Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione

Abstract

Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione are disclosed. Compositions comprising the polymorphic forms, methods of making the polymorphic forms and methods of their use are also disclosed.

1 - 28 . (canceled) 
     
     
         29 . A method of treating multiple myeloma which comprises administering to a patient a composition comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ. 
     
     
         30 . The method of  claim 29 , wherein the composition further comprises amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         31 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative differential scanning calorimetry thermogram provided in  FIG. 4 . 
     
     
         32 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative thermal gravimetric analysis curve provided in  FIG. 4 . 
     
     
         33 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative infrared spectrum provided in  FIG. 2 . 
     
     
         34 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative Raman spectrum provided in  FIG. 3 . 
     
     
         35 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that does not exhibit a significant weight gain from 5% to 95% relative humidity. 
     
     
         36 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative moisture sorption/desorption isotherm provided in  FIG. 5 . 
     
     
         37 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the solubility curve provided in  FIG. 51 . 
     
     
         38 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 1 . 
     
     
         39 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that has a differential scanning calorimetry thermogram having an endotherm at approximately 270° C. 
     
     
         40 . The method of  claim 29 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that has a thermogravimetric analysis curve indicative of an unsolvated material. 
     
     
         41 . The method of  claim 30 , wherein the composition comprises:
 a) less than 50% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 50% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         42 . The method of  claim 30 , wherein the composition comprises:
 a) less than 25% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 75% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         43 . The method of  claim 30 , wherein the composition comprises:
 a) less than 10% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 90% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione-having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         44 . The method of  claim 30 , wherein the composition comprises:
 a) less than 5% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 95% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         45 . A method of treating myelodysplastic syndromes which comprises administering to a patient a composition comprising 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ. 
     
     
         46 . The method of  claim 45 , wherein the composition further comprises amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         47 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative differential scanning calorimetry thermogram provided in  FIG. 4 . 
     
     
         48 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative thermal gravimetric analysis curve provided in  FIG. 4 . 
     
     
         49 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative infrared spectrum provided in  FIG. 2 . 
     
     
         50 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative Raman spectrum provided in  FIG. 3 . 
     
     
         51 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that does not exhibit a significant weight gain from 5% to 95% relative humidity. 
     
     
         52 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative moisture sorption/desorption isotherm provided in  FIG. 5 . 
     
     
         53 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the solubility curve provided in  FIG. 51 . 
     
     
         54 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 1 . 
     
     
         55 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that has a differential scanning calorimetry thermogram having an endotherm at approximately 270° C. 
     
     
         56 . The method of  claim 45 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that has a thermogravimetric analysis curve indicative of an unsolvated material. 
     
     
         57 . The method of  claim 46 , wherein the composition comprises:
 a) less than 50% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 50% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         58 . The method of  claim 46 , wherein the composition comprises:
 a) less than 25% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 75% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         59 . The method of  claim 46 , wherein the composition comprises:
 a) less than 10% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 90% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione-having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         60 . The method of  claim 46 , wherein the composition comprises:
 a) less than 5% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 95% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ.   
     
     
         61 . A method of treating multiple myeloma which comprises administering to a patient a composition comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate. 
     
     
         62 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 16, 22, and 27 degrees 2θ. 
     
     
         63 . The method of  claim 62 , wherein the crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate has an X-ray powder diffraction pattern further comprising a peak at approximately 18 degrees 2θ. 
     
     
         64 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 15.8, 22.2, and 26.7 degrees 2θ. 
     
     
         65 . The method of  claim 64 , wherein the crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate has an X-ray powder diffraction pattern further comprising a peak at approximately 18.2 degrees 2θ. 
     
     
         66 . The method of  claim 61 , wherein the composition further comprises amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         67 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 6 . 
     
     
         68 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 32 . 
     
     
         69 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 33 . 
     
     
         70 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 34 . 
     
     
         71 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at about 268° C. 
     
     
         72 . The method of  claim 71 , wherein the thermogram further comprises an endotherm corresponding to dehydration. 
     
     
         73 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 9 . 
     
     
         74 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 42 . 
     
     
         75 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 43 . 
     
     
         76 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 44 . 
     
     
         77 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has between approximately 0.46 and approximately 0.59 moles of water per mole of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         78 . The method of  claim 61 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a thermal gravimetric analysis curve comprising a weight loss of between about 3.1% and about 4.0% when heated from about 30° C. to about 175° C. 
     
     
         79 . The method of  claim 66 , wherein the composition comprises:
 a) less than 50% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 50% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         80 . The method of  claim 66 , wherein the composition comprises:
 a) less than 25% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 75% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         81 . The method of  claim 66 , wherein the composition comprises:
 a) less than 10% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 90% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         82 . The method of  claim 66 , wherein the composition comprises:
 a) less than 5% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 95% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         83 . A method of treating myelodysplastic syndromes which comprises administering to a patient a composition comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate. 
     
     
         84 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 16, 22, and 27 degrees 2θ. 
     
     
         85 . The method of  claim 84 , wherein the crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate has an X-ray powder diffraction pattern further comprising a peak at approximately 18 degrees 2θ. 
     
     
         86 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 15.8, 22.2, and 26.7 degrees 2θ. 
     
     
         87 . The method of  claim 86 , wherein the crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate has an X-ray powder diffraction pattern further comprising a peak at approximately 18.2 degrees 2θ. 
     
     
         88 . The method of  claim 83 , wherein the composition further comprises amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         89 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 6 . 
     
     
         90 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 32 . 
     
     
         91 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 33 . 
     
     
         92 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 34 . 
     
     
         93 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at about 268° C. 
     
     
         94 . The method of  claim 93 , wherein the thermogram further comprises an endotherm corresponding to dehydration. 
     
     
         95 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 9 . 
     
     
         96 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 42 . 
     
     
         97 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 43 . 
     
     
         98 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 44 . 
     
     
         99 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has between approximately 0.46 and approximately 0.59 moles of water per mole of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         100 . The method of  claim 83 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate that has a thermal gravimetric analysis curve comprising a weight loss of between about 3.1% and about 4.0% when heated from about 30° C. to about 175° C. 
     
     
         101 . The method of  claim 88 , wherein the composition comprises:
 a) less than 50% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 50% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         102 . The method of  claim 88 , wherein the composition comprises:
 a) less than 25% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 75% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         103 . The method of  claim 88 , wherein the composition comprises:
 a) less than 10% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 90% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         104 . The method of  claim 88 , wherein the composition comprises:
 a) less than 5% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 95% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.   
     
     
         105 . A method of treating multiple myeloma which comprises administering to a patient a composition comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate. 
     
     
         106 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 20, 24.5, and 29 degrees 2θ. 
     
     
         107 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 20.0, 24.7, and 28.6 degrees 2θ. 
     
     
         108 . The method of  claim 105 , wherein the composition further comprises amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         109 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 23 . 
     
     
         110 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 35 . 
     
     
         111 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at about 269° C. 
     
     
         112 . The method of  claim 111 , wherein the thermogram further comprises an endotherm at about 99° C. 
     
     
         113 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 24 . 
     
     
         114 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 45 . 
     
     
         115 . The method of  claim 105 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a thermal gravimetric analysis curve comprising a weight loss of about 12% up to about 175° C. 
     
     
         116 . The method of  claim 108 , wherein the composition comprises:
 a) less than 50% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 50% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.   
     
     
         117 . The method of  claim 108 , wherein the composition comprises:
 a) less than 25% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 75% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.   
     
     
         118 . The method of  claim 108 , wherein the composition comprises:
 a) less than 10% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 90% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.   
     
     
         119 . The method of  claim 108 , wherein the composition comprises:
 a) less than 5% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 95% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.   
     
     
         120 . A method of treating myelodysplastic syndromes which comprises administering to a patient a composition comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate. 
     
     
         121 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 20, 24.5, and 29 degrees 2θ. 
     
     
         122 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has an X-ray powder diffraction pattern comprising peaks at approximately 20.0, 24.7, and 28.6 degrees 2θ. 
     
     
         123 . The method of  claim 120 , wherein the composition further comprises amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         124 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 23 . 
     
     
         125 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that corresponds to the representative X-ray powder diffraction pattern provided in  FIG. 35 . 
     
     
         126 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at about 269° C. 
     
     
         127 . The method of  claim 126 , wherein the thermogram further comprises an endotherm at about 99° C. 
     
     
         128 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 24 . 
     
     
         129 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a differential scanning calorimetry thermogram corresponding to the representative differential scanning calorimetry thermogram provided in  FIG. 45 . 
     
     
         130 . The method of  claim 120 , comprising crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate that has a thermal gravimetric analysis curve comprising a weight loss of about 12% up to about 175° C. 
     
     
         131 . The method of  claim 123 , wherein the composition comprises:
 a) less than 50% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 50% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.   
     
     
         132 . The method of  claim 123 , wherein the composition comprises:
 a) less than 25% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 75% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.   
     
     
         133 . The method of  claim 123 , wherein the composition comprises:
 a) less than 10% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 90% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.   
     
     
         134 . The method of  claim 123 , wherein the composition comprises:
 a) less than 5% by weight of amorphous 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione; and   b) greater than 95% by weight of crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione dihydrate.