the literature, the solubility of vanillin in water
mixtures were determined and validated at T 298.15e318.15 K at room temperature (T 298.15 K) has been reported as 1.17
103
and p 0.1 MPa using an isothermal method (Higuchi & Connors, and 1.22
103 (Noubigh et al., 2008; Shakeel, Haq, & Siddiqui, 2015).
1965). The resulting solubility data of vanillin was treated ther- However, the solubility of vanillin in Carbitol at T 298.15 K has been
modynamically using the combined approach of Van't Hoff and reported as 2.38
101 (Shakeel, Haq, & Siddiqui, 2015). In the
Krug et al. in order to calculate various thermodynamic parameters present work, the solubility of vanillin in water and Carbitol at
and to evaluate the dissolution behavior of vanillin in Carbitol- T 298.15 K was found to be 1.23
103 and 2.37
101, respectively.
water mixtures. These results indicated good agreement of experimental solubilities
with literature solubilities of vanillin in water and Carbitol at
T 298.15 K. The graphical correlation of experimental solubilities of
2. Experimental vanillin with literature solubilities in water and Carbitol at
T 298.15e318.15 K are also shown in Figs. 2 and 3, respectively. The
2.1. Materials data presented in Figs. 2 and 3 showed good correlation in both
solvents at each temperature investigated. Generally, the xe values of
Vanillin (IUPAC name: 3-methoxy-4-hydroxybenzaldehyde) vanillin at constant pressure (p 0.1 MPa) were found to be
and Carbitol (IUPAC name: diethyleneglycol monoethyl ether) were increasing with increase in temperature and mass fraction of Carbitol
obtained from Sigma Aldrich (St. Louis, MO) and Gattefosse (Lyon, in Carbitol-water mixtures. The xe values of vanillin were found to be
France), respectively. Water was collected from Milli-Q water pu- highest in pure Carbitol (2.37
101 at T 298.15 K) at
rication system (Berlin, Germany). The detailed information and T 298.15e318.15 K. However, the lowest ones were recorded in pure
characteristics about materials used in the experiment is listed in water (1.23
103 at T 298.15 K) at T 298.15e318.15 K. The
Table 1. highest solubilities of vanillin in pure Carbitol were possibly due to
lower polarity of pure Carbitol as compared to pure water (Shakeel,
Haq, et al., 2015, Shakeel, Haq, Siddiqui, et al., 2015). The inuence
of mass fraction of Carbitol on solubility of vanillin at
2.2. Measurement of solubility of vanillin
T 298.15e318.15 K and p 0.1 MPa was also investigated as shown
in Fig. 4. From Fig. 4, it was observed that the solubility of vanillin was
The solubility of vanillin against mass fraction of Carbitol (m) in
found to be increasing with increase in mass fraction of Carbitol in
various Carbitol-water mixtures at temperature
Carbitol-water mixtures at T 298.15e318.15 K. The results of this
T 298.15e318.15 K and pressure p 0.1 MPa was measured using
work were in good agreement with previously published solubility
an isothermal method (Higuchi & Connors, 1965). The value of m
data of other bioactive compounds such as isatin and reserpine in
was varied from 0.0 to 1.0. For solubility experiments, the excess
amount of vanillin was added in known amounts of Carbitol-water
Table 2
mixtures and experiments were performed in triplicates. The Experimental solubility (xe) data of bioactive vanillin against mass fraction of Car-
detailed procedure for solubility measurement of vanillin is given bitol (m) in various Carbitol water cosolvent mixtures at T 298.15e318.15 K and
in our recently published article (Shakeel, Haq, & Siddiqui, 2015). pressure p 0.1 MPa.a
The analysis of vanillin in each sample was performed by reversed m
xe
phase high performance liquid chromatography method at 220 nm
T 298.15 K T 303.15 K T 308.15 K T 313.15 K T 318.15 K
as reported previously (Shakeel, Haq, & Siddiqui, 2015). The
3 3 3 3
experimental mole fraction solubilities (xe) of vanillin in various 0.0 1.23
10 1.53
10 1.86
10 2.19
10 2.54
103
0.1 2.15
103 2.60
103 3.10
103 3.62
103 4.16
103
Carbitol-water mixtures were calculated using Eq. (1):
0.2 3.60
103 4.28
103 4.99
103 5.74
103 6.49
103
0.3 6.07
103 7.04
103 8.09
103 9.08
103 1.02
102
m1 =M1 0.4 1.09
102 1.19
102 1.30
102 1.41
102 1.51
102
xe (1)
m1 =M1 m2 =M2 m3 =M3 0.5 1.73
102 1.96
102 2.21
102 2.42
102 2.68
102
0.6 2.96
102 3.24
102 3.56
102 3.91
102 4.20
102
In which, m1 is the mass of vanillin and m2 and m3 are the 0.7 4.94
102 5.40
102 5.83
102 6.28
102 6.73
102
masses of Carbitol and water, respectively. M1 is the molar mass of 0.8 8.33
102 8.87
102 9.51
102 1.01
101 1.09
101
0.9 1.41
101 1.49
101 1.57
101 1.64
101 1.71
101
vanillin and M2 and M3 are the molar masses of Carbitol and water,
1.0 2.37
101 2.43
101 2.52
101 2.59
101 2.67
101
respectively.
a
The standard uncertainties u are u(T) 0.13 K, ur(m) 0.1%, u(p) 0.003 MPa
and ur(xe) 1.28%.
Table 1
A sample table for materials used in this work.

Material Molecular formula Molar mass (g mol1) Purity (mass fraction) Purication method Analysis method Source

Vanillin C8H8O3 152.15 0.990 None HPLC Sigma Aldrich

Carbitol C6H14O3 134.17 0.999 None GC Gattefosse
Water H2O 18.01 1.000 None Conductivity < 1 mS cm1 Milli-Q purication unit

HPLC: high performance liquid chromatography; GC: gas chromatography.

1280 F. Shakeel et al. / LWT - Food Science and Technology 64 (2015) 1278e1282

Fig. 2. Comparison of experimental solubilities (xe) of vanillin in water with literature

values at T 298.15e318.15 K; the symbol represents the literature solubilities of Fig. 4. Inuence of mass fraction of Carbitol (m) on mole fraction solubility (ln xe) of
vanillin taken from Noubigh et al. (2008); the symbol represents the literature vanillin at T 298.15e318.15 K; 298.15 K, 303.15 K, 308.15 K, 313.15 K
solubilities taken from Shakeel, Haq, and Siddiqui (2015) and solid line represents the and 318.15 K.
experimental solubilities of vanillin.

the modied Apelblat and Yalkowsky models (Apelblat &

Manzurola, 1999; Shakeel, Haq, & Siddiqui, 2015; Yalkowsky &
Roseman, 1981). According to the Van't Hoff model, the calculated
solubility of vanillin (ln xVan't) at temperature (T/K) in various
Carbitol-water mixtures can be determined using Eq. (2) (Shakeel,
Haq, & Siddiqui, 2015):

0
b
ln xVan t a (2)
T
In which, the coefcients a and b are the parameters of Van't
Hoff model which were determined by regression analysis of ln xe
values of vanillin as a function of reciprocal of temperature (1/T).
The correlation between xe and xVan't values of vanillin was per-
formed by calculating the values of root mean square deviations
(RMSD) using Eq. (3).

"  #12
N 
1 X xc  xe 2
RMSD (3)
N i1 xe

In which, N is the number of data points used in the experiment

Fig. 3. Comparison of experimental solubilities (xe) of vanillin in Carbitol with litera-
ture solubilities at T 298.15e318.15 K; the symbol represents the experimental
solubilities of vanillin and solid line represents the solubilities taken from Shakeel,
Haq, and Siddiqui (2015).
Carbitol-water mixtures at T 298.15e338.15 K and p 0.1 MPa and
silymarin in PEG 400-water mixtures at T 298.15e333.15 K and
p 0.1 MPa (Shakeel & Anwer, 2015; Shakeel, Haq, et al., 2015,
Shakeel, Haq, Siddiqui, et al., 2015). Based on these results, vanillin
has been considered as soluble in water and freely soluble in Carbitol
according to USP and BP classication of solubility (Shakeel, Haq, &
Siddiqui, 2015). Hence, Carbitol could be used as a good cosolvent
in preformulation studies and formulation development of vanillin.
3.2. Correlation of measured solubilities of vanillin with calculated
solubilities
The measured solubilities of vanillin were correlated with three
different semiempirical mathematical models namely Van't Hoff,
and xc is the calculated solubility of vanillin for respective model.
The graphical correlation between experimental and calculated
solubilities of vanillin for Van't Hoff model in various Carbitol-
water mixtures is presented in supplementary Figure 1 (Figure S1).
The resulting data of Van't Hoff correlation are listed in
supplementary Table 1 (Table S1). The RMSD values and correlation
coefcients (R2) in various Carbitol-water mixtures were observed
in the range of 0.24e1.48 % and 0.9960e0.9990, respectively
(Table S1). The low values of RMSD and higher values of R2 indicated
good correlation and curve tting of experimental solubilities of
vanillin with Van't Hoff model.
Another correlation of experimental solubilities of vanillin was
performed with the modied Apelblat model. According to this
model, the calculated solubility of vanillin (xApl) can be calculated
using Eq. (4) (Apelblat & Manzurola, 1999):
B
ln xApl A C lnT (4)
T
 F. Shakeel et al. / LWT - Food Science and Technology 64 (2015) 1278e1282
In which, the symbols A, B and C are the parameters of the
modied Apelblat model which were determined by multivariate
regression analysis (Shakeel, Haq, & Siddiqui, 2015, Shakeel, Haq,
et al., 2015). The graphical correlation between experimental and
calculated solubilities of vanillin for the modied Apelblat model in
various Carbitol-water mixtures is presented in Figure S2.
For the correlation of experimental solubilities with the modi-
ed Apelblat model, the RMSD values were calculated again using
previous Eq. (3). The resulting data of the modied Apelblat cor-
relation are listed in Table S2. The RMSD and R2 values in various
Carbitol-water mixtures were found to be 0.18e0.49 % and
0.9993e0.9999, respectively. The low values of RMSD and higher
values of R2 again indicated good correlation of experimental sol-
ubilities of vanillin with the modied Apelblat model.
Finally, the experimental solubilities of vanillin were correlated
with the log-linear model of Yalkowsky and Roseman. According to
this model, the calculated solubility of vanillin (log xYal) in various
Carbitol-water mixtures can be calculated using Eq. (5) (Yalkowsky
& Roseman, 1981):
Log xYal m1 logx1 m2 logx2
In which, x1 and x2 are the solubilities of vanillin in pure solvent
1 (Carbitol) and pure solvent 2 (water), respectively; and m1 and m2
are the mass fractions of Carbitol and water in the absence of
vanillin, respectively.
The experimental solubilities of vanillin were correlated with
Yalkowsky model by calculating RMSD values again using Eq. (3).
The resulting data of Yalkowsky correlation are listed in Table S3.
The RMSD values in various Carbitol-water mixtures were recorded
as 1.00e5.62 %. These results again indicated good correlation of
experimental solubilities of vanillin with Yalkowsky model.
3.3. Thermodynamic analysis for vanillin dissolution
Thermodynamic analysis of solutes in terms of standard disso-
lution enthalpy (DsolH0), standard dissolution entropy (DsolS0) and
standard Gibbs energy (DsolG0) in water-cosolvent mixtures is
important in evaluation of dissolution and solvation behavior of
solutes. Therefore, the DsolH0 values for vanillin dissolution in
various Carbitol-water mixtures were determined by Van't Hoff
analysis with the help of Eq. (6) (Holgun, Rodrguez, Cristancho,
Delgado, & Martnez, 2012; Ruidiaz, Delgado, Martnez, & Marcus,
2010):
 
vlnx D H0
 sol
v1=T  1=Thm P R
In which, R represents the universal gas constant and Thm is the
mean harmonic temperature (Thm was 307.98 K in current study).
With the help of Eq. (6), the Van't Hoff plots were constructed
between ln xe and 1=T  1=Thm (Figure S3). These plots of vanillin in
all Carbitol-water mixtures were found to be linear with R2 values
in the range of 0.9960e0.9990 as shown in Table 3.
The DsolG0 values for vanillin dissolution in various Carbitol-
water mixtures were calculated at Thm by thermodynamic
approach reported by Krug, Hunter, and Grieger (1976) using Eq. (7)
(Krug et al., 1976):
Dsol G0 RThm
intercept
In which, the values of intercept for each Carbitol-water mixture
were determined from Van't Hoff plots presented in Figure S3.
Finally, the DsolS0 values for vanillin dissolution in various
Carbitol-water mixtures were calculated by the combined
approach of Van't Hoff and Krug et al. analysis with the help of Eq.
1281
(8) (Holguin et al., 2012; Krug et al., 1976):
Dsol H0  Dsol G0
Dsol S0 (8)
Thm
The resulting data of thermodynamic analysis of vanillin
dissolution in various Carbitol-water mixtures are listed in Table 3.
The DsolH0 values were recorded as positive values in the range
of 4.8e28.5 kJ mol1. The DsolH0 value was recorded highest in pure
water (28.5 kJ mol1) and lowest in pure Carbitol (4.8 kJ mol1). The
DsolG0 values were also observed as positive values in the range of
3.5e16.1 kJ mol1. The DsolG0 value was also found to be highest in
pure water (16.1 kJ mol1) and lowest in pure Carbitol
(3.5 kJ mol1). Due to positive values of DsolH0 and DsolG0, the
dissolution of vanillin was considered as an endothermic and
spontaneous in all Carbitol-water mixtures investigated. The DsolS0
values were also found to be positive values in the range of
4.2e40.2 J mol1 K1. The results of DsolS0 indicated an entropy-
driven dissolution of vanillin in all Carbitol-water mixtures inves-
tigated. This observation was due to the stronger molecular in-
teractions between solvent and vanillin molecules as compared to
(5)
those between solventesolvent and vanillinevanillin molecules
(Shakeel, Haq, & Siddiqui, 2015; Shakeel, Haq, et al., 2015).
3.4. Solvation behavior of vanillin solution
Solvation behavior of vanillin in various Carbitol-water mixtures
was investigated by an enthalpy-entropy compensation analysis
(Bustamante, Romero, & Reillo, 1995; Ruidiaz et al., 2010). An
enthalpy-entropy compensation analysis was performed by con-
structing weighted plots between DsolH0 and DsolG0. Such type of
analysis permits the observation of similar mechanism for solvation
mechanism of solutes in solutions as per tendencies obtained at
Thm (Tomlinson, 1983). The results of enthalpy-entropy compen-
sation effects for solvation mechanism of vanillin in various
Carbitol-water mixtures are presented in Fig. 5. From Fig. 5, it was
clearly observed that vanillin in all Carbitol-water mixtures pre-
sents nonlinear DsolH0 vs. DsolG0 curve with a positive slope value of
greater than unity. Hence, the driving mechanism for solvation of
vanillin was proposed as an enthalpy-driven in all Carbitol-water
mixtures. This observation was probably due to better solvation
of vanillin in Carbitol molecules (Ahumada, Delgado, & Martnez,
2012).
(6) 4. Conclusion
The solubilities of bioactive vanillin in various Carbitol-water
mixtures were measured at different temperatures and atmo-
spheric pressure. The solubilities of vanillin were found to be
increased with increase in temperature and mass fraction of Car-
bitol in Carbitol-water mixtures. The experimental solubilities of
vanillin were correlated well with the solubilities calculated by
Van't Hoff, the modied Apelblat and YalkowskyeRoseman models.
Thermodynamic analysis of vanillin solubilities indicated an
endothermic, spontaneous and an entropy-driven dissolution of
vanillin in all Carbitol-water mixtures investigated. The driven
mechanism for solvation behavior of vanillin in all Carbitol-water
(7) mixtures was proposed as enthalpy-driven.
Conict of interest
The authors report no conict of interest related with this
manuscript.
1282 F. Shakeel et al. / LWT - Food Science and Technology 64 (2015) 1278e1282

Table 3
Thermodynamic parameters with R2 values for dissolution of vanillin in various Carbitol water cosolvent mixtures (m) calculated by Van't Hoff and Krug et al. analysis.

Parameters m 0.0 m 0.1 m 0.2 m 0.3 m 0.4 m 0.5 m 0.6 m 0.7 m 0.8 m 0.9 m 1.0

DsolH0/kJ mol1 28.5 26.0 23.2 20.4 13.0 17.0 13.9 12.1 10.7 7.6 4.8
DsolG0/kJ mol1 16.1 14.8 13.6 12.3 11.1 9.7 8.54 7.2 6.0 4.7 3.5
DsolS0/J mol1 K1 40.2 36.4 30.3 26.2 6.1 23.6 17.4 15.6 15.2 9.36 4.2
R2 0.996 0.998 0.997 0.998 0.999 0.998 0.999 0.999 0.995 0.998 0.996

Fig. 5. DsolH0 versus DsolG0 enthalpyeentropy compensation plot for solvation behavior of vanillin in various Carbitol-water mixtures at mean harmonic temperature of 307.98 K.

Acknowledgment
The project was nancially supported by King Saud University,
Vice Deanship of Research Chairs, Kayyali Chair for Pharmaceutical
Industry (Grant no. FN-2015).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.lwt.2015.07.043.
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