Research Center Pharmaceutical Engineering, Inffeldgasse 13, 8010 Graz, Austria.
Research Center Pharmaceutical Engineering, Inffeldgasse 13, 8010 Graz, Austria; Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, 8010 Graz, Austria.
Int J Pharm. 2023 Jun 25;641:122915. doi: 10.1016/j.ijpharm.2023.122915. Epub 2023 Apr 2.
Residence time distribution (RTD) modeling has proven to be a valuable tool for material tracking in continuous pharmaceutical processes. Refilling is thoroughly studied in the literature, but the main focus lies on the feed rate disturbances. The impact of the feeders themselves on intermixing of different material batches is often overlooked. Since the experimental methods to measure the RTD feeder discharging processes feeder are complex and material intensive, there is only limited experimental RTD data available in the literature. A DEM (discrete element method) simulation of a discharge of a twin-screw feeder shows that a large fraction of material that is moved and intermixed by the agitator. In addition to the intermixing, there is a tendency to discharge material located above the agitator early. In order to predict the behavior during multiple refill events, three models in order of increasing complexity are presented: (1) A simple exponential RTD assuming perfect intermixing of material batches; (2) a RTD model based on DEM results; (3) particle-level material tracking by extrapolation of the DEM results. All three of these models are able to predict the survival function of old material for late refills at low fill levels, however, earlier refills at high fill levels require more complex models to accurately represent the dynamics inside the hopper of the feeder.
停留时间分布（RTD）建模已被证明是连续制药过程中物料跟踪的一种有效工具。再填充在文献中得到了深入研究，但主要关注点在于进料速率干扰。进料器本身对不同物料批次混合的影响往往被忽视。由于测量 RTD 进料器卸料过程的实验方法复杂且耗费材料，因此文献中只有有限的实验 RTD 数据。双螺杆进料器卸料的 DEM（离散元法）模拟表明，搅拌器会移动和混合大量物料。除了混合之外，还有一种早期排出位于搅拌器上方的物料的趋势。为了预测多次再填充事件的行为，提出了三种按复杂程度递增的模型：（1）假设物料批次完全混合的简单指数 RTD；（2）基于 DEM 结果的 RTD 模型；（3）通过 DEM 结果外推进行颗粒级别的物料跟踪。所有这三种模型都能够预测低填充水平下后期再填充的旧物料的生存函数，但高填充水平下的早期再填充需要更复杂的模型来准确表示进料器料斗内的动态。
