Claims
- 1. An anhydrous crystal comprisng a malic acid salt of a compound having the structure:
- 2. The crystal of claim 1, wherein the malic acid is L-malic acid.
- 3. An anhydrous crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
- 4. A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has characteristic diffraction peaks at about 13.2 and 24.2 degrees two-theta in a powder X-ray diffraction pattern.
- 5. The crystal of claim 4 having characteristic diffraction peaks at about 13.2, 19.4, 24.2, and 25.5 degrees two-theta in a powder X-ray diffraction pattern.
- 6. The crystal of claim 5 having characteristic diffraction peaks in a powder X-ray diffraction pattern as listed in Table 1 for Crystal Form I.
- 7. The crystal of claim 4 further comprising at most about 2% by weight water.
- 8. The crystal of claim 7 comprising at most about 0.5% by weight water.
- 9. The crystal of claim 8 comprising at most about 0.2% by weight water.
- 10. A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has a melting point of at least about 190° C.
- 11. The crystal of claim 10 having a melting point of at least about 195° C.
- 12. The crystal of claim 10 further comprising at most about 2% by weight water.
- 13. The crystal of claim 12 comprising at most about 0.5% by weight water.
- 14. The crystal of claim 13 comprising at most about 0.2% by weight water.
- 15. A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has characteristic diffraction peaks at about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
- 16. The crystal of claim 15 having characteristic diffraction peaks at about 3.0, 12.1, 14.5, and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
- 17. The crystal of claim 16 having characteristic diffraction peaks in a powder X-ray diffraction pattern as listed in Table 1 for Crystal Form II.
- 18. The crystal of claim 15, wherein the crystal absorbs at least about 5% by weight water upon exposure to 80% relative humidity.
- 19. A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has a melting point of at most about 185° C.
- 20. The crystal of claim 19, wherein the crystal absorbs at least about 5% by weight water upon exposure to 80% relative humidity.
- 21. A method of preparing an anhydrous crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the method comprising:
combining malic acid; N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide; and a solvent; and inducing the salt to crystallize under crystallization conditions comprising one or more factors comprising: a difference between the initial and final temperatures of the crystallization solution of at most about 100° C.; a rate of cooling of at most about 50° C. per hour; no seeding; a supersaturation ratio of at most about 10; no precipitant; and/or combinations thereof.
- 22. The method of claim 21, wherein the malic acid is L-malic acid.
- 23. The method of claim 21, wherein the one or more factors comprise: a difference between the initial and final temperatures of the crystallization solution of at most about 50° C.; a rate of cooling of at most about 20° C. per hour; a supersaturation ratio of at most about 5; and/or combinations thereof.
- 24. The method of claim 23, wherein the one or more factors comprise: a difference between the initial and final temperatures of the crystallization solution of at most about 25° C.; a rate of cooling of at most about 2° C. per hour; a supersaturation ratio of at most about 1.5; and/or combinations thereof.
- 25. The method of claim 24, wherein the initial and final temperatures of the crystallization solution are the same.
- 26. The method of claim 21, wherein the solvent is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, toluene, n-butanol, tetrahydrofuran, N,N-dimethylformamide, acetone, water, and combinations thereof.
- 27. The method of claim 21, wherein the anhydrous crystal has characteristic diffraction peaks at about 13.2 and 24.2 degrees two-theta in a powder X-ray diffraction pattern.
- 28. The crystal of claim 27 having characteristic diffraction peaks at about 13.2, 19.4, 24.2, and 25.5 degrees two-theta in a powder X-ray diffraction pattern.
- 29. The crystal of claim 28 having characteristic diffraction peaks in a powder X-ray diffraction pattern as listed in Table 1 for Crystal Form I.
- 30. A method of preparing an anhydrous crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the method comprising contacting a crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide with a solvent in which the contacting crystal has substantial solubility, wherein the contacting crystal has characteristic diffraction peaks at about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
- 31. The method of claim 30, wherein the contacting crystal has characteristic diffraction peaks at about 3.0, 12.1, 14.5, and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
- 32. The method of claim 31, wherein the contacting crystal has characteristic diffraction peaks in a powder X-ray diffraction pattern as listed in Table 1 for Crystal Form II.
- 33. The method of claim 30, wherein the solvent is selected from the group consisting of acetonitrile, ethanol, methanol, and combinations thereof.
- 34. The method of claim 30, wherein contacting the crystal with the solvent forms a slurry.
- 35. The method of claim 34 further comprising stirring the slurry.
- 36. The method of claim 34 further comprising heating the slurry.
- 37. The method of claim 34 further comprising removing the anhydrous crystal from the slurry.
- 38. The method of claim 30, wherein the anhydrous crystal has characteristic diffraction peaks at about 13.2 and 24.2 degrees two-theta in a powder X-ray diffraction pattern.
- 39. The method of claim 38, wherein the anhydrous crystal has characteristic diffraction peaks at about 13.2, 19.4, 24.2, and 25.5 degrees two-theta in a powder X-ray diffraction pattern.
- 40. The method of claim 39, wherein the anhydrous crystal has characteristic diffraction peaks in a powder X-ray diffraction pattern as listed in Table 1 for Crystal Form I.
- 41. A method of preparing a crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the method comprising:
combining malic acid; N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide; and a solvent; and inducing the salt to crystallize under crystallization conditions comprising one or more factors comprising: a difference between the initial and final temperatures of the crystallization solution of at least about 25° C.; a rate of cooling of at least about 25° C. per hour; seeding; a supersaturation ratio of at least about 2; presence of a precipitant; and/or combinations thereof.
- 42. The method of claim 41, wherein the malic acid is L-malic acid.
- 43. The method of claim 41, wherein the one or more factors comprise: a difference between the initial and final temperatures of the crystallization solution of at least about 50° C.; a rate of cooling of at least about 100° C. per hour; a supersaturation ratio of at least about 5; and/or combinations thereof.
- 44. The method of claim 43, wherein the one or more factors comprise: a difference between the initial and final temperatures of the crystallization solution of at least about 100° C.; a rate of cooling of at least about 300° C. per hour; a supersaturation ratio of at least about 10; and/or combinations thereof.
- 45. The method of claim 41, wherein the solvent is selected from the group consisting of methanol, water, tetrahydrofuran/water mixtures, and combinations thereof.
- 46. The method of claim 41, wherein the crystal has characteristic diffraction peaks at about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
- 47. The method of claim 46, wherein the crystal has characteristic diffraction peaks at about 3.0, 12.1, 14.5, and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
- 48. The method of claim 47, wherein the crystal has characteristic diffraction peaks in a powder X-ray diffraction pattern as listed in Table 1 for Crystal Form II.
- 49. A composition comprising anhydrous crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
- 50. The composition of claim 49 further comprising an excipient.
- 51. A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have characteristic diffraction peaks at about 13.2 and 24.2 degrees two-theta in a powder X-ray diffraction pattern.
- 52. A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have a melting point of at least about 190° C.
- 53. A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have characteristic diffraction peaks at about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
- 54. A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have a melting point of at most about 185° C.
Parent Case Info
[0001] This application claims the benefit of the U.S. Provisional Application Serial No. 60/312,353, filed Aug. 15, 2001, which is incorporated herein by reference in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60312353 |
Aug 2001 |
US |