Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
Described herein are certain crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one, as well as pharmaceutical compositions employing the crystalline forms. Also provided are particles (e.g., nanoparticles) comprising such crystalline forms or pharmaceutical compositions. In certain examples, the particles are mucus penetrating particles (MPPs). Also described are methods of treating and/or preventing diseases using the crystalline forms or pharmaceutical compositions described herein.
1. 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one in crystalline Form II, wherein the crystalline Form II has an X-ray powder diffraction (XRPD) pattern with peaks at about 8.44, 10.57, 14.92, 17.22, 21.26 and 22.42±0.2 degrees two theta, or 10.47, 8.36, 5.93, 5.15, 4.18 and 3.96±0.2 Å in d-spacing.
2. The crystalline Form II of claim 1 having the X-ray powder diffraction pattern as shown in FIG. 2 .
3. 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one in crystalline Form III, wherein the crystalline Form III has an X-Ray Powder Diffraction (XRPD) pattern with peaks at about 9.60, 10.45, 19.30, 19.71, 21.84, and 23.42±0.2 degrees two theta or 9.21, 8.46, 4.60, 4.50, 4.07 and 3.80±0.2 Å in d-spacing.
4. The crystalline Form III of claim 3 having the X-ray powder diffraction pattern as shown in FIG. 3 .
5. A process for preparing crystalline Form II of claim 1 , wherein said process comprises the steps of:
a) stirring a suspension of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one in water; and
b) isolating crystalline Form II from the suspension.
6. A process for preparing crystalline Form III of claim 3 , wherein said process comprises wet-milling an aqueous slurry comprising crystalline Form I of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and a non-ionic surfactant to obtain nanoparticles of crystalline Form III of the compound.
7. A pharmaceutical composition comprising:
a plurality of coated particles, comprising:
a core particle comprising a crystalline form of claim 1 , wherein the crystalline form constitutes at least about 80 wt % of the core particle; and
a coating comprising one or more surface-altering agents surrounding the core particle.
8. The pharmaceutical composition of claim 7 , wherein the one or more surface-altering agents comprises a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer.
9. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is suitable for topical administration, injection, delivery to the eye, oral administration, or inhalation.
10. A pharmaceutical composition comprising:
a plurality of coated particles, comprising:
a core particle comprising a crystalline form of claim 3 , wherein the crystalline form constitutes at least about 80 wt % of the core particle; and
a coating comprising one or more surface-altering agents surrounding the core particle.
11. The pharmaceutical composition of claim 10 , wherein the one or more surface-altering agents comprises a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer.
12. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is suitable for topical administration, injection, delivery to the eye, oral administration, or inhalation.
13. A method of treating an ocular disease comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form of claim 1 .
14. A method of treating an ocular disease comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form of claim 3 .
15. The method of claim 13 , wherein the ocular disease is retinopathy, age-related macular degeneration, corneal neovascularization, diabetic macular edema, or retinal vein occlusion.
16. The method of claim 14 , wherein the ocular disease is retinopathy, age-related macular degeneration, corneal neovascularization, diabetic macular edema, or retinal vein occlusion.