Duddu S P, Dal Monte P R
Department of Pharmaceutical Technologies, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Pharm Res. 1997 May;14(5):591-5. doi: 10.1023/a:1012144810067.
The purpose of this study is to highlight the importance of knowing the glass transition temperature, Tg, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data.
Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography.
Sucrose formulation (Tg approximately 59 degrees C) when stored at 60 degrees C was found to undergo significant aggregation, while the trehalose formulation (Tg approximately 80 degrees C) was stable at 60 degrees C. The instability observed with sucrose formulation at 60 degrees C can be attributed to its Tg (approximately 59 degrees C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the Tgs of the formulations containing sucrose or trehalose, but to different degrees.
Since the formulations exist in glassy state during their shelf-life, accelerated stability data generated in the glassy state (40 degrees C) is perhaps a better predictor of the relative stability of formulations than the data generated at a higher temperature (60 degrees C) where one formulation is in the glassy state while the other is near or above its Tg.
本研究旨在强调了解主要由糖和蛋白质组成的冻干无定形固体的玻璃化转变温度（Tg）在解释加速稳定性数据中的重要性。
使用差示扫描量热法（DSC）和介电弛豫光谱法测量玻璃化转变温度。使用尺寸排阻色谱法监测固态蛋白质的聚集情况。
发现蔗糖制剂（Tg约为59℃）在60℃储存时会发生显著聚集，而海藻糖制剂（Tg约为80℃）在60℃时稳定。蔗糖制剂在60℃观察到的不稳定性可归因于其Tg（约59℃）接近测试温度。发现蛋白质/糖比例的增加会提高含有蔗糖或海藻糖的制剂的Tg，但程度不同。
由于制剂在其保质期内以玻璃态存在，在玻璃态（40℃）下产生的加速稳定性数据可能比在较高温度（60℃）下产生的数据更能预测制剂的相对稳定性，在较高温度下一种制剂处于玻璃态而另一种接近或高于其Tg。
