Polymorph Screening of the Antitumor Drug Ripretinib─Selective Preference of Dimer Synthons

Ripretinib is commercialized as a medication to treat patients suffering from advanced gastrointestinal stromal tumor. The USFDA-approved drug (2020) is highly water-insoluble and belongs to the biopharmaceutics classification system (BCS) class II category. Solid form screening was performed to initiate its structural landscape and establish thermodynamic relationship between the crystalline forms. This resulted in two anhydrous polymorphs (Forms 1 and 2), one hydrate, and a series of solvates with acetone, ethanol, isoamyl alcohol–water, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and tetrahydrofuran (THF)–water that were characterized by powder X-ray diffraction (XRD), vibrational spectroscopy (FT-IR), thermal analysis (DSC/TGA), and finally single-crystal XRD. Both Form 1 (Z′ = 2) and Form 2 (Z′ = 1) constitute an N–H···O (mono/bifurcated) hydrogen-bonded centrosymmetric dimer. They are designated as packing polymorphs. Note that there is also a minor conformational difference observed in the N-methyl fraction of the polymorphs. Interestingly, all the crystalline solid forms of the drug maintain a robust N–H···O H-bonded dimer in the polymorphs as well as solvates that was supported by a similar CO vibration. Comparatively, the acetone, ethanol, isoamyl alcohol–water, and THF–water solvates transformed to Form 1 following desolvation. Form 1 is supposed to be the thermodynamically most stable form based on its higher crystal density, melting point/enthalpy of fusion, and lower solubility compared to Form 2. Among the Forms 1 and 2 and hydrate, the hydrate was more soluble in pure ethanol than the anhydrous forms and their solubility order is hydrate > Form 2 > Form 1.