National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
J Pharm Sci. 2019 Sep;108(9):3020-3028. doi: 10.1016/j.xphs.2019.04.031. Epub 2019 May 5.
At present, coamorphous systems have attracted increasing interest in the pharmaceutical field owing to their enhanced stabilities, increased solubilities, and improved bioavailabilities compared with those of their pure amorphous and crystalline counterparts. In this study, a novel coamorphous solid form of ibrutinib (IBT) and saccharin (SAC) (1:1 molar ratio) was prepared through rotary vacuum evaporation and then characterized. Differential scanning calorimetry and X-ray powder diffraction indicated the formation of the coamorphous IBT-SAC after rotary vacuum evaporation. Compared with amorphous IBT, coamorphous IBT-SAC exhibited enhanced stability owing to the intermolecular interaction between IBT and SAC. Moreover, the solubility and dissolution of the coamorphous IBT-SAC were increased up to 4.0-7.7 times and 4.3 times, respectively, compared with those of its crystalline Form A. In addition to the superior behaviors of coamorphous IBT-SAC in vitro, the in vivo bioavailability study revealed notable increases in the C and area under the curve of the coamorphous form compared with those of its crystalline Form A. The current study demonstrates that the coamorphization of IBT and SAC presents a promising technology to overcome the limitations of solubility and stability that arise from IBT and can therefore contribute to a major improvement in the bioavailability of IBT.
目前，共晶系统因其相对于纯无定形和晶型对应物具有更高的稳定性、增加的溶解度和改善的生物利用度而在药物领域引起了越来越多的关注。在这项研究中，通过旋转真空蒸发制备了伊布替尼（IBT）和糖精（SAC）（1:1 摩尔比）的新型共晶固体形式，然后对其进行了表征。差示扫描量热法和 X 射线粉末衍射表明，旋转真空蒸发后形成了共晶 IBT-SAC。与无定形 IBT 相比，共晶 IBT-SAC 由于 IBT 和 SAC 之间的分子间相互作用而表现出增强的稳定性。此外，与晶型 Form A 相比，共晶 IBT-SAC 的溶解度和溶解速度分别提高了 4.0-7.7 倍和 4.3 倍。除了共晶 IBT-SAC 在体外的优越行为外，体内生物利用度研究表明，与晶型 Form A 相比，共晶形式的 C 和曲线下面积有显著增加。本研究表明，IBT 和 SAC 的共晶化提供了一种有前途的技术，可以克服 IBT 溶解度和稳定性的限制，从而大大提高 IBT 的生物利用度。
