Accepted Manuscript

Solubility and thermodynamic function of a new anti-cancer drug ibrutinib in

{2-(2-ethoxyethoxy)ethanol + water} mixtures at different temperatures
Faiyaz Shakeel, Muzaffar Iqbal, Nazrul Haq
PII:
DOI:
Reference:

S0021-9614(15)00106-8
http://dx.doi.org/10.1016/j.jct.2015.04.014
YJCHT 4206

To appear in:

J. Chem. Thermodynamics

Received Date:
Revised Date:
Accepted Date:

25 February 2015
6 April 2015
8 April 2015

Please cite this article as: F. Shakeel, M. Iqbal, N. Haq, Solubility and thermodynamic function of a new anti-cancer
drug 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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Solubility and thermodynamic function of a new anti-cancer drug ibrutinib in {2-(2ethoxyethoxy)ethanol + water} mixtures at different temperatures
Faiyaz Shakeela*, Muzaffar Iqbalb,c, Nazrul Haqa

Center of Excellence in Biotechnology Research (CEBR), College of Science, King Saud

University, Riyadh 11451, Saudi Arabia

b

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O.

Box 2457, Riyadh 11451, Saudi Arabia

c

Bioavailability 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: faiyazs@fastmail.fm

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 entropydriven 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.

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 cosolvents 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 cosolvents 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-(2ethoxyethoxy)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

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
4

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.
Values

Measured solubility data of ibrutinib

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 cosolvent 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 cosolvent mixtures. The xe values of ibrutinib were observed highest in pure 2-(2ethoxyethoxy)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
5

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-(2ethoxyethoxy)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-(2ethoxyethoxy)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 cosolvent 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)

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-(2ethoxyethoxy)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 cosolvent 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

7

According to this model, the logarithmic solubility of ibrutinib (log xYal) in various {2-(2ethoxyethoxy)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-(2ethoxyethoxy)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 cosolvent 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.

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-(2ethoxyethoxy)ethanol + water} co-solvent mixtures are listed in table S4.
The solHo values for the dissolution behaviour of ibrutinib in various {2-(2ethoxyethoxy)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
9

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-(2ethoxyethoxy)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 semi10

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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13

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;
K and

298.15 K,

303.15 K,

308.15 K,

313.15

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

14

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-(2ethoxyethoxy)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

The

standard

uncertainties

are

u(T)

0.12

K,

ur(m)

0.1

%,

u(p)

0.003

MPa

and

ur(xe)

1.34

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;
K and

323.15 K

298.15 K,

303.15 K,

308.15 K,

313.15

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

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