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Journal of Molecular Liquids 207 (2015) 274278

Contents lists available at ScienceDirect

Journal of Molecular Liquids


journal homepage: www.elsevier.com/locate/molliq

Thermodynamics of solubility of isatin in Carbitol + water mixed solvent


systems at different temperatures
Faiyaz Shakeel a,, Nazrul Haq a, Mounir M. Salem-Bekhit a,b
a
b

Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

a r t i c l e

i n f o

Article history:
Received 15 February 2015
Received in revised form 18 March 2015
Accepted 20 March 2015
Available online 2 April 2015
Keywords:
Apelblat model
Isatin
Solubility
Thermodynamics
Van't Hoff model
Yalkowsky model

a b s t r a c t
Thermodynamics of solubility of natural pharmacologically active compound isatin in various Carbitol + water
mixed solvent systems was studied. The solubilities of isatin were measured at T = (298.15 to 338.15) K at atmospheric pressure using an isothermal method. The measured solubility data of isatin was correlated and regressed
by three semiempirical models. The values of root mean square deviations were observed less than 0.040 by all
three semiempirical models. The mole fraction solubility of natural isatin was found to be highest in pure Carbitol
(5.20 101 at 298.15 K) and lowest in pure water (5.13 105 at 298.15 K) at T = (298.15 to 338.15) K. The
resulting data of Van't Hoff and Krug analyses showed an endothermic, spontaneous and an entropy-driven dissolution of isatin in all Carbitol + water mixed solvent systems.
2015 Elsevier B.V. All rights reserved.

1. Introduction
The chemical name of isatin has been proposed as indoline-2,3dione and its molecular structure is presented in Fig. 1 [1,2]. It occurs
as a yellow to red needle crystalline powder [3,4]. It is a pharmacologically active natural bioactive compound which showed broad range of
therapeutic effects [37]. The mole fraction solubility of isatin in water
has been reported as 5.13 10 5 at T = 298.15 K [1]. According to
the literature solubility of isatin, it has been considered as poorly
water-soluble bioactive compound which is the main barrier for formulation development of these bioactive compounds [1,2]. In order to enhance the solubilization and stabilization of poorly water-soluble
bioactive compounds in aqueous media, various approaches have been
investigated in literature [8,9]. Among these approaches, cosolvency approach is one of the simplest and the commonly used approach which requires simple cosolvents for the solubilization and stabilization of poorly
water-soluble compounds [8,1012]. Recently, Carbitol has been investigated as a potential cosolvent for solubility enhancement of various poorly water-soluble compounds [1319]. Although, various temperaturedependent semiempirical models have been reported for correlation of
solubility data of solutes, the modied Apelblat and Van't Hoff models
are commonly used models for this purpose [2,10,1820]. However,
Yalkowsky model is commonly used cosolvency model for correlation of
solubility data of solutes [21]. Liu et al. reported the solubility data of
Corresponding author.
E-mail address: faiyazs@fastmail.fm (F. Shakeel).

http://dx.doi.org/10.1016/j.molliq.2015.03.038
0167-7322/ 2015 Elsevier B.V. All rights reserved.

crystalline isatin in nine different pure solvents such as water, dichloromethane (DCM), toluene, acetone, ethyl acetate (EA), 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran and acetonitrile at
T = (278.15 to 333.15) K and p = 0.1 MPa [2]. Baluja et al. also reported
the solubility data of isatin in DCM, water, 1,2-dichloroethane, chloroform, carbon tetrachloride, methanol, ethanol and 1-butanol at T =
(298.15 to 318.15) K and p = 0.1 MPa [1]. The solubility data of isatin in
various biosolvents such as water, ethanol, butanol-2, Carbitol, EA, ethylene glycol, isopropyl alcohol, propylene glycol and polyethylene glycol
400 (PEG 400) and various PEG 400 + water mixed solvent systems at
T = (298.15 to 338.15) K and p = 0.1 MPa have also been reported in literature [10,22]. However, the solubility data of crystalline isatin in various
Carbitol + water mixed solvent systems are not available in literature.
Therefore, the thermodynamics and solvation behavior of solubilities of
crystalline isatin in various Carbitol + water mixed solvent systems
were investigated in this work. The solubilities were measured at T =
(298.15 to 338.15) K and p = 0.1 MPa using an isothermal method [23].
The solubility data of this work could be extremely useful in purication,
crystallization, separation/extraction, preformulation studies and formulation development of isatin in chemical and pharmaceutical industries.
2. Experimental
2.1. Materials
Isatin was obtained from E-Merck (Hamburg, Germany). Carbitol
(IUPAC name: diethylene glycol monoethyl ether) was obtained as a

F. Shakeel et al. / Journal of Molecular Liquids 207 (2015) 274278

Fig. 1. Molecular structure of isatin.

kind gift sample from Gattefosse (Lyon, France). The water was collected from Milli-Q water purication unit (Millipore Corporation, Berlin,
Germany). The detailed information about all these materials is presented in a sample Table 1. All the materials were used without any further
purication because of their high purity.
2.2. Measurement of isatin solubility
The solubility of isatin against mass fraction of Carbitol (m = 0.0 to
1.0) in various Carbitol + water mixed solvent systems was measured
at T = (298.15 to 338.15) K and atmospheric pressure of 0.1 MPa
using an isothermal method [23]. The excess amount of isatin was
added in known amounts of Carbitol + water mixed solvent systems.
The concentrated suspensions of isatin in each Carbitol + water
mixed solvent system were shaken continuously in a biological shaker
(Julabo, PA) at 100 rpm for 72 h [10,22]. All the experiments were repeated in triplicates. After 72 h, all the concentrated suspensions were
taken out from the shaker and allowed to settle isatin particles for 2 h
[1719]. The upper layer of each sample was taken and centrifuged
further at 5000 rpm for 15 min in order to remove any ne particles.
The supernatants from each sample were taken, diluted suitably with
respective cosolvent mixture and subjected for the analysis of isatin
content using UVVisible spectrophotometer at 240 nm [22]. The experimental mole fraction solubilities (xe) of crystalline isatin in each
Carbitol + water mixed solvent systems were calculated as reported
previously [10,22].
3. Results and discussion
3.1. Measured solubility data of isatin
The measured solubilities of crystalline isatin in various
Carbitol + water mixed solvent systems at T = (298.15 to
338.15) K and atmospheric pressure of 0.1 MPa are presented in
Table 2. The mole fraction solubility data of isatin in pure water
(m = 0.0) and pure Carbitol (m = 1.0) at T = (298.15 to 338.15) K and
atmospheric pressure are available in literature [22]. However, its solubility data in various Carbitol + water mixed solvent systems are not reported in previous literature. The xe values of isatin in water and Carbitol at
298.15 K have been reported as 5.14 105 and 5.23 101, respectively
[22]. In this work, the xe values of isatin in water and Carbitol at 298.15 K
were recorded as 5.13 105 and 5.20 101, respectively. The graphical comparison between experimental and literature solubilities of isatin

275

in water and Carbitol is presented in Fig. 2 at T = (298.15 to 338.15) K.


Fig. 2 showed good correlation between experimental and literature solubilities of isatin at T = (298.15 to 338.15) K. Overall, these results indicated good agreement of the results of this work with reported
solubility data of isatin in water and Carbitol at T = (298.15 to
338.15) K. Generally, the xe values of crystalline isatin were found to
be increasing with the rise in temperature and mass fraction of Carbitol
in Carbitol + water mixed solvent systems. The xe values of crystalline
isatin were observed highest in pure Carbitol (5.20 101 at 298.15 K)
at T = (298.15 to 338.15) K. However, the lowest xe values of crystalline
isatin were observed in pure water (5.13 105 at 298.15 K) at T =
(298.15 to 338.15) K. The highest xe values of crystalline isatin in pure
Carbitol were probably due to lower polarity of Carbitol as compared
to pure water [17,18]. The impact of mass fraction of Carbitol on mole
fraction solubility of crystalline isatin at T = (298.15 to 338.15) K is
presented in Fig. 3. The solubility of crystalline isatin was increasing
continuously with increase in mass fraction of Carbitol in
Carbitol + water mixed solvent systems at T = (298.15 to 338.15)
K (Fig. 3). Overall, these results were in good agreement with previously published solubility data of other natural bioactive compounds
such as reserpine in Carbitol + water, isatin in PEG 400 + water and
silymarin in PEG 400 + water mixed solvent systems [1012]. Compared with previously published solubility data of isatin in various
pure solvents and cosolvent mixtures, Carbitol was found to be the
best cosolvent for solubility enhancement of isatin [1,2,10,22].
Based on solubility data of this work, isatin has been considered as
poorly soluble in water and very soluble in Carbitol.
3.2. Correlation of experimental solubilities with Van't Hoff model
According to the Van't Hoff model, the mole fraction solubility of
crystalline isatin in various Carbitol + water mixed solvent systems
can be calculated with the help of Eq. (1) [2,10]:
ln x

Van t

b
a :
T

In which, xVan't is the Van't Hoff model solubility of crystalline isatin


and T represents the absolute temperature (K). Parameters a and b are
the Van't Hoff model parameters. Parameters a and b were determined
by regression analysis of ln xe against 1/T. For the correlation of xe with
xVan't, the root mean square deviations (RMSD) were calculated in each
cosolvent mixture using Eq. (2).
2

N
1X
xVan t xe
RMSD 4
xe
N i1

!2 312
5

In which, N represents the number of temperature points used in the


experiment. The graphical correlations between xe and xVan't of isatin in
various Carbitol + water mixed solvent systems are presented in Fig. S1.
The values of model parameters a and b, correlation coefcients (R2)
and RMSD in various Carbitol + water mixed solvent systems are listed
in Table S1. The RMSD values in various Carbitol + water mixed solvent
systems were obtained in the range of 0.002 to 0.031. The R2 values for
isatin were obtained as 0.9951 to 0.9997. These data indicated good

Table 1
A sample table for drug (isatin) and materials used in the experiment.
Material

Molecular formula

Molar mass (gmol1)

Purity (mass fraction)

Purication method

Analysis method

Source

Isatin
Carbitol
Water

C8H5NO2
C6H14O3
H2O

147.13
134.17
18.01

0.998
0.999

None
None
None

HPLC
GC

E-Merck
Gattefosse
Milli-Q purication unit

High performance liquid chromatography (HPLC); gas chromatography (GC).

276

F. Shakeel et al. / Journal of Molecular Liquids 207 (2015) 274278

Table 2
Experimental mole fraction solubilities (xe) of crystalline isatin against mass fraction of Carbitol (m) in various Carbitol + water cosolvent mixtures in the absence of solute at temperatures
T = (298.15 to 338.15) K and pressure p = 0.1 MPaa (the values in parentheses are standard deviations of three measurement).
m

xe
T = 298.15 K

0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
a

T = 308.15 K
5

5.13 (0.03) 10
1.34 (0.01) 104
3.49 (0.04) 104
8.11 (0.05) 104
2.00 (0.01) 103
5.35 (0.02) 103
1.28 (0.01) 102
3.31 (0.03) 102
8.19 (0.04) 102
2.08 (0.03) 101
5.20 (0.00) 101

T = 318.15 K
5

T = 328.15 K
4

8.06 (0.04) 10
1.90 (0.02) 104
4.71 (0.05) 104
1.07 (0.06) 103
2.71 (0.02) 103
6.58 (0.04) 103
1.52 (0.01) 102
3.85 (0.02) 102
9.32 (0.03) 102
2.25 (0.02) 101
5.36 (0.01) 101

1.13 (0.05) 10
2.63 (0.02) 104
6.22 (0.06) 104
1.39 (0.07) 103
3.29 (0.03) 103
7.92 (0.03) 103
1.78 (0.02) 102
4.40 (0.01) 102
1.02 (0.05) 101
2.43 (0.01) 101
5.57 (0.01) 101

T = 338.15 K
4

1.51 (0.07) 10
3.43 (0.03) 104
7.83 (0.08) 104
1.80 (0.08) 103
3.99 (0.05) 103
9.41 (0.05) 103
2.08 (0.02) 102
5.02 (0.02) 102
1.13 (0.06) 101
2.56 (0.04) 101
5.79 (0.02) 101

2.00 (0.08) 104


4.50 (0.04) 104
9.62 (0.07) 104
2.23 (0.09) 103
4.86 (0.04) 103
1.07 (0.01) 102
2.44 (0.03) 102
5.58 (0.03) 102
1.25 (0.06) 101
2.73 (0.03) 101
5.94 (0.03) 101

The standard uncertainties u are u(T) = 0.10 K, ur(m) = 0.1%, u(p) = 0.003 MPa and ur(xe) = 1.20%.

correlation of measured solubility data of crystalline isatin with Van't


Hoff model.
3.3. Correlation of experimental solubilities with the modied Apelblat
model
According to this model, the mole fraction solubility of crystalline
isatin can be calculated using Eq. (3) [20]:
ln x

Apl

B
A C ln T :
T

In which, xApl is the mole fraction solubility of isatin calculated by the


modied Apelblat model. The parameters A, B and C are the model
coefcients which were calculated by multivariate regression analysis
[10,22]. The graphical correlations between xe and xApl in various
Carbitol + water mixed solvent systems are presented in Fig. S2.
The values of the modied Apelblat parameters along with R2 and
RMSD values in various Carbitol + water mixed solvent systems are presented in Table S2. The RMSD values in various Carbitol + water mixed
solvent systems were observed in the range of 0.002 to 0.016. However,
the R2 values in various Carbitol + water mixed solvent systems were
obtained as 0.9967 to 0.9999. The data of R2 and RMSD indicated again
good correlation of experimental solubility data of isatin with the modied Apelblat model.

Fig. 2. Comparison of experimental mole fraction solubilities (xe) of crystalline isatin with
Carbitol and
water (solid lines repreliterature values at T = (298.15 to 338.15) K;
sent the literature values of isatin taken from reference 22).

3.4. Correlation of experimental solubilities with Yalkowsky model


According to the log-linear model of Yalkowsky, the solubility of
crystalline isatin in various Carbitol + water mixed solvent systems
can be calculated using Eq. (4) [21]:
Log x

Yal

m1 logS1 m2 logS2 :

In which, xYal is the Yalkowsky model solubility of crystalline isatin


in Carbitol + water mixed solvent systems; S1 and S2 are the solubility
of isatin in pure solvent 1 (Carbitol) and pure solvent 2 (water), respectively; and m1 and m2 are the mass fractions of solvents 1 and 2 in the
absence of solute (isatin). For the correlation of xe with xYal, RMSD values
were calculated again using Eq. (2).
The log xYal values of crystalline isatin along with RMSD values
in various Carbitol + water mixed solvent systems at T = (298.15
to 338.15) K are listed in Table S3. The RMSD values in various
Carbitol + water mixed solvent systems were obtained as 0.014 to
0.033 which indicated good correlation of measured solubility data of
isatin with the Yalkowsky model.
3.5. Thermodynamic parameters for isatin dissolution
The dissolution enthalpy (solH0) for crystalline isatin in various
Carbitol + water mixed solvent systems was determined by wellknown Van't Hoff analysis [24,25]. Hence, the solH0 values were

Fig. 3. Impact of mass fraction of Carbitol (m) on mole fraction solubility (xe) of crystalline
328.15 K and
isatin at T = (298.15 to 338.15) K; 298.15 K, 308.15 K, 318.15 K,
338.15 K.

F. Shakeel et al. / Journal of Molecular Liquids 207 (2015) 274278

277

calculated at mean harmonic temperature (Thm = 317.52 K) using


Eq. (5):
0

1
0
@   ln x A sol H :
1
1
R

T
T
hm

In which, R represents the universal gas constant. The ln xe values of




crystalline isatin were plotted against 1 T 1 T . These plots were obhm

served linear with R2 values in the range of 0.9950 to 0.9990 (Table S4).
The solH0 values in Carbitol + water mixed solvent systems were
determined from the slope of each plot presented in Fig. S3. The Gibbs
free energies (solG0) in various Carbitol + water mixed solvent systems were determined at Thm = 317.52 K using Krug analysis with
the help of Eq. (6) [26]:
0

sol G RT hm  intercept:

In which, the intercept values in each cosolvent mixtures were determined from Fig. S3.
The dissolution entropies (solS0) in various Carbitol + water mixed
solvent systems were calculated using Eq. (7):
0

sol S

sol H sol G
:
T hm

The values of solH0, solG0, solS0 and R2 in various Carbitol + water


mixed solvent systems are listed in Table S4.
The solH0 values in various Carbitol + water mixed solvent systems
were observed as positive values in the range of (2.88 to 28.10)
kJmol1. The solH0 value was observed highest in pure water (m =
0.0) (28.10 kJmol1). However, the lowest one was observed in pure
Carbitol (m = 1.0) (2.88 kJmol1). The solG0 values were also recorded as positive values in the range of (1.54 to 24.13) kJmol1. The solG0
value was also observed highest in pure water (24.13 kJmol1) and
lowest in pure Carbitol (1.54 kJmol1). The positive values of solH0
and solG0 in all Carbitol + water mixed solvent systems indicated an
endothermic and spontaneous dissolution of crystalline isatin in all binary solvent mixtures investigated. The solS0 values were also recorded
as positive values in the range of (4.21 to 12.52) Jmol1K1, indicating an entropy-driven dissolution of isatin. The positive values of solH0
for the dissolution of crystalline isatin were probably due to the stronger
molecular interactions between isatin and the solvent molecules as
compared to those between the solventsolvent and isatinisatin molecules [10,22].

Fig. 4. solH0 versus solG0 enthalpyentropy compensation plot for the dissolution of
crystalline isatin in Carbitol + water cosolvent mixtures at mean harmonic temperature
of 317.52 K.

4. Conclusion
The solubilities of pharmacologically active natural bioactive compound isatin in various Carbtol + water mixed solvent systems were
measured at T = (298.15 to 338.15) K. Generally, the solubilities of crystalline isatin were found to be increased with the rise in temperature
and mass fraction of Carbitol in Carbitol + water mixed solvent systems.
The highest solubility of isatin was observed in pure Carbitol and lowest
one was observed in pure water. The measured solubility data of isatin
were correlated well with all three mathematical models. Van't Hoff
and Krug analyses showed endothermic, spontaneous and an entropydriven dissolution of isatin in all Carbitol + water mixed solvent systems investigated. Enthalpyentropy compensation studies indicated
an entropy-driven mechanism for isatin solvation from m = 0.0 to 0.3
and an enthalpy-driven mechanism from m = 0.4 to 1.0.
Conict of interest
The authors report no conict of interest related with this manuscript.
Acknowledgment
The authors would like to extend their sincere appreciation to the
Deanship of Scientic Research at King Saud University for funding the
work through the research group project no. RGP-VPP-202.
Appendix A. Supplementary data

3.6. Enthalpyentropy compensation of isatin solution


The purpose of studying the enthalpyentropy compensation effect of
isatin solution was to evaluate the mechanism of co-solvent action [24,
27]. The weighted plots of solH0 as a function of solG0 at permits the observation of similar mechanism for solvation process according to the tendencies obtained Thm [28]. The results of enthalpyentropy compensation
effects for isatin solvation behavior are presented in Fig. 4. From Fig. 4, it
was observed that crystalline isatin in Carbitol + water mixed solvent
systems presents nonlinear solH0 vs. solG0 curve with a variable positive
slope value (less than 1) for up to m = 0.3 (where the maxima were
reached). Beyond this Carbitol proportion, a positive slope value of greater
than 1 was obtained. Hence, the driving mechanism for solvation behavior of isatin was proposed as an entropy-driven in former case that was
probably due to water-structure loosening. However, in latter case (second case), the driving mechanism was proposed as enthalpy-driven,
that was probably due to better solvation of crystalline isatin in Carbitol
molecules [29].

Supplementary data associated with this article can be found, in the


online version, at http://dx.doi.org/10.1016/j.molliq.2015.03.038.
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