Improving physicochemical properties of Ibrutinib with cocrystal strategy based on structures and natures of the carboxylic acid co-formers

Ibrutinib(IBR) is an irreversible Bruton's tyrosine kinase inhibitor and has been classified as the Biopharmaceutical Classification System (BCS) class II drug. The objective of the current study was to improve the physicochemical properties of IBR by co-crystallization. Based on Delta pKa analysis and structure analysis, we reported seven IBR pharmaceutical cocrystals with different structure types of co-formers such as hydroxy-2-naphthoic acids, mono-hydroxybenzoic acids, and aliphatic acids via the slurry method and ultrasonic method. The seven prepared cocrystals were characterized by powder X-ray diffraction(PXRD), differential scanning calorimetry(DSC), thermogravimetric analysis(TGA) and Fourier transform infrared spectroscopy(FT-IR). The solubility and accumulative dissolution of IBR cocrystals were explored. It was found that the solubility and dissolution were optimally increased up to 6.64 times and 1.85 times than that of IBR Form A, respectively. Moreover, all the IBR cocrystals maintained a stable cocrystal state after 90-d under 40 degrees C/75% RH condition and after 30-d under 60 degrees C/0% RH condition. According to the results analysis, there may be hydrogen bond(H-bond) and pi-pi stacking interactions in the IBR cocrystal system. The current study demonstrated that the cocrystallization of IBR with specific co-formers proposed a prospective technology and optional strategy to modify the physicochemical nature of IBR.