New Multicomponent Solid Forms of the Antitumor Drug Ripretinib: The Role of Conformations in Dictating Dissolution and Photostability

Ripretinib (RIP), a medication to treat gastrointestinal stromal tumors, possesses very poor aqueous solubility and bioavailability and is prone to degrade under sunlight. In order to overcome the bottlenecks of the drug, salt screening was performed that resulted in hydrochloride, acetate, 2,6-dihydroxybenzoate, and ferulate salts, along with a solvate with formic acid and an unexpected methanol solvate. The new multicomponent solids were characterized by PXRD, DSC, TGA, FT-IR, and SC-XRD. In all these RIP multicomponent solids, the N-H···O hydrogen-bonded centrosymmetric dimer involving urea NH groups and the carbonyl group of the naphthyridine ring is consistent as the reported polymorphs and solvates. In RIP salts, a proton is transferred from the acid to the N-methyl pyridine fraction of the RIP. Even though formic acid is a stronger acid than acetic acid, RIP-formic acid (1:2) is crystallized as a cocrystal (solvate), whereas the RIP acetate acetic acid salt hydrate (1:1:2:1) is crystallized as a mixed ionized state. RIP-2,6-dihydroxybenzoate is crystallized as a solvate (or hydrate), whereas RIP-ferulate forms an anhydrous phase. Solubility experiments in 75% EtOH-water medium indicated that the HCl salt improved up to 4-fold solubility, whereas the RIP-2,6-dihydroxybenzoate and ferulate salts exhibited comparable solubility as the native drug. Similarly, RIP-HCl salt offered 1.5-fold improved chemical stability during photolysis compared to the native drug. The improved solubility and chemical stability of the RIP multicomponent solids are partially correlated to the extended conformation of the native drug and their melting points.