Yoshioka Sumie, Aso Yukio, Kojima Shigeo
National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Pharm Res. 2003 Jun;20(6):873-8. doi: 10.1023/a:1023831102203.
To examine whether the glass transition temperature (Tg) of freeze-dried formulations containing polymer excipients can be accurately predicted by molecular dynamics simulation using software currently available on the market. Molecular dynamics simulations were carried out for isomaltodecaose, a fragment of dextran, and alpha-glucose, the repeated unit of dextran. in the presence or absence of water molecules. Estimated values of Tg were compared with experimental values obtained by differential scanning calorimetry (DSC).
Isothermal-isobaric molecular dynamics simulations (NPTMD) and isothermal molecular dynamics simulations at a constant volume (NVTMD) were carried out using the software package DISCOVER (Material Studio) with the Polymer Consortium Force Field. Mean-squared displacement and radial distribution function were calculated.
NVTMD using the values of density obtained by NPTMD provided the diffusivity of glucose-ring oxygen and water oxygen in amorphous alpha-glucose and isomaltodecaose, which exhibited a discontinuity in temperature dependence due to glass transition. Tg was estimated to be approximately 400K and 500K for pure amorphous a-glucose and isomaltodecaose, respectively, and in the presence of one water molecule per glucose unit, Tg was 340K and 360K, respectively. Estimated Tg values were higher than experimentally determined values because of the very fast cooling rates in the simulations. However, decreases in Tg on hydration and increases in Tg associated with larger fragment size could be demonstrated.
The results indicate that molecular dynamics simulation is a useful method for investigating the effects of hydration and molecular weight on the Tg of lyophilized formulations containing polymer excipients. although the relationship between cooling rates and Tg must first be elucidated to predict Tg vales observed by DSC measurement. January 16.
研究使用市场上现有的软件通过分子动力学模拟能否准确预测含有聚合物辅料的冻干制剂的玻璃化转变温度（Tg）。对异麦芽十糖（一种葡聚糖片段）和葡聚糖的重复单元α-葡萄糖在有水分子存在或不存在的情况下进行了分子动力学模拟。将估计的Tg值与通过差示扫描量热法（DSC）获得的实验值进行比较。
使用带有聚合物联合力场的DISCOVER软件包（材料工作室）进行等温等压分子动力学模拟（NPTMD）和恒容等温分子动力学模拟（NVTMD）。计算了均方位移和径向分布函数。
使用NPTMD获得的密度值进行的NVTMD给出了无定形α-葡萄糖和异麦芽十糖中葡萄糖环氧和水氧的扩散率，由于玻璃化转变，其在温度依赖性上表现出不连续性。对于纯无定形α-葡萄糖和异麦芽十糖，估计的Tg分别约为400K和500K，并且在每个葡萄糖单元存在一个水分子的情况下，Tg分别为340K和360K。由于模拟中的冷却速率非常快，估计的Tg值高于实验测定值。然而，可以证明水合作用导致Tg降低以及与较大片段尺寸相关的Tg升高。
结果表明分子动力学模拟是研究水合作用和分子量对含有聚合物辅料的冻干制剂Tg影响的有用方法。尽管必须首先阐明冷却速率与Tg之间的关系才能预测DSC测量中观察到的Tg值。1月16日。
