Solubility measurement and correlation of the form A of ibrutinib in organic solvents from 278.15 to 323.15 K
Graphical abstract
Introduction
Recrystallization from solution is an important purification unit operation whose development and design heavily relies on the equilibrium solubility data which normally vary with the temperature and the solution composition [1], [2]. Ibrutinib (Imbruvica™, formerly PCI-32765, CAS No. 936563-96-1), chemically 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one is a small molecule, first-in-class, once-daily, orally available, Bruton’s tyrosine kinase inhibitor that is under development for the treatment of B cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM), follicular lymphoma (FL) and Waldenstrom’s macroglobulinemia (WM) [3], [4], [5]. The chemical structure of ibrutinib is shown in Fig. 1. Several polymorphs of ibrutinib have been reported in the patent literature, which revealed three anhydrous forms (A, B and C) that are characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy and form A is used in the pharmaceutical formulation [6].
To establish an ideal crystallization strategy for the separation and purification as well as to obtain products with high purity and yield, it is of great importance to acquire the solubility of ibrutinib in appropriate solvents. To our knowledge, though much work has been done on this compound, most research mainly focused on its synthesis and application, and the information on its solubility in commonly used solvents is scarce in the literature. To date, only Shakeel et al. reported the solubility data of ibrutinib in carbitol + water mixtures [7] and ethanol + water mixtures [8] with the purpose to enhance its aqueous solubility.
In the present study, the solubility of ibrutinib (form A) in isopropanol, 1-butanol, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone (MEK) and methyl tertiary butyl ether (MTBE) from 278.15 to 323.15 K at atmospheric pressure was firstly measured by a gravimetric method. Then the modified Apelblat equation, the Buchowski-Ksiazczak λh equation and an empirical quartic polynomial equation were applied to correlate the experimental data. Computational results showed that the three models well fitted the experiment data, and the empirical quartic polynomial equation had a higher accuracy than the other two.
Section snippets
Materials
The raw material of ibrutinib used in this work was purchased from Arromax Pharmatech Co., Ltd. (Suzhou, China), with mass fraction purity and chiral purity greater than 0.994, as determined by high performance liquid chromatography (HPLC). The material was confirmed to be form A by powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). Analytical grade solvents, including isopropanol, 1-butanol, ethyl acetate, acetonitrile, acetone, MEK, MTBE were purchased from
Measured mole fraction solubility
The measured mole fraction solubility of ibrutinib in isopropanol, 1-butanol, ethyl acetate, acetonitrile, acetone, MEK and MTBE, as a function of temperature, is depicted in Table 2 and the x/T curves are presented in Fig. 6. It can be observed from Table 2 and Fig. 6 that the solubility in the seven solvents increases with the increase of temperature, meanwhile, the solubility in isopropanol is close to that in acetonitrile but the solubility in isopropanol shows a bit stronger temperature
Conclusions
In this work, the solubility data of ibrutinib in isopropanol, 1-butanol, ethyl acetate, acetonitrile, acetone, MEK and MTBE was measured by a gravimetric method at the temperature range from 278.15 to 323.15 K at atmospheric pressure. The solubility of ibrutinib in all the investigated solvents increased with temperature in the measured temperature range. At the room temperature, the sequence of the solubility in the solvents studied from high to low was: MEK > acetone > ethyl acetate > 1-butanol >
Acknowledgments
This research work was financially supported by the National Natural Science Foundation of China (Nos. 21176102, 21176215 & 21476136), the Natural Science Foundation of Jiangsu Province (No. BK20131100), the Connotation Construction Project of SUES (No. Nhky-2015-05), the Science and Technology Commission of Shanghai Municipality (No. 15430501200) and the Sino-German Center for Research Promotion (No. GZ935).
References (24)
- et al.
Fluid Phase Equilib.
(2015) - et al.
J. Chem. Thermodyn.
(2015) - et al.
J. Mol. Liq.
(2015) - et al.
J. Chem. Thermodyn.
(2016) - et al.
Dent. Mater.
(2003) Polymer
(1997)- et al.
Fluid Phase Equilib.
(2012) - et al.
J. Mol. Liq.
(2013) J. Chem. Educ.
(1977)- et al.
J. Chem. Thermodyn.
(2016)
Fluid Phase Equilib.
J. Chem. Thermodyn.
Cited by (23)
Solubility determination and thermodynamic model analysis of L-α-glyceryl phosphorylcholine in different organic solvents of 278.15 K to 323.15 K
2024, Journal of Pharmaceutical and Biomedical AnalysisSolubility of ibrutinib in supercritical carbon dioxide (Sc-CO<inf>2</inf>): Data correlation and thermodynamic analysis
2023, Journal of Chemical Thermodynamics