New drug-drug salts of palbociclib and nonsteroidal anti-inflammatory drugs with enhanced physicochemical properties and antitumor activities

Palbociclib (PAL) is a selective cyclin-dependent kinase 4/6 inhibitor and widely used in the clinical management of advanced breast cancer. However, its clinical utility is restricted by poor bioavailability, stemming from its negligible aqueous solubility, and dose-limiting adverse effects. Drug-drug salts are intensively investigated to tailor physicochemical properties of drug candidates and achieve synergistic effects. Non-steroidal anti-inflammatory drugs (NSAIDs) have garnered increasing attention for their antitumor potential in recent years. In this study, three novel drug-drug salts of PAL with diclofenac (DIC), aceclofenac (ACE), and naproxen (NAP) were synthesized via evaporative crystallization. Single-crystal and powder X-ray diffraction, thermal analysis, infrared spectroscopy, and Hirshfeld surface analysis were employed to confirm their molecular structures. Equilibrium solubility studies revealed a 1.5 to 2.8-fold solubility enhancement for PAL-NSAIDs salts at pH 7.4 buffer. Accelerated stability studies demonstrated excellent physical stability of the PAL-NSAIDs salts for 2 months. In vitro cytotoxicity assays against bladder cancer J82 cell lines demonstrated significantly improved antitumor activity for PAL-DIC, PAL-ACE, and PAL-NAP, with 2.1-fold, 1.6-fold, and 4.9-fold improvement over PAL alone, respectively. Moreover, the oral bioavailability of PAL in PAL-NAP was improved 2.5 times in rats when compared to the single PAL. This study proposed a robust strategy to enhance PAL’s solubility and anticancer efficacy by designing drug-drug salts.