Field of the Invention
This invention, in general, relates to a process for preparing 3-pyridyl-l- hydroxyethylidine-1,1 -bisphosphonic acid sodium hemipentahydrate (Risedronate sodium hemipentahydrate). More specifically, but without restriction to the particular embodiment herein after described in accordance with the best mode of practice, the present invention provides a novel process for preparation of Risedronate sodium hemipentahydrate employing a novel crystallizing solvent system.
Background of the Invention
Risedronate sodium (3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid mono sodium salt), the subject of present invention under the trade name Actonel® is used for the treatment of osteoporosis. The chemical structure of Risedronate sodium is the following:

Biphosphonates such as 3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid (Risedronate) are therapeutically used in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, arthritis, neuritis, tendonitis and other inflammatory conditions. Risedronate sodium inhibits osteoclast-mediated bone resorption and modulates bone metabolism.
Risedronate sodium has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent (Hydroxyapatite is the major component, and an essential ingredient, of normal bone and teeth. It is hydroxyapatite that makes up bone mineral and the matrix of teeth. Hydroxyapatite molecules can group together (crystallize) to form microscopic clumps, called hydroxyapatite crystals. Tiny crystals of hydroxyapatite sometimes form in or around joints and can cause inflammation of joints and tissues around the joints, such as tendons and ligaments).
At the cellular level, risedronate sodium inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g. lack of ruffled border). Osteoporosis is also characterized by low bone mass and architectural deterioration of bone tissue leading to enhanced bone fragility and increase in the risk of bone fracture. Biphosphonates treatment is to achieve the goal in the treatment of osteoporosis and is to improve calcium absorption and decrease urinary excretion of calcium thus reversing hyperparathyroidism. Other biphosphonates are etidronate and pamidronate which are also useful in treating osteoporosis.
US Patent No. 5,583,122 describe the preparation of risedronic acid by reaction of 3- pyridyl acetic acid with phosphorous acid and phosphorous trichloride in chlorobenzene to obtain the oily to viscous semi solid material which on hydrolysis in presence of water followed by the crystallization of product by adding methanol to obtain only 52% yield. This process is complicated, as the reaction mixture being in semi solid form, which creates difficulty in safe scale up.
US Patent No. 6,410,520 discloses the polymorphic forms of risedronate sodium i.e. hemipentahydrate, monohydrate and anhydrous form. In this patent hemipentahydrate and monohydrate is prepared by selective crystallization. The characterization data for these forms are not reported in the said patent The patent also discloses selective crystallization of mono and hemipentahydrates by heating an aqueous solution of Risedronate sodium from about 45-75°C and crystallization of product by the addition of isopropanol and cooling the reaction mixture with different ramp.
US Patent Application No. 20030195170 discloses various crystalline forms e.g. B, C, D, E, F, G and H of risedronate sodium and methods for their preparation. The patent discloses PXRD, TGA and IR of various forms of Risedronate sodium prepared by different ratio of alcoholic solvents in water.
PCT Application No. WO 2005012314 discloses a process for controlling the crystal form of risedronate sodium hemipentahydrate. The process employs a pH adjustment step to induce the proper hydrate form and thereby avoiding inadvertent nucleation of undesired hydrate forms.
PCT Application No. WO 2006051553 discloses a process for the preparation of risedronate sodium Form A (hemipentahydrate) and Form B (monohydrate) using the organic solvents selected from the group comprising alcohols, amides, esters, ethers, ketones or nitriles by employing in appropriate ratio.
The present invention discloses a convenient, industrially feasible and efficient process for the preparation of pure polymorphic form of risedronate sodium i.e. hemipentahydrate without the contamination of other forms.
Summary of the Invention
In accordance with the principal aspect of the present invention, there is provided a novel process for preparing a pure form of risedronate sodium to improve upon limitations in the prior art. The process comprises of selecting the suitable solvent system for obtaining the polymorphic form of risedronate sodium.
In accordance with another aspect of the present invention, there is provided a novel process for preparing pure polymorphic form of 3-pyridyl-l-hydroxyethylidene-l,l- bisphosphonic acid sodium salt (Risedronate sodium), in particular to prepare the polymorphic form hemipentahydrate employing novel solvent system comprising a mixture of organic solvent such as dimethylsulfoxide with water.
In accordance with still another aspect, there is provided a novel process for preparing a pure form of polymorph of 3-pyridyl-l-hydroxyethylidine-l,l-bisphosphonic acid sodium salt (Risedronate sodium), wherein the process comprises of treating 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid and suspending the solid Risedronic acid in water and dimethylsulfoxide mixture and adding sodium base into the same to obtain the pure polymorphic form of risedronate sodium.
Detailed Description of the Invention
The present invention describes a convenient, industrially feasible and efficient process for the preparation of polymorphic form of monosodium salt of Risedronic acid, without the contamination of other forms.
The present invention provides the process for the preparation of polymorphic form of risedronate sodium specifically hemipentahydrate by treating the 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid, further followed by preparation of sodium salt in mixture of water and water miscible solvent and then isolation from it at room temperature to reflux temperature.
The preparation of risedronate sodium described herein is also a preferred mode of the present invention, wherein the process comprises the step of stirring a combination of Risedronic acid, a sodium base in water and a water miscible solvent preferably dimethylsulfoxide at room temperature to reflux temperature preferably 25-75°C optionally seeding with the crystalline risedronate sodium hemipentahydrate.
The present invention describes the preparation of Risedronoic acid by reacting 3-pyridyl acetic acid with phosphorous acid in chlorobenzene and phosphorous oxychloride at about 80-95°C for 2hrs followed by hydrolysis with water. The aqueous and organic layers are separated and aqueous layer is heated to reflux for 10 hrs and cooled to about 20-30°C, followed by the addition of acetone to get crystalline compound of Risedronoic acid. The compound is filtered and washed with water followed by acetone.
The crystalline Risedronic acid is taken in a mixture of water and DMSO at ambient temperature and heated to about 55 to 75°C followed by the slow addition of sodium hydroxide solution and maintained for lhr. Cooled the reaction mass to 40-50°C, and the reaction mixture is optionally seeded with the crystals of risedronate sodium hemipentahydrate and the reaction is maintained for lhr. Reaction mass is cooled to 0-5°C and maintained for 3 hrs to get the pure crystalline Risedronate Sodium hemipentahydrate.
The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.
Example 1
Preparation of Risedronic acid
3-Pyridyl acetic acid (100.0 gm) was taken in chlorobenzene (720.0 ml) and phosphorous acid (209.0 gm) was added at 25-30°C and maintained at this temperature for 5 min. Heated the reaction mass to 80-85°C and followed by the addition of phosphorous oxychloride (203.7 ml, 335.09 gm) in 3 hrs. Temperature was raised to 90-95°C and maintained for 2 hrs. The reaction mass was cooled to 60-65°C and water (720 ml) was added followed by further cooling to 25-30°C. Both the layers were separated and the aqueous layer was heated to reflux for lOhrs followed by cooling to 25-35°C and then acetone (600 ml) was added. The reaction mass was maintained for 2hrs to get crystalline Risedronoic acid. Filtered the crystals and washed with DM water (1330 ml) .Washed the wet cake with acetone (100 ml) and dried.
Example 2
Preparation of Risedronate Sodium hemipentahydrate
Risedronic acid (100.0 gm) was taken in a mixture of DM water (500 ml) and DMSO (25.0 ml) at 25-35°C and heated the solution to 60-70°C. Aqueous NaOH solution (1.41 gm in 30 ml of water) was added slowly and maintained for lhr. The reaction mass was filtered and cooled to 40-50°C. The reaction mass was seeded with the crystals of hemipentahydrate (1.0 gm) and maintained for lhr. The reaction mixture was further cooled to 0-5°C and maintained for 3hrs. Filtered and washed the product with acetone (100 ml). Dried the wet product for 6hrs below 50°C.
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Field of the Invention
This invention, in general, relates to a process for preparing 3-pyridyl-l- hydroxyethylidine-1,1 -bisphosphonic acid sodium hemipentahydrate (Risedronate sodium hemipentahydrate). More specifically, but without restriction to the particular embodiment herein after described in accordance with the best mode of practice, the present invention provides a novel process for preparation of Risedronate sodium hemipentahydrate employing a novel crystallizing solvent system.
Background of the Invention
Risedronate sodium (3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid mono sodium salt), the subject of present invention under the trade name Actonel® is used for the treatment of osteoporosis. The chemical structure of Risedronate sodium is the following:

Biphosphonates such as 3-pyridyl-l-hydroxyethylidene-l,l-biphosphonic acid (Risedronate) are therapeutically used in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, arthritis, neuritis, tendonitis and other inflammatory conditions. Risedronate sodium inhibits osteoclast-mediated bone resorption and modulates bone metabolism.
Risedronate sodium has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent (Hydroxyapatite is the major component, and an essential ingredient, of normal bone and teeth. It is hydroxyapatite that makes up bone mineral and the matrix of teeth. Hydroxyapatite molecules can group together (crystallize) to form microscopic clumps, called hydroxyapatite crystals. Tiny crystals of hydroxyapatite sometimes form in or around joints and can cause inflammation of joints and tissues around the joints, such as tendons and ligaments).
At the cellular level, risedronate sodium inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g. lack of ruffled border). Osteoporosis is also characterized by low bone mass and architectural deterioration of bone tissue leading to enhanced bone fragility and increase in the risk of bone fracture. Biphosphonates treatment is to achieve the goal in the treatment of osteoporosis and is to improve calcium absorption and decrease urinary excretion of calcium thus reversing hyperparathyroidism. Other biphosphonates are etidronate and pamidronate which are also useful in treating osteoporosis.
US Patent No. 5,583,122 describe the preparation of risedronic acid by reaction of 3- pyridyl acetic acid with phosphorous acid and phosphorous trichloride in chlorobenzene to obtain the oily to viscous semi solid material which on hydrolysis in presence of water followed by the crystallization of product by adding methanol to obtain only 52% yield. This process is complicated, as the reaction mixture being in semi solid form, which creates difficulty in safe scale up.
US Patent No. 6,410,520 discloses the polymorphic forms of risedronate sodium i.e. hemipentahydrate, monohydrate and anhydrous form. In this patent hemipentahydrate and monohydrate is prepared by selective crystallization. The characterization data for these forms are not reported in the said patent The patent also discloses selective crystallization of mono and hemipentahydrates by heating an aqueous solution of Risedronate sodium from about 45-75°C and crystallization of product by the addition of isopropanol and cooling the reaction mixture with different ramp.
US Patent Application No. 20030195170 discloses various crystalline forms e.g. B, C, D, E, F, G and H of risedronate sodium and methods for their preparation. The patent discloses PXRD, TGA and IR of various forms of Risedronate sodium prepared by different ratio of alcoholic solvents in water.
PCT Application No. WO 2005012314 discloses a process for controlling the crystal form of risedronate sodium hemipentahydrate. The process employs a pH adjustment step to induce the proper hydrate form and thereby avoiding inadvertent nucleation of undesired hydrate forms.
PCT Application No. WO 2006051553 discloses a process for the preparation of risedronate sodium Form A (hemipentahydrate) and Form B (monohydrate) using the organic solvents selected from the group comprising alcohols, amides, esters, ethers, ketones or nitriles by employing in appropriate ratio.
The present invention discloses a convenient, industrially feasible and efficient process for the preparation of pure polymorphic form of risedronate sodium i.e. hemipentahydrate without the contamination of other forms.
Summary of the Invention
In accordance with the principal aspect of the present invention, there is provided a novel process for preparing a pure form of risedronate sodium to improve upon limitations in the prior art. The process comprises of selecting the suitable solvent system for obtaining the polymorphic form of risedronate sodium.
In accordance with another aspect of the present invention, there is provided a novel process for preparing pure polymorphic form of 3-pyridyl-l-hydroxyethylidene-l,l- bisphosphonic acid sodium salt (Risedronate sodium), in particular to prepare the polymorphic form hemipentahydrate employing novel solvent system comprising a mixture of organic solvent such as dimethylsulfoxide with water.
In accordance with still another aspect, there is provided a novel process for preparing a pure form of polymorph of 3-pyridyl-l-hydroxyethylidine-l,l-bisphosphonic acid sodium salt (Risedronate sodium), wherein the process comprises of treating 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid and suspending the solid Risedronic acid in water and dimethylsulfoxide mixture and adding sodium base into the same to obtain the pure polymorphic form of risedronate sodium.
Detailed Description of the Invention
The present invention describes a convenient, industrially feasible and efficient process for the preparation of polymorphic form of monosodium salt of Risedronic acid, without the contamination of other forms.
The present invention provides the process for the preparation of polymorphic form of risedronate sodium specifically hemipentahydrate by treating the 3-pyridyl acetic acid with phosphorous acid and phosphorous oxychloride in the presence of a solvent such as chlorobenzene, hydrolyzing the same using water, followed by acetone addition and collecting the solid as Risedronic acid, further followed by preparation of sodium salt in mixture of water and water miscible solvent and then isolation from it at room temperature to reflux temperature.
The preparation of risedronate sodium described herein is also a preferred mode of the present invention, wherein the process comprises the step of stirring a combination of Risedronic acid, a sodium base in water and a water miscible solvent preferably dimethylsulfoxide at room temperature to reflux temperature preferably 25-75°C optionally seeding with the crystalline risedronate sodium hemipentahydrate.
The present invention describes the preparation of Risedronoic acid by reacting 3-pyridyl acetic acid with phosphorous acid in chlorobenzene and phosphorous oxychloride at about 80-95°C for 2hrs followed by hydrolysis with water. The aqueous and organic layers are separated and aqueous layer is heated to reflux for 10 hrs and cooled to about 20-30°C, followed by the addition of acetone to get crystalline compound of Risedronoic acid. The compound is filtered and washed with water followed by acetone.
The crystalline Risedronic acid is taken in a mixture of water and DMSO at ambient temperature and heated to about 55 to 75°C followed by the slow addition of sodium hydroxide solution and maintained for lhr. Cooled the reaction mass to 40-50°C, and the reaction mixture is optionally seeded with the crystals of risedronate sodium hemipentahydrate and the reaction is maintained for lhr. Reaction mass is cooled to 0-5°C and maintained for 3 hrs to get the pure crystalline Risedronate Sodium hemipentahydrate.
The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.
Example 1
Preparation of Risedronic acid
3-Pyridyl acetic acid (100.0 gm) was taken in chlorobenzene (720.0 ml) and phosphorous acid (209.0 gm) was added at 25-30°C and maintained at this temperature for 5 min. Heated the reaction mass to 80-85°C and followed by the addition of phosphorous oxychloride (203.7 ml, 335.09 gm) in 3 hrs. Temperature was raised to 90-95°C and maintained for 2 hrs. The reaction mass was cooled to 60-65°C and water (720 ml) was added followed by further cooling to 25-30°C. Both the layers were separated and the aqueous layer was heated to reflux for lOhrs followed by cooling to 25-35°C and then acetone (600 ml) was added. The reaction mass was maintained for 2hrs to get crystalline Risedronoic acid. Filtered the crystals and washed with DM water (1330 ml) .Washed the wet cake with acetone (100 ml) and dried.
Example 2
Preparation of Risedronate Sodium hemipentahydrate
Risedronic acid (100.0 gm) was taken in a mixture of DM water (500 ml) and DMSO (25.0 ml) at 25-35°C and heated the solution to 60-70°C. Aqueous NaOH solution (1.41 gm in 30 ml of water) was added slowly and maintained for lhr. The reaction mass was filtered and cooled to 40-50°C. The reaction mass was seeded with the crystals of hemipentahydrate (1.0 gm) and maintained for lhr. The reaction mixture was further cooled to 0-5°C and maintained for 3hrs. Filtered and washed the product with acetone (100 ml). Dried the wet product for 6hrs below 50°C.
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.