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

Abstract

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.

Assemblies of Sulfathiazole- and Sulfamethazine-Derived Thiourea: Polymorphs, Solvates, and Fluoride Detection

“…The homodimer formation may be suggested to be an extended domain formation, which helps in better packing arrangements through a gain in considerable amounts of energy. Polymorphic systems based on different homodimers are available in the literature …”

A Peptoid-like Approach Led to Lactam–Lactam Dimer Formation in 2-Hydroxy-N-alkyl-N-phenyl-nicotinamides and Their Polymorphism and Solvatomorphism

“…To answer these questions, crystals were grown in a variety of apolar, polar aprotic, and polar protic solvents. Solvatomorphism − was observed in compounds 1 and 2 , and polymorphism was revealed in compounds 3 and 4 . The dominant synthon observed in all four molecules is the LLD.…”

Structural analysis of anti-retroviral drug raltegravir and its potential impurity C: investigation of solubility and stability

“…It is very important for pharmaceutical companies to find the most stable and suitable polymorphic form before formulation and commercialization in order to avoid setbacks in the later stages of drug development. 4 Evaluation and control of impurities during synthesis of a drug is very challenging for the development team as impurities may cause serious side effects to the patients and their presence is generally not recommended. 5 Recently, at least ten drugs such as ranitidine, irbesartan, losartan, metformin, nizatidine, rifampin, quinapril, sitagliptin, varenicline and valsartan were recalled from the market due to carcinogenic nitrosoamine impurities.…”