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1. WO2016135755 - AMORPHOUS APREMILAST, PREMIXES THEREOF, AND NOVEL CRYSTALLINE FORMS OF APREMILAST

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[ EN ]

We claim:

1. A process for preparing amorphous apremilast, comprising the steps of:

a. dissolving apremilast in a solvent;

b. removing the solvent;

c. adding a non-polar solvent; and

d. isolating amorphous apremilast.

2. The process according to claim 1, wherein the solvent is selected from the group consisting of an alcohol solvent, a ketone solvent, a chlorinated solvent, a polar hydrocarbon solvent, and mixtures thereof.

3. The process according to claim 1, wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

4. The process according to claim 1, wherein the non-polar solvent is selected from the group consisting of an ethereal solvent, a non-polar hydrocarbon solvent, and mixtures thereof.

5. The process according to claim 1, wherein the non-polar solvent is selected from the group consisting of heptane, hexane, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.

6. A process for preparing amorphous apremilast, comprising the steps of:

a. dissolving apremilast in a solvent to form a solution;

b. cooling the solution; and

c. isolating amorphous apremilast.

7. The process according to claims 6, wherein the solvent is an alcohol solvent.

8. The process according to claim 7, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, and mixtures thereof.

9. A process for preparing a premix containing amorphous apremilast, comprising the steps of:

a. dissolving apremilast and a pharmaceutical excipient in a solvent;

b. removing the solvent;

c. adding a non-polar solvent;

d. isolating the premix containing amorphous apremilast.

10. The process according to claims 9, wherein the solvent is selected from the group consisting of alcohol solvents, ketone solvents, chlorinated solvents, polar hydrocarbon solvents, and mixtures thereof.

11. The process according to claim 9, wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

12. The process according to claim 9, wherein the non-polar solvent is selected from the group consisting of ethereal solvents, non-polar hydrocarbon solvents, and mixtures thereof.

13. The process according to claim 9, wherein the non-polar solvent is selected from the group consisting of heptane, hexane, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.

14. The process according to either of claims 1 or 9, wherein the solvent is removed by distillation.

15. The process according to claim 9, wherein the pharmaceutical excipient is selected from the group consisting of polysaccharides, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C6 polyalkylene glycols, and mixtures thereof.

16. The process according to claim 15, wherein the polysaccharide is selected from the group consisting of hydroxypropyl methyl cellulose, croscarmellose, carboxymethyl cellulose, a sodium salt of carboxymethyl cellulose, a calcium salt of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, optionally substituted a-cyclodextrins, optionally substituted β-cyclodextrins, optionally substituted γ-cyclodextrins, and mixtures thereof.

17. The process according to claim 15, wherein the vinylpyrrolidone-vinyl acetate copolymer is a vinylpyrrolidone-vinyl acetate copolymer comprising N-vinyl-2-pyrrolidone and vinyl acetate in a 60:40 ratio, by mass.

18. A premix comprising amorphous apremilast and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is a polyvinylpyrrolidone-vinyl acetate copolymer with a ratio of 60:40 polyvinylpyrrolidone to vinyl acetate by mass.

19. An anisole solvate of apremilast.

20. The anisole solvate of apremilast of claim 19, wherein the anisole solvate of apremilast is characterized by a PXRD pattern having significant peaks at 11.89, 16.30, 17.63, 22.34, 25.30, and 26.19 ± 0.2 °2Θ.

21. The anisole solvate of apremilast of claim 19, wherein the anisole solvate of apremilast is characterized by a PXRD pattern as depicted in Figure 3.

22. A process for preparing an anisole solvate of apremilast, comprising:

a. dissolving apremilast in anisole;

b. adding a solvent; and

c. isolating an anisole solvate of apremilast.

23. The process according to claim 22, wherein the solvent is selected from the group consisting of isopropanol, heptane, hexane, methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, and mixtures thereof.

24. A process for preparing an anisole solvate of apremilast, comprising:

a. dissolving apremilast in anisole to form a solution;

b. adding the solution to a solvent; and

c. isolating an anisole solvate of apremilast.

25. The process according to claim 24, wherein the solvent is selected from the group consisting of isopropanol, heptane, hexane, methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, and mixtures thereof.

26. A process for preparing an anisole solvate of apremilast, comprising:

a. dissolving apremilast in anisole; and

b. isolating an anisole solvate of apremilast.

27. A methyl ethyl ketone solvate of apremilast.

28. The methyl ethyl ketone solvate of apremilast of claim 27, wherein the methyl ethyl ketone solvate of apremilast is characterized by a PXRD pattern having significant peaks at 7.37, 11.12, 17.61, 22.38, 24.65, and 26.23 ± 0.2 °2Θ.

29. The methyl ethyl ketone solvate of apremilast of claim 27, wherein the methyl ethyl ketone solvate of apremilast is characterized by a PXRD pattern as depicted in Figure 5.

30. A process for preparing a methyl ethyl ketone solvate of apremilast, comprising:

a. dissolving apremilast in methyl ethyl ketone to form a solution;

b. cooling the solution; and

c. isolating a methyl ethyl ketone solvate of apremilast.

31. A pharmaceutical dosage form comprising the premix of amorphous apremilast made according to the process of claim 9.

32. A pharmaceutical dosage form comprising the anisole solvate of apremilast of claim 19.

33. A pharmaceutical dosage form comprising the methyl ethyl ketone solvate of apremilast of claim 27.

34. The premix of claim 18, wherein said premix is stable for at least six months when stored at 40 °C with 75% relative humidity.

35. The premix of claim 18, wherein said premix is stable for at least six months when stored at 25 °C with 60% relative humidity.