Molecular Dynamics and Physical Stability of Coamorphous Ezetimib and Indapamide Mixtures

Low physical stability is the main reason limiting the widespread use of amorphous pharmaceuticals. One approach to overcome this problem is to mix these drugs with various excipients. In this study coamorphous drug-drug compositions of different molar ratios of ezetimib and indapamid (i.e., EZB 10:1 IDP, EZB 5:1 IDP, EZB 2:1 IDP, EZB 1:1 IDP and EZB 1:2 IDP) were prepared and investigated using differential scanning calorimetry (DSC), broadband dielectric spectroscopy (BDS), and X-ray diffraction (XRD). Our studies have shown that the easily recrystallizing ezetimib drug can be significantly stabilized in its amorphous form by using even a small amount of indapamid (8.8 wt %). DSC experiments indicate that the glass transition temperature (Tg) of the tested mixtures changes with the drug concentration in accordance with the Gordon-Taylor equation. We also investigated the effect of indapamid on the molecular dynamics of the ezetimib. As a result it was found that, with increasing indapamid content, the molecular mobility of the binary drug-drug system is slowed down. Finally, using the XRD technique we examined the long-term physical stability of the investigated binary systems stored at room temperature. These measurements prove that low-molecular-weight compounds are able to significantly improve the physical stability of amorphous APIs.