Pharmaceutical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach, Germany; Department of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach, Germany.
Eur J Pharm Sci. 2018 Nov 1;124:328-338. doi: 10.1016/j.ejps.2018.09.005. Epub 2018 Sep 6.
Biphasic dissolution models were proposed to provide good predictive power for in vivo absorption kinetics. However, up to date the impact of hydrodynamics in mini-scale models are not well understood. Consequently, the aim of this work was to investigate different setups of a previously published mini-scale biphasic dissolution model (miBIdi-pH-II) to better understand the relevance of hydrodynamics for evaluating kinetic parameters and to simultaneously increase the robustness of the experimental model. As a first step, the hydrodynamics within the aqueous phase were characterized by in silico simulations of the flow patterns. Different settings, such as higher rotation speeds of the paddles, the implementation of a second propeller into the aqueous phase, and different shapes of aqueous stirrers were investigated. Second, to evaluate the results of the in silico simulations, in vitro experiments with glitter were carried out. Last, the same settings were applied in the miBIdi-pH-II using dipyridamole (DPD) as model compound to estimate kinetic parameters by applying a compartment-based modelling approach. Both in vitro experiments with glitter or DPD demonstrated the adequateness of the previous in silico hydrodynamic simulations. The use of higher rotation speeds and a second aqueous propeller resulted in more homogeneous mixing of the aqueous phase. This resulted in faster distribution of dissolved active pharmaceutical ingredient (API) into the octanol phase. A kinetic model was successfully applied to quantify the influence of hydrodynamics on the partitioning rate of the API into the octanol phase. In conclusion, the combination of in silico and in vitro methods was demonstrated to be powerful for investigating the flow patterns within the miBIdi-pH-II. A comprehensive understanding of the hydrodynamics and the respective influence on the dissolution and apparent partitioning into the octanol phase in the biphasic dissolution model was obtained and completed by using a compartmental kinetic model. This model allowed successful quantification of how the hydrodynamics influence the partitioning of API into the octanol phase.
双相溶解模型被提出以提供对体内吸收动力学的良好预测能力。然而，截至目前，微型模型中的流体动力学的影响尚未得到很好的理解。因此，本工作的目的是研究先前发表的微型双相溶解模型（miBIdi-pH-II）的不同设置，以更好地了解流体动力学对评估动力学参数的相关性，并同时提高实验模型的稳健性。作为第一步，通过对流动模式的计算机模拟来描述水相中的流体动力学。研究了不同的设置，例如提高桨叶的旋转速度、在水相内安装第二个螺旋桨以及使用不同形状的水搅拌器。其次，为了评估计算机模拟的结果，使用闪光剂进行了体外实验。最后，使用二吡啶酰胺（DPD）作为模型化合物，将相同的设置应用于 miBIdi-pH-II 中，通过应用基于隔室的建模方法来估计动力学参数。闪光剂或 DPD 的体外实验均证明了先前的计算机流体动力学模拟的适当性。使用较高的旋转速度和第二个水螺旋桨导致水相的混合更加均匀。这导致溶解的活性药物成分（API）更快地分布到辛醇相中。成功应用了动力学模型来量化流体动力学对 API 分配到辛醇相的速率的影响。总之，证明了计算机模拟和体外方法的结合对于研究 miBIdi-pH-II 内的流动模式非常有效。通过使用隔室动力学模型，全面了解了流体动力学及其对双相溶解模型中溶解和API 向辛醇相的表观分配的各自影响。该模型成功地量化了流体动力学如何影响 API 向辛醇相的分配。
