PROCESSES FOR THE PREPARATION OF PURE ZOLEDRONIC ACID

Field of the Invention [0001] The field of the invention relates to processes for the preparation of pure zoledronic acid or pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions that include the pure zoledronic acid.

Background of the Invention

[0002] 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 the treatment of multiple myeloma and bone metastases of solid tumors. Zoledronic acid is chemically, (l-Hydroxy-2-imidazol-l-yl-phosphonoethyl)phosphonic acid monohydrate of structural Formula I.

FORMULA I

[0003] A process for the preparation of zoledronic acid is disclosed for example, in U.S. Patent number 4,939,130 and Izv. Akad. Nauk. USSR, Ser. KUm., 1987, 2, 433-437. In general, the process involves the treatment of imidazol-1-yl acetic acid hydrochloride with phosphoric acid and phosphorous trichloride in chlorobenzene as solvent at 100 ⁰ C. During the reaction, the reaction mass becomes very thick. This leads to incomplete reaction and results in a low overall yield and impure product.

[0004] US Application No. 2004/0230076 provides a process for the purification of zoledronic acid. The process includes obtaining a clear solution of crude zoledronic acid by raising the pH of an aqueous suspension; lowering the pH of the solution; and isolating the zoledronic acid from the solution.

[0005] US Application No. 2005/0054616 provides processes for the preparation of crystalline and amorphous forms of zoledronic acid. In general, the process involves the use of chlorobenzene or toluene as solvent along with silicon oil, polyethylene glycol or

diatomaceous earth compounds such as celite, keisulgurh etc. as diluents to keep the reaction mass stirrable. However, the product is not obtained in high purity.

Summary of the Invention [0006] The present inventors have noticed that zoledronic acid when prepared as per the processes reported in the prior art is not pure and yields are low. It also was observed by the present inventors that the reaction mass becomes thick and is very difficult to stir. [0007] The present inventors have found that there is no need to use solvent in the condensation reaction between imidazole- 1-yl acetic acid or salts thereof and phosphorous acid in presence of phosphorous trichloride to get zoledronic acid. A small excess of phosphorous acid can act as a solvent and the reaction mass remains homogeneous and is easily stirrable. Further, the inventors have also found that the reaction can be accomplished at temperatures less than 80 ⁰ C in less than 10 hours reaction time. The yield of zoledronic acid obtained is about 80% with purity in excess of 99%. This significantly improves the process economics and commercial viability.

[0008] It also was observed by the present inventors that use of phosphorous trichloride is a safety hazard because of the presence of free phosphorous in commercially available phosphorous trichloride. This free phosphorous sublimes and settles at the top surface of the reaction vessel under the reaction conditions. During the aqueous work-up stage, this free phosphorous comes in contact with air and water whereby it ignites leading to generation of fire. This leads to hazardous consequences and therefore great care must be taken in order to prevent this.

[0009] While working on this problem, it was found by the present inventors that phosphorous oxychloride can be used in place of phosphorous trichloride without compromising on safety because commercially available phosphorous oxychloride (POCl ₃ ) does not contain free phosphorous. Additionally, the boiling point Of POCl ₃ is about 105 ⁰ C, which is well above the reaction temperature, and therefore the disadvantages such as addition at reflux temperature can also be taken care off. [0010] Accordingly, in one general aspect there is provided a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. The process includes reacting imidazol-1-yl acetic acid or salts thereof with phosphorous acid at 8O ⁰ C or less to obtain a homogeneous solution; adding phosphorous trichloride at 80 ⁰ C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.

[0011] Embodiments of the process may include one or more of the following features. For example, the reaction of imidazol-1-yl acetic acid or salt thereof with phosphorous acid may be carried out without any solvent. The reaction may be carried out in the presence of one or more solvents. The solvent may be one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil. The process may include further purification of the product obtained. [0012] The process may include further drying of the product obtained. [0013] The process may produce the pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. In particular, it may produce the pure zoledronic acid or salts thereof having purity more than 99.9% by HPLC.

[0014] In another general aspect there is provided a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. The process includes reacting imidazol-1-yl acetic acid or salts thereof with phosphorous acid at 80 ⁰ C or less to obtain a homogeneous solution; adding phosphorous oxychloride at 80 ⁰ C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.

[0015] Embodiments of the process may include one or more of the following features. For example, the reaction of imidazol-1-yl acetic acid or salt thereof with phosphorous acid may be carried out without any solvent. The reaction may be carried out in the presence of one or more solvents. The solvent may be one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil.

[0016] In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC; and one or more pharmaceutically acceptable carriers, excipients or diluents. [0017] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Description of the Drawings

[0018] Figure 1 is an X-Ray Diffraction Pattern of zoledronic acid.

Detailed Description of the Invention

[0019] A first aspect of the present invention provides a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. The process includes the steps of: (a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 80 ⁰ C or less to obtain a homogeneous solution;

(b) adding phosphorous trichloride at 80 ⁰ C or less; and

(c) isolating the zoledronic acid or salts thereof from the reaction mass thereof.

[0020] Imidazole 1-yl acetic acid or salts thereof may be treated with phosphorous acid and the resultant mass may be heated to get a homogeneous solution. Phosphorous trichloride may be added to this homogeneous solution under controlled rate of addition at a temperature less than 8O ⁰ C. This reaction may be carried out in the absence of a solvent. Such reactions are normally termed as "neat reactions". Alternatively, the reaction may be carried out in the presence of one or more solvents. A suitable solvent may include one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil. The reaction may be continued at the same temperature until completion of the reaction. In general, it may be required to maintain the reaction temperature for about 10 hours. After completion of the reaction, the reaction mass may be acidified. The acidified mixture may be further heated for about 8-15 hours. It may be treated with activated charcoal and filtered. The filtrate may be treated with acetone or any other suitable anti-solvent to precipitate zoledronic acid from the solution. The precipitated mass may be filtered and dried suitably.

[0021] The product may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. [0022] The zoledronic acid has a purity of more than purity 99% when measured by HPLC. More particularly, the purity is more than 99.7%, for example more than 99.9%. [0023] A second aspect of the present invention provides a process for preparing zoledronic acid or salts thereof. The process includes the steps of:

(a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 80 ⁰ C or less to obtain a homogeneous solution;

(b) adding phosphorous oxychloride at 80 ⁰ C or less; and

(c) isolating the zoledronic acid or salts thereof from the reaction mass thereof.

[0024] Imidazole 1-yl acetic acid or salts thereof may be treated with phosphorous acid and mass may be heated to get a homogeneous solution. Phosphorous oxychloride may be added to this homogeneous solution under controlled rate of addition at a temperature less than 8O ⁰ C. This reaction may be carried out in the absence of a solvent. Such reactions are normally termed as "neat reactions". Alternatively, the reaction may be carried out in the presence of one or more solvents. A suitable solvent may include one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil. The reaction may be continued at the same temperature until completion of the reaction. In general, it may be required to maintain the reaction temperature for about 10 hours. After completion of the reaction, the reaction mass may be acidified. The acidified mixture may be further heated for about 8-15 hours. It may be treated with activated charcoal and filtered. The filtrate may be treated with acetone or any other suitable anti-solvent to precipitate zoledronic acid from the solution. The precipitated mass may be filtered and dried suitably. [0025] Imidazol-1-yl acetic acid to be used as the starting material can be prepared the resultant by any process known in the literature. In particular, it can be prepared by reacting imidazole with alkyl haloacetate in the absence of a phase transfer catalyst to get imidazole- 1-yl acetate. The hydrolysis of imidazol-1-yl acetate in water gives imidazol-1-yl acetic acid. The alkyl haloacetate can be methyl chloroacetate or ethyl bromoacetate. [0026] A third aspect of the present invention provides a process for preparing zoledronic acid or salt thereof. The process includes the steps of: a) reacting imidazole with alkyl haloacetate in one or more organic solvents in the absence of a phase transfer catalyst, to get alkyl imidazole- 1-yl acetate; b) hydrolyzing the alkyl imidazole- 1-yl acetate in water to get imidazol-1-yl acetic acid; c) treating imidazol-1-yl acetic acid or salts thereof with phosphorous acid and phosphorous trichloride optionally in the presence of one or more solvents; and d) isolating the zoledronic acid or salts thereof from the reaction mass thereof.

[0027] The reaction of imidazole and alkyl haloacetate may be carried out in the presence of one or more suitable solvents. The term "suitable solvents" include, for example, halogenated hydrocarbons, non-polar aprotic solvents, polar aprotic solvents, and mixtures thereof. The reaction may also be carried out in the presence of a base. The base can be selected from carbonates, bicarbonates, hydroxide or alkoxides of metals. Additionally metal halides such as potassium iodide can be effectively used as catalysts to accelerate the rate of reaction. For practical purpose, base, imidazole and catalyst are mixed with solvent and to this stirred

mixture is added alkyl haloacetate at controlled rate. The resultant mass after stirring for approximately 30 to 45 minutes can be heated to reflux. After completion of the reaction, the resultant mass can be cooled to room temperature and filtered to remove inorganics. The organic layer containing the product can be then concentrated under reduced pressure to get crude mass of methyl /ethyl imidazol-1-yl acetate. This crude mass can be purified suitably or can be used as such for its hydrolysis to get imidazol-1-yl acetic acid or salt thereof. [0028] The hydrolysis of methyl/ethyl imidazol-1-yl acetate can be carried out under aqueous conditions at higher temperature. The ester can be mixed with water and the resultant mass can be heated to reflux for about 4 to 10 hours, and cooled. The aqueous layer can be treated with activated carbon and concentrated under reduced pressure to get a residue, which upon addition of suitable anti-solvent such as methanol or isopropanol gives imidazol-1-yl acetic acid as solid. The solid can be filtered and dried suitably to get imidazol-1-yl acetic acid. [0029] A fourth aspect of the present invention provides a process for the purification of zoledronic acid or salts thereof. The process includes the steps of: a) obtaining a solution of zoledronic acid or salts thereof in water by heating; b) cooling the solution; and c) recovering the pure zoledronic acid or salts thereof having purity more than 99.7% from the solution thereof by the removal of water.

In general, the solution of zoledronic acid may be obtained by dissolving zoledronic acid in water. Alternatively, such a solution may be obtained directly from a reaction in which zoledronic acid is formed. The mixture containing zoledronic acid may be heated to obtain a solution. It can be heated from about 30 ⁰ C to about reflux temperature of the solvent used, for example from about 30 ⁰ C to about 100 ⁰ C. The resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities. The clear solution is cooled to a temperature of 30 °C or less and an optionally pre-cooled anti-solvent is added to it. The anti-solvent is characterized by the fact that zoledronic acid is insoluble, practically insoluble or very slightly soluble in the anti- solvent. The terms insoluble, practically insoluble or very slightly soluble have their ordinary meanings as defined in United States Phamacopoeia 2002. [0030] The term "obtaining" includes dissolving, slurrying, stirring or a combination thereof. [0031] The pure zoledronic acid may be recovered from the solution by a technique/which includes, for example, distillation, distillation under vacuum, filtration, filtration under vacuum, evaporation, decantation and centrifugation.

The product may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. [0032] The zoledronic acid has a purity of more than purity 99.7% when measured by HPLC. More particularly, the purity is more than 99.9%. The pure zoledronic acid may be in its monohydrate form and has a moisture content of about 6 to 8% w/w.

[0033] A fifth aspect of the present invention provides a pharmaceutical composition comprising as its active ingredient pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. With the active ingredient, the pharmaceutical composition includes one or more pharmaceutically acceptable excipients/diluents. The pharmaceutical composition of the present invention may be in the form of a solid or liquid dosage forms for oral, parenteral or topical use and may have immediate or sustained release characteristics.- The dosage forms possible include tablets, capsules, powders, granules, creams, lotions, ointments, injectables, ophthalmic or otic solutions, suspensions, elixirs, and the like.

[0034] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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. [0035] Example- 1 : Preparation of methyl imidazol-1-yl acetate

To a suspension of potassium carbonate (400 gm) and potassium iodide (5 gm) in dichloromethane (2 Lit), imidazole (100 gm) was added and the mixture was stirred vigorously. Methyl chloroacetate (205 gm) was added slowly and the mass was stirred further for 30 minutes followed by heating to reflux for 6-8 hours. The mass was cooled to ambient temperature and filtered. The residue was washed with dichloromethane (500 ml) and the washings were combined with the filtrate. The combined dichloromethane layers were distilled under reduced pressure to get methyl imidazole- 1-yl acetate. Yield: 235 gm [0036] Example- 2: Preparation of imidazol-1-yl acetic acid Water (500 ml) was added to methyl imidazol-1-yl acetate (235 gm) and the resultant mass was refluxed for 4 to 8 hours. After completion of the reaction, it was cooled. The organic layer was separated and discarded. The aqueous layer was treated with activated charcoal, filtered to remove charcoal and concentrated under reduced pressure to get a residue. The

residue obtained was treated with methanol (250 ml) and the resultant mixture was stirrejl for 2 hours and filtered. The solid obtained was washed with methanol (100 ml) and dried at 70- 8O ⁰ C to get imidazol-1-yl acetic acid. Yield: 158 gm [0037] Example- 3: Preparation of zoledronic acid

A mixture of imidazol-1-yl acetic acid (100 gm) and phosphorous acid (324 gm) was heated under stirring to about 60-80 ⁰ C to get a homogeneous solution. Phosphorous trichloride (324 gm) was added slowly at a temperature of about 75 ⁰ C to the homogeneous solution. The resultant mass was stirred for 6 hours and cooled. A solution of hydrochloric acid (9N, 465 ml) was added over 30 minutes and the entire mass was heated at 75-8O ⁰ C for about 12 hours, treated with activated carbon (3.8 gm) and filtered. Acetone (1200 ml) was added to the filtrate and the resultant mixture was cooled to 15-2O ⁰ C. After complete precipitation of the product, the mass was filtered and the wet cake was washed with acetone (300 ml) and dried at 50-6O ⁰ C to get zoledronic acid as a white crystalline solid. Yield: 161 gm

HPLC Purity: 99.92%

[0038] Example- 4: Purification of zoledronic acid

A mixture of zoledronic acid (100 gm) and water (2.4 Lit) was heated at a temperature of about 9O ⁰ C. The hot solution was treated with activated charcoal and filtered to remove charcoal. The filtrate was cooled to 5-10 ⁰ C under stirring and filtered. The wet cake was washed with water (100 ml) and dried at 50-60 ⁰ C to get white crystals of pure zoledronic acid.

Yield: 82 gm HPLC Purity: 99.99% [0039] Example-5: Preparation of zoledronic acid

A mixture of imidazol-1-yl acetic acid (100 gm) and phosphorous acid (324 gm) was heated under stirring to about 60-80 ⁰ C to get a homogeneous solution. Phosphorous oxychloride (364 gm) was added slowly at a temperature of about 75 ⁰ C to the homogeneous solution. The resultant mass was stirred for 5 hours and cooled. A solution of hydrochloric acid (9N, 465 ml) was added over 30 minutes and the entire mass was heated at 9O ⁰ C for about 12 hours, cooled and filtered. Acetone (1200 ml) was added to the filtrate and the resultant mixture was cooled to 15-2O ⁰ C. After complete precipitation of the product, the mass was filtered and the

wet cake was washed with acetone (300 ml) and dried at 50-60 ⁰ C to get crystals of zoledronic acid.

Yield: 170 gm

HPLC Purity: 99.92%

[0040] 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.