Highly Pure Paliperidone or a Pharmaceutically Acceptable Salt Thereof Substantially Free of Keto Impurity

1 . Paliperidone or a pharmaceutically acceptable salt thereof comprising a paliperidone keto impurity in an amount of less than 0.2 wt % as measured by HPLC, wherein the paliperidone keto impurity is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-7,8-dihydro-6H-pyrido[1,2-a]pyrimidin-4,9-dione.

2 . Paliperidone of claim 1 , having a purity of about 99% to about 99.99% as measured by HPLC.

3 . (canceled)

4 . (canceled)

5 . Paliperidone of claim 1 , comprising the paliperidone keto impurity in an amount of about 0.01 wt % to about 0.15 wt %.

6 . (canceled)

7 . Paliperidone of claim 1 , wherein the pharmaceutically acceptable salt of paliperidone is selected from the group consisting of hydrochloride, hydrobromide, oxalate, nitrate, sulfate, phosphate, fumarate, succinate, maleate, fumarate, besylate, tosylate, palmitate and tartrate.

8 . (canceled)

9 . A purification process for obtaining highly pure paliperidone or a pharmaceutically acceptable salt thereof having less than 0.2 wt % of a paliperidone keto impurity, comprising:

a) providing a first solution or suspension of crude paliperidone in a first organic solvent;

b) isolating or recovering the paliperidone as a solid from the first solution or suspension obtained in step-(a);

c) dissolving the solid from step-(b) in a second organic solvent to form a second solution;

d) combining the second solution obtained in step-(c) with a reducing agent to produce a reaction mass;

e) optionally, filtering the reaction mass obtained in step-(d) to remove extraneous matter; and

f) isolating highly pure paliperidone from the reaction mass, and optionally converting the highly pure paliperidone obtained into its pharmaceutically acceptable salts;

wherein the paliperidone keto impurity is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-7,8-dihydro-6H-pyrido[1,2-a]pyrimidin-4,9-dione.

10 . The process of claim 9 , wherein the first organic solvent used in step-(a) is selected from the group consisting of alcohols, amides, organosulfur solvents, and mixtures thereof.

11 . The process of claim 10 , wherein the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, sulfolane, and mixtures thereof.

12 . (canceled)

13 . The process of claim 11 , wherein the organic solvent is sulfolane.

14 . The process of claim 9 , wherein the first solution in step-(a) is provided by dissolving the crude paliperidone in the first organic solvent at a temperature of about 25° C. to about 110° C.

15 . (canceled)

16 . The process of claim 9 , wherein the suspension in step-(a) is provided by suspending crude paliperidone in the first organic solvent while stirring at a temperature below boiling temperature of the solvent used.

17 . (canceled)

18 . (canceled)

19 . The process of claim 9 , wherein the first solution or suspension in step-(a) is prepared by reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole in the presence of a base, optionally in the presence of a phase transfer catalyst, in a reaction inert solvent to produce a reaction mass containing crude paliperidone; subjecting the reaction mass to washings, extractions or evaporations; and dissolving or suspending the resulting crude paliperidone in the first organic solvent at a temperature of about 25° C. to about 110° C.

20 . The process of claim 9 , wherein the first solution or suspension in step-(a) is prepared by treating an acid addition salt of paliperidone with a base to produce paliperidone; and extracting, dissolving or suspending the paliperidone in first the organic solvent.

21 . The process of claim 9 , wherein the first solution or suspension obtained in step-(a) is optionally stirred at a temperature of about 30° C. to the reflux temperature of the solvent used from about 20 minutes to about 6 hours.

22 . The process of claim 9 , wherein isolating in step-(b) is carried out by forcible or spontaneous crystallization, and wherein the forcible crystallization is initiated by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.

23 . (canceled)

24 . (canceled)

25 . The process of claim 22 , wherein the crystallization is carried out by cooling the solution at about 0° C. to about 25° C. from about 30 minutes to about 20 hours.

26 . The process of claim 9 , wherein recovering of solid paliperidone in step-(b) is accomplished by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

27 . (canceled)

28 . The process of claim 9 , wherein the solid paliperidone obtained in step-(b) is optionally washed with a solvent selected from the group consisting of water, alcohols, and mixtures thereof prior to dissolving in the second organic solvent.

29 . The process of claim 9 , wherein the second organic solvent used in step-(c) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, and mixtures thereof.

30 . (canceled)

31 . The process of claim 29 , wherein the solvent is methanol.

32 . The process of claim 9 , wherein the dissolution in step-(c) is carried out at a temperature of about 25° C. to about 110° C., and wherein the second solution obtained is optionally stirred at a temperature of about 30° C. to the reflux temperature of the solvent used for at least 10 minutes.

33 . The process of claim 9 , wherein the second solution obtained in step-(c) is optionally subjected to carbon treatment or silica gel treatment.

34 . (canceled)

35 . The process of claim 9 , wherein the reducing agent used in step-(d) is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium bis(2-methoxyethoxy)aluminium hydride, lithium borohydride, potassium borohydride, and combinations comprising one or more of the foregoing reducing agents.

36 . The process of claim 35 , wherein the reducing agent is sodium borohydride.

37 . The process of claim 9 , wherein the reaction mass obtained in step-(d) is stirred at a temperature of about 20° C. to about 70° C. for at least about 10 minutes.

38 . The process of claim 37 , wherein the reaction mass is stirred at a temperature of about 35° C. to about 55° C. from about 30 minutes to about 10 hours.

39 . The process of claim 9 , wherein the reducing agent in step-(d) is used in a molar ratio of about 0.002 to 0.15 moles per 1 mole of paliperidone.

40 . The process of claim 39 , wherein the reducing agent is used in the molar ratio of about 0.005 to 0.01 moles per 1 mole of paliperidone.

41 . The process of claim 9 , wherein isolating in step-(f) is carried out by forcible or spontaneous crystallization, and wherein the forcible crystallization is initiated by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof.

42 . (canceled)

43 . (canceled)

44 . The process of claim 41 , wherein the crystallization is carried out by cooling the solution at about 0° C. to about 30° C. from about 30 minutes to about 20 hours.

45 . The process of claim 9 , wherein the solid obtained in step-(f) is collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof; and wherein the highly pure paliperidone obtained is further dried under vacuum or at atmospheric pressure, at a temperature of about 35° C. to about 70° C.

46 . (canceled)

47 . The process of claim 9 , wherein the paliperidone obtained in step-(f) has a purity of about 99% to about 99.95%.

48 . The process of claim 47 , wherein the paliperidone contains the keto impurity in an amount of about 0.01 wt % to about 0.15 wt %.

49 . The process of claim 47 , wherein the paliperidone is essentially free of paliperidone keto impurity.

50 . (canceled)

51 . A process for purifying paliperidone, comprising:

a) providing a first solution of paliperidone in an organic solvent;

b) subjecting the first solution to silica gel treatment to provide a second solution; and

c) isolating highly pure paliperidone from the second solution obtained in step-(b), and optionally converting the highly pure paliperidone obtained into its pharmaceutically acceptable salts.

52 . The process of claim 51 , wherein the organic solvent used in step-(a) is selected from the group consisting of alcohols, amides, organosulfur solvents, and mixtures thereof.

53 . The process of claim 52 , wherein the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, sulfolane, and mixtures thereof.

54 . The process of claim 53 , wherein the organic solvent is selected from the group consisting of methanol, isopropanol, dimethylformamide, sulfolane, and mixtures thereof.

55 . The process of claim 51 , wherein the subjecting to silica gel treatment in step-(b) is carried out by stirring the solution with silica gel at a temperature of below about 70° C. for at least 10 minutes.

56 . The process of claim 51 , wherein the isolation of highly pure paliperidone in step-(c) is carried out by forcible or spontaneous crystallization.

57 . A pharmaceutical composition comprising highly pure paliperidone or a pharmaceutically acceptable salt thereof having a paliperidone keto impurity in an amount of less than about 0.2 wt % and one or more pharmaceutically acceptable excipients, wherein the paliperidone keto impurity is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-7,8-dihydro-6H-pyrido[1,2-a]pyrimidin-4,9-dione.

58 . The pharmaceutical composition of claim 57 , wherein the pharmaceutical composition is a solid dosage form, an oral suspension, a liquid, a powder, an elixir, an aerosol, syrups or an injectable solution.

59 . The pharmaceutical composition of claim 57 , wherein the highly pure paliperidone or a pharmaceutically acceptable salt thereof has a D 90 particle size of less than or equal to about 400 microns.

60 . The pharmaceutical composition of claim 59 , wherein the 90 volume-% of the particles (D 90 ) have a size of less than or equal to about 300 microns; less than or equal to about 100 microns; less than or equal to about 60 microns; or less than or equal to about 15 microns.

61 . A method of treating a patient suffering from psychotic diseases, comprising administering a therapeutically effective amount of highly pure paliperidone or a pharmaceutically acceptable salt thereof having a paliperidone keto impurity in an amount of less than about 0.2 wt %, or a pharmaceutical composition that comprises a therapeutically effective amount of highly pure paliperidone or a pharmaceutically acceptable salt thereof having a paliperidone keto impurity in an amount of less than about 0.2 wt %, along with pharmaceutically acceptable excipients.