Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation Number:7,435,827 from the United States Patent and Trademark Office (PTO) owispatent The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt, and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt.<H preparation, zoledronate, Zoledronic, acid, 7435827.html, Patent, pto, 7435827

Title: Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation

Abstract: The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt, and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt.

Patent Number: 7,435,827 Issued on 10/14/2008 to Aronhime, et al.

Inventors: Aronhime; Judith (Rehovot, IL), Lifshitz-Liron; Revital (Herzlia, IL)
Assignee: Teva Pharmaceutical Industries Ltd (Petah Tiqva, IL)

Appl. No.: 11/527,254

Filed: September 25, 2006

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10886099	Jul., 2004
60484876	Jul., 2003

Current U.S. Class: 548/112

Current International Class: C07F 9/6506 (20060101)

Field of Search: 548/112

References Cited [Referenced By]

U.S. Patent Documents


4594466	June 1986	Reeves
4777163	October 1988	Bosies et al.
4939130	July 1990	Jaeggi et al.
7138524	November 2006	McCarty et al.
7250527	July 2007	Godbole et al.
2004/0077683	April 2004	Reddy et al.

Foreign Patent Documents


WO 03/093282	Nov., 2003	WO

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Primary Examiner: Anderson; Rebecca L
Assistant Examiner: Chu; Yong
Attorney, Agent or Firm: Kenyon & Kenyon LLP

Parent Case Text

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No. 10/886,099, filed Jul. 6, 2004, now abandoned, which claims the benefit of U.S. provisional application Ser. No. 60/484,876, filed Jul. 3, 2003, the contents of all of which is incorporated herein.

Claims

What is claimed:

1. Crystalline solid zoledronic acid (Form XII) characterized by a powder X-ray pattern having peaks at 9.0.degree., 13.9.degree., 14.8.degree., 21.5.degree., 24.7.degree., and 29.8.degree. 2.theta..+-.0.2.degree. 2.theta..

2. The crystalline zoledronic acid of claim 1, further characterized by a powder X-ray diffraction pattern with peaks at 17.0.degree., 20.6.degree., 20.8.degree., 22.4.degree., 25.8.degree., 27.7.degree., 28.4.degree., 28.7.degree., 29.1.degree., 30.8.degree., 31.9.degree., 32.3.degree., and 32.9.degree. 2.theta..+-.0.2.degree. 2.theta..

Description

FIELD OF THE INVENTION

The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt.

BACKGROUND OF THE INVENTION

Zoledronic acid is a bisphosphonic acid, which is an inhibitor of osteoclastic bone resorption. Zoledronic acid, designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid is marketed in the U.S. under the name Zometa.RTM. (zoledronic acid for injection). Zometa.RTM. is available in vials as a sterile powder for reconstitution for intravenous infusion. The prescribing information for Zometa.RTM. states that each vial of Zometa.RTM. contains 4.264 mg of zoledronic acid monohydrate (corresponding to 4 mg zoledronic acid on an anhydrous basis).

U.S. Pat. No. 4,939,130 discloses a method for making substituted alkanediphosphonic acids. Example 10 describes a method for making zoledronic acid. In this example, at the end of the reaction, the product, which is recrystallized from water, has a melting point of 239.degree. C. with decomposition. However, repetition of the procedure described in Example 10 (which requires stirring under reflux imidazol-1-ylacetic acid hydrochloride and phosphoric acid in chlorobenzene) did not lead to zoledronic acid; instead, the starting material was collected at the end of the reaction. Moreover, the last step of crystallization could not be repeated exactly since the detailed experimental parameters are not given (different cooling regimes, for instance, can produce different polymorphs when crystallized in the same solvent).

In the paper Drugs of the future 2000, 25(3): 259-268 the following forms of Zoledronate are listed: 1) Zoledronic acid disodium salt tetrahydrate CAS No. 165800-07-7 2) Zoledronic acid magnesium salt CAS No. 157432-59-2 3) Zoledronic acid zinc salt CAS No. 157432-58-1 4) Zoledronic acid disodium salt anhydrous CAS No. 131654-46-1 5) Zoledronic acid anhydrous CAS No. 118072-93-8 6) Zoledronic acid monohydrate CAS No. 165800-06-6

It is also disclosed in the paper that the free acid has a melting point of 239.degree. C. with decomposition, and the disodium salt dihydrate has a melting point of 291-293.degree. C. with decomposition. However, the paper does not describe any procedure to obtain the forms mentioned therein, nor does it give any additional data by which they can be identified. Moreover, there is nothing in the literature that discloses polymorphs or different crystal forms of zoledronic acid.

The solid state physical properties of a compound can be influenced by controlling the conditions under which the compounds are obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

These practical physical characteristics are determined by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray diffraction (PXRD), solid state .sup.13C NMR spectrometry and infrared spectrometry.

The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. The invention provides for new polymorphic forms of zoledronic acid and zoledronate sodium, and for amorphous zoledronate sodium.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative PXRD pattern of zoledronic acid Form I.

FIG. 2 is a representative DSC curve of zoledronic acid Form I.

FIG. 3 is a representative PXRD pattern of zoledronic acid Form II.

FIG. 4 is a representative PXRD pattern of zoledronic acid Form XII.

FIG. 5 is a representative PXRD pattern of zoledronic acid Form XV.

FIG. 6 is a representative PXRD pattern of zoledronic acid Form XVIII.

FIG. 7 is a representative PXRD pattern of zoledronic acid Form XX.

FIG. 8 is a representative PXRD pattern of zoledronic acid Form XXVI.

FIG. 9 is a representative PXRD pattern of zoledronate monohydrate Form VIII.

FIG. 10 is a representative PXRD pattern of zoledronate monosodium Form XVI.

FIG. 11 is a representative PXRD pattern of zoledronate monosodium Form XVII.

FIG. 12 is a representative PXRD pattern of zoledronate disodium Form V.

FIG. 13 is a representative PXRD pattern of zoledronate disodium Form VI.

FIG. 14 is a representative PXRD pattern of zoledronate disodium Form VII.

FIG. 15 is a representative PXRD pattern of zoledronate disodium Form X.

FIG. 16 is a representative PXRD pattern of zoledronate disodium Form XIII.

FIG. 17 is a representative PXRD pattern of zoledronate disodium Form XIV.

FIG. 18 is a representative PXRD pattern of zoledronate disodium Form XIX.

FIG. 19 is a representative PXRD pattern of zoledronate disodium Form XXV.

FIG. 20 is a representative PXRD pattern of zoledronate disodium Form XXVII.

FIG. 21 is a representative PXRD pattern of zoledronate disodium Form IX.

FIG. 22 is a representative PXRD pattern of zoledronate disodium Form XI.

FIG. 23 is a representative PXRD pattern of zoledronate sodium amorphous.

FIG. 24 is a representative TGA curve of zoledronic acid Form I.

FIG. 25 is a representative TGA curve of zoledronic acid Form II.

FIG. 26 is a representative TGA curve of zoledronic acid Form XII.

FIG. 27 is a representative TGA curve of zoledronic acid Form XV.

FIG. 28 is a representative TGA curve of zoledronic acid Form XVIII.

FIG. 29 is a representative TGA curve of zoledronic acid Form XX.

FIG. 30 is a representative TGA curve of zoledronic acid Form XXVI.

FIG. 31 is a representative TGA curve of zoledronate monosodium Form VIII.

FIG. 32 is a representative TGA curve of zoledronate monosodium Form XVI.

FIG. 33 is a representative TGA curve of zoledronate monosodium Form XVII.

FIG. 34 is a representative TGA curve of zoledronate disodium Form V.

FIG. 35 is a representative TGA curve of zoledronate disodium Form VI.

FIG. 36 is a representative TGA curve of zoledronate disodium Form VII.

FIG. 37 is a representative TGA curve of zoledronate disodium Form X.

FIG. 38 is a representative TGA curve of zoledronate disodium Form XIII.

FIG. 39 is a representative TGA curve of zoledronate disodium Form XIV.

FIG. 40 is a representative TGA curve of zoledronate disodium Form XIX.

FIG. 41 is a representative TGA curve of zoledronate disodium Form XXV.

FIG. 42 is a representative TGA curve of zoledronate disodium Form XXVII.

FIG. 43 is a representative TGA curve of zoledronate disodium Form IX.

FIG. 44 is a representative TGA curve of zoledronate disodium Form XI.

SUMMARY OF THE INVENTION

The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt. The invention can be understood by reference to the following numbered embodiments.

1. Crystalline solid zoledronic acid (Form I) characterized by a powder X-ray diffraction pattern having peaks at 12.1.degree., 12.8.degree., 15.7.degree., and 18.9.degree. 2.theta..+-.0.2.degree. 2.theta..

2. The crystalline solid zoledronic acid of embodiment 1, further characterized by a powder XRD pattern with peaks at 20.9.degree., 21.3.degree., 21.8.degree., 22.2.degree., 25.8.degree., 27.6.degree., 29.2.degree., 32.5.degree., and 32.9.degree. 2.theta..+-.0.2.degree. 2.theta..

3. The crystalline solid zoledronic acid of embodiment 1, which contains less than about 5% of other polymorphic forms of zoledronic acid.

4. The crystalline solid zoledronic acid of embodiment 1, of which no more than about 5% transforms to zoledronic acid Form II upon exposure to 100% relative humidity (RH) for 7 days.

5. The crystalline solid zoledronic acid of embodiment 4, of which no more than about 5% transforms to other polymorphic forms of zoledronic acid upon exposure to 100% relative humidity (RH) for 7 days.

6. The crystalline solid zoledronic acid of embodiment 1, which, upon exposure to 100% relative humidity (RH) for 7 days, absorbs less than about 0.2% water.

7. The crystalline solid zoledronic acid of embodiment 1, which, upon exposure to 100% relative humidity (RH) for 7 days, retains its X-ray diffraction pattern substantially as shown in figure no. 1.

8. The crystalline solid zoledronic acid of embodiment 1, of which no more than about 5% transforms to zoledronic acid form II upon exposure to 75% relative humidity (RH) at 40.degree. C. for 3 months.

9. The crystalline solid zoledronic acid of embodiment 8, of which no more than about 5% transforms to other polymorphic forms of zoledronic acid upon exposure to 75% relative humidity (RH) at 40.degree. C. for 3 months.

10. The crystalline solid zoledronic acid of embodiment 1, which, upon exposure to 75% relative humidity (RH) at 40.degree. C. for 3 months, absorbs less than about 0.2% water.

11. The crystalline solid zoledronic acid of embodiment 1, which, upon exposure to 75% relative humidity (RH) at 40.degree. C. for 3 months, retains its X-ray diffraction pattern substantially as shown in figure no. 1.

12. A pharmaceutical composition comprising the crystalline zoledronic acid of any of embodiments 1 to 11.

13. The crystalline solid zoledronic acid of embodiment 1, which is a monohydrate.

14. Crystalline solid zoledronic acid (Form II) characterized by a powder X-ray diffraction pattern having peaks at 14.6.degree., 15.4.degree., 19.1.degree., 22.9.degree., and 23.9.degree. 2.theta..+-.0.2.degree. 2.theta..

15. The crystalline zoledronic acid of embodiment 14, further characterized by a powder X-ray diffraction pattern with peaks at 20.8.degree., 21.7.degree., 25.1.degree., 26.7.degree., 29.5.degree., and 29.9.degree. 2.theta..+-.0.2.degree. 2.theta..

16. The crystalline solid zoledronic acid of embodiment 14, which is a monohydrate.

17. Crystalline solid zoledronic acid (Form XII) characterized by a powder X-ray pattern having peaks at 9.0.degree., 13.9.degree., 14.8.degree., 21.5.degree., 24.7.degree., and 29.8.degree. 2.theta..+-.0.2.degree. 2.theta..

18. The crystalline zoledronic acid of embodiment 17, further characterized by a powder X-ray diffraction pattern with peaks at 17.0.degree., 20.6.degree., 20.8.degree., 22.4.degree., 25.8.degree., 27.7.degree., 28.4.degree., 28.7.degree., 29.1.degree., 30.8.degree., 31.9.degree., 32.3.degree., and 32.9.degree. 2.theta..+-.0.2.degree. 2.theta..

19. The crystalline solid zoledronic acid of embodiment 17, which is a monohydrate.

20. Crystalline solid zoledronic acid (Form XV) characterized by a powder X-ray diffraction pattern having peaks at 10.1.degree., 17.3.degree., 19.3.degree., and 23.2.degree. 2.theta..+-.0.2.degree. 2.theta..

21. The crystalline zoledronic acid of embodiment 2, further characterized by a powder X-ray diffraction pattern with peaks at 14.5.degree., 16.7.degree., 18.1.degree., 24.5.degree., 25.1.degree., 25.7.degree., 28.5.degree., 29.1.degree., 29.6.degree., and 30.4.degree. 2.theta..+-.0.2.degree. 2.theta..

22. The crystalline solid zoledronic acid of embodiment 20, which is anhydrous.

23. Crystalline solid zoledronic acid (Form XVIII) characterized by a powder X-ray diffraction pattern having peaks at 10.7.degree., 13.0.degree., 16.4.degree., 17.4.degree., and 28.5.degree. 2.theta..+-.0.2.degree. 2.theta..

24. The crystalline zoledronic acid of embodiment 23, further characterized by a powder X-ray diffraction pattern with peaks at 13.3.degree., 18.1.degree., 19.3.degree., 21.3.degree., 23.7.degree., 25.9.degree., 31.5.degree., and 34.5.degree. 2.theta..+-.0.2.degree. 2.theta..

25. The crystalline solid zoledronic acid of embodiment 23, which is a monohydrate.

26. Crystalline solid zoledronic acid (Form XX) characterized by a powder X-ray diffraction pattern having peaks at 12.2.degree., 19.3.degree., 20.2.degree., 21.3.degree., 25.1.degree., and 27.25.degree. 2.theta..+-.0.2.degree. 2.theta..

27. The crystalline zoledronic acid of embodiment 26, further characterized by a powder X-ray diffraction pattern with peaks at 11.4.degree., 14.9.degree., 15.5.degree., 17.2.degree., 18.2.degree., and 30.5.degree. 2.theta..+-.0.2.degree. 2.theta..

28. The crystalline solid zoledronic acid of embodiment 26, which is anhydrous.

29. Crystalline solid zoledronic acid (Form XXVI) characterized by a powder X-ray diffraction pattern having peaks at 9.8.degree., 14.5.degree., 17.1.degree., 17.6.degree., and 18.3.degree. 2.theta..+-.0.2.degree. 2.theta..

30. The crystalline zoledronic acid of embodiment 29, further characterized by a powder X-ray diffraction pattern with peaks at 18.8.degree., 19.7.degree., 21.4.degree., 25.7.degree., 26.6.degree., and 28.1.degree. 2.theta..+-.0.2.degree. 2.theta..

31. The crystalline solid zoledronic acid of embodiment 29, which is anhydrous.

32. A pharmaceutical composition comprising the crystalline solid zoledronic acid of any of embodiments 12 to 31.

33. Crystalline solid zoledronate monosodium.

34. Crystalline solid zoledronate monosodium hydrate.

35. The crystalline solid zoledronate monosodium of embodiment 33, characterized by a powder X-ray diffraction pattern having peaks at 8.2.degree., 15.5.degree., 18.6.degree., 23.6.degree., and 26.8.degree. 2.theta..+-.0.2.degree. 2.theta. (Form VIII).

36. The crystalline solid zoledronate monosodium of embodiment 35, further characterized by a powder X-ray diffraction pattern with peaks at 11.8.degree., 17.6.degree., 20.1.degree., 24.7.degree., 25.0.degree., 28.4.degree., 31.7.degree., and 32.8.degree. 2.theta..+-.0.2.degree. 2.theta..

37. The crystalline solid zoledronate monosodium of embodiment 35, which is a trihydrate.

38. The crystalline solid zoledronate monosodium of embodiment 33, characterized by a powder X-ray diffraction pattern having peaks at 7.3.degree., 8.8.degree., 14.7.degree., 21.8.degree., and 29.6.degree. 2.theta..+-.0.2.degree. 2.theta. (form XVI).

39. The crystalline solid zoledronate monosodium of embodiment 38, further characterized by a powder X-ray diffraction pattern with peaks at 13.8.degree., 16.8.degree., 20.4.degree., 21.4.degree., 24.4.degree., 25.6.degree., 27.5.degree., 28.2.degree., and 31.7.degree. 2.theta..+-.0.2.degree. 2.theta..

40. The crystalline solid zoledronate monosodium of embodiment 38, which is a dihydrate.

41. The crystalline solid zoledronate monosodium of embodiment 33, characterized by a powder X-ray diffraction pattern having peaks at 8.2.degree., 9.0.degree., 14.5.degree., 21.4.degree., 24.5.degree., and 29.2.degree. 2.theta..+-.0.2.degree. 2.theta. (Form XVII).

42. The crystalline solid zoledronate monosodium of embodiment 41, further characterized by a powder X-ray diffraction pattern with peaks at 13.9.degree., 15.5.degree., 16.8.degree., 18.6.degree., 22.3.degree., 23.6.degree., 26.7.degree., 27.7.degree., and 32.3.degree. 2.theta..+-.0.2.degree. 2.theta..

43. The crystalline solid zoledronate monosodium of embodiment 41, which is a dihydrate.

44. Crystalline solid zoledronate disodium.

45. Crystalline solid zoledronate disodium hydrate.

46. Crystalline solid zoledronate disodium anhydrous.

47. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having at 11.3.degree., 14.8.degree., 15.5.degree., 17.4.degree., and 19.9.degree. 2.theta..+-.0.2.degree. 2.theta. (Form V).

48. The crystalline solid zoledronate disodium of embodiment 47, further characterized by a powder X-ray diffraction pattern with peaks at 18.0.degree., 18.9.degree., 19.7.degree., 22.7.degree., 25.0.degree., 26.7.degree., 30.9.degree., and 34.5.degree. 2.theta..+-.0.2.degree. 2.theta..

49. The crystalline solid zoledronate disodium of embodiment 47, which is a dihydrate.

50. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having peaks at 7.2.degree., 13.3.degree., 13.7.degree., 14.5.degree., and 21.7.degree. 2.theta..+-.0.2.degree. 2.theta. (Form VI).

51. The crystalline solid zoledronate disodium of embodiment 50, further characterized by a powder X-ray diffraction pattern with peaks at 8.2.degree., 16.6.degree., 16.9.degree., 17.3.degree., 25.9.degree., 26.6.degree., 30.7.degree., 31.9.degree., and 32.9.degree. 2.theta..+-.0.2.degree. 2.theta..

52. The crystalline solid zoledronate disodium of embodiment 50, which is a trihydrate.

53. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having peaks at 6.2.degree., 11.6.degree., 12.6.degree., and 13.7 2.theta..degree..+-.0.2.degree. 2.theta. (Form VII).

54. The crystalline solid zoledronate disodium of embodiment 53, further characterized by a powder X-ray diffraction pattern with peaks at 22.0.degree., 23.2.degree., 26.4.degree., 27.1.degree., 28.6.degree., 28.8.degree., and 34.2.degree. 2.theta..+-.0.2.degree. 2.theta..

55. The crystalline solid zoledronate disodium of embodiment 53, which is a tetrahydrate.

56. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having peaks at 6.7.degree., 14.4.degree., 18.2.degree., 20.4.degree., and 20.7.degree. 2.theta..+-.0.2.degree. 2.theta. (Form X).

57. The crystalline solid zoledronate disodium of embodiment 56, further characterized by a powder X-ray diffraction pattern with peaks at 8.8.degree., 13.7.degree., 17.0.degree., 19.8.degree., 21.3.degree., 24.4.degree., 27.5.degree., 27.9.degree., 30.9.degree., and 33.4.degree. 2.theta..+-.0.2.degree. 2.theta..

58. The crystalline solid zoledronate disodium of embodiment 56, which is a hemihydrate.

59. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having peaks at 6.5.degree., 13.0.degree., 16.1.degree., 17.2.degree., and 30.7.degree. 2.theta..+-.0.2.degree. 2.theta. (Form XIII).

60. The crystalline solid zoledronate disodium of embodiment 59, further characterized by a powder X-ray diffraction pattern with peaks at 10.2.degree., 19.0.degree., 20.0.degree., 20.6.degree., 22.3.degree., 27.4.degree., 28.6.degree., 28.9.degree., and 34.8.degree. 2.theta..+-.0.2.degree. 2.theta..

61. The crystalline solid zoledronate disodium of embodiment 59, which is a hemihydrate.

62. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having peaks at 6.6.degree., 19.9.degree., 28.5.degree., and 34.8.degree. 2.theta..+-.0.2.degree. 2.theta. (Form XIV).

63. The crystalline solid zoledronate disodium of embodiment 62, further characterized by a powder X-ray diffraction pattern with peaks at 13.0.degree., 15.1.degree., 17.1.degree., 20.5.degree., 27.7.degree., 29.6.degree., 30.7.degree., and 33.5.degree. 2.theta..+-.0.2.degree. 2.theta..

64. The crystalline solid zoledronate disodium of embodiment 62, which is anhydrous.

65. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having peaks at 11.6.degree., 12.5.degree., 13.7.degree., 22.0.degree., and 23.1 .degree. 2.theta..+-.0.2.degree. 2.theta. (Form XIX).

66. The crystalline solid zoledronate disodium of embodiment 65, further characterized by a powder X-ray diffraction pattern with peaks at 6.2.degree., 14.3.degree., 15.3.degree., 16.0.degree., 18.5.degree., 24.3.degree., and 28.6.degree. 2.theta..+-.0.2.degree. 2.theta..

67. The crystalline solid zoledronate disodium of embodiment 65, which is a pentahydrate.

68. The crystalline solid zoledronate disodium of embodiment 44, characterized by a powder X-ray diffraction pattern having peaks at 7.4.degree., 13.7.degree., 17.6.degree., and 21.9.degree. 2.theta..+-.0.2.degree. 2.theta. (Form XXV).

69. The crystalline solid zoledronate disodium of embodiment 68, further characterized by a powder X-ray diffraction pattern with peaks at 6.3.degree., 9.5.degree., 12.6.degree., 14.6.degree., 26.2.degree., 27.1.degree., and 28.6.degree. 2.theta..+-.0.2.degree. 2.theta..

70. The crystalline solid zoledronate disodium of embodiment 68, which is a sesquihydrate.

71. The crystalline solid zoledronate disodium of embodiment 44, which is a monohydrate characterized by a powder X-ray diffraction pattern having peaks at 6.4.degree., 8.2.degree., 16.0.degree., 17.4.degree., 19.0.degree., and 28.8.degree. 2.theta..+-.0.2.degree. 2.theta. (Form XXVII).

72. The crystalline solid zoledronate disodium of embodiment 71, further characterized by a powder X-ray diffraction pattern with peaks at 7.7.degree., 10.2.degree., 17.2.degree., 18.1.degree., 21.6.degree., 25.7.degree., and 25.9.degree. 2.theta..+-.0.2.degree. 2.theta..

73. The crystalline solid zoledronate disodium of embodiment 71, which is a monohydrate.

74. Crystalline solid zoledronate trisodium.

75. The crystalline solid zoledronate trisodium of embodiment 74, characterized by a powder X-ray diffraction pattern having peaks at 8.3.degree., 10.9.degree., 15.0.degree., 16.6.degree., and 22.8.degree. 2.theta..+-.0.2.degree. 2.theta. (Form IX).

76. The crystalline solid zoledronate trisodium of embodiment 75, further characterized by a powder X-ray diffraction pattern with peaks at 13.1.degree., 20.2.degree., 20.6.degree., 20.9.degree., 25.0.degree., 27.8.degree., and 29.0.degree. 2.theta..+-.0.2.degree. 2.theta..

77. The crystalline solid zoledronate trisodium of embodiment 75, which is a trihydrate.

78. The crystalline solid zoledronate trisodium of embodiment 74, characterized by a powder X-ray diffraction pattern having peaks at 6.2.degree., 7.9.degree., 8.8.degree., 10.6.degree., and 12.2.degree. 2.theta..+-.0.2.degree. 2.theta. (Form XI).

79. The crystalline solid zoledronate trisodium of embodiment 78, further characterized by a powder X-ray diffraction pattern with peaks at 15.0.degree., 15.4.degree., 17.5.degree., 18.8.degree., 19.6.degree., 20.5.degree., 22.3.degree., 23.7.degree., 25.7.degree., 29.6.degree., and 31.7.degree. 2.theta..+-.0.2.degree. 2.theta..

80. The crystalline solid zoledronate trisodium of embodiment 78, which is a dihydrate.

81. A process for preparing a solid crystalline zoledronate sodium salt comprising:

a) dissolving zoledronic acid in water to form a solution;

b) adding a base, preferably sodium hydroxide, to the solution; and

c) cooling the solution, optionally with the addition of an organic solvent such as isopropyl alcohol, to precipitate crystalline zoledronate sodium.

82. The process of embodiment 81, wherein the crystalline solid zoledronate sodium salt is the monosodium salt.

83. The process of embodiment 82, wherein the crystalline solid zoledronate monosodium is selected from the group consisting of Form VIII, Form XVI and Form XVII.

84. The process of embodiment 81, wherein the crystalline solid zoledronate sodium salt is the disodium salt.

85. The process of embodiment 84, wherein the crystalline solid zoledronate disodium is selected from the group consisting of Form V, Form VI, Form VII, Form X, Form XIII, Form XIV, Form XIX, Form XXV, and Form XXVII.

86. The process of embodiment 81, wherein the crystalline solid zoledronate sodium salt is the trisodium salt.

87. The process of embodiment 86, wherein the crystalline solid zoledronate trisodium is selected from the group consisting of Form IX and Form XI.

88. A process for preparing a crystalline solid zoledronate sodium salt comprising:

a) suspending zoledronic acid in a mixture of alcohol/water, preferably at reflux temperature

b) adding to the suspension of a) a solution of a base, preferably sodium hydroxide, in an equivalent mixture of alcohol/water as that used in the suspension of a), to form a reaction mixture; and

c) stirring the reaction mixture for a time sufficient to precipitate a crystalline solid zoledronate sodium salt.

89. The process of embodiment 88, wherein the reaction mixture is stirred at reflux for about 10 to about 20 hours, preferably about 14-16.

90. The process of embodiment 88, wherein the volume ratio of alcohol/water to zoledronic acid in a) and b) is 6-14 volumes, preferably 10 volumes.

91. The process of embodiment 88, wherein the alcohol in a) and b) is selected from the group consisting of methanol, ethanol, isopropanol and dimethylformamide.

92. The process of embodiment 88, wherein the zoledronic acid is zoledronic acid Form I and the ratio of acid to base is 1:1.

93. The process of embodiment 88, wherein the zoledronic acid is zoledronic acid Form I and the ratio of acid to base is 1:2.

94. The process of embodiment 88, wherein the zoledronic acid is zoledronic acid Form XII and the ratio of acid to base is 1:1.1.

95. The process of embodiment 92, wherein the crystalline solid zoledronate sodium salt is the monosodium salt.

96. The process of embodiment 95, wherein the crystalline solid zoledronate monosodium is selected from the group consisting of Form VIII, Form XVI and Form XVII.

97. The process of embodiment 93 or embodiment 94, wherein the crystalline solid zoledronate sodium salt is the disodium salt.

98. The process of embodiment 97, wherein the crystalline solid zoledronate disodium is selected from the group consisting of Form V, Form VI, Form VII, Form X, Form XIII, Form XIV, Form XIX, Form XXV, and Form XXVII.

99. The process of embodiment 0, wherein the zoledronic acid is zoledronic acid Form XII and the ratio of acid to base is 1:2.1.

100. The process of embodiment 99, wherein the crystalline solid zoledronate sodium salt is the trisodium salt.

101. The process of embodiment 100, wherein the crystalline solid zoledronate trisodium is selected from the group consisting of Form IX and Form XI.

102. A process for preparing a solid crystalline zoledronate sodium salt comprising:

a) dissolving a crystal form of zoledronate sodium in water, preferably at reflux, to form a solution; and

b) cooling the solution to precipitate a crystal form of zoledronate sodium which is different from the starting form in a).

103. The process of embodiment 102, wherein the water is added in an amount of between 20-30 volumes, preferably 25 volumes, per volume of zoledronate sodium.

104. A process for preparing crystalline solid zoledronate monosodium Form VIII comprising:

a) adding a solution of a base in an 80%/20% v/v mixture of water/ethanol to a suspension of zoledronic acid form I in an 80%/20% v/v mixture of water/ethanol at elevated temperature, preferably reflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form VIII.

105. The process of embodiment 104, wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.

106. The process of embodiment 104, wherein the volume ratio of water/ethanol to zoledronic acid form I in the suspension and the solution is between 6 and 14, preferably 10.

107. A process for preparing crystalline solid zoledronate monosodium Form VIII comprising:

a) adding a solution of a base in an 80%/20% v/v mixture of water/methanol to a suspension of zoledronic acid form I in an 80%/20% v/v mixture of water/methanol at elevated temperature, preferably reflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form VIII.

108. The process of embodiment 107, wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.

109. The process of embodiment 107, wherein the volume ratio of water/methanol to zoledronic acid form I in the suspension and the solution is between 6-14, preferably 10.

110. A process for preparing crystalline solid zoledronate monosodium Form VIII comprising:

a) adding a solution of a base in an 60%/40% v/v mixture of water/isopropanol to a suspension of zoledronic acid form I in an 60%/40% v/v mixture of water/isopropanol at elevated temperature, preferably reflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form VIII.

111. The process of embodiment 110, wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.

112. The process of embodiment 110, wherein the volume ratio of water/isopropanol to zoledronic acid form I in the suspension and the solution is between 6 and 14, preferably 10.

113. A process for preparing crystalline solid zoledronate monosodium Form XVI comprising:

a) adding a solution of a base in a 50%/o/50% v/v mixture of water/ethanol to a suspension of zoledronic acid form I in a 50%/50% v/v mixture of water/ethanol at elevated temperature, preferably reflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form XVI.

114. The process of embodiment 113, wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.

115. The process of embodiment 113, wherein the volume ratio of water/ethanol to zoledronic acid form I in the suspension and the solution is between 6 and 14, preferably 10.

116. A process for preparing crystalline solid zoledronate monosodium Form XVI comprising:

a) adding a solution of a base in a 50%/50% v/v mixture of water/isopropanol to a suspension of zoledronic acid Form I in a 50%/50% v/v mixture of water/isopropanol at elevated temperature, preferably reflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours, preferably 14 to 16 hours; and

c) precipitating zoledronate monosodium Form XVI.

117. The process of embodiment 116, wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.

118. The process of embodiment 116, wherein the volume ratio of water/isopropanol to zoledronic acid form I in the suspension and the solution is between 6 and 14, preferably 10.

119. A process for preparing crystalline solid zoledronate monosodium Form XVI comprising:

a) adding a solution of a base in a 50%/50% v/v mixture of water/methanol to a suspension of zoledronic acid form I in a 50%/50% v/v mixture of water/ethanol at elevated temperature, preferably reflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20 hours, preferably 14 to 16 hours; and

c) precipitating zoledronate monosodium Form XVI.

120. The process of embodiment 119, wherein the base is sodium hydroxide, which is added in an amount of a 1:1 molar ratio to the zoledronic acid.

121. The process of embodiment 119, wherein the volume ratio of water/methanol to zoledronic acid form I in the solution is between 6 and 14, preferably 10, and the volume ratio of water/ethanol in the suspension is between 6 and 14, preferably 10.

122. A process for preparing solid crystalline zoledronate sodium Form XVII comprising: a) dissolving zoledronic acid Form I in water to form a solution; b) adding a base, preferably sodium hydroxide, to the solution; and c) cooling the solution, optionally with the addition of an organic solvent, to precipitate crystalline zoledronate sodium Form XVII.

123. A pharmaceutical composition comprising the crystalline solid zoledronate monosodium of any of embodiments 35 to 43.

124. A pharmaceutical composition comprising the crystalline solid zoledronate disodium of any of embodiments 47 to 73.

125. A pharmaceutical composition comprising the crystalline solid zoledronate trisodium of any of embodiments 75 to 80.

126. Amorphous monosodium zoledronate.

127. Amorphous disodium zoledronate.

128. Amorphous trisodium zoledronate.

129. A pharmaceutical composition comprising the amorphous solid zoledronate of any of embodiments 126, 127 and 128.

130. A process for preparing zoledronate amorphous sodium comprising: treating zoledronic acid and a base, preferably sodium hydroxide, in water at room temperature and precipitating zoledronate amorphous sodium.

131. The process of embodiment 130, wherein the ratio of acid:base is 1:1.1.

132. The process of embodiment 130, wherein the ratio of acid:base is 1:2.1.

DETAILED DESCRIPTION OF THE INVENTION

Powder X-ray diffraction ("PXRD") analysis was performed on a Scintag X-Ray powder diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 .ANG. was used. A round aluminum sample holder with round zero background quartz plate, with a cavity of 25 mm diameter and 0.5 mm depth, was used.

Loss on drying ("LOD") was measured by Thermal Gravimetric Analysis ("TGA") using a Mettler TG50. The sample size was about 9-15 mg. The samples were scanned at a rate of 10.degree. C./min from 25.degree. C. to 250.degree. C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard alumina crucibles covered by lids with one hole were used.

DSC analysis was done using a Mettler 821 Star.sup.e. The weight of the samples was about 3 mg. The samples were scanned at a rate of 10.degree. C./min from 30.degree. C. to 300.degree. C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 40 ml aluminum crucibles covered by lids with three holes were used.

Applicants have discovered that different crystal forms of Zoledronic acid may be obtained. Different forms of the zoledronic acid may have improved properties with regards to dissolution (since the dosage form is for injection, the material needs to be reconstituted in water; faster dissolution rate would mean faster reconstitution). The recrystallization of Zoledronic acid leads to a material with a purity of at least 99.5% area by HPLC.

The novel forms of zoledronic acid are hydrated. The level of water in Zoledronic acid is estimated by TGA the (thermogravimetric analysis) weight loss.

Zoledronic acid can be found in the anhydrous state (weight loss up to 2%), monohydrate (weight loss 5-8%), sesquihydrate (weight loss 9-11%).

A typical DSC scan of zoledronic acid shows an endothermic peak below about 160-170.degree. C. due mainly to water desorption, and a subsequent endotherm at about 200.degree. C. concomitant to an exotherm reaction (see FIG. 2). From this DSC scan there is no clear detection of a melting point.

Zoledronic Acid Form I

In a first aspect, the invention provides a novel crystalline solid form of Zoledronic acid that has been denominated Form I. Zoledronic acid Form I identified by its PXRD pattern, a representative example of which is provided in the diffractogram of FIG. 1. Particular characteristic peaks occur at 12.1, 12.8, 15.7, and 18.9.+-.0.2.degree. 2.theta.. Additional peaks occur at 20.9, 21.3, 21.8, 22.2, 25.8, 27.6, 29.2, 32.5, and 32.9.+-.0.2.degree. 2.theta.. The hydration level of Zoledronic acid Form I is indicated by a LOD of 5% to 8% (monohydrate) on heating from about 25-220.degree. C.

Zoledronic acid Form I is substantially free of Zoledronic acid Form II. In addition, Zoledronic acid Form I is substantially free of other polymorphic forms of Zoledronic acid. Substantially free means less than about 5%. A suitable method for detecting other phases and mixtures of polymorphs is the X-Ray powder diffraction method (see "Polymorphism in molecular crystals", Joel Bernstein, Oxford Science Publications, or "Polymorphism in pharmaceutical solids" edited by Harry G. Brittain).

Zoledronic acid Form I is physically stable and does not substantially transform to any other crystal form when exposed to 100% relative humidity (RH) or less, for one week, or stored at 40.degree. C. and 75% RH for 3 months. After exposure to 100% RH or less, for one week, there is no significant gain of moisture in Form I (not significant means that it absorbs less than about 0.2% water). "Substantially transforms to any other crystal form" means that more than about 5% of the crystal form converts or rearranges to Form II or any other crystal form.

Accordingly in one embodiment, the invention provides a pharmaceutical composition comprising zoledronic acid Form I substantially free of other polymorphic forms of zoledronic acid and at least one pharmaceutically acceptable excipient. Preferably the pharmaceutical composition is in the form of an oral solid dosage form.

In another embodiment, the invention provides a pharmaceutical composition comprising zoledronic acid Form I, which is physically stable and does not substantially transform to any other crystal form when stored at 40.degree. C. and 75% RH for 3 months, and at least one pharmaceutically acceptable excipient. Preferably the pharmaceutical composition is in the form of an oral solid dosage form.

The novel crystal forms of Zoledronic acid preferably have a particle size distribution such that 100% of the particles have a size below 100 microns, preferably below 50 microns.

Accordingly, another aspect of the invention is a pharmaceutical composition comprising a novel crystal form of zoledronic acid, which has a particle size distribution such that 100% is below 100 microns, preferably below 50 microns, and at least one pharmaceutically acceptable excipient.

Zoledronic acid Form I can be prepared by a phosphorylation reaction of 1-Imidazoleacetic acid (IAA) in the presence of Phosphorous acid and Phosphorous oxychloride in a diluent, such as, Toluene, Chlorobenzene, PEG-400 and Silicon oil. Phosphorous oxychloride is added to a mixture of Phosphorous acid and IAA at 75.degree. C. to 80.degree. C. The reaction mixture is then stirred at 80.degree. C.-100.degree. C., preferably at 80.degree. C. for 1-34 hours, preferably 5-25 hours. Then water is added at 80.degree. C.-100.degree. C. and the aqueous phase is separated. Hydrolysis occurs in about 10-20 hrs, preferably 14-16 hours. At the end of hydrolysis, a solvent like ethanol or acetone may be added to obtain a precipitate of ZLD-Ac after stirring at 5.degree. C. for 1-6 hours, preferably 2.5-4 hours.

Zoledronic Acid Form II

In a second aspect, the invention provides a novel crystalline solid form of Zoledronic acid that has been denominated Form II. Zoledronic acid Form II can be identified by its PXRD pattern, a representative example of which is provided in the diffractogram of FIG. 3. Particular characteristic peaks occur at 14.6.degree., 15.4.degree., 19.1.degree., 22.9.degree., and 23.9.degree. 2.theta..+-.0.2.degree. 2.theta.. Additional peaks occur at 20.8.degree., 21.7.degree., 25.1.degree., 26.7.degree., 29.5.degree., and 29.9.degree. 2.theta..+-.0.2.degree. 2.theta.. The hydration level of Zoledronic acid Form II is indicated by a LOD of about 5% (monohydrate) on heating from about 25-220.degree. C.

Form II can be prepared by a phosphorylation reaction of 1-Imidazoleacetic acid (IAA, 1 eq.) in the presence of Phosphorous acid (2 eq.) and Phosphorous oxychloride (.NET.) in silicon oil as a diluent. Phosphorous oxychloride is added to a mixture of phosphorous acid and IAA at 75.degree. C. The reaction mixture is then heated to 80.degree. C. for about 27 hours. Then water is added at 80.degree. C. and the aqueous phase is separated. Hydrolysis usually occurs within about 10-20 hrs, preferably 14-16 hours. At the end of hydrolysis, ethanol is added to obtain a precipitate of ZLD-Ac after stirring at 5.degree. C. for 1-6 hours, preferably 2.5-4 hours.

Zoledronic acid Form II can also be prepared by treating Zoledronic acid form I in Toluene, preferably at reflux temperature, for a duration of 5-20 hours, most preferably 10-16 hours.

Zoledronic Acid Form XI

In a third aspect, the invention provides a novel crystalline solid form of Zoledronic acid that has been denominated Form XII. Zoledronic acid Form XII can be identified by its PXRD pattern, a representative example of which is provided in the diffractogram of FIG. 4. Particular characteristic peaks occur at 9.0, 13.9, 14.8, 21.5, 24.7, and 29.8.+-.0.2.degree. 2.theta.. Additional peaks occur at 17.0.degree., 20.6.degree., 20.8.degree., 22.4.degree., 25.8.degree., 27.7.degree., 28.4.degree., 28.7.degree., 29.1.degree., 30.8.degree., 31.9.degree., 32.3.degree., and 32.9.degree. 2.theta..+-.0.2.degree. 2.theta.. The hydration level of Zoledronic acid form XII is indicated by a LOD of about 6-10%, preferably 6% (monohydrate) on heating from about 25-220.degree. C.

Zoledronic acid Form XII can be prepared by treating Zoledronic acid form XVIII in water at reflux temperature, the diluent/solid ratio being 10-30 volumes, preferably 24-26 volumes, and cooling the solution to room temperature or less.

Zoledronic Form XII can be also be prepared by stirring Form I in acetic acid.

Zoledronic Acid Form XV

In a fourth aspect, the invention provides a novel crystalline solid form of Zoledronic acid denominated Form XV. Zoledronic acid Form XV can be identified by its PXRD pattern, a representative example of which is provided in FIG. 5. Particular characteristic peaks occur at 10.1.degree., 17.3.degree., 19.3.degree., and 23.2.degree. 2.theta..+-.0.2.degree. 2.theta.. Additional peaks occur at 14.5.degree., 16.7.degree., 18.1.degree., 24.5.degree., 25.1.degree., 25.7.degree., 28.5.degree., 29.1.degree., 29.6.degree., and 30.4.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA of form XV shows a LOD of 1% (anhydrous) within the temperature range 25-220.degree. C.

Zoledronic acid Form XV can be prepared by treating any form of Zoledronic acid (preferably form I) and sodium hydroxide (1:1 mole ratio) in absolute ethanol (10 volumes per grams of ZLD-Ac) at reflux temperature for a duration of 5-20 hours, most preferably 10-16 hours.

Zoledronic acid Form XV can also be prepared by treating any form of Zoledronic acid (preferably form I or form XII) and sodium hydroxide (1:1 mole ratio) in methanol (10 volumes per grams of ZLD-Ac) at reflux temperature for a duration of 5-20 hours, most preferably 10-16 hours.

Zoledronic Acid Form XVIII

In a fifth aspect, the invention provides a novel crystalline solid form of Zoledronic acid denominated Form XVIII. Zoledronic acid Form XVIII can be identified by its PXRD pattern, a representative example of which is provided in FIG. 6. Particular characteristic peaks occur at 10.7.degree., 13.0.degree., 16.4.degree., 17.4.degree., and 28.5.degree. 2.theta..+-.0.2.degree. 2.theta.. Additional peaks occur at 13.3.degree., 18.1.degree., 19.3.degree., 21.3.degree., 23.7.degree., 25.9.degree., 31.5.degree., and 34.5.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA weight loss curve of Zoledronic acid form XVIII shows a LOD between 0.3% and about 6%, preferably 6% (monohydrate) within the temperature range 25-220.degree. C.

Zoledronic acid Form XVIII can be prepared by a reaction of 1-Imidazoleacetic acid, Phosphorous acid and Silicon oil. Phosphorous oxychloride is added to the reaction mixture at 80.degree. C. and the reaction mixture is stirred at this temperature for 22 hours. The aqueous phase is separated after addition of water and heated to reflux temperature for a 16 hours. Then absolute ethanol is added and the solution is kept at reflux temperature for 2 hours. Then the solution is cooled gradually to 25.degree. C. to obtain a precipitate of ZLD-Ac.

Zoledronic acid Form XVIII can be also prepared by treating Zoledronic acid form I in methanol, 1-butanol, MTBE, acetonitrile, methanol/water 1:1 or ethanol water 1:1 (10 volumes per grams of ZLD-Ac), at room temperature or reflux temperature, for a duration of 5-20 hours, most preferably 10-16 hours.

Zoledronic Acid Form XX

In a sixth aspect, the invention provides a novel crystalline solid form of Zoledronic acid denominated Form XX. Zoledronic acid Form XX can be identified by its PXRD pattern, a representative example of which is provided in FIG. 7. Particular characteristic peaks occur at 12.2.degree., 19.3.degree., 20.2.degree., 21.3.degree., 25.1.degree., and 27.2.degree. 2.theta..+-.0.2.degree. 2.theta.. Additional peaks occur at 11.4.degree., 14.9.degree., 15.5.degree., 17.2.degree., 18.2.degree., and 30.5.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA weight loss curve of Zoledronic acid form XX shows a LOD of about 0.5% (anhydrous) within the temperature range 25-220.degree. C.

Zoledronic acid Form XX can be prepared by treating Zoledronic acid form I in ethanol, (preferably absolute), 1-propanol, 2-propanol (IPA), preferably at reflux temperature, the diluent/solid ratio being 15-25 volumes, preferably 10 volumes, for a duration of 5-20 hours, most preferably 10-16 hours.

Zoledronic Acid Form XXVI

In a seventh aspect, the invention provides a novel crystalline solid form of Zoledronic acid, denominated Form XXVI. Zoledronic acid Form XXVI can be identified by its PXRD pattern, a representative example of which is provided in FIG. 8. Particular characteristic peaks occur at 9.8.degree., 14.5.degree., 17.1.degree., 17.6.degree., and 18.3.degree. 2.theta..+-.0.2.degree. 2.theta.. Additional peaks occur at 18.8.degree., 19.7.degree., 21.4.degree., 25.7.degree., 26.6.degree., and 28.1.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA weight loss curve of Zoledronic acid form XXVI shows typically a LOD of about 1.3% (anhydrous) within the temperature range 25-220.degree. C.

Zoledronic acid Form XXVI can be prepared by treating Zoledronic acid form I in 2-butanol, preferably at reflux temperature. The diluent/solid ratio being 15-25 volumes, preferably 10 volumes, for a duration of 5-20 hours, most preferably 10-16 hours.

Crystal Forms of Zoledronic Acid Sodium Salt

In addition, it was also discovered that Zoledronic acid sodium salt in a crystalline form could be obtained. Use of salts in drugs is very diffused, due to the improved physico-chemical properties over the free acid or free base, mainly solubility or crystallinity properties. The crystalline state of a drug, in general, has an advantage over the amorphous state in that the physical (and chemical) properties are fully controlled and reproduced, and the capability of a material to crystallize in a solid form makes this material feasible for pharmaceutical uses. Hence, the novel crystalline Zoledronate sodium salt may have improved solubility. In addition, it was found that the sodium salts obtained have a purity of at least 99.9% area by HPLC.

Surprisingly, it was also discovered that Zoledronate sodium salt can crystallize in different crystal forms.

The level of sodium is measured by methods known in the art, like atomic absorption.

Zoledronate sodium can be found in a monosodium salt, disodium salt, trisodium salt, each of them in various hydration states. The Zoledronate monosodium salt has a sodium content in the range of 6-8% w/w. Zoledronate disodium has a sodium content in the range of 11-13% w/w, and Zoledronate trisodium has a sodium content in the range of 17-19% w/w.

The level of water in Zoledronate sodium is estimated by TGA (thermogravimetric analysis) weight loss. The Zoledronate sodium salt can be anhydrous (weight loss up to 2%), a hemihydrate (weight loss 3-4% w/w), a monohydrate (weight loss 5-6%), a sesquihydrate (weight loss 7-8%), a dihydrate (weight loss 9-12% w/w), a trihydrate (13-16% weight loss), or a tetrahydrate (weight loss 17-19% w/w).

In general, sodium salts of Zoledronic acid may be prepared by treating Zoledronic acid with a base, preferably NaOH, in organic solvents, like lower alcohols or DMF, and water in different proportions relative to the organic solvent. The reaction is preferably carried out at reflux temperature. In these procedures a solution of a base in a mixture of alcohol/water is added to a suspension of Zoledronic acid in an equivalent mixture of alcohol/water at reflux temperature. The volume ratio of diluent/Zoledronic acid is 6-14, preferably 10 volumes. The reaction mixture is stirred at reflux temperature for 10-20 hours, preferably 14-16 hours. The reaction mixture can be cooled to room temperature or less, and filtered, or filtered at higher temperatures.

Alternatively, sodium salts of Zoledronic acid may be prepared by dissolving Zoledronic acid in water, adding a base, preferably NaOH, and precipitating it by cooling, optionally with the aid of an organic solvent such as isopropyl alcohol.

Alternatively, sodium salts of Zoledronic acid may be recrystallized by treating the sodium salt of Zoledronic acid in water (20-30 volumes, preferably 25 volumes) at reflux temperature and then cooling the solution to less than room temperature to obtain a precipitate of ZLD-Na.

Zoledronate Monosodium Crystal Forms

Zoledronate monosodium can be found in crystal Form VIII, characterized by typical PXRD peaks at 8.2.degree., 15.5.degree., 18.6.degree., 23.6.degree., and 26.8.degree. 2.theta..+-.0.2.degree. 2.theta., and additional peaks at 11.8.degree., 17.6.degree., 20.1.degree., 24.7.degree., 25.0.degree., 28.4.degree., 31.7.degree., 32.8.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA of form VIII shows a weight loss of 15-16% (trihydrate) within the temperature range 25-220.degree. C.

Zoledronate monosodium can be found in crystal form XVI, characterized by typical XRD peaks at 7.3.degree., 8.8.degree., 14.7.degree., 21.8.degree., and 29.6.degree. 2.theta..+-.0.2.degree. 2.theta., and additional peaks at 13.8.degree., 16.8.degree., 20.4.degree., 21.4.degree., 24.4.degree., 25.6.degree., 27.5.degree., 28.2.degree., and 31.7.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA curve of form XVI shows a weight loss of 9-10% (dihydrate) within the temperature range 25-220.degree. C.

Zoledronate monosodium can be found in crystal form XVII, characterized by typical XRD peaks at 8.2.degree., 9.0.degree., 14.5.degree., 21.4.degree., 24.5.degree., 29.2.degree. 2.theta..+-.0.2.degree. 2.theta., and additional peaks at 13.9.degree., 15.5.degree., 16.8.degree., 18.6.degree., 22.3.degree., 23.6.degree., 26.7.degree., 27.7.degree., and 32.3.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA of form XVII shows a weight loss of about 10% (dihydrate) within the temperature range 25-220.degree. C.

Zoledronate monosodium form VIII may be prepared by dissolving Zoledronic acid in water, adding NaOH in pellets or in aqueous solution (40%). IPA may be added to improve the yield of crystallization. This solution is cooled to get form VIII.

Zoledronate monosodium form VIII may be also obtained by treating Zoledronic acid, preferably form I, and sodium hydroxide (ratio of acid/base 1:1) in water/ethanol 80%:20% v/v, water/methanol 80%:20% v/v, water/isopropanol 80%:20% v/v or 60%:40% v/v.

Zoledronate monosodium form XVI may be obtained by treating Zoledronic acid, preferably form I, and sodium hydroxide (ratio of acid/base 1:1) in water/ethanol 50%:50% v/v or water/isopropanol 50%:50% v/v, or water/methanol 50%:50% v/v.

Zoledronate monosodium form XVII may be obtained by dissolving Zoledronic acid in water, adding NaOH in aqueous solution (29%) drop-wise (ratio of acid/base 1:0.7)

Zoledronate Disodium Crystal Forms

Zoledronate disodium can be found in form V, characterized by typical peaks at 11.3.degree., 14.8.degree., 15.5.degree., 17.4.degree., 19.9.degree. 2.theta..+-.0.2.degree. 2.theta., and additional peaks at 18.0.degree., 18.9.degree., 19.7.degree., 22.7.degree., 25.0.degree., 26.7.degree., 30.9.degree., and 34.5.degree. 2.theta..+-.0.2.degree. 2.theta.. The TGA curve of form V shows a weight loss of about 10-11% (dihydrate) within the temperature range 25.degree. to 220.degree. C.

Zoledronate disodium form V may be prepared by treating Zoledronic acid, preferably form XII, and sodium hydroxide (ratio of acid/base 1:1.1) in water/ethanol ratios between 20%-50% v/v water in ethanol, water/methanol ratios between 40%-50