Physicochemical and thermodynamic evaluation of ibrutinib cocrystal formation with a long-chain fatty acid†
Abstract
Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor used in the treatment of certain leukemias and a few lymphomas. In this study, we report a novel cocrystal (IBT–PAL) of ibrutinib with a long-chain fatty acid, palmitic acid. The cocrystal is characterized by crystallographic, thermal, and spectroscopic techniques. Crystallographic analysis shows a contribution of the component structures on the crystal structure of the cocrystal, while thermal analysis is used to determine the effect of temperature on the free energy of formation of the cocrystal. Thermal studies also elucidate the role of entropy in the formation of the cocrystal. Further, the effect of temperature on the crystal structure is evaluated using variable-temperature X-ray diffractometry and spectroscopy studies. The cocrystal is observed to have lower solubility than ibrutinib itself and its potential causes are discussed. Finally, the physical stability of the cocrystal in the presence of common pharmaceutical excipients is also evaluated, showing the feasibility of the cocrystal as a viable pharmaceutical option.