Novel Conformational Polymorph and Mixed Solvates of Anti-tumor Drug Ripretinib: Selection of High Soluble and Stable Mixed Solvate

Ripretinib (hereafter RIP) is an antitumor drug that is practically insoluble in water and belongs to the BCS class II category. In addition to the reported two polymorphs (Forms 1 and 2), a novel anhydrous Form 3 ( Z ′ = 2), along with three other solvates, including mixed solvate hydrates, is structurally investigated. Form 3 is conformationally distinguishable from the reported polymorphs. However, it retained the robust centrosymmetric hydrogen-bonded dimer between the urea NH groups and the carbonyl group of the naphthyridine ring, identical to Forms 1 and 2. The novel Form 3 ( Z ′ = 2) was crystallized during cocrystallization attempted with l -serine and l -threonine. In addition to the reported seven RIP solvates, three additional novel solvates with acetone (2:0.8), mixed hydrated solvates with MeOH (1:0.6:0.4) and isopropanol (1:1:0.5) with variable stoichiometry are structurally confirmed. Although Form 3 crystallization was challenging, a bulk amount was prepared through the desolvation of RIP-MeOH-water solid phase. All the novel solid forms were additionally characterized by PXRD, FT-IR, and DSC/TGA techniques. Solubility studies of the RIP solid forms in a 75% EtOH-water medium confirmed the superior solubility and stability of RIP-water-2PrOH mixed solvate compared to others. On the other hand, Form 3 exhibited a 6-fold higher dissolution rate before transforming to the stable commercial form. The ground-state-optimized energies of RIP polymorphs suggest the stability order as Form 1 > Form 3 > Form 2. The dissolution of the RIP solid forms is correlated with the “L” shape conformation compared to the “V” one.