Structure–stability relationships of pure cannabinoids and their cocrystals under forced degradation conditions

Cannabinoids have attracted increasing scientific interest due to their diverse activities and therapeutic potential. However, cannabinoids suffer from limited physicochemical properties, including low melting point, low aqueous solubility, and stability issues. Cocrystal formation offers a promising approach to overcome these limitations. In this study, we investigate the solid-state stability of cannabinoids, namely cannabidiol (CBD), cannabinol (CBN), and cannabigerol (CBG), and their cocrystals under thermal, pH-dependent, oxidative, and photolytic degradation stress conditions, with a focus on exploring the structure-stability relationships. The results revealed distinct stability trends. We observed that 4,4’-bipyridine improved the thermal stability compared to the pure cannabinoids, highlighting the role of coformer selection. pH-dependent studies generally showed higher degradation rates at intermediate pH values, whereas photostability experiments showed negligible instability in most samples. Oxidative stressing indicated that radical-mediated oxidation had a stronger impact on stability than peroxide-mediated oxidation. Overall, the results indicate that coformer choice and surface exposure of heteroatoms are key factors influencing the stability of cannabinoid cocrystals.