Claims for Patent: 11,072,614

Summary for Patent: 11,072,614

Title:	Polymorphs of sepiapterin and salts thereof
Abstract:	Disclosed are crystalline forms of sepiapterin free base selected from polymorphs A, B, C, D, E, F, and G, and combinations thereof, as well as crystalline polymorphs of salts of sepiapterin. Also disclosed are pharmaceutical compositions containing one or more such polymorphs and methods for preparing such polymorphs. Sepiapterin is useful in the treatment of a number diseases associated with low cellular levels of BH4, for example, phenylketonuria.
Inventor(s):	Daniel E. Levy
Assignee:	PTC Therapeutics MP Inc
Application Number:	US16/464,771
Patent Claims:	1. Crystalline Form B of sepiapterin free base having peaks at diffraction angle 2θ (°) of 8.4°±0.5, 14.9°±0.5, 16.9°±0.5, 25.4°±0.5, and 34.1°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 2. Crystalline Form C of sepiapterin free base having peaks at diffraction angle 2θ (°) of 5.7°±0.5, 7.8°±0.5, 9.1°±0.5 11.5°±0.5, and 25.4°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 3. Crystalline Form D of sepiapterin free base having peaks at diffraction angle 2θ (°) of 8.9°±0.5, 10.3°±0.5, 10.9°±0.5, 26.0°±0.5, and 26.8°±0.5, as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 4. Crystalline Form F of sepiapterin free base having peaks at diffraction angle 2θ (°) of 9.7°±0.5, 10.2°±0.5, and 11.3°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 5. Crystalline Form F of sepiapterin free base of claim 4 having peaks at diffraction angle 2θ (°) of 9.7°±0.5, 10.2°±0.5, 11.3°±0.5, 14.0°±0.5, 14.6°±0.5, 19.9°±0.5, 22.2°±0.5, 25.3°±0.5, and 32.4°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 6. Crystalline Form F of sepiapterin free base of claim 4 having the X-ray powder diffraction spectrum as shown in FIG. 4. 7. Crystalline Form F of sepiapterin free base of claim 4 having an endotherm at about 72° C. or 233° C. in differential scanning calorimetry (DSC) profile. 8. Crystalline Form F of sepiapterin free base of claim 4 having an endotherm at about 72° C. and 233° C. in differential scanning calorimetry (DSC) profile. 9. Crystalline Form G of sepiapterin free base having peaks at diffraction angle 2θ (°) of 10.0°±0.5, 10.6°±0.5, 15.3°±0.5, 24.4°±0.5, 25.7°±0.5, and 26.6°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 10. A pharmaceutical composition comprising the crystalline Form F of sepiapterin free base of claim 4 and a pharmaceutically acceptable carrier. 11. The pharmaceutical composition of claim 10, wherein the crystalline Form F of sepiapterin free base is formulated as particles less than 100 μm in size. 12. The pharmaceutical composition of claim 10, wherein the crystalline Form F of sepiapterin free base is present in an amount of at least 90 percent by weight of the composition. 13. A method for preparing a crystalline form of sepiapterin free base comprising preparing a slurry of a first crystalline form of sepiapterin in water, acetone/water, isopropanol/isopropyl acetate, or tetrahydrofuran/n-hexane, isolating crystalline Form D of sepiapterin free base from the slurry, and drying the crystalline Form D. 14. A crystalline form of a salt of sepiapterin, wherein the crystalline form of a salt of sepiapterin is selected from the group consisting of: (a) a crystalline form of the methanesulfonate salt of sepiapterin having at least one peak at diffraction angle 2θ °(of 7.9°±0.5, 23.5°±0.5, and 29.0°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (b) a crystalline form of the methanesulfonate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 21.7°±0.5, 26.1°±0.5, and 28.9°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry (c) a crystalline form of the nicotinate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 9.5°±0.5, 9.9°±0.5, and 24.5°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (d) a crystalline form of the p-toluenesulfonate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 6.5°±0.5, 15.1°±0.5, and 23.4°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (e) a crystalline form of the benzenesulfonate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 6.5°±0.5, 14.8°±0.5, and 19.6°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (f) a crystalline form of the phosphate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 16.6°±0.5, 22.2°±0.5, and 25.6°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (g) a crystalline form of the malonate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 6.9°±0.5, 22.7°±0.5, and 23.8°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (h) a crystalline form of the tartrate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 7.4°±0.5, 14.2°±0.5, and 21.8°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (i) a crystalline form of the gentisate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 7.1°±0.5, 8.7°±0.5, and 26.7°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (j) a crystalline form of the fumarate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 11.4°±0.5, 24.0°±0.5, and 28.3°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (k) a crystalline form of the glycolate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 7.6°±0.5, 10.7°±0.5, and 24.0°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (l) a crystalline form of the acetate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 6.2°±0.5, 12.0°±0.5, and 18.1°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; (m) a crystalline form of the sulfate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 5.1°±0.5, 7.8°±0.5, and 23.0°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry; and (n) a crystalline form of the sulfate salt of sepiapterin having at least one peak at diffraction angle 2θ (°) of 7.9°±0.5, 8.8°±0.5, and 24.2°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 15. A method for treating primary tetrahydrobiopterin deficiency in a patient in need thereof, the method comprising administering to the patient an effective amount of crystalline Form F of sepiapterin free base of claim 4. 16. A method of decreasing phenylalanine levels in a patient in need thereof, the method comprising administering to the patient an effective amount of crystalline Form F of sepiapterin free base of claim 4. 17. A method of treating phenylketonuria in a patient in need thereof, the method comprising administering to the patient an effective amount of crystalline Form F of sepiapterin free base of claim 4. 18. A method of preparing a liquid formulation comprising dispersing crystalline Form F of sepiapterin free base of claim 4 in a liquid. 19. The method of claim 18, wherein the liquid formulation is a suspension. 20. The method of claim 13, further comprising drying crystalline Form D at 40-60° C. for 5-10 hours to produce crystalline Form F of sepiapterin free base. 21. Crystalline Form D of sepiapterin free base of claim 3 having peaks at diffraction angle 2θ (°) of 8.9°±0.5, 10.3°±0.5, 10.9°±0.5, 17.8°±0.5, 24.9°±0.5, 26.0°±0.5, 26.7°±0.5, 26.8°±0.5, and 28.3°±0.5 as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 22. Crystalline Form D of sepiapterin free base of claim 3 having the X-ray powder diffraction spectrum as shown in FIG. 3. 23. Crystalline Form D of sepiapterin free base of claim 3 having an endothermic onset at about 43° C., 66° C., or 233° C. in differential scanning calorimetry (DSC) profile. 24. Crystalline Form D of sepiapterin free base of claim 3 having an endothermic onset at about 43° C., 66° C., and 233° C. in differential scanning calorimetry (DSC) profile. 25. Crystalline Form F of sepiapterin free base having peaks at diffraction angle 2θ (°) of about 9.7°, about 10.2°, and about 11.3° as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 26. Crystalline Form F of sepiapterin free base of claim 25 having peaks at diffraction angle 2θ (°) of about 9.7°, about 10.2°, about 11.3°, about 14.0°, about 14.6°, about 19.9°, about 22.2°, about 25.3°, and about 32.4° as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 27. Crystalline Form D of sepiapterin free base having peaks at diffraction angle 2θ (°) of about 8.9°, about 10.3°, and about 26.0° as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 28. Crystalline Form D of sepiapterin free base of claim 27 having peaks at diffraction angle 2θ (°) of about 8.9°, about 10.3°, about 10.9°, about 26.0°, and about 26.8° as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 29. Crystalline Form D of sepiapterin free base of claim 27 having peaks at diffraction angle 2θ (°) of about 8.9°, about 10.3°, about 10.9°, about 17.8°, about 24.9°, about 26.0°, about 26.7°, about 26.8°, and about 28.3° as measured by X-ray diffractometry by irradiation with Cu Kα X-rays or calculated from X-ray diffractometry. 30. A pharmaceutical composition comprising the crystalline Form F of sepiapterin free base of claim 5 and a pharmaceutically acceptable carrier.