Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof

Abstract

The present invention provides crystals, and compositions thereof, wherein the crystals include 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. Methods of preparing such crystals are also disclosed.

What is claimed is:  
     
         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 3   1 , 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.