WO2008065542A2

WO2008065542A2 - An improved process for the preparation of risedronate sodium

Info

Publication number: WO2008065542A2
Application number: PCT/IB2007/004344
Authority: WO
Inventors: Siripragada Mahender Rao; Thangavel Arulmoli; Venu Sanjeevi Lakshmipathi; Vasanthakumar Jagannath
Original assignee: Orchid Chemicals and Pharmaceuticals Ltd
Current assignee: Orchid Pharma Ltd
Priority date: 2006-09-22
Filing date: 2007-09-24
Publication date: 2008-06-05
Anticipated expiration: 2009-03-22
Also published as: WO2008065542A3

Abstract

The present invention relates to an improved process for the preparation of pure hydrate forms of Risedronate monosodium, which is used for the treatment of osteoporosis.

Description

PROVED PROCESS FOR THE PREPARATION OF RISEDRONATE

SODIUM

Field of the invention

The present invention relates to an improved process for the preparation of hydrates of Risedronate monosodium, which is used for the treatment of osteoporosis.

Background of the invention

Risedronate monosodium of formula (I) is chemically known as l-Hydroxy-2-(3- pyridyl)εthane-l ,l-diphosphonic acid monosodium salt, which is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism.

Formula (I)

It is known in the literature that some bisphosphonic acids and their salts are capable of forming hydrates. Risedronate sodium exists as monohydrate, hemipentahydrate and anhydrous forms. Processes selectively yielding pure forms of hemipentahydrate and monohydrate are industrially desirable.

Risedronic acid and its salt were first reported in US Patent No. 5,583,122 (henceforth '122). The ' 122 teaches the preparation of Risedronic acid by reaction of 3-pyridylacetic acids with phosphorous acid and phosphorous trichloride in chlorobenzene.

US Patent No. 6,410,520 (henceforth '520) discloses the existence of Risedronate monosodium in three hydration states: hemipentahydrate, monohydrate and anhydrous. The '520 patent also discloses selective crystallization of mono- and hemipentahydrates by heating an aqueous solution of 3-pyridyl-l-hydroxyethylidine-l,l-bisphosphonic acid sodium from about 45⁰C to about 75⁰C and crystallization of product by the addition of isopropanol, and cooling with different cooling ramp. According to '520 patent, monohydrate crystals were converted to the hemipentahydrate form.

US Patent application No. 2003 / 0195170 Al teaches the preparation of form B (monohydrate) of Risedronate sodium by refluxing a mixture of Risedronic acid, a sodium base, and a liquid comprising about 40% to about 60% v/v lower alkanol in water. The alkanol may be methanol, ethanol or isopropanol. According to this patent publication, the '520 patent publication yields Risedronate sodium as a mixture of monohydrate and hemipentahydrate forms.

PCT Application No.WO 2005 / 044831 teaches the preparation of bisphosphonic acid by reacting a carboxylic acid and phosphorus compound in sulfolane. This patent does not provide enablement conditions for preparing Risedronate sodium monohydrate or Risedronate sodium hemipentahydrate.

US 7,002,014 discloses the preparation of Risedronate sodium hemipentahydrate by dissolving Risedronic acid in an admixture of isopropyl alcohol and water using sodium hydroxide in sufficient amount to provide a pH of 6 at high temperature, followed by acidification and cooling to isolate the desired hemipentahydrate.

We focused our research for developing an industrial process for the production of pure Risedronate sodium hemipentahydrate or monohydrate without any contamination of other form, and succeeded with a process, which consistently yields the desired form and make the process more economical and industrially viable.

Object of the invention

An objective of the present invention is to provide an improved process for the preparation of pure form of Risedronate sodium hemipentahydrate without having contamination of other form. Another objective of the present invention is to provide an improved process for the preparation of pure form of Risedronate sodium monohydrate without having contamination of other form.

Still another objective of the present invention is to provide an improved process by which the desired form of hemipentahydrate or monohydrate of compound of formula (I) can be obtained consistently.

Summary of the invention

The present invention provides a process for the preparation of desired form of Risedronate monosodium such as hemipentahydrate or monohydrate, comprising the steps of: a) dissolving Risedronic acid in water in the presence of a base containing sodium ion; b) optionally adjusting the pH to 4.5 to 5.0; c) optionally adding sulfolane solvent; d) optionally seeding with Risedronate monosodium hemipentahydrate or monohydrate; e) isolating Risedronate monosodium monohydrate or its hemipentahydrate.

Detailed description of the invention

In an embodiment, the present invention provides a process for preparing Risedronate sodium hemipentahydrate or Risedronate sodium monohydrate in pure form. The process reported in '520 patent yields Risedronate sodium in a mixture of hemipentahydrate or monohydrate forms, the present invention provides a process in which the individual forms are isolated in pure form without having contamination of another form. In another embodiment of the present invention the Risedronate sodium hemipentahydrate, according to the present invention is prepared by a) dissolving Risedronic acid in water using a base containing sodium ion (b) adjusting the pH of the solution to 4.S-S.0 using an acid (c) optionally adding sulfolane to the reaction mass at a temperature in the range of 45 - 75°C (d) slowly cooling and isolating Risedronate sodium hemipentahydrate. Accordingly the present invention provides a simple and industrially viable process for the production of Risedronate sodium hemipentahydrate on commercial scales.

In yet another embodiment of the present invention the Risedronate sodium monohydrate, according to the present invention is prepared by a) dissolving Risedronic acid in water using a base containing sodium ion by adjusting the pH to 4.5 to 5.0; (b) adding preheated (45 - 75° C) sulfolane to step (a) mass; (c) optionally seeding with Risedronate monohydrate (d) slowly cooling and isolating Risedronate sodium monohydrate. Accordingly the present invention provides a simple and industrially viable process for the production of Risedronate monohydrate in pure form with having contamination of other forms. The addition of preheated sulfolane yields the Risedronate monohydrate in pure form without having contamination of other forms. The addition of sulfolane at room temperature results in anhydrous form, and the nature of the reaction mass becomes thick resulting in difficulty in the filtration.

In one more embodiment of the invention the base used is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, most preferably sodium hydroxide.

In one more embodiment of the invention, the acid used is selected from hydrochloric acid, sulfuric acid and the like, most preferably hydrochloric acid.

In one more embodiment of the present invention the Risedronate sodium monohydrate or hemihydrate prepared according to the present invention is stable and does not convert back to another form. The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Example (1)

Preparation of Risedronate sodium hemipentahydrate

To purified water (600 mL), Risedronic acid (50 g) was charged followed by slow addition of sodium hydroxide solution (50% w/w) at 75-80° C to get a clear solution at pH 6.0. The solution was filtered through celite bed and the filtrate heated to 75-80° C. Cone, hydrochloric acid was added to adjust the pH to 4.7. The reaction mass was digested for 2 hrs at 75 to 80° C. Sulfolane (250 mL) was added dropwise at 75 to 80⁰C. Then the homogeneous clear solution was gradually cooled to 0 - 5° C and stirred for 2 to 4 hrs. The slurry was filtered, washed with acetone and dried to get Risedronate monosodium hemipentahydrate (40 g).

Example (2)

Preparation of Risedronate sodium hemipentahydrate

To purified water (60 mL), Risedronic acid (25 g) was charged followed by slow addition of sodium hydroxide solution (50% w/w) at 75-80° C to get a clear solution at pH 6.0. The solution was filtered through celite bed and the filtrate heated to 75-80° C. Cone, hydrochloric acid was added to adjust the pH to 4.7. The reaction mass was digested for 2 hrs. at 75 to 85° C. Then the solution was gradually cooled to 0 - 5° C and stirred for 3 hrs. The slurry was filtered, washed with chilled water and dried to get Risedronate monosodium hemipentahydrate (20 g).

Example (3)

Preparation of Risedronate sodium hemipentahydrate

To purified water (715 mL), Risedronic acid (119 g) was charged followed by slow addition of sodium hydroxide solution (50% w/w) at 28-30° C to get a clear solution at pH 6.0. The solution was filtered through celite bed. To the filtrate, cone, hydrochloric acid was added to adjust the pH to 4.7. The solution was gradually cooled to 0 - 5° C and stirred for 4 hrs. The slurry was filtered, washed with chilled water and dried to get Risedronate monosodium hemipentahydrate (117 g).

Example (4)

Preparation of Risedronate sodium monohydrate

Risedronic acid (100 g) in purified water (1.6 Lit) was stirred 28-30 ⁰C, and the pH adjusted to 4.7-4.8 using sodium hydroxide solution (40% w/w) to obtain a clear solution. The clear solution was filtered. To the filtrate preheated (50-55⁰C) sulfolane was added in one lot while seeding with Risedronate sodium monohydrate. The reaction mass was stirred and cooled to 0-5⁰C over 1 hr. The reaction mass was filtered, washed with acetone and dried under vacuum to get Risedronate monosodium monohydrate (105 g). The dry product was taken in acetone and heated under reflux for 3 hrs. The contents were cooled, filtered and dried under vacuum to get pure Risedronate monosodium monohydrate.

Claims

We Claim:

1. An improved process for the preparation of Risedronate monosodium monohydrate and Risedronate monosodium hemipentahydrate, comprising the steps of: a) dissolving Risedronic acid in water in the presence of a base containing sodium ion; b) optionally adjusting the pH to 4.5 to 5.0; c) optionally adding sulfolane solvent; d) optionally seeding with Risedronate monosodium monohydrate or hemipentahydrate; and e) isolating Risedronate monosodium monohydrate or hemipentahydrate.

2. An improved process for the preparation of Risedronate monosodium monohydrate, comprising the steps of: a) dissolving Risedronic acid in water using a base containing sodium ion by adjusting the pH to 4.5 to 5.0; b) adding preheated sulfolane to step (a) reaction mass; c) optionally seeding with Risedronate monosodium monohydrate; d) slowly cooling and isolating Risedronate sodium monohydrate.

3. An improved process for the preparation of Risedronate monosodium hemipentahydrate, comprising the steps of: a) dissolving Risedronic acid in water using a base containing sodium ion b) adjusting the pH of the solution to 4.5 to 5.0 using an acid; c) optionally adding sulfolane at a temperature in the range of 45 - 75°C, d) cooling slowly and isolating Risedronate sodium hemipentahydrate.

4. A process of purification of Risedronate monosodium, which comprises a) heating a mixture of Risedronate monosodium and acetone b) cooling and isolating Risedronate monosodium in pure form.

5. A process according to claim 2, wherein sulfolane was heated in the range of 45-75° C, before adding into step (a) solution.

6. A process as claimed in claim 2, wherein the acid is selected is selected from the group consisting of hydrochloric acid, and sulfuric acid.

7. A Process as claimed in claim 6, wherein the most preferred acid is hydrochloric acid.

8. A Process as claimed in 1, 2 and 3, wherein the base is selected from the group consisting sodium hydroxide, sodium carbonate and sodium bicarbonate.

9. A Process as claimed in 8, the most preferred base is sodium hydroxide.

Dated this Twenty first (21^st) day of September 2007 for Orchid Chemicals & Pharmaceuticals Ltd.,

Dr. C. B. Rao

Dy. Managing Director