-
Accepted ManuscriptSolubility and thermodynamic function of a
new anti-cancer drug ibrutinib in{2-(2-ethoxyethoxy)ethanol +
water} mixtures at different temperaturesFaiyaz Shakeel, Muzaffar
Iqbal, Nazrul HaqPII: S0021-9614(15)00106-8DOI:
http://dx.doi.org/10.1016/j.jct.2015.04.014Reference: YJCHT 4206To
appear in: J. Chem. ThermodynamicsReceived Date: 25 February
2015Revised Date: 6 April 2015Accepted Date: 8 April 2015
Please cite this article as: F. Shakeel, M. Iqbal, N. Haq,
Solubility and thermodynamic function of a new anti-cancerdrug
ibrutinib in {2-(2-ethoxyethoxy)ethanol + water} mixtures at
different temperatures, J. Chem.Thermodynamics (2015), doi:
http://dx.doi.org/10.1016/j.jct.2015.04.014
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1
Solubility and thermodynamic function of a new anti-cancer drug
ibrutinib in {2-(2-
ethoxyethoxy)ethanol + water} mixtures at different
temperatures
Faiyaz Shakeela*, Muzaffar Iqbalb,c, Nazrul Haqa
aCenter of Excellence in Biotechnology Research (CEBR), College
of Science, King Saud
University, Riyadh 11451, Saudi Arabia
bDepartment of Pharmaceutical Chemistry, College of Pharmacy,
King Saud University, P.O.
Box 2457, Riyadh 11451, Saudi Arabia
cBioavailability Laboratory, Department of Pharmaceutical
Chemistry, College of Pharmacy,
King Saud University, P.O. Box 2457, Riyadh 11451, Saudi
Arabia
*Corresponding Author:
Dr. Faiyaz Shakeel
Center of Excellence in Biotechnology Research,
College of Science, King Saud University,
Riyadh, Saudi Arabia
Phone: +966-537507318
Email: [email protected]
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ABSTRACT
Ibrutinib is a recently approved anti-cancer drug recommended
for the treatment of mantle
cell lymphoma and chronic lymphocytic leukemia. It has been
reported as practically
insoluble in water and hence it is available in the market at
higher doses. Poor solubility of
ibrutinib limits its development to oral solid dosage forms
only. In this work, the solubility of
ibrutinib was measured in various {2-(2-ethoxyethoxy)ethanol
(Carbitol) + water} mixtures
at T = (298.15 to 323.15) and p = 0.1 MPa. The solubility of
ibrutinib was measured using an
isothermal method. The thermodynamics functions of ibrutinib
were also studied. The
measured solubility of ibrutinib was correlated and fitted with
Vant Hoff, the modified
Apelblat and Yalkowsky models. The results of curve fitting of
all three models showed good
correlation of experimental solubility of ibrutinib with
calculated values. The mole fraction
solubility of ibrutinib was observed highest in pure
2-(2-ethoxyethoxy)ethanol (2.67 x 10-2 at
298.15 K) and lowest in pure water (1.43 x 10-7 at 298.15 K) at
T = (298.15 to 323.15) K.
The thermodynamics data of ibrutinib show an endothermic,
spontaneous and an entropy-
driven dissolution behaviour of ibrutinib in all
{2-(2-ethoxyethoxy)ethanol + water}
mixtures. Based on these results, ibrutinib has been considered
as practically insoluble in
water and freely soluble in 2-(2-ethoxyethoxy)ethanol.
Therefore, 2-(2-ethoxyethoxy)ethanol
could be used as a physiologically compatible co-solvent for
solubilization and stabilization
of ibrutinib in an aqueous media. The solubility results of this
work could be extremely useful
in pre-formulation studies and formulation development of
ibrutinib.
Keywords: Apelblat model; Ibrutinib; Solubility; Thermodynamics;
Vant Hoff model;
Yalkowsky model.
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1. Introduction
The chemical name of ibrutinib is
(R)1(3(4amino3(4phenoxyphenyl)1Hpyrazolo
[3,4d] pyrimidin1yl) piperidin1yl) prop2en1one and its molecular
structure is shown
in figure 1 [1, 2]. It occurs as a white crystalline powder with
molar mass of 440.50 gmol-1
and molecular formula of C25H24N6O2 [2, 3]. It has been recently
approved as an anti-cancer
drug and commercially available in oral capsules with very high
doses (560 mg once daily)
[3]. It is an irreversible Brutons tyrosine kinase inhibitor
which is recommended orally for
the treatment of mantle cell lymphoma and chronic lymphocytic
leukemia [4-6]. The oral
bioavailability of ibrutinib is very low upon oral
administration due to extensive first pass
metabolism and poor water solubility [3]. Due to low
bioavailability, it is available in higher
dosage forms. Values of the solubility of ibrutinib are not
available in the literature.
According to recent data available in FDA, it has been reported
as practically insoluble in
water (mole fraction solubility: 1.30 x 10-7) at room
temperature [3]. Due to poor water
solubility and extensive first pass metabolism of ibrutinib, its
parentenal and liquid dosage
forms are not available commercially. Due to high doses of
ibrutinib, large amounts of co-
solvents are required for its solubilization, which is not
feasible from a pharmaceutical point
of view [7]. If scientists are able to find potentially
physiologically compatible and safe co-
solvents to enhance aqueous solubility of ibrutinib, the
development of its parenteral and
liquid dosage forms could be possible. Although, various
approaches have been reported for
solubility enhancement of low-water soluble drugs, but the
co-solvency approach is one of
the simplest and error free approaches for this purpose [8-11].
The solubility of low- water
soluble drugs in co-solvent mixtures could be useful in
pre-formulation studies, formulation
development and drug release studies [12-14]. The chemical name
of Carbitol is 2-(2-
ethoxyethoxy)ethanol and it has been investigated as a highly
competent co-solvent for
solubilization of several low-water soluble drugs [7, 11,
15-19]. The temperature dependent
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4
solubility of ibrutinib in various {2-(2-ethoxyethoxy)ethanol +
water} co-solvent mixtures
are not available in the literature. Therefore, in this work,
the mole fraction solubility of
ibrutinib in various {2-(2-ethoxyethoxy)ethanol + water}
co-solvent mixtures was measured
using an isothermal method at T = (298.15 to 323.15) K and p =
0.1 MPa [20]. From the
temperature dependent solubility of ibrutinib, various
thermodynamic functions such as the
dissolution enthalpy (solHo), Gibbs energy (solGo) and
dissolution entropy (solSo) of
ibrutinib were also determined using Vant Hoff and Krug analysis
approach. The solubility
results of this work could be useful in pre-formulation studies
and formulation development
of ibruninb especially in terms of liquid and parenteral dosage
forms.
2. Experimental
2.1. Materials
Ibrutinib was purchased from Beijing Mesochem Technology Co.
Ltd. (Beijing, China) and
the 2-(2-Ethoxyethoxy)ethanol was procured from Gattefosse
(Lyon, France). The water was
obtained from Milli-Q water purification system (Millipore
Corporation, Berlin, Germany) in
the laboratory. A sample table with detailed information
regarding all these materials is
furnished in table 1. Further purification of these materials
was not carried out due to their
high purity.
2.2. Determination of ibrutinib solubility
The solubility of crystalline ibrutinib against mass fraction of
2-(2-ethoxyethoxy)ethanol (m
= 0.0 to 1.0) in various {2-(2-ethoxyethoxy)ethanol + water}
mixtures was determined at T =
(298.15 to 323.15) K and p = 0.1 MPa using a well-known
isothermal method [20]. For
solubility determination, the excess amount of crystalline
ibrutinib was added in known
amounts of co-solvent mixtures. The concentrated samples of
ibrutinib in each co-solvent
mixtures were shaken continuously in a biological shaker
(Julabo, PA) at shaking speed of
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5
100 rpm for 72 h [15, 16]. The experiments were conducted in
triplicates. After 72 h, all the
samples were taken and ibrutinib particles allowed to settle for
2 h [10, 13]. The supernatants
from each concentrated sample were taken, diluted and subjected
for the analysis of ibrutinib
content spectrophotometrically at 260 nm. The experimental mole
fraction solubility (xe) of
crystalline ibrutinib in each co-solvent mixture was calculated
as reported in literature [7, 13].
3. Results and discussion
3.1. Measured solubility data of ibrutinib
Values of the measured solubility of crystalline ibrutinib in
various {2-(2-
ethoxyethoxy)ethanol + water} mixtures at T = (298.15 to 323.15)
K and p = 0.1 MPa are
listed in table 2. The temperature dependent solubility of
ibrutinib in any pure solvent or co-
solvent mixtures including {2-(2-ethoxyethoxy)ethanol + water}
co-solvent mixtures are
neither available in the literature nor in any pharmacopoeia or
regulatory bodies. However, it
has been reported as practically insoluble in water as per FDA
[3]. In the FDA database, the
mole fraction solubility of ibrutinib in pure water at T =
298.15 K has been reported as 1.30 x
10-7 [3]. In this work, the mole fraction solubility of
ibrutinib in water at 298.15 K was
observed as 1.43 x 10-7. These results indicate good agreement
of the results of this work with
reported solubility of ibrutinib in water. Generally, the xe
values of ibrutinib were found to
increase with increase in temperature and mass fraction of
2-(2-ethoxyethoxy)ethanol in co-
solvent mixtures. The xe values of ibrutinib were observed
highest in pure 2-(2-
ethoxyethoxy)ethanol (2.67 x 10-2 at 298.15 K) at T = (298.15 to
323.15) K. However, the
lowest xe values of ibrutinib were observed in pure water (1.43
x 10-7 at 298.15 K) at T =
(298.15 to 323.15) K. The highest xe values of ibrutinib in pure
2-(2-ethoxyethoxy)ethanol
were possibly due to the lower polarity of
2-(2-ethoxyethoxy)ethanol compared to higher
polarity of pure water as reported in previous studies [7, 11].
The impact of mass fraction of
2-(2-ethoxyethoxy)ethanol on solubility of ibrutinib at T =
(298.15 to 323.15) K was also
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6
investigated and results are presented in figure 2. From figure
2, it is observed that the
solubility of ibrutinib increases rapidly with increase in mass
fraction of 2-(2-
ethoxyethoxy)ethanol in co-solvent mixtures at T = (298.15 to
323.15) K. The results of this
work are similar to those previously published for other
practically insoluble drugs such as
glibenclamide, gliclazide, metronidazole, risperidone and
tadalafil in {2-(2-
ethoxyethoxy)ethanol + water} co-solvent mixtures [15-17, 19,
21]. Based on these results,
ibrutinib is to be practically insoluble in water and freely
soluble in 2-(2-
ethoxyethoxy)ethanol according to USP definition of solubility.
Because, 2-(2-
ethoxyethoxy)ethanol enhances the solubility of ibrutinib
sufficiently in water, it can be used
as a physiologically compatible co-solvent in pre-formulation
studies and formulation
development of ibrutinib.
3.2. Correlation of the measured solubility of ibrutinib with
the Vant Hoff model
According to this model, the mole fraction solubility of
ibrutinib (ln xVant) in different co-
solvent mixtures is calculated using equation 1 [11, 22]:
(1)
where, T is the absolute temperature (K) and symbols a and b are
the Vant Hoff model
parameters. The values of a and b were determined by plotting ln
xe values of ibrutinib
against 1/T. The correlation of measured solubility of ibrutinib
(xe) with the Vant model
(xVant) was investigated by calculating the root mean square
deviations (RMSD). The RMSD
was calculated using equation 2.
(2)
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7
in which, N is the number of experimental data points. The
graphical correlations and curve
fitting between xe and xVant of ibrutinib in various co-solvent
mixtures are presented in figure
S1.
The values from this correlation are listed in table S1. The
values of RMSD in various {2-(2-
ethoxyethoxy)ethanol + water} co-solvent mixtures are observed
(0.73 to 3.21) %. However,
the values of correlation coefficients (R2) are observed to lie
in the range of 0.9920 to 0.9970.
The values of R2 and RMSD indicate a good correlation of
measured solubility of ibrutinib
with the Vant Hoff model.
3.3. Correlation of measured solubility of ibrutinib with the
modified Apelblat
model
According to the modified Apelblat model, the mole fraction
solubility of solute (xApl) is
temperature dependent which is calculated using equation 3
[23]:
(3)
in which, the parameters A, B and C are the model parameters
which were determined by
non-linear multivariate regression analysis of measured
solubility of ibrutinib listed in table 2
[10, 11]. The graphical correlations and curve fitting between
xe and xApl in various co-
solvent mixtures are presented in figure S2 which shows good
correlation between xe and
xApl
.
The resulting values from this correlation are listed in table
S2. The values of RMSD in
various {2-(2-ethoxyethoxy)ethanol + water} co-solvent mixtures
lie within the range of
(0.65 to 2.47) %. However, the values of R2 are in the range of
0.9971 to 0.9990. These
results again indicate good correlation of measured solubility
of ibrutinib with the modified
Apelblat model.
3.4. Correlation of measured solubility of ibrutinib with the
Yalkowsky model
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8
According to this model, the logarithmic solubility of ibrutinib
(log xYal) in various {2-(2-
ethoxyethoxy)ethanol + water} co-solvent mixtures is calculated
using equation 4 [24]:
(4)
in which, S1 and S2 are the mole fraction solubility of
ibrutinib in pure solvent 1 (2-(2-
ethoxyethoxy)ethanol) and pure solvent 2 (water), respectively;
and m1 and m2 are the mass
fractions of 2-(2-ethoxyethoxy)ethanol and water in the absence
of solute. The RMSD values
were calculated again for the correlation of measured solubility
of ibrutinib with the
Yalkowsky model.
The results from this correlation are listed in table S3. The
values of RMSD in various co-
solvent mixtures lie within the range of (1.31 to 7.86) %. These
results again indicate good
correlation of measured solubility of ibrutinib with the
log-linear model of Yalkowsky.
3.5. Thermodynamic parameters for ibrutinib dissolution
The values of solHo for ibrutinib in various
{2-(2-ethoxyethoxy)ethanol + water} co-solvent
mixtures were determined by Vant Hoff analysis as reported
previously [25, 26]. According
to this analysis, the solHo values of ibrutinib were calculated
at mean harmonic temperature
(Thm = 308.91 K) using equation 5:
(5)
Here R is the universal gas constant. The graphs are plotted
between ln xe values of ibrutinib
and (figure S3). These graphs were found to be linear with R2
values of 0.9920
to 0.9980 as shown in table S4.
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9
The values of solGo in various {2-(2-ethoxyethoxy)ethanol +
water} co-solvent mixtures
were calculated at Thm = 308.91 K using the approach of Krug
analysis with the help of
equation 6 [27]:
(6)
in which, the values of the intercept were determined from
figure S3.
Finally, the values of solSo in various
{2-(2-ethoxyethoxy)ethanol + water} co-solvent
mixtures were calculated using equation 7:
(7)
The resulting values for the thermodynamic parameters along with
R2 values in various {2-(2-
ethoxyethoxy)ethanol + water} co-solvent mixtures are listed in
table S4.
The solHo values for the dissolution behaviour of ibrutinib in
various {2-(2-
ethoxyethoxy)ethanol + water} co-solvent mixtures are positive
over the range of (12.3 to
52.9) kJmol-1. The solHo value for ibrutinib dissolution is
highest in pure water (m = 0.0)
(52.9 kJmol-1) and lowest in pure 2-(2-ethoxyethoxy)ethanol (m =
1.0) (12.3 kJ.mol-1). The
solG0 values for ibrutinib dissolution are also observed as
positive in the range of (8.8 to
38.4) kJmol-1. The solG0 value for ibrutib dissolution is also
observed highest in pure water
(38.4 kJmol-1) and lowest in pure 2-(2-ethoxyethoxy)ethanol (8.8
kJmol-1). The values of
solHo and solGo for ibrutinib dissolution are found to decrease
with increase in mass fraction
of 2-(2-ethoxyethoxy)ethanol in co-solvent mixtures. These
results are in good agreement
with solubility of ibrutinib in all co-solvent mixtures. The
positive values of these
thermodynamic parameters (solHo and solGo) indicates endothermic
and spontaneous
dissolution behaviour of ibrutinib in all
{2-(2-ethoxyethoxy)ethanol + water} co-solvent
mixtures. Moreover, the solS0 values for ibrutinib dissolution
were also observed as positive
values within the range of (11.0 to 45.8) J.K-1.mol-1 as shown
in table S4. These results
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10
indicated an entropy-driven dissolution of ibrutitib in all
co-solvent mixtures investigated.
The positive values of these thermodynamic parameters could be
due to the stronger
molecular interactions between ibrutinib and the solvent
molecules compared to those
between the solvent-solvent and ibrutinib-ibrutinib molecules
[16, 17].
3.6. Enthalpy-entropy compensation of ibrutinib solution
An enthalpy-entropy compensation analysis of crystalline
ibrutinib solution was carried out
to investigate the mechanism of co-solvent action [25, 28]. In
order to perform these studies,
the weighed plots were constructed between solHo and solGo.
These compensation effects
permit the observation of a similar mechanism for the solvation
process as per tendencies
obtained at Thm [29]. The results of these effects for solvation
behaviour of crystalline
ibrutinib are presented in Figure 3. From Figure 3, it was
observed that crystalline ibrutinib in
{2-(2-ethoxyethoxy)ethanol + water} co-solvent mixtures results
in a non-linear solHo vs.
solGo curve with a variable positive slope value (less than 1)
for up to m = 0.3 (where the
maximumwas reached). Beyond this 2-(2-ethoxyethoxy)ethanol
proportion, a positive slope
value of greater than 1 was obtained. Therefore, the driving
mechanism for solvation of
crystalline ibrutinib is considered to be entropy-driven in the
former case that was probably
due to water-structure loosening. However, in latter case, the
driving mechanism is
considered as enthalpy-driven, that is probably due to better
solvation of crystalline ibrutinib
in 2-(2-ethoxyethoxy)ethanol molecules [30].
4. Conclusions
The solubility of the recently approved anti-cancer drug
ibrutinib in various {2-(2-
ethoxyethoxy)ethanol + water} co-solvent mixtures was measured
at T = (298.15 to 323.15)
K and p = 0.1 MPa. Values of the solubility of ibrutinib were
found to be increase
continuously with increase in temperature and mass fraction of
2-(2-ethoxyethoxy)ethanol in
co-solvent mixtures. The measured solubility of ibrutinib
correlated well with all three semi-
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11
empirical mathematical models investigated. Thermodynamic
studies indicate endothermic,
spontaneous and an entropy-driven dissolution behaviour of
ibrutinib in all co-solvent
mixtures investigated. Based on solubility values of this work,
ibrutinib is considered to be
practically insoluble in water and freely soluble in
2-(2-ethoxyethoxy)ethanol. Because of the
freely soluble nature of ibrutinib in 2-(2-ethoxyethoxy)ethanol,
it could be used as a
physiologically compatible co-solvent in pre-formulation studies
and formulation
development of ibrutinib especially in terms of liquid and
parenteral dosage forms.
Conflict of interest
The authors report no conflict of interest related with this
manuscript.
Acknowledgement
The authors would like to extend their sincere appreciation to
the Deanship of Scientific
Research, College of Science Research Centre, King Saud
University, Riyadh, Saudi Arabia
for supporting this project.
Appendix A. Supplementary information
Supplementary information (Figures S1-S3 and Tables S1-S4)
related to this article can be
found online.
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Figure captions
Figure 1 Molecular structure of anti-cancer drug ibrutinib
Figure 2 Influence of mass fraction of 2-(2-ethoxyethoxy)ethanol
(m) on ln xe of
ibrutinib at T = (298.15 to 323.15) K; 298.15 K, 303.15 K,
308.15 K, 313.15
K and 323.15 K
Figure 3 solHo versus solGo enthalpyentropy compensation curve
for dissolution of
ibrutinib in {2-(2-ethoxyethoxy)ethanol + water} mixtures at
mean harmonic
temperature of 308.91 K
-
Table 1 A sample table for the anti-cancer drug ibrutinib and
solvents used in the experiment
Material Molecular formula Molar mass (gmol-1) Mass fraction
purity Purification method Analysis method Source
Ibrutinib C25H24N6O2 440.50 0.990 None HPLC Beijing Mesochem
2-(2-Ethoxyethoxy)ethanol C6H14O3 134.17 0.999 None GC
Gattefosse
Water H2O 18.01 1.000 None Conductivity < 1 S.cm-1 Milli-Q
purification unit HPLC: high performance liquid chromatography; GC:
gas chromatography
-
Table 2 Experimental mole fraction solubility (xe) of
crystalline anti-cancer drug ibrutinib against mass fraction of
2-(2-
ethoxyethoxy)ethanol (m) in various {2-(2-ethoxyethoxy)ethanol +
water} mixtures in the absence of solute at temperatures T =
(298.15
to 323.15) K and pressure p = 0.1 MPaa
m xe
T = 298.15 K T = 303.15 K T = 308.15 K T = 313.15 K T = 323.15
K
0.0 1.43 x 10-7 2.21 x 10-7 3.11 x 10-7 4.13 x 10-7 7.69 x 10-7
0.1 5.24 x 10-7 7.84 x 10-7 1.02 x 10-6 1.35 x 10-6 2.32 x 10-6 0.2
1.66 x 10-6 2.35 x 10-6 3.15 x 10-6 4.02 x 10-6 6.79 x 10-6 0.3
5.49 x 10-6 7.62 x 10-6 1.01 x 10-5 1.26 x 10-5 2.07 x 10-5 0.4
1.94 x 10-5 2.63 x 10-5 3.28 x 10-5 3.99 x 10-5 6.07 x 10-5 0.5
6.28 x 10-5 8.08 x 10-5 1.03 x 10-4 1.23 x 10-4 1.78 x 10-4 0.6
2.13 x 10-4 2.64 x 10-4 3.32 x 10-4 3.83 x 10-4 5.36 x 10-4 0.7
7.11 x 10-4 8.46 x 10-4 1.04 x 10-3 1.24 x 10-3 1.60 x 10-3 0.8
2.40 x 10-3 2.87 x 10-3 3.22 x 10-3 3.72 x 10-3 4.54 x 10-3 0.9
7.97 x 10-3 8.90 x 10-3 1.02 x 10-2 1.12 x 10-2 1.35 x 10-2 1.0
2.67 x 10-2 2.88 x 10-2 3.18 x 10-2 3.41 x 10-2 3.92 x 10-2
aThe standard uncertainties u are u(T) = 0.12 K, ur(m) = 0.1 %,
u(p) = 0.003 MPa and ur(xe) = 1.34 %
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Figure 1 Molecular structure of anti-cancer drug ibrutinib
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Figure 2 Influence of mass fraction of 2-(2-ethoxyethoxy)ethanol
(m) on ln xe of
ibrutinib at T = (298.15 to 323.15) K; 298.15 K, 303.15 K,
308.15 K, 313.15
K and 323.15 K
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Figure 3 solHo versus solGo enthalpyentropy compensation curve
for dissolution of
ibrutinib in {2-(2-ethoxyethoxy)ethanol + water} mixtures at
mean harmonic
temperature of 308.91 K
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Solubility of ibrutinib in 2-(2-ethoxyethoxy)ethanol + water
mixtures was measured
Measured solubilities of ibrutinib were correlated well with
calculated solubilities
Ibrutinib dissolution was found to be endothermic, spontaneous
and entropy-driven