State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China.
State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China.
Eur J Pharm Sci. 2020 Apr 30;147:105294. doi: 10.1016/j.ejps.2020.105294. Epub 2020 Mar 5.
Co-amorphization of drugs has been a promising approach to enhance the apparent solubility and dissolution rate of poorly-water soluble drugs. Nimesulide, a BCS Ⅱ drug, was combined with indomethacin to form three co-amorphous systems at molar ratios of 2:1, 1:1 and 1:2 via quench cooling. The aim of this research was mainly to probe the relationship between physical stability (long-term stability and temperature sensitivity) and intermolecular interaction modes among three co-amorphous systems. The calculated glass transition temperature by the Gordon-Taylor equation shows the presence of intermolecular interactions within co-amorphous systems. FTIR spectra further verify that there are hydrogen bonds and π-π stacking in intermolecular interactions. Specific atomic groups involved in the intermolecular hydrogen bonding were investigated using radial distribution function analysis based on molecular dynamic simulation. Gaussian calculation visually gives dominant molecular aggregate composed of multiple hydrogen bonding modes in co-amorphous systems and explains the stability difference of 1:2>1:1>2:1. Finally, powder dissolution profiles were conducted and the 1:2 system has the greatest dissolution advantage with six-fold improvement of dissolution rate compared with pure NMS.
共晶化已成为提高难溶性药物表观溶解度和溶出速率的一种有前途的方法。尼美舒利是一种 BCS Ⅱ类药物，与吲哚美辛以摩尔比 2:1、1:1 和 1:2 形成了三种共晶体系，通过淬火冷却。本研究的主要目的是探讨三种共晶体系的物理稳定性（长期稳定性和温度敏感性）与分子间相互作用模式之间的关系。通过 Gordon-Taylor 方程计算的玻璃化转变温度表明共晶体系内存在分子间相互作用。傅里叶变换红外光谱进一步证实了分子间相互作用中存在氢键和 π-π 堆积。使用基于分子动力学模拟的径向分布函数分析研究了参与分子间氢键的特定原子基团。高斯计算直观地给出了由多种氢键模式组成的主要分子聚集体，并解释了共晶体系中稳定性的差异，即 1:2＞1:1＞2:1。最后，进行了粉末溶解曲线研究，结果表明 1:2 体系具有最大的溶解优势，与纯 NMS 相比，其溶解速率提高了六倍。
