School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland.
Department of Mechanical, Manufacturing & Biomedical Engineering, Trinity College Dublin, Ireland.
Eur J Pharm Sci. 2022 Jul 1;174:106185. doi: 10.1016/j.ejps.2022.106185. Epub 2022 Apr 6.
The definition of the local dissolution environment is central to accurate particle dissolution simulation, and is determined by the apparatus and conditions used. In the flow-through apparatus dissolution occurs in the cell, often in a low velocity environment, with the reservoir considered the relevant volume for dissolution kinetics. Dissolution simulations were conducted using a reduced-order model based on the Ranz-Marshall correlation for mass transfer from spherical particles. Using ibuprofen as a model drug, the effect of defining a local volume to simulate dynamic bulk concentration conditions in the flow-through and paddle apparatus was assessed by comparing use of a near particle volume (NPV), extending a distance of one radius from the particle surface, with a flow-through apparatus cell volume or paddle apparatus vessel volume as the relevant instantaneous volume for dissolution. The instantaneous inlet concentration to NPV or cell volume is the reservoir/vessel concentration at that simulation time point, reflecting the continuous input to the cell of more dilute solution from the reservoir (closed system). Additionally, inputting particle size distribution (PSD) instead of a median particle size (MPS) and enabling or disabling particle motion were investigated, in two media (resulting in low and high solubility) and with two fluid velocity conditions in each apparatus. The NPV predicted effects of fluid velocity differences on dissolution in the high solubility medium in the flow-through apparatus, but had no effect on predictive ability in the paddle apparatus. In both apparatuses, simulations were reasonable for the high solubility environment but underpredicted dissolution in the low solubility environment. The PSD option and disabling particle motion increased the predictive ability of the simulations in low solubility media in the flow-through apparatus. The results highlight the necessity to incorporate the local dynamic dissolution conditions in the flow-through apparatus for accurate dissolution simulation, and the challenges of defining an effective particle size for dissolution simulation and of reflecting hydrodynamic complexity in simulating dissolution in the paddle apparatus.
局部溶解环境的定义是准确模拟颗粒溶解的核心，由所使用的仪器和条件决定。在流动池仪器中，溶解发生在池内，通常处于低流速环境中，储液器被认为是溶解动力学的相关体积。使用基于球形颗粒质量传递的 Ranz-Marshall 相关系数的降阶模型进行了溶解模拟。以布洛芬为模型药物，通过比较使用接近颗粒体积 (NPV)（从颗粒表面延伸一个半径距离）与流动池仪器池体积或桨式仪器容器体积作为溶解的相关瞬时体积，评估了定义局部体积以模拟流动池和桨式仪器中动态总体浓度条件的效果。NPV 或池体积的瞬时入口浓度是该模拟时间点的储液器/容器浓度，反映了更稀溶液从储液器连续输入到池内（封闭系统）。此外，研究了在两种介质（导致低溶解度和高溶解度）中，以及在每种仪器中具有两种流体速度条件下，输入粒度分布 (PSD) 而不是中值粒径 (MPS) 并启用或禁用颗粒运动的情况。NPV 预测了流体速度差异对高溶解度介质中流动池内溶解的影响，但对桨式仪器的预测能力没有影响。在两种仪器中，对于高溶解度环境的模拟都是合理的，但对低溶解度环境的溶解预测不足。PSD 选项和禁用颗粒运动增加了流动池在低溶解度介质中模拟的预测能力。结果强调了在准确模拟溶解时必须考虑流动池内的局部动态溶解条件，以及在定义溶解模拟的有效粒径和反映桨式仪器中溶解的流体动力学复杂性方面的挑战。
