Abstract The design of pharmaceutical tablets involves the determination of formulation parameters that define the tablet composition and internal microstructure. These parameters must be chosen so that the release of an active pharmaceutical ingredient (API) from the tablet follows a prescribed dissolution curve. In the case of immediate release formulations, the dissolution process typically consists of tablet disintegration, followed by the dissolution of the disintegration fragments. In order to find the appropriate values of formulation parameters, numerous experiments are typically required. In the present work, we propose a computational methodology for in silico design of tablet formulations with the aim of reducing the amount experimental work required during tablet design. The methodology is based on the coupling of two modelling approaches: (i) tablet fragmentation triggered by the swelling of the disintegrant is simulated by the discrete element method (DEM), and (ii) the dissolution of the resulting population of disintegration fragments is simulated using a finite volume grid-based model. The final API release curve is then obtained by the superposition of dissolution curves originating from the individual disintegration fragments. Using directly compressed tablets containing ibuprofen as the API and croscarmellose sodium as the disintegrant, the model was validated against experimental data. The fragment size distribution was evaluated by static light scattering and the dissolution profiles were obtained by a standard dissolution apparatus with UV/Vis spectroscopic detection. We demonstrate that the computational methodology is able to quantitatively predict the effect of disintegrant content and API primary particle size on the fragment size distribution and the final dissolution profiles, and is therefore useful as a tool for computer-assisted tablet formulation design.

中文翻译：

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基于微结构的速释药片崩解和溶出模拟

摘要 药物片剂的设计涉及确定片剂成分和内部微观结构的配方参数。必须选择这些参数，以便片剂中活性药物成分 (API) 的释放遵循规定的溶出曲线。在速释制剂的情况下，溶解过程通常包括片剂崩解，然后是崩解片段的溶解。为了找到合适的配方参数值，通常需要进行大量实验。在目前的工作中，我们提出了一种用于片剂配方计算机设计的计算方法，目的是减少片剂设计过程中所需的实验工作量。该方法基于两种建模方法的耦合：(i) 由崩解剂溶胀引发的片剂破碎通过离散元方法 (DEM) 进行模拟，以及 (ii) 对所得崩解碎片群的溶解进行模拟使用基于有限体积网格的模型。最终的 API 释放曲线是通过叠加源自各个崩解片段的溶出曲线来获得的。使用含有布洛芬作为 API 和交联羧甲基纤维素钠作为崩解剂的直接压片，该模型根据实验数据进行了验证。片段大小分布通过静态光散射评估，溶出曲线通过具有 UV/Vis 光谱检测的标准溶出度仪获得。