Division of Product Quality Research (HFD-940), Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, Maryland 20993, USA.
J Pharm Sci. 2011 May;100(5):1969-86. doi: 10.1002/jps.22430. Epub 2010 Dec 28.
The objective of this study was to demonstrate the feasibility of using an integrated process analytical technology (PAT) approach to determine nucleation and growth mechanisms of a dynamic naproxen (drug)-Eudragit L100 (polymer) coprecipitation process. The influence of several thermodynamically important formulation and process variables (drug/polymer ratio, alcohol, and water usages) on coprecipitation process characteristics was investigated via real-time in situ focused beam reflectance measurement (FBRM) monitoring and near real-time particle vision microscopy measurement. The final products were characterized by near-infrared (NIR) spectroscopy and NIR chemical imaging microscopy. The coprecipitation nucleation induction time (t(ind) ) was measured by both FBRM trend statistics and process trajectory method, respectively. Furthermore, nucleation kinetics was evaluated based on t(ind) measurement and corresponding supersaturation ratio (S) estimated. It was found that plots of ln(t(ind) ) versus (ln(2) S)(-1) consist of two linear segments and are consistent with classical primary nucleation mechanisms. Apparently, the coprecipitation process is governed by heterogeneous primary nucleation mechanism at low S (14 ≤ S ≤ 503) and by homogeneous primary nucleation mechanism at high S (1216 ≤ S ≤ 3649). Off-line characterizations collectively supported this statement. Therefore, it demonstrated that integration real-time PAT process monitoring with first-principles modeling and off-line product characterization could enhance understanding to coprecipitation process dynamics and nucleation/growth mechanisms, which is impossible via off-line techniques alone.
本研究旨在展示使用集成过程分析技术（PAT）方法来确定动态萘普生（药物）-Eudragit L100（聚合物）共沉淀过程成核和生长机制的可行性。通过实时原位聚焦光束反射测量（FBRM）监测和近实时颗粒视觉显微镜测量，研究了几个热力学上重要的配方和过程变量（药物/聚合物比、醇和水的用量）对共沉淀过程特性的影响。最终产品通过近红外（NIR）光谱和 NIR 化学成像显微镜进行表征。通过 FBRM 趋势统计和过程轨迹方法分别测量了共沉淀成核诱导时间（t（ind））。此外，基于 t（ind）测量和相应的过饱和度比（S）估算，评估了成核动力学。结果发现，ln（t（ind））与（ln（2）S）（-1）的关系图由两个线性段组成，与经典的初级成核机制一致。显然，在低 S（14≤S≤503）时，共沉淀过程受异质初级成核机制控制，而在高 S（1216≤S≤3649）时，共沉淀过程受均相成核机制控制。离线表征共同支持这一说法。因此，这表明将实时 PAT 过程监测与第一性原理建模和离线产品表征相结合，可以增强对共沉淀过程动力学和成核/生长机制的理解，而这是仅通过离线技术无法实现的。
