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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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: faiyazs@fastmail.fm

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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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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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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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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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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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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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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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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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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 %

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

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