Solubility of ibrutinib in supercritical carbon dioxide (Sc-CO2): Data correlation and thermodynamic analysis

Abstract

Ibrutinib (PCI-32765), marketed under the trade name IMBRUVICA, is a first-in-class irreversible inhibitor drug of Bruton tyrosine kinase (BTK). In the current research, its solubility was measured at operational conditions 120-270 bar and 308-338 K, for the first time. The drug solubility has been reported between 3.90×〖10〗^(-6)to 1.30×〖10〗^(-5)based on mole fraction. Analysis of the curves confirms strong dependency of ibrutinib solubility to operational conditions due to their direct effect on solvating power of solvent. Also, pressure effect was more pronounced at the higher temperatures and the cross-over point was located around 170 bar. Besides, theoretical investigation and computational approach were carried out to correlate and extrapolate the experimental solubility of this medicine using thermodynamic models based on different approaches; semi-empirical models, activity coefficient (modified model of Margules), fugacity coefficient (mPR and mRK cEoSs) and dilute solution theory by the model of Wang-Tavlarides. Best correlation results were obtained by the modified model of Margules (AARD=6.68%) and the empirical model of Jouybanet al., (9.62%). Additionally, different enthalpies of ibrutinib-Sc-CO2 system were estimated.