Predicting the Formation and Stability of Amorphous Small Molecule Binary Mixtures from Computationally Determined Flory-Huggins Interaction Parameter and Phase Diagram
Predicting the Formation and Stability of Amorphous Small Molecule Binary Mixtures from Computationally Determined Flory-Huggins Interaction Parameter and Phase Diagram
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DOI：
10.1021/mp900304p
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发表时间：
2010-05-01
影响因子：
4.9
通讯作者：
Korhonen, Ossi
中科院分区：
文献类型：
--
作者：
Pajula, Katja;Taskinen, Markku;Korhonen, Ossi
弗洛里-哈金斯相互作用参数已被证明可用于预测二元混合物中聚合物和小分子的热力学混溶性。在本文中，对这一概念进行了扩展和评估，以确定弗洛里-哈金斯相互作用参数是否可以应用于小分子二元混合物，以及该参数是否可以预测此类无定形二元混合物的相稳定性。这项研究基于这样的假设：热力学上可混溶的二元系统是稳定的并且不能结晶，并且在各个组分结晶之前相分离是必不可少的。二元系统的稳定性被认为源自固体分散体中组分之间的分子相互作用，其特征在于弗洛里-哈金斯相互作用参数。基于DSC实验，本研究中的药物分子（39）根据其结晶倾向分为三个不同的类别；即，高度结晶、中等结晶和非结晶化合物。系统地计算了每个药物对的弗洛里-哈金斯相互作用参数。该方法的有效性通过热台偏振光显微镜进行了实证验证。如果这对化合物中的两种化合物都属于高度结晶化合物类别，则弗洛里-哈金斯相互作用预测无定形或结晶相的置信度约为 88%（26 中的 23）。如果该对中的一种或两种化合物是适度结晶或非结晶化合物，则二元混合物在冷却阶段期间保持在无定形相，而不管相互作用参数如何。人们发现 Flory-Huggins 相互作用参数是预测小分子二元混合物相稳定性的一个相当好的指标。所述方法可以快速筛选生产稳定的无定形二元混合物所需的潜在稳定剂。
The Flory-Huggins interaction parameter has been shown to be useful in predicting the thermodynamic miscibility of a polymer and a small molecule in a binary mixture. In the present paper, this concept was extended and evaluated to determine whether or not the Flory-Huggins interaction parameter can be applied to small molecule binary mixtures and if this parameter can predict the phase stability of such amorphous binary mixtures. This study was based on the assumption that a thermodynamically miscible binary system is stable and cannot crystallize, and that phase separation is essential before the individual components can crystallize. The stabilization of a binary system is thought to derive from molecular interactions between components in a solid dispersion, which are characterized by the Flory-Huggins interaction parameter. Based on DSC experiments, drug molecules (39) in the present study were classified into three different categories according to their crystallization tendency; i.e., highly crystallizing, moderately crystallizing and noncrystallizing compounds. The Flory-Huggins interaction parameter was systematically calculated for each drug pair. The validity of this approach was empirically verified by hot-stage polarized light microscopy. If both compounds in the pair belonged to the category of highly crystallizing compound, the Flory-Huggins interaction predicted an amorphous or crystalline phase with approximately 88% (23 out of 26) confidence. If one or both compounds of the pair were either moderately crystallizing or noncrystallizing compounds, the binary mixture remained in the amorphous phase during the cooling phase regardless of the interaction parameter. The Flory-Huggins interaction parameter was found to be a reasonably good indicator for predicting the phase stability of small molecule binary mixtures. The method described can enable fast screening of the potential stabilizers needed to produce a stable amorphous binary mixture.