Faiz Afzal Mohammad Atif, Lehmkemper Kristin, Sobich Ekaterina, Hughes Thomas F, Giesen David J, Zhang Teng, Krauter Caroline M, Winget Paul, Degenhardt Matthias, Kyeremateng Samuel O, Browning Andrea R, Shelley John C
Materials Science, Schrödinger, LLC, Suite 1300, 101 SW Main Street, Portland, Oregon 97204, United States.
Formulation Sciences, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, Ludwigshafen 67061, Germany.
Mol Pharm. 2021 Nov 1;18(11):3999-4014. doi: 10.1021/acs.molpharmaceut.1c00289. Epub 2021 Sep 27.
Amorphous solid dispersions (ASDs) are commonly used to orally deliver small-molecule drugs that are poorly water-soluble. ASDs consist of drug molecules in the amorphous form which are dispersed in a hydrophilic polymer matrix. Producing a high-performance ASD is critical for effective drug delivery and depends on many factors such as solubility of the drug in the matrix and the rate of drug release in aqueous medium (dissolution), which is linked to bioperformance. Often, researchers perform a large number of design iterations to achieve this objective. A detailed molecular-level understanding of the mechanisms behind ASD dissolution behavior would aid in the screening, designing, and optimization of ASD formulations and would minimize the need for testing a wide variety of prototype formulations. Molecular dynamics and related types of simulations, which model the collective behavior of molecules in condensed phase systems, can provide unique insights into these mechanisms. To study the effectiveness of these simulation techniques in ASD formulation dissolution, we carried out dissipative particle dynamics simulations, which are particularly an efficient form of molecular dynamics calculations. We studied two stages of the dissolution process: the early-stage of the dissolution process, which focuses on the dissolution at the ASD/water interface, and the late-stage of the dissolution process, where significant drug release would have occurred and there would be a mixture of drug and polymer molecules in a predominantly aqueous environment. Experimentally, we used Fourier transform infrared spectroscopy to study the interactions between drugs, polymers, and water in the dry and wet states and the chromatographic technique to study the rate of drug and polymer release. Both experiments and simulations provided evidence of polymer microstructures and drug-polymer interactions as important factors for the dissolution behavior of the investigated ASDs, consistent with previous work by Pudlas et al. (, , 21-31). As experimental and simulation results are consistent and complementary, it is clear that there is significant potential for combined experimental and computational research for a detailed understanding of ASD formulations and, hence, formulation optimization.
无定形固体分散体（ASDs）通常用于口服递送水溶性差的小分子药物。ASDs由无定形形式的药物分子组成，这些分子分散在亲水性聚合物基质中。制备高性能的ASD对于有效的药物递送至关重要，并且取决于许多因素，例如药物在基质中的溶解度以及药物在水性介质中的释放速率（溶解），这与生物性能相关。通常，研究人员会进行大量的设计迭代来实现这一目标。对ASD溶解行为背后的机制进行详细的分子水平理解将有助于ASD制剂的筛选、设计和优化，并将最大限度地减少测试各种原型制剂的需求。分子动力学和相关类型的模拟，模拟凝聚相系统中分子的集体行为，可以为这些机制提供独特的见解。为了研究这些模拟技术在ASD制剂溶解中的有效性，我们进行了耗散粒子动力学模拟，这是分子动力学计算的一种特别有效的形式。我们研究了溶解过程的两个阶段：溶解过程的早期阶段，重点是ASD/水界面处的溶解；以及溶解过程的后期阶段，此时会发生大量药物释放，并且在主要为水性的环境中会存在药物和聚合物分子的混合物。在实验中，我们使用傅里叶变换红外光谱来研究药物、聚合物和水在干燥和湿润状态下的相互作用，并使用色谱技术来研究药物和聚合物的释放速率。实验和模拟都提供了证据，表明聚合物微观结构和药物-聚合物相互作用是所研究的ASD溶解行为的重要因素，这与Pudlas等人之前的工作一致（，，21 - 31）。由于实验和模拟结果一致且互补，很明显，结合实验和计算研究对于详细了解ASD制剂并因此进行制剂优化具有巨大潜力。
