Abstract：
Amorphous-Amorphous phase separation (AAPS) is an important phenomenon that can impede the performance of amorphous solid dispersions (ASDs). The purpose of this study was to develop a sensitive approach relying on dielectric spectroscopy (DS) to characterize AAPS in ASDs. This includes detecting AAPS, determining the size of the active ingredient (AI) discrete domains in the phase-separated systems, and accessing the molecular mobility in each phase. Using a model system consisting of the insecticide imidacloprid (IMI) and the polymer polystyrene (PS), the dielectric results were further confirmed by confocal fluorescence microscopy (CFM). The detection of AAPS by DS was accomplished by identifying the decoupled structural (α-)dynamics of the AI and the polymer phase. The α-relaxation times corresponding to each phase correlated reasonably well with those of the pure components, implying nearly complete macroscopic phase separation. Congruent with the DS results, the occurrence of the AAPS was detected by means of CFM, making use of the autofluorescent property of IMI. Oscillatory shear rheology and differential scanning calorimetry (DSC) detected the glass transition of the polymer phase but not that of the AI phase. Furthermore, the otherwise undesired effects of interfacial and electrode polarization, which can appear in DS, were exploited to determine the effective domain size of the discrete AI phase in this work. Here, stereological analysis of CFM images probing the mean diameter of the phase-separated IMI domains directly stayed in reasonably good agreement with the DS-based estimates. The size of phase-separated microclusters showed little variation with AI loading, implying that the ASDs have presumably undergone AAPS upon manufacturing. DSC provided further support to the immiscibility of IMI and PS, as no discernible melting point depression of the corresponding physical mixtures was detected. Moreover, no signatures of strong attractive AI-polymer interactions could be detected by mid-infrared spectroscopy within this ASD system. Finally, dielectric cold crystallization experiments of the pure AI and the 60 wt % dispersion revealed comparable crystallization onset times, hinting at a poor inhibition of the AI crystallization within the ASD. These observations are in harmony with the occurrence of AAPS. In conclusion, our multifaceted experimental approach opens new venues for rationalizing the mechanisms and kinetics of phase separation in amorphous solid dispersions.
摘要：
无定形-无定形相分离（AAPS）是阻碍无定形固体分散体（ASD）性能的重要现象。这项研究的目的是开发一种灵敏的方法，该方法依赖于介电谱（DS）来表征ASD中的AAPS。这包括检测AAPS，确定相分离系统中活性成分（AI）离散域的大小，并获得每个阶段的分子迁移率。使用由杀虫剂吡虫啉（IMI）和聚合物聚苯乙烯（PS）组成的模型系统，介电结果通过共聚焦荧光显微镜（CFM）进一步证实。DS对AAPS的检测是通过鉴定AI和聚合物相的解耦结构（α-）动力学来完成的。对应于每个阶段的α弛豫时间与纯组分的α弛豫时间相当好地相关，意味着几乎完全的宏观相分离。与DS结果一致，通过CFM检测到AAPS的发生，利用IMI的自发荧光特性。振荡剪切流变学和差示扫描量热法（DSC）检测到聚合物相的玻璃化转变，但未检测到AI相的玻璃化转变。此外，否则不希望的界面和电极极化的影响，它可以出现在DS中，在这项工作中，它们被用来确定离散AI相的有效域大小。这里,对探测相分离IMI域平均直径的CFM图像的体视学分析与基于DS的估计值直接保持相当好的一致性。相分离的微团簇的大小随AI负载变化不大，这意味着ASD可能在制造时经历了AAPS。DSC为IMI和PS的不混溶性提供了进一步的支持，因为没有检测到相应物理混合物的可辨别的熔点降低。此外，在该ASD系统中,中红外光谱无法检测到强烈的AI-聚合物相互作用的特征.最后,纯AI和60重量%分散体的介电冷结晶实验揭示了可比的结晶开始时间，暗示ASD内AI结晶的抑制作用较差。这些观察结果与AAPS的发生是一致的。总之,我们多方面的实验方法为合理化无定形固体分散体中相分离的机理和动力学开辟了新的途径。
