Solubility Enhancement of Anticancer Drug Belinostat via the Co-crystallization Strategy: Synthesis, Characterization, and Antitumor Activity In Vitro Evaluation

Belinostat (PXD101), a biopharmaceutical classification system II (BCSII) drug approved for treating refractory T-cell lymphoma, is currently administered by intravenous injection. To improve patient compliance, the development of oral formulations of PXD101 has attracted attention. Because the solubility and dissolution rate of active pharmaceutical ingredients can affect the therapeutic effect of the oral formulations, this work explores solid-state form modification of PXD101 by co-crystallization with four coformers, namely, theophylline, isonicotinamide (INA), isoniazid (INH), and L-proline (L-Pro) to solve the problem of poor water solubility. The four cocrystals were obtained on the basis of N-H center dot center dot center dot O, O-H center dot center dot center dot O, and O-H center dot center dot center dot N synthons. All the four obtained multicomponent crystals were characterized by powder X-ray diffraction (PXRD) and thermal analysis, meanwhile, crystal structure determination was performed by single-crystal XRD. The results of CrystalCMP show the similar packing patterns of PXD101-INA and PXD101-INH cocrystals. The data analysis from powder dissolution experiments suggested that the apparent solubility of the obtained multicomponent crystals is 1.14-2.22 times more than that of PXD101, and PXD101-L-Pro shows a completely different dissolution behavior from that of the other three cocrystals. Finally, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay experiments demonstrated that the PXD101INA cocrystal can significantly inhibit the proliferation of Michigan Cancer Foundation-7 (MCF-7) cells even at a low concentration (0.01 mu M). Such results shed light on the potential value of multicomponent crystals in the further development of pharmaceutical products.

Automated summary

This study explores the solid-state form modification of Belinostat (PXD101) through co-crystallization with other substances to improve its water solubility and enhance the efficacy of oral formulations. The results show that the obtained multicomponent crystals have higher apparent solubility compared to PXD101 alone, with PXD101-INA cocrystal demonstrating significant inhibition of cancer cell proliferation even at low concentrations. These findings shed light on the potential of multicomponent crystals in the development of pharmaceutical products.