Integrative green synthesis and molecular simulation of ibrutinib cocrystals for enhanced biopharmaceutical performance and in vivo pharmacokinetics

Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib (IBR), belongs to class II of the Biopharmaceutics Classification System (BCS). CYP3A4 enzyme forces IBR to have a very limited oral bioavailability. This study employed hot-melt extrusion (HME) with carboxylic and carboxamide coformers, guided by computational screening, to prepare and characterize IBR cocrystals (IBR-CC). Several carboxylic acid and carboxyl amide coformers were chosen in accordance with computational evaluations and predictions for the solubility parameter to formulate IBR-CC. According to the computational results, the formulated IBR-CC systems had multiple hydrogen bonds and π-π-stacking interactions. The IBR-CC formulations were further evaluated for powder dissolution studies, flow properties, and in vitro release studies. Furthermore, IBR-CC formulations were correlated with better anticancer action in K562-CCL-243 cancer cells when compared with IBR. From the in vivo pharmacokinetic evaluation studies, it was proven that the IBR oral bioavailability in IBR-Nicotinamide-cocrystal formulation has shown a 4.58-fold improvement, IBR-Fumaric acid-cocrystal formulation has shown a 2.66-fold improvement, and IBR-3-Hydroxy benzoic acid has shown a 1.76-fold enhancement when compared with pure IBR suspension. Biodistribution studies showed greater drug release in the intestine and other lymphoid organs when administered with IBR-Nicotinamide-cocrystal formulation than pure IBR suspension. As a result, the IBR-CC formulations produced utilizing the HME approach serve as an effective method of drug delivery that increases IBR's solubility and oral bioavailability.