FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF ANHYDROUS ZOLEDRONIC ACID OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Sandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for preparation of anhydrous 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 preparation of anhydrous 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 an efficient process for the preparation of anhydrous zoledronic acid, which involves removal of moisture from zoledronic acid or hydrate thereof and crystallizing the anhydrous zoledronic acid from suitable organic solvent. The process of present invention is easily scalable at commercial scale.
2

In one of the aspect of the present invention there is provided a one-pot process for preparation of anhydrous zoledronic acid, wherein the said process comprises of
a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid and phosphorous oxychloride
b) to the mixture of step a) organic solvent is added
c) isolating the anhydrous zoledronic acid from the reaction mass thereof.
In another aspect of the present invention there is provided a process for preparation of anhydrous zoledronic acid, wherein the process comprises of,
a) adding organic solvent to the aqueous solution of zoledronic acid,
b) isolating the anhydrous zoledronic acid from the reaction mass thereof.
A yet another aspect of the present invention provides anhydrous zoledronic acid having purity 99.9% or more when measured by HPLC.
A one-pot process for preparation of anhydrous zoledronic acid involves reacting the mixture of imidazol-1-yl acetic acid or salt thereof and phosphorous acid by heating. To this phosphorous oxychloride was added slowly at a temperature of about 75°C. A solution of hydrochloric acid was added and the entire mass was heated to above 75°C for till the completion of reaction and then cooled to below 40°C. The organic solvent such as acetone was added to the reaction mixture and further cooled to 15-20°C. After complete precipitation of the product, the anhydrous zoledronic acid was isolated from the reaction mass thereof as white crystalline solid.
Alternatively, the zoledronic acid was prepared by the methods known in the art. The zoledronic acid solution was prepared in water either by heating to temperature more than 75°C or acidifying by using acids such as hydrochloric acid, sulphuric acid, acetic acid and the like. The product is precipitated, by adding organic solvent to the clear mixture. The resultant mixture was cooled to below 35°C for complete precipitation of the product and the anhydrous zoledronic acid was isolated from the reaction mass thereof as white crystalline solid. The organic solvents are same as defined above.
3

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.
EXAMPLE 1
A mixture of imidazol-1-yl acetic acid (45 gm) and phosphorous acid (146 gm) was heated under stirring to about 60-80°C to get a homogeneous solution. To the reaction mixture phosphorous oxychloride (162 gm) was added at a temperature of about 75°C. The resultant mass was stirred for 5-6 hours and cooled. A solution of hydrochloric acid (9N, 209 ml) was added over 30 minutes and the entire mass was heated at 90°C for about 12 hours, cooled and filtered. Acetone (510 ml) was added to the filtrate and the resultant mixture was cooled to 15-20°C. After complete precipitation of the product, the anhydrous zoledronic acid was isolated from the reaction mass thereof as white crystalline solid. Yield: 75 gm Purity by HPLC: 99.9%
EXAMPLE 2
Zoledronic acid (10 gm) was suspended in water (300 ml). The resultant reaction mixture was heated to temperature of about 90°C. The hot solution was treated with activated charcoal and filtered. To The filtrate acetone (500 ml) was added. Reaction mass was stirred for 2 hours at 15-20 °C. After complete precipitation of the product, the anhydrous zoledronic acid was isolated from the reaction mass thereof as white crystalline solid. Yield: 9.7 gm Purity by HPLC: 99.95%
EXAMPLE 3 Zoledronic acid (10 gm) was suspended in water (40 ml) at room temperature. To the suspension dilute hydrochloric acid (40 ml) was added. Stirred the reaction mass for 20 minutes and charcolised. To The filtrate acetone (160 ml) was added. The resulting mass was cooled to 5-10°C and stirred 2 hours. After complete precipitation of the product, the anhydrous zoledronic acid was isolated from the reaction mass thereof as white crystalline solid. Yield: 8.4 gm Purity by HPLC: 99.99
4

WE CLAIM:
1. One-pot process for preparation of anhydrous zoledronic acid, wherein the said
process comprises of
a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid and phosphorous oxychloride
b) to the mixture of step a) organic solvent is added
c) isolating the anhydrous zoledronic acid from the reaction mass thereof.

2. A process of claim 1 wherein the organic solvent is acetone.
3. A process of claim 1 wherein the anhydrous zoledronic acid is isolated by cooling to temperature below 35°C.
4. Process for preparation of anhydrous zoledronic acid, wherein the process
comprises of
a) adding organic solvent to the aqueous solution of zoledronic acid
b) isolating the anhydrous zoledronic acid from the reaction mass thereof.

5. A process of claim 4, wherein the organic solvent is acetone.
6. A process of claim 4, wherein the aqueous solution of zoledronic acid is obtained in water either by heating to temperature more than 75°C or acidifying by using acids such as hydrochloric acid, sulphuric acid, acetic acid and the like.
7. A process of claim 4, wherein the anhydrous zoledronic acid is isolated by cooling to temperature below 35°C.
8. Anhydrous zoledronic acid of purity 99.9% w/w or more.
9. Anhydrous zoledronic acid having characteristic powdered X-Ray Diffraction (XRD) pattern as depicted in Figure 1.
Dated this1 st day of December 2006 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory