Study On Improving Water Solubility Of Rucaparib By Co-crystallization Technology

In the pharmaceutical field,only a few active pharmaceutical ingredients（APIs）can be successfully developed and marketed.Many candidate drugs with pharmacological activities are facing elimination due to the defects of physicochemical properties.Therefore,improving the physicochemical properties of API is an important challenge in the process of drug research and development.Pharmaceutical cocrystallization is based on crystal engineering strategy,which refers to the phenomenon that API and cocrystallization co formers（CCFs）are combined to form multicomponent crystals through hydrogen bonds and other non-covalent bonds.Cocrystallization can directionally regulate the solid form of drugs by the designing hydrogen bonded supramolecular synthons.Rucaparib,developed by Clovis tumor company,is the second approved PARP inhibitor which can be used for the treatment of patients with ovarian cancer.Rucaparib was developed in the form of its camphorsulfonate,which has poor water solubility（less than 0.25 mg/mL）and high oral dose（600 mg/d）,causing great toxic and side effects.In order to develop new solid forms of rucaparib and improve its water solubility,cocrystallization research was carried out on rucaparib.Herein,a variety of salt forms of rucaparib,including rucaparib adipate（1:1）,rucaparib heptanoate（1:1）,rucaparib fumarate（2:1）and its hydrate（2:1:5）,and multiple polymorphs of rucaparib succinate,were prepared by liquid-assisted grinding,slurry and solution evaporation methods.The salt forms were fully characterized by powder X-ray diffraction,thermal analysis,infrared spectroscopy and nuclear magnetic resonance spectroscopy,and the crystal structures of the salts were analyzed by single crystal X-ray diffraction.In addition,the powder dissolution experiment,dynamic vapor sorption experiment,and stability test were carried out with rucaparib camphorsulfonate as the control group.The results show that the dissolution property of the salts is improved in varying degrees compared with the commercial form;The salts hygroscopicity of rucaparib adipate and rucaparib heptanoate are better than the commercial form.The stability of the salts is similar to the commercial form except for rucaparib fumarate and rucaparib succinate form Ⅱ,which can be converted into the hydrates form under accelerated stability test condition.In this study,several new solid forms of rucaparib were synthesized based on cocrystallization technology,which can effectively improve the aqueous solubility of rucaparib,and provide a research basis for reducing the oral dose of rucaparib and developing its improved preparation.