Synthesis and structural characterization of a novel palbociclib-kaempferol cocrystal with improved tabletability and synergistic antitumor activity

Palbociclib (PAL), a highly selective inhibitor of cell cycle protein-dependent kinases (CDK) 4/6, is pri-marily used for treating advanced breast cancer. However, the use of PAL has been limited by its poor tabletability and dose-related toxic side effects. In this study, to improve the tabletability of PAL and re-duce its effective dose, a flavonoid-kaempferol (KAE) was selected as the coformer to synthesize cocrys-tal with PAL. The novel cocrystal PAL-KAE was prepared by antisolvent cocrystallization and character-ized by various techniques including X-ray diffraction (SCXRD and PXRD), thermal analysis (DSC and TG), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), Hirshfeld surface (HS), HOMO -LUMO analysis, and molecular electrostatic potential (MEP). Powder compaction experi-ments indicated that PAL-KAE cocrystal significantly improved the tabletability of PAL. The cytotoxicity test suggested that PAL-KAE also exerted synergistic antitumor effect against human ovarian cancer cell line OVCAR3 in MTT assay. Docking results indicated that PAL-KAE had lower binding energy with CDK 6 than PAL. Furthermore, the cocrystal PAL-KAE exhibits excellent stability in long-term testing, accelerated testing and stressing test. This paper provides a promising strategy for improving the tabletability of PAL and enhancing its anticancer activity, thus reducing the dose-related side effects of PAL.(c) 2023 Elsevier B.V. All rights reserved.