FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PROCESS FOR PURIFICATION OF ZOLEDRONIC ACID OR SALT
THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai -400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for purification of Zoledronic acid or pharmaceutically acceptable salt thereof. The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to an efficient process for purification of zoledronic acid or pharmaceutically acceptable salt thereof.
Zoledronic acid, a bisphosphonic acid, is an inhibitor of osteoclastic bone resorption indicated in the treatment of hypercalcemia of malignancy. It is also indicated for treatment of multiple myeloma and bone metastases of solid tumors. Zoledronic acid is chemically known as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid monohydrate having structure depicted in Formula I.

FORMULA I
US Patent number 4,939,130 and Kabachnick et al, Izv. Akad. Nauk. USSR, Ser. Khim., 2, 433-437 (1987) provides process for preparation of zoledronic acid or salt thereof. The process involves treatment of imidazol-1-yl acetic acid hydrochloride with phosphoric acid and phosphorous trichloride in chlorobenzene as solvent at 100°C.
US Application No 2004-0230076 provides process for purification of zoledronic acid.
US Application No 2005-0054616 provides crystalline and amorphous forms of zoledronic acid or salt thereof and processes for their preparation.
The present inventors have found the easy process of purification of zoledronic acid through acidic pH. This significantly improved purity of zoledronic acid and salt thereof to 99.9 % and more when measured by HPLC.
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In one of the aspect of the present invention there is provided a process for purification of zoledronic acid or salt thereof, wherein the said process comprises of
a) adding the hydrochloric acid to aqueous suspension of zoledronic acid,
b) addiing base solution to adjust the pH of the solution of step a)
c) isolating the zoledronic acid that has precipitated from the solution of step (b).
In another aspect of the present invention there is provided a process for purification of zoledronic acid or salt thereof wherein the process comprises of
a) adding the base solution to aqueous suspension of zoledronic acid
b) adding acid solution to adjust the pH of the solution of step a)
c) isolating the zoledronic acid that has precipitated from the solution of step (b).
A yet another aspect of the present invention provides zoledronic acid or salt thereof having purity 99.9% or more when measured by HPLC.
Zoledronic acid was purified by dissolving in water in presence of hydrochloric acid. To clear solution the aqueous base solution such as ammonia solution, sodium hydroxide solution and the like was added to adjust the pH of reaction mixture to 1.5 or less. The reaction mixture was cooled 35 °C and the zoledronic acid or salt was isolated from the reaction mass thereof. The pure zoledronic acid thus obtained has purity having 99.9% or more when measured by HPLC.
Alternatively the zoledronic acid was purified by dissolving in presence of aqueous base solution such as sodium hydroxide and the like at the pH 6.5 or less. The clear solution is treated with the acid solution such as hydrochloric acid and the like to adjust the pH of reaction mixture to 1.5 or less. Zoledronic acid is isolated from the reaction mixture thereof as discussed above.
The zoledronic acid used can be prepared by the methods known in the art.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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EXAMPLE 1
Zoledronic acid (10 gm) was suspended in water (40 ml). Hydrochloric acid (25 ml)
was added to get clear solution. pH of the solution was adjusted to 1 by using
aqueous ammonia. The solution was cooled to 5°C and stirred to precipitate the
material. The precipitated material was isolated, washed and dried to get zoledronic
acid and salt thereof.
Yield: 7.7 gm.
Purity by HPLC: 99.98%
EXAMPLE 2
Zoledronic acid (10 gm) was suspended in water (40 ml). Hydrochloric acid (25 ml) was added to get clear solution. pH of the solution was adjusted to 1 by using aqueous sodium hydroxide. The solution was cooled to 5°C and stirred to precipitate the material. The precipitated material was isolated, washed and dried to get zoledronic acid and salt thereof. Yield: 7.3 gm HPLC Purity 99.98%
EXAMPLE 3
Zoledronic acid (10 gm) was suspended in water (100 ml). The sodium hydroxide solution (36 ml) was added to adjust the pH of the suspension to 6.5 or less. The reaction mixture pH was adjusted to 1 or less by hydrochloric acid. The solution was cooled to 5°C to precipitate the material. The precipitated material was isolated, washed and dried to get Zoledronic acid and salt thereof. Yield: 8.8 gm Purity by HPLC: 99.98 %
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WE CLAIM:
1. Process for purification of zoledronic acid or salt thereof, wherein the said
process comprises of
a) adding the hydrochloric acid to aqueous suspension of zoledronic acid,
b) adding base solution to adjust the pH of the solution of step a)
c) isolating the zoledronic acid that has precipitated from the solution of step (b).

2. A process of claim 1 wherein the pH of solution is adjusted to 1.5 or less.
3. A process of claim 2 wherein the pH is adjusted by using aqueous base solution such as ammonia solution, sodium hydroxide solution and the like.
4. A process for purification of zoledronic acid or salt thereof wherein the process comprises of

a) adding the base solution to aqueous suspension of zoledronic acid
b) adding acid solution to adjust the pH of the solution of step a)
c) isolating the zoledronic acid that has precipitated from the solution of step (b).

5. A process of claim 4 wherein the pH of solution is adjusted to 1.5 or less.
6. A process of claim 4 wherein the pH is adjusted by using aqueous hydrochloric acid solution and the like.
7. A process according to claim 1 and 4 wherein Zoledronic acid is isolated at temperature below 10°C.
8. A process according to claim 1 and 4 wherein Zoledronic acid is isolated at temperature below 35°C.
9. Zoledronic acid or salt thereof of purity 99.9% w/w or more.
Dated this 1st day of December 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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