Stoichiometric-dependent physical stability of atorvastatin-lisinopril co-amorphous in stress testing

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 in vitro 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.