Barrera Jiménez Ana Alejandra, Van Hauwermeiren Daan, Peeters Michiel, De Beer Thomas, Nopens Ingmar
BIOMATH-Department of Data Analysis and Mathematical Modelling, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
Pharmaceutics. 2021 May 11;13(5):692. doi: 10.3390/pharmaceutics13050692.
Recently, the pharmaceutical industry has undergone changes in the production of solid oral dosages from traditional inefficient and expensive batch production to continuous manufacturing. The latest advancements include increased use of continuous twin-screw wet granulation and application of advanced modeling tools such as Population Balance Models (PBMs). However, improved understanding of the physical process within the granulator and improvement of current population balance models are necessary for the continuous production process to be successful in practice. In this study, an existing compartmental one-dimensional PBM of a twin-screw granulation process was improved by altering the original aggregation kernel in the wetting zone as a result of an identifiability analysis. In addition, a strategy was successfully applied to reduce the number of model parameters to be calibrated in both the wetting zone and kneading zones. It was found that the new aggregation kernel in the wetting zone is capable of reproducing the particle size distribution that is experimentally observed at different process conditions as well as different types of formulations, varying in hydrophilicity and API concentration. Finally, it was observed that model parameters could be linked not only to the material properties but also to the liquid to solid ratio, paving the way to create a generic PBM to predict the particle size distribution of a new formulation.
最近，制药行业在固体口服制剂生产方面经历了变革，从传统低效且昂贵的批次生产转向连续制造。最新进展包括更多地使用连续双螺杆湿法制粒以及应用先进的建模工具，如群体平衡模型（PBMs）。然而，要使连续生产过程在实践中取得成功，有必要更好地理解制粒机内部的物理过程并改进当前的群体平衡模型。在本研究中，通过可识别性分析改变了润湿区的原始聚集核，从而改进了现有的双螺杆制粒过程的一维隔室PBM。此外，成功应用了一种策略来减少在润湿区和捏合区中需要校准的模型参数数量。结果发现，润湿区的新聚集核能够重现不同工艺条件以及不同类型制剂（亲水性和原料药浓度各异）下实验观察到的粒度分布。最后，观察到模型参数不仅可以与材料特性相关联，还可以与液固比相关联，为创建通用PBM以预测新制剂的粒度分布铺平了道路。
