Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Campus for Research Excellence and Technological Enterprise, Singapore 138602, Singapore.
ACS Appl Mater Interfaces. 2024 Jul 3;16(26):34409-34418. doi: 10.1021/acsami.4c06815. Epub 2024 Jun 18.
Nanosizing drug crystals has emerged as a successful approach to enabling oral bioavailability, as increasing drug crystal surface area improves dissolution kinetics and effective solubility. Recently, bottom-up methods have been developed to directly assemble nanosized crystals by leveraging polymer and surfactant excipients during crystallization to control crystal size, morphology, and structure. However, while significant research has investigated how polymers and other single additives inhibit or promote crystallization in pharmaceutical systems, there is little work studying the mechanistic interactions of multiple excipients on drug crystal structure and the extent of crystallinity, which can influence formulation performance. This study explores how the structure and crystallinity of a model hydrophobic drug crystal, fenofibrate, change as a result of competitive interfacial chemisorption between common nonionic surfactants (polysorbate 80 and sorbitan monooleate) and a surface-active polymer excipient (methylcellulose). Classical molecular dynamics simulations highlight how key intermolecular interactions, including surfactant-polymer complexation and surfactant screening of the crystal surface, modify the resulting crystal structure. In parallel, experiments generating drug nanocrystals in hydrogel thin films validate that drug crystallinity increases with an increasing weight fraction of surfactant. Simulation results reveal a connection between accelerated dynamics in the bulk crystal and the experimentally measured extent of crystallinity. To our knowledge, these are the first simulations that directly characterize structural changes in a drug crystal as a result of excipient surface composition and relate the experimental extent of crystallinity to structural changes in the molecular crystal. Our approach provides a mechanistic understanding of crystallinity in nanocrystallization, which can expand the range of orally deliverable small molecule therapies.
药物晶体的纳米化已成为提高口服生物利用度的成功方法，因为增加药物晶体表面积可以改善溶解动力学和有效溶解度。最近，已经开发出了自下而上的方法，通过在结晶过程中利用聚合物和表面活性剂赋形剂来直接组装纳米级晶体，从而控制晶体的大小、形态和结构。然而，尽管有大量研究调查了聚合物和其他单一添加剂如何在药物体系中抑制或促进结晶，但很少有研究探讨多种赋形剂对药物晶体结构和结晶度的机械相互作用，而结晶度会影响制剂性能。本研究探讨了模型疏水性药物晶体非诺贝特的结构和结晶度如何因常见非离子表面活性剂（聚山梨酯 80 和山梨坦单油酸酯）和表面活性聚合物赋形剂（甲基纤维素）之间的竞争界面化学吸附而发生变化。经典分子动力学模拟突出了关键的分子间相互作用，包括表面活性剂-聚合物络合和表面活性剂对晶体表面的屏蔽，如何改变所得晶体结构。同时，在水凝胶薄膜中生成药物纳米晶体的实验验证了药物结晶度随表面活性剂重量分数的增加而增加。模拟结果揭示了晶体中扩散动力学与实验测量的结晶度之间的联系。据我们所知，这些是首次直接描述赋形剂表面组成导致药物晶体结构变化并将实验测量的结晶度与分子晶体结构变化联系起来的模拟。我们的方法提供了对纳米结晶中结晶度的机制理解，这可以扩展可口服小分子疗法的范围。
