Methods for isolating crystalline form I of 5-azacytidine
The invention includes methods for isolating crystalline Form I of 5-azacytidine substantially free of other forms, wherein 5-azacytidine is represented by the formula: The invention also includes pharmaceutical compositions comprising Form I of 5-azacytidine.
1. A method for isolating crystalline Form I of 5-azacytidine substantially free of other forms, the method comprising:
recrystallizing 5-azacytidine from a solvent mixture comprising at least one polar aprotic solvent and at least one co-solvent selected from the group consisting of:
1,1,2-trichloroethene,
1,2-dichloroethene,
1,2-dimethoxyethane,
1,4-dioxane,
1-butanol,
1-pentanol,
1-propanol,
2-butanol,
2-ethoxyethanol,
2-methoxyethanol,
2-methyl-1-propanol,
2-propanol,
3-methyl-1-butanol,
acetone,
acetonitrile,
anisole,
butyl acetate,
chlorobenzene,
cumene,
cyclohexane,
dichloromethane,
ethyl acetate,
ethyl ether,
ethyl formate,
ethyleneglycol,
formamide,
isobutyl acetate,
isopropyl acetate,
methyl acetate,
methylbutyl ketone,
methylcyclohexane,
methylisobutyl ketone,
N,N-dimethylacetamide,
N,N-dimethylformamide,
nitromethane,
propyl acetate,
pyridine,
sulfolane,
tert-butylmethyl ether,
tetrahydrofuran, and
tetralin,
by cooling the solvent mixture from a temperature at which the 5-azacytidine dissolves completely to about −20° C.; and
isolating the recrystallized 5-azacytidine.
2. The method of claim 1 , wherein said polar aprotic solvent is selected from the group consisting of dimethylsulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidinone.
3. The method of claim 1 , wherein said polar aprotic solvent is dimethylsulfoxide.
4. The method of claim 1 , wherein said co-solvent is acetonitrile.
5. The method of claim 1 , wherein said co-solvent is 2-propanol.
6. The method of claim 1 , wherein said co-solvent is 1-propanol.
7. The method of claim 2 , wherein said co-solvent is acetonitrile.
8. The method of claim 2 , wherein said co-solvent is 2-propanol.
9. The method of claim 2 , wherein said co-solvent is 1-propanol.
10. The method of claim 3 , wherein said co-solvent is acetonitrile.
11. The method of claim 3 , wherein said co-solvent is 2-propanol.
12. The method of claim 3 , wherein said co-solvent is 1-propanol.