Cocrystals of Apixaban with Improved Solubility and Permeability: Formulation, Physicochemical Characterization, Pharmacokinetic Evaluation, and Computational Studies.

Abstract

The objective of the current study was to develop new cocrystals of Apixaban (APX) to improve its solubility and permeability. The molecular interaction between APX and caffeine (CFFN) was further studied by Raman spectroscopy. The results of all eight studied conformers revealed that the synthesized APX-CFFN cocrystals had the highest solubility and permeability. The water solubility and permeability of APX in the cocrystal were simultaneously enhanced as compared with pure APX in the physiological pH environment (pH 6.8 and pH 7.4). The X-ray diffraction analysis revealed that the cocrystal has a component molar ratio of 1:1. This was dominated by a three-dimensional hydrogen bonding supramolecular structure. The in vivo pharmacokinetic (PK) study indicated that the mean area under curve (AUC) of APX from the synthesized cocrystal was enhanced more than three-folds than the pure APX. Tablets of APX and APX-CFFN cocrystals were prepared using direct compression method and evaluated for in vitro dissolution profile in phosphate buffers (pH 6.8 and pH 7.4). Computational investigations with molecular dynamics simulations also supported the formation of stable cocrystals. The drug release of APX from the tablets was considerably increased when compared with the pure APX in both pH conditions and it was found to increase with an increase in media pH. The present investigation represents an alternative approach for optimizing physicochemical and PK properties of Biopharmaceutical Classification System class-III drugs without changing its molecular structure and intrinsic bioactivities.