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

• Published in: Journal of molecular structure 2023-06, Vol.1281, p.135101, Article 135101
• Main Authors: Zhou, Huiling, Duan, Chenxin, Qin, Huimin, Huang, Chaonan, Hou, Jingxuan, Chen, Yanming, Zhu, Jin, Xu, Cangcang, Jin, Jian, Zhuang, Tao
• Format: Article
• Language: English
• Subjects: Characterization; Kaempferol; Palbociclib; Synergistic anticancer activity; Tabletability
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2023.135101

•A novel palbociclib-kaempferol (PAL-KAE) cocrystal was synthesized by antisolvent cocrystallization.•The obtained PAL-KAE cocrystal was characterized comprehensively by SCXRD, PXDR, DSC, FT-IR, SEM, HS, and MEP.•The tabletability of palbociclib was improved through cocrystallization with kaempferol.•PAL-KAE cocrystal showed significantly improved antitumor activity than PAL and KAE over OVCAR3. Palbociclib (PAL), a highly selective inhibitor of cell cycle protein-dependent kinases (CDK) 4/6, is primarily 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 reduce its effective dose, a flavonoid–kaempferol (KAE) was selected as the coformer to synthesize cocrystal with PAL. The novel cocrystal PAL-KAE was prepared by antisolvent cocrystallization and characterized 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 experiments 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. [Display omitted]