Rucaparib cocrystal: Improved solubility and bioavailability over camsylate

[Display omitted] 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 improv...

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Bibliographic Details
Published in:International journal of pharmaceutics 2023-01, Vol.631, p.122461-122461, Article 122461
Main Authors: Xia, Mengyuan, Jiang, Yihua, Cheng, Yinxiang, Dai, Wenjuan, Rong, Xiaoyi, Zhu, Bingqing, Mei, Xuefeng
Format: Article
Language:English
Subjects:
Animals
Bioavailability
Biological Availability
Calorimetry, Differential Scanning
Chemical Phenomena
Cocrystal
Crystallization - methods
Dissolution
Powder Diffraction
Rats
Rucaparib
Solubility
Spectroscopy, Fourier Transform Infrared - methods
X-Ray Diffraction
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Summary:[Display omitted] 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 spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption were utilized 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 cocrystallization in addressing absorption issues in drug development.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2022.122461