The present study evaluates the physical stability and intermolecular interactions of Rivaroxaban (RXB) amorphous solid dispersions (ASDs) in polymeric carriers via thermodynamic modelling and molecular simulations. Specifically, the Flory-Huggins (FH) lattice solution theory was used to construct thermodynamic phase diagrams of RXB ASDs in four commonly used polymeric carriers (i.e. copovidone, coPVP, povidone, PVP, Soluplus, SOL and hypromellose acetate succinate, HPMCAS), which were stored under 0%, 60% and 75% relative humidity (RH) conditions. In order to verify the phase boundaries predicted by FH modelling (i.e. truly amorphous zone, amorphous-amorphous demixing zones and amorphous-API recrystallization zones), samples of ASDs were examined via polarized light microscopy after storage for up to six months at various RH conditions. Results showed a good agreement between the theoretical and the experimental approaches (i.e. coPVP and PVP resulted in less physically-stable ASDs compared to SOL and HPMCAS) indicating that the proposed FH-based modelling may be a useful tool in predicting long-term physical stability in high humidity conditions. In addition, molecular dynamics (MD) simulations were employed in order to interpret the observed differences in physical stability. Results, which were verified via differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), suggested the formation of similar intermolecular interactions in all cases, indicating that the interaction with moisture water plays a more crucial role in ASD physical stability compared to the formation of intermolecular interactions between ASD components.

本研究通过热力学建模和分子模拟评估了利伐沙班（RXB）无定形固体分散体（ASD）在聚合物载体中的物理稳定性和分子间的相互作用。具体来说，采用Flory-Huggins（FH）晶格溶液理论在四种常用的聚合物载体（即共聚维酮，coPVP，聚维酮，PVP，Soluplus，SOL和羟丙甲酸酯琥珀酸酯，HPMCAS）中构建RXB ASD的热力学相图。将其储存在0％，60％和75％的相对湿度（RH）条件下。为了验证通过FH建模预测的相界（即真正的非晶区，非晶-非晶混合区和非晶API重结晶区），在各种RH条件下存储长达六个月后，通过偏振光显微镜检查了ASD样品。结果表明理论方法与实验方法之间具有很好的一致性（即与SOL和HPMCAS相比，coPVP和PVP导致的物理稳定ASD减少），表明基于FH的模型可能是预测长期物理稳定性的有用工具在高湿度条件下。另外，为了解释观察到的物理稳定性差异，采用了分子动力学（MD）模拟。通过差示扫描量热法（DSC）和傅里叶变换红外光谱（FTIR）验证的结果表明，在所有情况下均形成相似的分子间相互作用，这表明与水相比，与水分的相互作用在ASD物理稳定性中起着更为关键的作用。 ASD组件之间的分子间相互作用的形成。