用MD模拟预测非晶态固体分散体中药物-聚合物的相容性:关于溶剂化自由能的陷阱

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
T. Higginbotham, K. Meier, J. Ramírez and A. Garaizar*, 
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引用次数: 0

摘要

无定形固体分散体(ASDs)是提高难溶性药物的生物利用度和表观溶解度的常用方法。因此,广泛的研究,包括实验和计算方法,一直致力于开发评估影响其稳定性的关键因素的方法,特别是药物-聚合物相互作用。对药物与一组溶剂或聚合物的相容性进行排序的一种常用计算方法是比较热力学观察值,例如无限稀释时的溶剂化自由能。然而,聚合物赋形剂的分子量对这些相互作用的影响仍未得到充分研究。本研究通过对吲哚美辛在PVP(- VA)和HPMC中的原子模拟,以及使用粗粒度模型的模拟,深入研究了这种影响,强调了其至关重要的意义。首先,我们证明了聚合物的分子量在决定药物的溶剂化自由能方面起着关键作用,有时比聚合物的特定化学特性产生更大的影响。此外,我们的模拟表明,高分子量聚合物导致较低的溶剂化自由能,从而表明与药物的相容性更好。然而,较低的自由能溶剂化的药物在较长的聚合物并不转化为更高的溶解度。这项工作强调了聚合物分子量在测量非晶固体分散体中的热力学观察物时所起的微妙作用,这是优化药物配方时必须考虑的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Predicting Drug-Polymer Compatibility in Amorphous Solid Dispersions by MD Simulation: On the Trap of Solvation Free Energies

Predicting Drug-Polymer Compatibility in Amorphous Solid Dispersions by MD Simulation: On the Trap of Solvation Free Energies

Amorphous solid dispersions (ASDs) are a prevalent method for increasing the bioavailability and apparent solubility of poorly soluble drugs. Consequently, extensive research, encompassing both experimental and computational approaches, has been dedicated to developing methods for assessing the key factors influencing their stability, notably drug-polymer interactions. A common computational approach to rank the compatibility of a drug with a set of solvents or polymers is to compare thermodynamic observables, such as solvation free energies at infinite dilution. However, the impact of the molecular weight of the polymer excipient on these interactions remains underexplored. This study delves into this impact through atomistic simulations of Indomethacin in PVP(−VA) and HPMC, and through simulations using a coarse-grained model, emphasizing its critical importance. First, we demonstrate that the molecular weight of the polymer plays a pivotal role in determining the solvation free energy of the drug, at times exerting a more significant influence than the specific chemical identity of the polymer. Additionally, our simulations suggest that higher molecular weight polymers lead to lower solvation free energies and, thus, suggest better compatibility with the drug. Yet, the lower free energy of solvation of the drug in longer polymers does not translate into a higher solubility. This work highlights the subtle role polymer molecular weight plays when measuring thermodynamic observables in amorphous solid dispersions, a role which must be considered when optimizing pharmaceutical formulations.

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来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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