Improving the physicochemical and pharmacokinetic properties of olaparib through cocrystallization strategy

Xia-Lin Dai; Bo-Wen Pang; Wen-Ting Lv; Jian-Feng Zhen; Lu Gao; Cai-Wen Li; Jing Xiong; Tong-Bu Lu; Jia-Mei Chen

doi:10.1016/j.ijpharm.2023.123497

Improving the physicochemical and pharmacokinetic properties of olaparib through cocrystallization strategy

Int J Pharm. 2023 Nov 25:647:123497. doi: 10.1016/j.ijpharm.2023.123497. Epub 2023 Oct 11.

Authors

Xia-Lin Dai¹, Bo-Wen Pang¹, Wen-Ting Lv¹, Jian-Feng Zhen², Lu Gao¹, Cai-Wen Li¹, Jing Xiong³, Tong-Bu Lu², Jia-Mei Chen⁴

Affiliations

¹ School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China.
² Institute for New Energy Materials and Low Carbon Technologies, School of Materials Science and Engineering, Tianjin University of Technology, Tianjin 300384, China.
³ National Institutes for Food and Drug Control, Beijing 102629, China. Electronic address: xiongjing@nifdc.org.cn.
⁴ School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China. Electronic address: chenjiamei@email.tjut.edu.cn.

PMID: 37827390
DOI: 10.1016/j.ijpharm.2023.123497

Abstract

Olaparib (OLA) is the first PARP inhibitor worldwide used for the treatment of ovarian cancer. However, the oral absorption of OLA is extremely limited by its poor solubility. Herein, pharmaceutical cocrystallization strategy was employed to optimize the physicochemical and pharmacokinetic properties. Four cocrystals of OLA with oxalic acid (OLA-OA), malonic acid (OLA-MA), fumaric acid (OLA-FA) and maleic acid (OLA-MLA) were successfully discovered and characterized. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirmed the formation of cocrystals rather than salts, and the possible hydrogen bonding patterns were analyzed through molecular surface electrostatic potential calculations. The in vitro and in vivo evaluations indicate that all of the cocrystals demonstrate significantly improved dissolution performance, oral absorption and tabletability compared to pure OLA. Among them, OLA-FA exhibit sufficient stability and the most increased C_max and AUC_0-24h values that were 11.6 and 6.1 times of free OLA, respectively, which has great potential to be developed into the improved solid preparations of OLA.

Keywords: Cocrystal; Dicarboxylic acid; Olaparib; Pharmacokinetic; Solubility.

MeSH terms

Chemical Phenomena
Crystallization / methods
Piperazines*
Solubility
X-Ray Diffraction

Substances

olaparib
Piperazines