Seventh Street Development Group, PO Box 251, Kure Beach NC 28449, United States.
School of Pharmacy, University of Wisconsin-Madison, United States.
J Pharm Sci. 2023 Jan;112(1):8-18. doi: 10.1016/j.xphs.2022.08.007. Epub 2022 Aug 7.
In this Commentary, the authors expand on their earlier studies of the solid-state long-term isothermal crystallization of amorphous API from the glassy state in amorphous solid dispersions, and focus on the effects of polymer concentration, and its implications for producing high load API doses with minimum polymer concentration. After presenting an overview of the various mechanistic factors which influence the ability of polymers to inhibit API crystallization, including the chemical structure of the polymer relative to the API, the nature and strength of API-polymer noncovalent interactions, polymer molecular weight, impact on primary diffusive molecular mobility, as well as on secondary motions in the bulk and surface phases of the glass, we consider in more detail, the effects of polymer concentration. Here, we examine the factors that appear to allow relatively low polymer concentrations, i.e., less than 10%w/w polymer, to greatly reduce crystallization, including a focus on the heterogeneous structure of the glassy state, and the possible spatial distribution and concentration of polymer in certain key regions of the glass. This is followed by a review and analysis of examples in the recent literature focused on determining the minimum polymer concentration in an amorphous solid dispersion, capable of producing optimally stable high drug load amorphous dispersions.
在这篇评论中，作者扩展了他们之前关于无定形 API 从无定形固体分散体中的玻璃态进行固态长期等温结晶的研究，并重点研究了聚合物浓度的影响，以及其对用最小聚合物浓度生产高载药量 API 的意义。在介绍了影响聚合物抑制 API 结晶能力的各种机制因素概述后，包括聚合物相对于 API 的化学结构、API-聚合物非共价相互作用的性质和强度、聚合物分子量、对初级扩散分子迁移率的影响，以及对玻璃的体相和表面相的次级运动的影响，我们更详细地考虑了聚合物浓度的影响。在这里，我们研究了似乎允许相对低聚合物浓度（即低于 10%w/w 聚合物）的因素，以大大降低结晶的因素，包括关注玻璃态的非均相结构，以及聚合物在玻璃某些关键区域的可能空间分布和浓度。随后，回顾和分析了近期文献中的一些例子，这些例子侧重于确定能够产生最佳稳定高药物载量无定形分散体的无定形固体分散体中的最小聚合物浓度。
