초록 ▼

A Sitagliptin phosphate characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 4.7, 13.5, and 15.5±0.2 degrees two theta and at least another two peaks s

A Sitagliptin phosphate characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 4.7, 13.5, and 15.5±0.2 degrees two theta and at least another two peaks selected from the following list: 14.0, 14.4, 18.3, 19.2, 19.5 and 23.7±0.2 degrees two theta; and a powder XRD pattern with peaks at about 13.5, 19.2, and 19.5±0.2 degrees two theta and at least another two peaks selected from the following list: 4.7, 14.0, 15.1, 15.5, 18.3, and 18.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 13.5, 15.5, 19.2, 23.7, and 24.4±0.2 degrees two theta; and a powder XRD pattern with peaks at about 4.65, 13.46, 17.63, 18.30, and 23.66±0.10 degrees two theta, processes for preparing said Sitagliptin crystalline form, and pharmaceutical compositions thereof, are provided.

대표청구항 ▼

What is claimed: 1. A process for preparing a crystalline form of Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, the process selected from the group consisting of: a. a process comprising combining Sitagli

What is claimed: 1. A process for preparing a crystalline form of Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, the process selected from the group consisting of: a. a process comprising combining Sitagliptin base, phosphoric acid, and a solvent selected from the group consisting of ethyl acetate, dioxane, methyl isobutyl ketone, isobutyl acetate, butyl acetate, a mixture of acetonitrile and toluene, or a mixture of tetrahydrofuran and water to form a slurry; and obtaining a Sitagliptin phosphate precipitate; b. a process comprising combining Sitagliptin phosphate or Sitagliptin base and phosphoric acid with a mixture of a first organic solvent and a second organic solvent selected from the group consisting of acetone:n-hexane, acetone:n-heptane, acetone:cyclopentyl methyl ether, acetone:dibutyl ether, acetone:isopropylacetate, dimethylsulfoxide:methyl isobutyl ketone, and dimethylsulfoxide:methyl tert butyl ether, forming a mixture, and crystallizing Sitagliptin phosphate from the mixture, wherein, when acetone:cyclopentyl methyl ether, acetone:isopropylacetate, and dimethylsulfoxide:methyl tert butyl ether, are used, the crystallized Sitagliptin phosphate is further dried; c. a process comprising drying wet Sitagliptin phosphate Form II; d. a process comprising heating a mixture of Sitagliptin phosphate Form II and the crystalline form characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, to a temperature of about 40° C. to about 100° C. under reduced pressure; and e. a process comprising drying a mixture of Sitagliptin phosphate Form II and a crystalline form, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, in a fluidized bed dryer at a temperature of about 30° C. to about 60° C. 2. The process of claim 1, wherein Sitagliptin phosphate or Sitagliptin base and phosphoric acid are combined with the mixture of the first organic solvent and the second organic solvent. 3. The process of claim 2, wherein the first organic solvent and the second organic solvent ratio is about 1:1 to about 1:15. 4. The process of claim 2, wherein Sitagliptin phosphate is combined with the mixture of the first organic solvent and the second organic solvent. 5. The process of claim 2, wherein the solution is heated to a temperature of about 45° C. to about 80° C. 6. The process of claim 1, wherein the wet Sitagliptin phosphate Form II is dried. 7. The process of claim 6, wherein the wet Sitagliptin phosphate Form II is dried at about 40° C. to about 100° C. under reduced pressure. 8. The process of claim 6, wherein the Sitagliptin phosphate Form II is prepared in a process, comprising combining Sitagliptin base and phosphoric acid and an organic solvent selected from the group consisting of dimethyl carbonate, tetrahydrofuran, propylene glycol methyl ether, methyl ethyl ketone, ethanol, methyl acetate, dimethylformamide, diethyl carbonate, n-butanol, 1-propanol, toluene, isobutyl acetate, isopropyl acetate, isopropanol, and a mixture of acetonitrile and n-butanol, acetonitrile, dimethyl carbonate to form a slurry, and obtaining Sitagliptin phosphate Form II. 9. The process of claim 6, wherein the Sitagliptin phosphate Form II is prepared in a process comprising combining Sitagliptin base and phosphoric acid and a mixture of a first organic solvent and a second organic solvent selected from the group consisting of acetone:isopropylacetate, acetone:cyclohexane, acetone:isobutyl acetate, acetonitrile:n-butanol, and acetone:n-butanol, forming a mixture, and obtaining Sitagliptin phosphate Form II. 10. The process of claim 9, wherein the first organic solvent and the second organic solvent ratio is about 1:1 to about 1:15. 11. The process of claim 6, wherein the wet Sitagliptin phosphate Form II comprises a solvent selected from the group consisting of methyl isobutyl ketone, dimethyl carbonate, tetrahydrofuran, acetonitrile, propylene glycol methyl ether, methanol, n-butanol, 1-propanol, toluene, isobutyl acetate, isopropyl acetate, butyl acetate, isopropanol, dimethyl carbonate, n-hexane, acetone, cyclohexane, isobutyl acetate, and mixtures thereof. 12. The process of claim 1, wherein the mixture of Sitagliptin phosphate Form II and the crystalline form characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta are heated to a temperature of about 40° C. to about 100° C. under reduced pressure. 13. The process of claim 12, wherein the mixture is heated at a temperature of about 40° C. to about 60° C. 14. The process of claim 12, wherein said mixture is heated for about 10 to about 24 hours. 15. The process of claim 1, wherein the mixture of Sitagliptin phosphate Form II and the crystalline form, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is dried in a fluidized bed dryer at a temperature of about 30° C. to about 60° C. 16. A process for preparing Sitagliptin phosphate Form II, the process selected from the group consisting of: a. a process comprising providing a slurry of crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, and a solvent selected from the group consisting of acetonitrile, methanol, ethanol, 1-propanol, isopropanol, acetone, tetrahydrofuran, n-butanol, iso-butanol, toluene, propylene glycol, propylene glycol methyl ether, chloroform, diethyl carbonate, dimethylformamide, or mixtures of dimethylformamide with methyl isobutyl ketone, or n-butanol; heating the slurry; and obtaining Sitagliptin phosphate Form II; b. a process comprising combining Sitagliptin base and phosphoric acid in an organic solvent selected from the group consisting of dimethyl carbonate, tetrahydrofuran, propylene glycol methyl ether, methyl ethyl ketone, ethanol, methyl acetate, dimethylformamide, diethyl carbonate, n-butanol, 1-propanol, toluene, isobutyl acetate, isopropyl acetate, isopropanol, a mixture of acetonitrile and n-butanol, acetonitrile, dimethyl carbonate, and a mixture of dimethyl carbonate and n-hexane, forming a slurry; and obtaining Sitagliptin phosphate Form II; c. a process comprising combining Sitagliptin base and phosphoric acid and a mixture of a first organic solvent and a second organic solvent selected from the group consisting of acetone:isopropylacetate, acetone:cyclohexane, acetone:isobutyl acetate, acetonitrile:n-butanol, and acetone:n-butanol, forming a mixture; and crystallizing Sitagliptin phosphate from the mixture, obtaining Sitagliptin phosphate Form II; d. a process comprising dissolving Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, in dimethylsulfoxide; and adding an antisolvent selected from the group consisting of iso-butanol, acetonitrile, diethyl ether, diethyl carbonate, and tert-butyl ether; e. a process comprising granulating a crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta in the presence of isopropanol; and f. a process comprising exposing crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta to a C1-C4 alcohol, preferably the alcohol is selected from the group consisting of ethanol, methanol, and isopropanol. 17. The process of claim 16, wherein the slurry is heated to about 50° C. to about 80° C. 18. The process of claim 16, wherein the Sitagliptin base and phosphoric acid are combined in an organic solvent selected from the group consisting of dimethyl carbonate, tetrahydrofuran, propylene glycol methyl ether, methyl ethyl ketone, ethanol, methyl acetate, dimethylformamide, diethyl carbonate, n-butanol, 1-propanol, toluene, isobutyl acetate, isopropyl acetate, isopropanol, a mixture of acetonitrile and n-butanol, acetonitrile, dimethyl carbonate, and a mixture of dimethyl carbonate and n-hexane, forming a slurry. 19. The process of claim 16, wherein the Sitagliptin base and phosphoric acid and a mixture of a first organic solvent and a second organic solvent selected from the group consisting of acetone:isopropylacetate, acetone:cyclohexane, acetone:isobutyl acetate, acetonitrile:n-butanol, and acetone:n-butanol are combined forming a mixture; and Sitagliptin phosphate is crystallized from the mixture. 20. The process of claim 19, wherein the first organic solvent and the second organic solvent ratio is about 1:1 to about 1:15. 21. The process of claim 16, wherein the Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is dissolved in dimethylsulfoxide and an antisolvent selected from the group consisting of iso-butanol, acetonitrile, diethyl ether, diethyl carbonate, and tert-butyl ether is added. 22. The process of claim 16, wherein crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is granulated in the presence of isopropanol. 23. The process of claim 22, wherein the solvent/antisolvent ration is about 1:1 to about 1:20. 24. The process of claim 22, wherein the solvent/antisolvent ration is about 3:10. 25. The process of claim 16, wherein crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is exposed to a C1-C4 alcohol. 26. The process of claim 25, wherein the alcohol is selected from the group consisting of ethanol, methanol, and isopropanol.