Chen Beibei, Costello Mark A, Kuehster Louise, Lynd Nathaniel A, Qin Bin, Wang Yan, Zhang Feng
Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA.
McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas, USA.
AAPS PharmSciTech. 2025 Jan 8;26(1):24. doi: 10.1208/s12249-024-03018-y.
Poly(lactide-co-glycolide) (PLGA) is widely used in a variety of long-acting injectables. However, its biodegradable nature creates potential chemical stability challenges during melt extrusion, where PLGA is exposed to elevated temperature (100-140 °C) for several minutes. This study evaluated the thermal stability of three PLGA grades (Resomer® 502, 502H, and 505) with varying molecular weights and chain-ends using a differential scanning calorimeter and twin-screw extruder. DSC results revealed that both residual water content and chain-end groups significantly accelerate PLGA degradation. At 0.2% water content, all samples maintained good stability (less than 15% reduction in molecular weight). However, at 0.4% water content, Resomer 502H, which has acid end groups, experienced significant degradation (45% reduction in molecular weight) after 30 min at 140 °C due to catalyzed hydrolysis. The extruded samples remained stable across tested barrel temperatures (100 °C and 140 °C) and screw speeds (125 and 250 rpm). Further investigations of PLGA with 0.2% water content demonstrates that the hydrolysis rates of Resomer® 502 and 505 were comparable, indicating that molecular weight does not influence hydrolysis rate. In contrast, Resomer® 502H exhibited a higher hydrolysis rate and a slightly higher activation energy, suggesting a greater temperature dependency. Additionally, when subjected to 200 °C for one hour with less than 0.03% water content, Resomer® 505 showed a less than 7% reduction in molecular weight, indicating minimal thermal degradation. Conversely, Resomer® 502 and 502H experienced an increase in molecular weight, which was likely attributed to recombination reactions, particularly in Resomer® 502H, which has higher tin content (170 ppm).
聚乳酸-乙醇酸共聚物（PLGA）广泛应用于各种长效注射剂中。然而，其可生物降解的特性在熔融挤出过程中带来了潜在的化学稳定性挑战，在此过程中PLGA会在高温（100-140°C）下暴露几分钟。本研究使用差示扫描量热仪和双螺杆挤出机评估了三种不同分子量和链端的PLGA等级（Resomer® 502、502H和505）的热稳定性。DSC结果表明，残留水分含量和链端基团均会显著加速PLGA的降解。在水分含量为0.2%时，所有样品均保持良好的稳定性（分子量降低不到15%）。然而，在水分含量为0.4%时，具有酸端基的Resomer 502H在140°C下30分钟后由于催化水解而发生显著降解（分子量降低45%）。挤出后的样品在测试的料筒温度（100°C和140°C）和螺杆转速（125和250转/分钟）下均保持稳定。对水分含量为0.%的PLGA的进一步研究表明，Resomer® 502和505的水解速率相当，这表明分子量不影响水解速率。相比之下，Resomer® 502H表现出更高的水解速率和略高的活化能，表明其对温度的依赖性更大。此外，当在水分含量低于0.03%的情况下于200°C下处理一小时时，Resomer® 505的分子量降低不到7%，表明热降解最小。相反，Resomer® 502和502H的分子量增加，这可能归因于重组反应，特别是在锡含量较高（170 ppm）的Resomer® 502H中。
