Sodium ferric gluconate complexes and method of manufacture thereof

1. A process of preparing sodium ferric gluconate complex, substantially free of excipients, comprising the steps of:

(a) reacting ferric hydroxide, a sodium base and sodium gluconate, in an aqueous reaction mixture, at a pH in the range from about 7.5 to about 13; and

(b) isolating sodium ferric gluconate complex from the aqueous reaction mixture by:

(i) forming a mixture by adding to the aqueous reaction mixture at least one water-miscible organic solvent in an amount sufficient to precipitate sodium ferric gluconate complex from the mixture; and

(ii) collecting the precipitated sodium ferric gluconate complex, from the mixture formed in step (i).

2. A process according to claim 1 , wherein the isolated sodium ferric gluconate complex has a weight average molecular weight in the range from about 20,000 to about 150,000 Daltons.

3. A process according to claim 1 , wherein the reaction mixture comprises ferric iron in an amount from about 0.2% w/w to about 8% w/w based on the weight of the reaction mixture.

4. A process according to claim 1 , wherein the ferric hydroxide in step (a) is prepared by a process comprising the steps of:

(a) providing a reaction mixture comprising a ferric salt dissolved in an aqueous medium;

(b) adding to the reaction mixture from about 1 to about 2 equivalents of a first base based on the amount of ferric salt in the reaction mixture;

(c) allowing the reaction mixture to equilibrate for a time interval greater than about 10 minutes;

(d) adding a second base to the equilibrated reaction mixture; and

(e) collecting the ferric hydroxide from the reaction mixture.

5. A process according to claim 4 , wherein the first and second bases are independently selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and water-soluble amines.

6. A process according to claim 4 , wherein the first and second bases are independently selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium hydroxide, and tris-hydroxymethylaminoethane.

7. A process according to claim 4 wherein about one equivalent of the first base is added to the reaction mixture.

8. A process according to claim 4 wherein about two equivalents of the first base are added to the reaction mixture.

9. A process according to claim 4 , wherein the first base is added to the reaction mixture until the pH of the resulting mixture is from about 2.0 to about 2.5.

10. A process according to claim 4 , wherein in step (d) the second base is added in an amount sufficient to adjust the pH of the reaction mixture to a pH in the range from about 3.5 to about 9.

11. A process according to claim 10 , wherein the second base is added in an amount sufficient to adjust the pH of the reaction mixture to about 4.0.

12. A process according to claim 10 , wherein the second base is added in an amount sufficient to adjust the pH of the reaction mixture to about 7.0.

13. A process according to claim 10 , wherein second base is added in an amount sufficient to adjust the pH of the reaction mixture to about 8.3.

14. A process according to claim 4 , wherein the ferric salt is ferric chloride, ferric nitrate, or a mixture thereof.

15. A process according to claim 4 , wherein the ferric hydroxide is collected by filtration.

16. A process according to claim 15 , further comprising the step of forming a slurry of the collected ferric hydroxide in an aqueous solvent.

17. A process according to claim 16 , wherein the aqueous solvent comprises a mixture of water and a water-miscible organic solvent.

18. A process according to claim 17 , wherein the aqueous solvent comprises up to about 30% of the water-miscible organic solvent.

19. A process according to claim 1 , wherein, in step (a), the molar ratio of sodium gluconate to ferric hydroxide is from about 0.2:1 to about 5:1.

20. A process according to claim 19 , wherein, in step (a), the molar ratio of sodium gluconate to ferric hydroxide is from about 1:1 to about 5:1.

21. A process according to claim 1 , wherein the temperature in step (a) is in the range from about 75° C. to about 120° C.

22. A process according to claim 21 , wherein the temperature in step (a) is in the range from about 95° C. to about 115° C.

23. A process according to claim 1 , wherein, in step (a), the sodium gluconate and ferric hydroxide are reacted for a time interval in the range from about 2 minutes to about 36 hours.

24. A process according to claim 1 , wherein, in step (a), the sodium gluconate and ferric hydroxide are reacted for a time interval in the range from about 2 to about 300 minutes.

25. process according to claim 17 wherein the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, dioxane, acetonitrile and mixtures thereof.

26. A process according to claim 1 wherein the step of collecting the precipitated sodium ferric gluconate complex comprises collecting by filtration.

27. A process according to claim 1 wherein the step of collecting the precipitated sodium ferric gluconate complex comprises collecting by centrifugation.

28. The process according to claim 1 , further comprising purifying the isolated sodium ferric gluconate complex, said purifying comprising the steps of:

(a) dissolving the isolated sodium ferric gluconate complex in an aqueous solvent;

(b) forming a mixture by adding to the solution formed in step (a) at least one water-miscible organic solvent in an amount sufficient to precipitate purified sodium ferric gluconate complex from the solution; and

(c) collecting the purified sodium ferric gluconate complex from the mixture formed in step (b).

29. A process according to claim 28 wherein the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, dioxane, acetonitrile and mixtures thereof.

30. The process according to claim 28 , further comprising drying the purified sodium ferric gluconate complex.

31. A process of preparing a co-precipitate comprising sodium ferric gluconate complex and sucrose, comprising the steps of:

(a) reacting ferric hydroxide, a sodium base and sodium gluconate, in an aqueous reaction mixture, at a pH in the range from about 7.5 to about 13;

(b) isolating sodium ferric gluconate complex from the aqueous reaction mixture by:

(i) forming a mixture by adding to the aqueous reaction mixture at least one water-miscible organic solvent in an amount sufficient to precipitate sodium ferric gluconate complex from the mixture; and

(ii) collecting the precipitated sodium ferric gluconate complex, from the mixture formed in step (i);

(c) dissolving the isolated sodium ferric gluconate complex in an aqueous solvent to form a solution;

(d) forming a mixture by adding to the solution formed in step (c) at least one water-miscible organic solvent in an amount sufficient to precipitate sodium ferric gluconate complex from the solution;

(e) collecting the purified sodium ferric gluconate complex from the mixture formed in step (d);

(f) dissolving purified sodium ferric gluconate complex product prepared according to step (e) in an aqueous sucrose solution;

(g) forming a mixture by adding to the solution of sodium ferric gluconate complex formed in step (f) at least one water-miscible organic solvent in an amount sufficient to co-precipitate sodium ferric gluconate complex and sucrose; and

(h) collecting the co-precipitate formed in step (g).

32. A process according to claim 31 , further comprising the step of drying the co-precipitate.

33. A process according to claim 31 , wherein the ratio of purified ferric gluconate complex to aqueous sucrose solution is in the range from about 1:0.5 to about 1:10 by weight.

34. A process according to claim 31 , wherein the aqueous sucrose solution has a concentration in the range from about 10% to about 50% weight/volume.

35. A process according to claim 31 , wherein the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, dioxane, acetonitrile and mixtures thereof.

36. A process for preparing an aqueous solution of sucrose and sodium ferric gluconate complex, comprising the steps of:

(a) reacting ferric hydroxide, a sodium base and sodium gluconate, in an aqueous reaction mixture, at a pH in the range from about 7.5 to about 13;

(b) isolating sodium ferric gluconate complex from the aqueous reaction mixture by:

(i) forming a mixture by adding to the aqueous reaction mixture at least one water-miscible organic solvent in an amount sufficient to precipitate sodium ferric gluconate complex from the mixture; and

(ii) collecting the precipitated sodium ferric gluconate complex, from the mixture formed in step (i);

(c) dissolving the isolated sodium ferric gluconate complex in an aqueous solvent to form a solution;

(d) forming a mixture by adding to the solution formed in step (c) at least one water-miscible organic solvent in an amount sufficient to precipitate sodium ferric gluconate complex from the solution;

(e) collecting purified sodium ferric gluconate complex from the mixture formed in step (d); and

(f) dissolving the purified sodium ferric gluconate complex, prepared according to step (e), in a solution of sucrose in water.

37. A process of preparing an aqueous solution of sucrose and sodium ferric gluconate complex, comprising the steps of:

(a) reacting ferric hydroxide, a sodium base and sodium gluconate, in an aqueous reaction mixture, at a pH in the range from about 7.5 to about 13;

(b) isolating sodium ferric gluconate complex from the aqueous reaction mixture by:

(i) forming a mixture by adding to the aqueous reaction mixture at least one water-miscible organic solvent in an amount sufficient to precipitate sodium ferric gluconate complex from the mixture; and

(ii) collecting the precipitated sodium ferric gluconate complex, from the mixture formed in step (i);

(c) dissolving the isolated sodium ferric gluconate complex in an aqueous solvent to form a solution;

(d) forming a mixture by adding to the solution formed in step (c) at least one water-miscible organic solvent in an amount sufficient to precipitate sodium ferric gluconate complex from the solution;

(e) collecting the purified sodium ferric gluconate complex from the mixture formed in step (d);

(f) dissolving the purified sodium ferric gluconate complex formed in step (e) in an aqueous sucrose solution;

(g) forming a mixture by adding to the sodium ferric gluconate complex solution formed in step (f) at least one water-miscible organic solvent in an amount sufficient to co-precipitate sodium ferric gluconate complex and sucrose;

(h) collecting the co-precipitate formed in step (g); and

(i) dissolving the collected co-precipitate in water.

38. A process of preparing an aqueous solution of sucrose and sodium ferric gluconate complex, comprising the steps of:

combining ferric hydroxide, a sodium base and sodium gluconate, in an aqueous reaction mixture, at a temperature and at a pH in the range from about 7.5 to about 13;

(b) maintaining the mixture at the temperature for a time interval in the range from about 5 minutes to about 36 hours; and

(c) adding to the reaction mixture a selected quantity of sucrose.

39. The process according to claim 38 , wherein the temperature in steps (a) and (b) is a temperature in the range of from about 75° C. to about 120° C.

40. The process according to claim 38 , wherein the temperature in steps (a) and (b) is a temperature in the range of from about 95° C. to about 115° C.

41. The process according to claim 38 , wherein, the molar ratio of sodium gluconate to ferric hydroxide is in the range from about 0.2:1 to about 5:1.

42. The process according to claim 38 , wherein, the molar ratio of sodium gluconate to ferric hydroxide is in the range from about 1:1 to about 5:1.

43. A process according to claim 1 wherein the isolated sodium ferric gluconate complex comprises crystalline sodium ferric gluconate complex.

44. A process according to claim 1 wherein the isolated sodium ferric gluconate complex comprises amorphous sodium ferric gluconate complex substantially free of crystalline sodium ferric gluconate complex.

45. A process according to claim 1 wherein the isolated sodium ferric gluconate complex contains from about 1 to about 55% ferric iron by weight.

46. A process according to claim 1 wherein the isolated sodium ferric gluconate complex contains from about 1 to about 50% ferric iron by weight.

47. process according to claim 1 wherein the isolated sodium ferric gluconate complex contains from about 2 to about 15% ferric iron by weight.

48. A process according to claim 1 wherein the isolated sodium ferric gluconate complex contains from about 30 to about 50% ferric iron by weight.

49. A method according to claim 1 , wherein the ferric hydroxide used in step (a) is prepared by adding at least one base to an aqueous solution of a ferric salt and separating precipitated ferric hydroxide from the solution.

50. A method according to claim 49 , wherein the ferric hydroxide prepared comprises the ferric salt partially neutralized.

51. A method according to claim 1 , wherein, in step (b), the sodium base is sodium hydroxide.

52. A method according to claim 31 , wherein the ferric hydroxide used in step (a) is prepared by adding at least one base to an aqueous solution of a ferric salt and separating precipitated ferric hydroxide from the solution.

53. A method according to claim 52 , wherein the ferric hydroxide prepared comprises the ferric salt partially neutralized.

54. A method according to claim 31 , wherein, in step (a), the sodium base is sodium hydroxide.

55. A method according to claim 36 , wherein the ferric hydroxide used in step (a) is prepared by adding at least one base to an aqueous solution of a ferric salt and separating precipitated ferric hydroxide from the solution.

56. A method according to claim 55 , wherein the ferric hydroxide prepared comprises the ferric salt partially neutralized.

57. A method according to claim 36 , wherein, in step (a), the sodium base is sodium hydroxide.

58. A method according to claim 37 , wherein the ferric hydroxide used in step (a) is prepared by adding at least one base to an aqueous solution of a ferric salt and separating precipitated ferric hydroxide from the solution.

59. A method according to claim 58 , wherein the ferric hydroxide prepared comprises the ferric salt partially neutralized.

60. A method according to claim 37 , wherein, in step (a), the sodium base is sodium hydroxide.

61. A method according to claim 38 , wherein the ferric hydroxide used in step (a) is prepared by adding at least one base to an aqueous solution of a ferric salt and separating precipitated ferric hydroxide from the solution.

62. A method according to claim 61 , wherein the ferric hydroxide prepared comprises the ferric salt partially neutralized.

63. A method according to claim 61 , wherein, in step (a), the sodium base is sodium hydroxide.