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.

中文翻译：

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具有改善的溶解度和渗透性的阿哌沙班共晶：配方、理化表征、药代动力学评价和计算研究

本研究的目的是开发新的阿哌沙班 (APX) 共晶以提高其溶解性和渗透性。通过拉曼光谱进一步研究了 APX 和咖啡因 (CFFN) 之间的分子相互作用。所有八种构象异构体的研究结果表明，合成的 APX-CFFN 共晶具有最高的溶解度和渗透性。与生理pH环境（pH 6.8和pH 7.4）中的纯APX相比，APX在共晶中的水溶性和渗透性同时增强。X射线衍射分析表明共晶的组分摩尔比为1:1。这是由三维氢键超分子结构主导的。在体内药代动力学 (PK) 研究表明，合成共晶 APX 的平均曲线下面积 (AUC) 比纯 APX 提高了三倍以上。使用直接压片法制备 APX 和 APX-CFFN 共晶片剂并进行体外评价在磷酸盐缓冲液（pH 6.8 和 pH 7.4）中的溶解曲线。分子动力学模拟的计算研究也支持稳定共晶的形成。在两种 pH 条件下，与纯 APX 相比，片剂中 APX 的药物释放显着增加，并且发现它随着介质 pH 值的增加而增加。本研究代表了一种在不改变其分子结构和内在生物活性的情况下优化生物制药分类系统 III 类药物的理化和 PK 特性的替代方法。