Rucaparib cocrystal: Improved solubility and bioavailability over camsylate

Rucaparib (Ruc) is a drug used to treat advanced ovarian cancer associated with deleterious BRCA mutations. Its commercial form, the camsylate salt (Ruc-Cam), suffers from poor aqueous solubility and thus causes low and erratic oral bioavailability. In this work, we aimed to improve the oral exposure of Ruc through cocrystallization. Liquid-assisted grinding, slurry, and solvent evaporation methods were employed to prepare new solid forms of Ruc. Cocrystals of rucaparib-theophylline monohydrate (Ruc-Thp MH), rucaparib-maltol (Ruc-Mal), and rucaparib-ethyl maltol (Ruc-Emal) were obtained. Powder X-ray diffraction, Fourier transform infrared spec-troscopy, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption were uti-lized to characterize these multi-component systems. All cocrystals dissolve faster than Ruc-Cam at pH 2.0 and 4.5, and Ruc-Thp MH displays the highest apparent solubility in pH 4.5 and 6.8 buffers. Pharmacokinetic studies in rats show that Ruc-Thp MH exhibits 2.4 times the Cmax and 1.4 times the AUC0-24h at a single dose compared with Ruc-Cam. The enhanced solubility and bioavailability of Ruc-Thp MH showcase the power of cocrystalli-zation in addressing absorption issues in drug development.

Automated summary

In this study, new solid forms of Ruc were prepared through cocrystallization to improve its oral exposure. The cocrystals of Ruc-Thp MH, Ruc-Mal, and Ruc-Emal were obtained and characterized. It was found that Ruc-Thp MH had higher solubility and bioavailability compared to Ruc-Cam.