Co-amorphous (CAM) is an effective pharmaceutical strategy to improve the aqueous solubility of poorly water-soluble drugs, however, the physical stability problem of converting into their crystalline counterparts under high temperature and high humidity conditions significantly limits their development. Stress testing can rapidly evaluate the physical stability, distinguish the quality differences, and recommend storage conditions. This study aims to further understand the physical stability of the atorvastatin-lisinopril CAMs with various stoichiometric ratios by stress testings, and clarify the deep mechanism at the molecular level by systemic characterization. CAMs were prepared by a cryo-milling method. Molecular modeling and molecular dynamics were used to predict potential intermolecular forces of CAMs. Then, they were stored under stress conditions, and the collected samples were subjected to PLM, DSC, PXRD, and dissolution tests. Raman and FT-IR spectroscopy were used to identify the intermolecular forces. The results showed that the physical stability of CAMs was stoichiometric-dependent. Regardless of the conditions tested, CAMs exhibited excellent physical stability at stoichiometric ratios of 2:1 and 1:1 because of the strong intermolecular forces. This study sheds light on the stoichiometric-dependent physical stability of the CAM strategy in stress testing, provides a mechanism clarification at the molecule level, and offers useful information on CAM storage.

中文翻译：

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阿托伐他汀-赖诺普利共无定形物在压力测试中的化学计量依赖性物理稳定性

共无定形（CAM）是提高难溶性药物水溶性的有效药物策略，然而，在高温高湿条件下转化为结晶对应物的物理稳定性问题严重限制了其发展。压力测试可以快速评估物理稳定性，区分质量差异，并推荐储存条件。本研究旨在通过压力测试进一步了解不同化学计量比的阿托伐他汀-赖诺普利CAM的物理稳定性，并通过系统表征在分子水平上阐明其深层机制。 CAM 通过冷冻研磨方法制备。分子建模和分子动力学用于预测 CAM 潜在的分子间力。然后，将它们储存在应力条件下，并对收集的样品进行 PLM、DSC、PXRD 和溶出测试。拉曼光谱和傅立叶变换红外光谱用于识别分子间力。结果表明，CAM 的物理稳定性具有化学计量依赖性。无论测试条件如何，由于强大的分子间力，CAM 在 2:1 和 1:1 的化学计量比下都表现出优异的物理稳定性。这项研究揭示了压力测试中 CAM 策略的化学计量依赖性物理稳定性，提供了分子水平的机制澄清，并提供了有关 CAM 存储的有用信息。