Drug−Drug Salts of Rucaparib with Nonsteroidal Anti-Inflammatory Drugs: Crystal Structures, Intermolecular Interactions, Solubility Enhancement, and Antitumor Activity

Abstract

Abstract Rucaparib (RUCA) is an orally administered PARP inhibitor with an important clinical value in cancer therapy, but its poor aqueous solubility remains a major challenge for improving its dissolution behavior and pharmaceutical performance. In this study, drug−drug salt formation was adopted to improve the physicochemical properties of RUCA by selecting three nonsteroidal anti-inflammatory drugs, namely, flurbiprofen (FLU), ibuprofen (IBU), and naproxen (NAP), as salt-forming components. Three salts (RUCA-FLU, RUCA-IBU, and RUCA-NAP) were successfully obtained, and their structures and solid-state properties were systematically characterized by X-ray diffraction analysis, thermal analysis, FT-IR, 1H NMR, Hirshfeld surface analysis, independent gradient model based on Hirshfeld partition (IGMH) analysis, molecular electrostatic potential, and HOMO−LUMO. Structural results confirmed that three salts were formed through acid−base proton transfer with lattice stabilization arising from multiple N−H···O hydrogen-bonding interactions. Among them, RUCA-NAP showed the best overall performance, exhibiting a RUCA solubility 2.78-fold that of free RUCA and a cumulative dissolution percentage 1.66-fold that of free RUCA in water. All salts exhibited acceptable solid-state stability during the 8 week long-term stability study. In vitro antitumor assays against J82 bladder cancer cells showed that RUCA-FLU and RUCA-NAP displayed 3.38-fold and 1.95-fold stronger cytotoxicity than that of RUCA, respectively. Overall, this work demonstrates that drug−drug salt formation is a robust approach for modulating the solid-state properties, dissolution behavior, and biological performance of RUCA.