Two Cocrystals of Olaparib with Flavonoids toward Sustained Release: Structure, Dissolution Behavior, and Anticancer Activity Analysis

As the first FDA-approved PARP1/2 inhibitor, olaparib (OLA) is a blockbuster anticancer drug, but its use has been limited by the dose-limiting toxicity and short half life of commercially available immediate-release preparations. To realize the sustained release of OLA, the cocrystal of OLA with kaempferol (KAE) and the cocrystal solvate of OLA with quercetin (QUE) were screened and obtained in this study. The cocrystals were characterized by X-ray diffraction, Hirshfeld surface, thermal analysis, and spectroscopic analysis. Intrinsic dissolution rate (IDR) experiments showed that the IDR values of both OLA- KAE and OLA-QUE were 0.40 times that of pure OLA. In dissolution experiments, the dissolution of OLA-KAE and OLA-QUE in pH 6.8 medium was reduced to 21.4% and 18.6% of the original drug, respectively. The stability test indicates that OLA- KAE has excellent physical stability under accelerated conditions for 3 months. Moreover, OLA-KAE and OLA-QUE showed significantly increased inhibiting effects on ovarian cancer cells compared to OLA in MTT assays. This work provides a promising approach for developing sustained-release formulations of OLA via cocrystallization with enhanced pharmacological activity.