Patent EA-002739-B1 (EA)
Title: Novel htdrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical composition thereof
Inventor: FINKELSTEIN NINA
IPC: C07F9/38
Filed: 1999-08-27
Abstract: 1. The compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt having water content of 1.3 % to 11.7%. 2. A compound of claim 1 which is any of the hydrate forms selected from the group that consists of 1/4 hydrate, 1/3 hydrate, hemihydrate, 2/3 hydrate, 3/4 hydrate, monohydrate, 5/4 hydrate, 4/3 hydrate, 3/2 hydrate, and dehydrate. 3. Alendronate monosodium monohydrate. 4. The alendronate monosodium monohydrate according to claim 3 having water content of about 6.2%. 5. Alendronate monosodium monohydrate, characterized by stability to dehydration at a temperature up to 150 degree C. 6. Alendronate monosodium monohydrate according to claim 5, which is characterized by peaks in the powder xray diffraction at values of two theta of 12.7+-0.2, 16.2+-0.2, 17.3+-0.2, 17.6+-0.2, 24.8+-0.2, and 25.5+-0.2. 7. A method of preparing the compound of any of claims 3 through 6 comprising the steps of: a) suspending one equivalent of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid in a lower alkanol, b) adding solution of one equivalent of sodium base and 5 to 200 equivalents of water in a lower alkanol to suspension of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, c).isolating said alendronate monosodium monohydr. 8. A method according to claim 7 wherein the compound 4-amino-1-hydroxybutylidene- 1,1-bisphosphonic acid is in a monohydrate form. 9. A method according to claim 7 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and isopropanol. 10. A method according to claim 7 wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium methoxide and sodium ethoxide. 11. A method according to claim 7 wherein the compound 4-amino-1-hydroxybutylidene- 1, 1-bisphosphonic acid is in an anhydrous form. 12. A method of preparing the compound of any of claims 3 through 6 comprising the steps of: a) treating 4-amino-t-hydroxybutylidene-1, 1-bisphosphonic monosodium salt in a lower alkanol with 20-40 equivalents of water; and b) isolating said compound. 13. A method according to claim 12 wherein the lower alkanol of step a) is ethanol. 14. A method of preparing the compound of any of claims 3 through 6 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic disodium salt in a lower alkanol with 20-40 equivalents of water, and one equivalent of alendronic acid; and b) isolating said compound. 15. A method according to claim 16 wherein the lower alkanol of step a) is ethanol. 16. A method of preparing the compound of any of claims 3 through 6 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1,1-bisphosphonic trisodium salt in a lower alkanol with 20-40 equivalents of water and two equivalents of alendronic acid; and b) isolating said compound. 17. A method according to claim 16 wherein the lower alkanol of step a) is ethanol. 18. A method of preparing the compound of any of claims 3 through 6 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic tetrasodium salt in a lower alkanol with 20-40 equivalents of water and three equivalents of alendronic acid; and b) isolating said compound. 19. A method according to claim 18 wherein the lower alkanol of step a) is ethanol. 20. A method according to claim 12 in which the 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic sodium salt is a monosodium salt trihydrate. 21. A compound according to claim 3, which is characterized by peaks in the powder x-ray diffraction at values of two theta of 9.3+-0.2, 12.4+-0.2, 13.5+-0.2, 26.3+-0.2 and 30.0+-0.2. 22. A method of preparing the compound of claim 21 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1,1-bisphosphonic monosodium trihydrate with an effective amount of a drying agent; and b) isolating said compound. 23. A method according to claim 22 wherein the reaction of step a) is performed in ethanol. 24. Alendronate monosodium hemihydrate. 25. The compound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt having water content of 2.8% to 3.9%. 26. The compound according to claim 25, which is characterized by peaks in the powder x-ray diffraction at values of two theta of 7.0+-0.2, 9.3+-0.2, and 14.0+-0.2. 27. A method of preparing the compound of claim 24 or 25 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid in a lower alkanol with one equivalent of sodium base and 9 to 15 equivalents of water; and b) isolating said compound. 28. A method according to claim 27 wherein the compound 4-amino-1-hydroxybutylidene- 1, 1-bisphosphonic acid is in a monohydrate form. 29. A method according to claim 27 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and isopropanol. 30. A method according to claim 27 wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium methoxide and sodium ethoxide. 31. A method according to claim 27 wherein the compound 4-amino-1-hydroxybutylidene- 1, 1-bisphosphonic acid is in an anhydrous form. 32. The compound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt having water content of 2.5% to 3.5%. 33. The compound according to claim 33, which is characterized by peaks in the powder x-ray diffraction at values of two theta of 9.2+-0.2, 14.2+-.2, 15.0+-0.2, 17.1+-0.2, 20.7+-0.2, 22.0+-0.2, and 22.4+-0.2. 34. A method of preparing the compound of claim 2 or 32 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid in a lower alkanol with one equivalent of sodium base and 17 to 22 equivalents of water; and b) isolating said compound. 35. A method according to claim 34 in which the compound 4-amino-1 hydroxybutylidene-1, 1-bisphosphonic acid is in a monohydrate form. 36. A method according to claim 34 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and isopropanol. 37. A method according to claim 34 wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium methoxide and sodium ethoxide. 38. The compound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt having water content of 6.4% to 9.0%. 39. The compound according to claim 39, which is characterized by peaks in the powder x-ray diffraction at values of two theta of 12.2+-0.2, 13.3+-0.2, 14.8+-0.2, 15.8+-0.2, 16.3+-0.2, and 17.2+-0.2. 40. A method of preparing the compound of claim 2 or 38 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid in a lower alkanol with one equivalent of sodium base and 0 to 4 equivalents of water; and b) isolating said compound. 41. A method according to claim 40 in which the compound 4-amino-1-hydroxybutylidene- 1, 1-bisphosphonic acid is in a monohydrate form. 42. A method according to claim 40 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and isopropanol. 43. A method according to claim 40 wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium methoxide and sodium ethoxide. 44. The compound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt having water content of 3.2% to 5.8%. 45. The compound according to claim 45, which is characterized by peaks in the powder x-ray diffraction at values of two theta of 13.1+-0.2, 15.2+-0.2, 16.3+-0.2, 22.3+-0.2, 22.5+-0.2, 23.4+-0.2, and 23.7+-0.2. 46. A method of preparing the compound of 2 or 44 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid anhydrous in a lower alkanol with one equivalent of sodium base and 0 to 4 equivalents of water; and b) isolating said compound. 47. A method according to claim 47 in which the compound 4-amino-1-hydroxybutylidene- 1, 1-bisphosphonic acid is in an anhydrous form. 48. A method according to claim 47 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and isopropanol. 49. A method according to claim 47 wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium methoxide and sodium ethoxide. 50. The compound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt having water content of 1.3 % to 3.1 %. 51. The compound according to claim 51, which is characterized by peaks in the powder x-ray diffraction at values of two theta of 13.0+-0.2, 13.4+-0.2, 14.2+-0.2, 19.1+-0.2, and 19.4+-0.2. 52. A method of preparing the compound of claim 2 or 50 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid in a lower alkanol with one equivalent of sodium base and 3 to 20 equivalents of water; and b) isolating said compound. 53. A method according to claim 52 in which the compound 4-amino-1-hydroxybutylidene- 1, 1-bisphosphonic acid is in a monohydrate form. 54. A method according to claim 52 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and isopropanol. 55. A method according to claim 52 wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium methoxide and sodium ethoxide. 56. A method according to claim 52 wherein the compound 4-amino-1-hydroxybutylidene- 1, 1-bisphosphonic acid is in an anhydrous form. 57. Alendronate monosodium dehydrate. 58. The compound according to claim 57, which is characterized by peaks in the powder x-ray diffraction at values of two theta of 9.3+-0.2, 12.4+-0.2, 13.5+-0.2, 26.3+-0.2 and 30.0+-0.2. 59. A method for preparing a compound according to claim 57 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt trihydrate with an effective amount of drying agent; and b) isolating said compound. 60. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any of claims 1, 3, 25, 33, 39, 45 and 51. 61. A method for treating and/or preventing bone loss in a subject, comprising the step of administering