Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with multiple tumor supporting effects, including angiogenesis and immunosuppression. The increase of TGF-β expression is closely related to the progression of various tumors and poor clinical prognosis. Expression of TGF-β promotes tumor growth, inhibits the immune system, and enhances tumor spread.
Galunisertib (LY-2157299) is a TGF-β kinase inhibitor developed by Eli Lilly, which has the potential to treat myelodysplastic syndromes and solid tumors. The chemical name of Galunisertib is 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, and the structure is shown in formula I.

Polymorph or polymorphism is a particular property of certain molecule and molecular composition. Different crystalline forms of certain compounds arise from different molecular packing in the crystal lattice, and these crystalline forms have different crystal structures and physical properties, such as solubility; stability, thermal property, mechanical property, purification capability, X-ray diffraction pattern, infrared absorption spectroscopy, Raman spectroscopy, solid state nuclear magnetic resonance, etc. One or more analytical techniques can be used to distinguish different crystalline forms of the same molecule or molecular composition.
Novel crystalline forms (including anhydrates, hydrates and solvates) of the active pharmaceutical ingredients may offer better processing and physicochemical properties, such as bioavailability, stability, processability, and purification ability. Some novel crystalline forms may serve as intermediate crystal forms to facilitate solid state transformation to desired forms. Novel polymorphs of raw materials provide more solid forms in the formulation, and this can improve dissolution, improve shelf life, and make it easier to process.
A monohydrate crystalline form of Galunisertib (designated as Form 1 in the present disclosure) was disclosed in the patent application WO2007018818A1, which is hereby incorporated by reference. The X-ray powder diffraction pattern of Form 1 shows one or more characteristic peaks at 2theta values of 9.05°, 11.02°±0.1°, 11.95°±0.1°, and 14.84°±0.1°. However, the inventors of the present disclosure found an anhydrous crystalline form of Galunisertib (hereinafter referred to as Form A) during the research. The X-ray powder diffraction pattern of Form A shows characteristic peaks at 2theta values of 22.0°±0.2°, 10.4°±0.2°, and 25.3°±0.2°. Compared with the monohydrate Form 1 of the prior art, it has been found that Form A of the present disclosure has better solubility, hygroscopicity and stability. When Form 1 and Form A are placed in 80% RH, Form 1 is slightly hygroscopic. While Form A is non-hygroscopic or almost non-hygroscopic. In particular, Form A has a significant improvement in solubility compared to Form 1 of the prior art. For example, in FaSSIF (Fasted state simulated intestinal fluids, pH=6.5), the solubility of Form A is ten times higher than that of Form 1 at 24 h. The increase in solubility is beneficial to reduce drug load and improve the bioavailability of the drug products. No form change was observed for Form A of the present disclosure after being placed at 40° C./75% RH for one year or mechanical grinding, which indicates that Form A has good stability. Good stability can effectively avoid crystal transformation during drug storage and development, thus avoiding changes in bioavailability and efficacy.
USPTO Backgrounds
USPTO Backgrounds