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Rucaparib cocrystal: Improved solubility and bioavailability over camsylate
Mengyuan Xia1, Yihua Jiang1, Yinxiang Cheng1
1Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555, Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A, Yuquan Road, Beijing 100049, China.
Cocrystallization significantly improved the oral bioavailability of rucaparib (Ruc), a drug for BRCA-mutated ovarian cancer. The new rucaparib-theophylline monohydrate cocrystal showed enhanced solubility and pharmacokinetic properties compared to the original formulation.
Area of Science:
- Pharmaceutical Science
- Drug Delivery
- Materials Science
Background:
- Rucaparib (Ruc) treats advanced ovarian cancer with BRCA mutations.
- The commercial camsylate salt (Ruc-Cam) has poor aqueous solubility, leading to low oral bioavailability.
- Improving Ruc oral exposure is crucial for effective cancer therapy.
Purpose of the Study:
- To enhance the oral bioavailability of rucaparib through cocrystallization.
- To develop novel solid forms of rucaparib with improved physicochemical properties.
- To investigate the potential of cocrystals in overcoming drug absorption challenges.
Main Methods:
- Cocrystal screening using liquid-assisted grinding, slurry, and solvent evaporation.
- Characterization of cocrystals via Powder X-ray diffraction, FTIR, TGA, DSC, and DVS.
- In vitro dissolution studies at varying pH levels.
- Pharmacokinetic evaluation in rat models.
Main Results:
- Successfully prepared rucaparib cocrystals with theophylline monohydrate (Ruc-Thp MH), maltol (Ruc-Mal), and ethyl maltol (Ruc-Emal).
- All cocrystals exhibited faster dissolution than Ruc-Cam at pH 2.0 and 4.5.
- Ruc-Thp MH demonstrated superior apparent solubility in pH 4.5 and 6.8 buffers.
- Ruc-Thp MH showed a 2.4-fold increase in Cmax and 1.4-fold increase in AUC0-24h compared to Ruc-Cam in rats.
Conclusions:
- Cocrystallization is an effective strategy to enhance the solubility and oral bioavailability of rucaparib.
- Rucaparib-theophylline monohydrate (Ruc-Thp MH) represents a promising solid form for improved rucaparib drug delivery.
- This approach offers a viable solution for addressing absorption issues in poorly soluble drugs like rucaparib.
