PROCESS FOR PREPARING A PURE POLYMORPHIC FORM OF 3-PYRIDYL-l-HYDROXYETHYLIDINE-1,1-BISPHOSPHONIC ACID
SODIUM SALT
Field of the Invention
The present invention relates to a process for preparation of polymorphic form of 3-pyridyl-l-hydroxyethylidinel, 1-bisphosphonic acid sodium salt (Risedronate Sodium). Exclusively the present invention provides a process for preparation of stable anhydrous form of Risedronate Sodium by using glycols as an anti solvating agent.
Background of the Invention
The salts of Bisphosphonates such as 3-pyridyl-l-hydroxyethylidene~l,l-biphosphonic acid (Risedronic acid monosodium) have been proposed for the use in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia, malignancy, ostolytic bone metastases, myositis, ossificans progressive, calcinosis, universalis, arthritis, neuritis, tendonitis and other inflammatory conditions. All bisphosphonates do not exhibit same degree of biological activity. Some of the bisphosphonates have serious drawbacks with respect to toxicity. The salt and hydrate forms of bisphosphonates alter both their solubility and bioavailability.
The Monosodium Salt of Risedronate exists in three crystalline hydration states: anhydrous, monohydrate and hemipentahydrate as disclosed in U.S Patent No. 6,410,520, which even discloses the preparation of monohydrate and hemipentahydrates by selective crystallization.

Process for preparation of various crystalline forms B, C, D, E, F, G, H, of Sodium Risedronate is disclosed in European Patent EP149250 and its U.S equivalent U.S Patent Application No. 2003/0,195,170.
The present invention provides an efficient and industrially feasible process for the preparation 3 -pyridyl-1 -hydroxyethylidene-1,1 -biphosphonic acid Monosodium Salt stable anhydrous form.
Objective of the Invention:
Main objective of the present invention is to provide a process for the preparation of stable anhydrous form of Risedronate Sodium giving high yields and purity.
Another objective of the invention is to provide simplified process for the preparation of stable anhydrous form of Risedronate Sodium which meets economical demands and is ecologically safe and thus practicable industrially.
Another objective of the invention is to provide crystalline sodium risedronate as a stable anhydrous form having water content below 1.0% with desirable crystallinity.
Yet another objective of the present invention is to provide an improved process for preparation of stable anhydrous form of Risedronate Sodium by employing glycols as an anti solvating agent.
Summary of the Invention
The present applicant has now unexpectedly found that, using glycols as an anti solvating agent in the synthesis of the compounds described, it is possible to convert the Risedronate Monosodium Hemipentahydrate to the desired stable anhydrous form.

In another aspect of the present invention, there is provided a process where raw Risedronic acid is converted to the stable anhydrous form.
In another aspect of the present invention, there is provided a process where glycols are used for achieving the desired product.
In another aspect of the present invention, there is provided an improved process for the preparation of stable anhydrous form of Risedronate Monosodium by using the Poly ethylene glycol at a temperature of about 70-170°C on reaction with Risedronate Monosodium Hemipentahydrate.
In further aspect of the present invention, there is provided a process where alcohols are used in the preparation of stable anhydrous form of Risedronate Sodium at room temperature for washing the filtered product.
In yet another aspect of the present invention, a process for the preparation of stable anhydrous form of Risedronate Monosodium is provided by using alcohols containing from C1-C3 carbon atoms.
Accordingly, the present invention provides a process for the preparation of 3-pyridyl-l-hydroxyethylidene-1, 1-biphosphonic acid Monosodium salt stable anhydrous form.
(a) Addition of 3-pyridyl-l-hydroxyethylidene-l, 1-biphosphonic acid Monosodium salt Hemipentahydrate in water to a Polyethylene glycol at a temperature of about 70-85°C, then rising the temperature to about 95-110°C.
(b) Agitating the reaction mass at 100-170 °C for 20-40 minutes.
(c) Cool the reaction mass to 20-40°C.
(d) Filter the so obtained crystals

(e) Washing with alcohols containing from Cx to C3 carbon atoms. In another aspect of the present invention there is provided a process for the preparation of stable anhydrous form of Risedronate Monosodium by the reaction of raw Risedronic Acid with Polyethylene glycol at room temperature.
(a) 3-pyridyl-l-hydroxyethylidene-l, 1-biphosphonic acid
in water is adjusted pH to 6-7 with a basic solution. After Filtering the unwanted yellow material filtrate is again adjusted to pH 4.4-4.6 with acetic acid and added to Polyethylene glycol and heated upto 170°C
(b) Agitating the reaction mass at 100-170 °C for 20-40 minutes.
(c) Cool the reaction mass to 20-40°C.
(d) Filter the so obtained crystals.
(e) Washing with alcohols containing from C1 to C3 carbon atoms.
Detailed Description of the Invention:
The present invention provides an efficient and industrially feasible process for the preparation 3 -pyridyl-1 -hydroxyethylidene-1,1 -biphosphonic acid Monosodium Salt stable anhydrous form.
The process of the present invention is characterized by preparation of stable anhydrous form of bisphosphonic acid monosodium salt by adding 3-pyridyl-l-hydroxyethylidene-1,1-biphosphonic acid monosodium Salt Hemipentahydrate in water with polyethylene glycol and preferably PEG 200 at a temperature of about 70-85°C and preferably about 70-80°C and more preferably at 75°C.
In the present invention also given is a process for the preparation of stable anhydrous form of bisphosphonic acid monosodium salt by reacting 3-pyridyM-hydroxyethylidene-1, 1 -biphosphonic acid with polyethylene glycol and preferably PEG 200 and heating upto 170°C.

In the present invention, the reaction temperature for step (b) for agitating the reaction mass is in the range of about 100-170°C and preferably in the range of 100-165°C.
In the present invention, the time required for step (b) for agitating the reaction mass is about 20-40 minutes and preferably about 30 minutes.
In the present invention, cooling temperature for step (c) is in the range of about 20-40°C and more preferably at about 25-30°C.
In the present invention, for washing the crystals obtained in step (d) alcohols containing from d to C3 carbon atoms are employed for step (e) and more preferably methanol.
In the present invention, adjustment of pH of raw Risedronic Acid to pH 6-7 is by using alkaline solution preferably sodium hydroxide solution.
The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention.

Example: 1
Preparation of 3-pyridvl-l-hydroxy ethylidene-U-biphosphonic acid Mono
Sodium Salt anhydrous form;
3-pyridyl-l-hydroxy ethylidene-1,1-biphosphonic acid Mono Sodium Salt Hemi-pentahydrate (10 gm) was added into 40 ml water at room temperature. And the temperature was raised to 75°C. Then PEG 200 was added about 30gms then the temperature was raised to 100°C. The reaction mass was agitated at 100-105°C. for 30 minutes .cooled the reaction mass to 25- 30 °C. The obtained crystals was filtered and washed with methanol 10 ml to give 3 -pyridy 1-1 -hydroxy ethylidene-1, 1-biphosphonic acid Mono Sodium Salt anhydrous form (7.50 gm) moisture content is below 1.0 % w/w.
Example: 2
Preparation of 3-pyridyl-l-hvdroxy ethylidene-1,1-biphosphonic acid Mono
Sodium Salt anhydrous form:
3-pyridyl-l-hydroxy ethylidene-1,1-biphosphonic acid Mono Sodium SaltHemi-pentahydrate (20 gm) was added into 80 ml water at room temperature. And the temperature was raised to 75°C. Then PEG 200 was added about 50gms then the temperature was raised to 100 °C. distilled the water to reach the temperature 110°C. Then again added 50 Gms of PEG 200 and distilled the water to reach the reaction mass temperature to 160°C. The reaction mass was agitated at 160 to 165 °C. for 30 minutes and cooled to 25- 30 °C. The obtained crystals was filtered and again slurry washed with methanol 60 ml to give 3-pyridyl-l-hydroxy ethylidene-1, 1-biphosphonic acid Mono Sodium Salt anhydrous form (7.50 gm) moisture content is below 1.0 % w/w.

Example: 3
Preparation of 3-pyridyl-l-hvdroxv ethylidene-1,1-biphosphonic acid Mono
Sodium Salt anhydrous form:
3-pyridyl-1-hydroxy ethylidene-1, 1-biphosphonic acid (Raw Risedronic Acid) (20 gm) was added into 100 ml water at room temperature. And the pH was adjusted to 6-7 with sodium hydroxide solution. The unwanted yellow mass was filtered and the filtrate was again adjusted pH to 4.4-4.6 with acetic acid. PEG 200 was added (80 gm) then heated and distilled the water to reach the reaction mass temperature to 160°C. The reaction mass was agitated at 160 to 165 °C for 30 minutes and cooled to 25- 30 °C. The obtained crystals was filtered and again slurry washed with methanol 60 ml to give 3-pyridyl-l-hydroxy ethylidene-1, 1-biphosphonic acid Mono Sodium Salt stable stable anhydrous form (10 gm) moisture content is below 1.0 % w/w.
Samples were kept under 75%±5 and 60%±5 RH in open condition for 90 days and analyzed moisture content of the product for every 10 days.

We claim:
1. A process for the preparation of 3 -pyridyl-1 -hydroxyethylidene-1,1-biphosphonic acid monosodium salt stable anhydrous form which comprises: (a)) Addition of 3 -pyridyl-1 -hydroxyethylidene-1,1-biphosphonic acid Monosodium salt Hemipentahydrate in water to a Polyethylene glycol at a temperature of about 70-85°C, then rising the temperature to about 95-110°C

(b) Agitating the reaction mass at 150-170 °C for 20-40 minutes.
(c) Cool the reaction mass to 20-40°C.
(d) Filter the so obtained crystals
(e) Washing with alcohols containing from C1 to C3 carbon atoms.
2. A process for the preparation of 3-pyridyl-l-hydroxyethylidene-l,l- biphosphonic acid monosodium salt stable anhydrous form which comprises:
a) 3-pyridyl-l-hydroxyethylidene-l, 1-biphosphonic acid in water is adjusted pH to 6-7 with a basic solution. After Filtering the unwanted yellow material filtrate is again adjusted to pH 4.4-4.6 with acetic acid and added to Polyethylene glycol and heated upto 170°C
(b) Agitating the reaction mass at 150-170 °C for 20-40 minutes.
(c) Cool the reaction mass to 20-40°C.
(d) Filter the so obtained crystals.
(e) Washing with alcohols containing from C1 to C3 carbon atoms.
3. The process of claim 1&2 where in the glycols are Monoglycols and polyethylene glycols are used as an anti solvating agents such as MEG, MMG PEG 200,400,600 upto 6000.
4. The process of claim 1 wherein said Step (a) the addition of PEG 200 is at a temperature range of about 70-85°C and preferably about 70-80°C and more preferably at 75°C.
5. The process of claim 1 wherein said Step (a) rising the temperature of the reaction mass is in the range of about 95-110°C and preferably to 105-110°C.
6. The process of claim 1 wherein said Step (b) agitating the reaction mass in the range of about 100-170 °C and preferably in the range of 100-165°C.

7. The process of claim 1&2 wherein said Step (c) cooling the reaction mass to a temperature in the range of about 20-40°C and more preferably at about 25-30°C.
8. The process of claim 1&2 wherein said Step (e) for washing the crystals obtained in step(d) alcohols containing from C1 to C3 carbon atoms and more preferably methanol.
9. The process of claim 2 where in said step (a) adjustment of pH of raw Risedronic Acid to pH 6-7 is by using alkaline solution preferably sodium hydroxide solution.

10. The process of claim 2 wherein said Step (a) rising the temperature of the reaction mass is in the range to about 170°C and preferably to 160°C.
11. The process of claim 1&2 wherein said Step (e) Risedronate Monosodium Salt obtained is stable anhydrous form.

Example: 3
Preparation of 3-pyridyl-l-hvdroxv ethylidene-1,1-biphosphonic acid Mono
Sodium Salt anhydrous form:
3-pyridyl-1-hydroxy ethylidene-1, 1-biphosphonic acid (Raw Risedronic Acid) (20 gm) was added into 100 ml water at room temperature. And the pH was adjusted to 6-7 with sodium hydroxide solution. The unwanted yellow mass was filtered and the filtrate was again adjusted pH to 4.4-4.6 with acetic acid. PEG 200 was added (80 gm) then heated and distilled the water to reach the reaction mass temperature to 160°C. The reaction mass was agitated at 160 to 165 °C for 30 minutes and cooled to 25- 30 °C. The obtained crystals was filtered and again slurry washed with methanol 60 ml to give 3-pyridyl-l-hydroxy ethylidene-1, 1-biphosphonic acid Mono Sodium Salt stable stable anhydrous form (10 gm) moisture content is below 1.0 % w/w.
Samples were kept under 75%±5 and 60%±5 RH in open condition for 90 days and analyzed moisture content of the product for every 10 days.

We claim:
1. A process for the preparation of 3 -pyridyl-1 -hydroxyethylidene-1,1-biphosphonic acid monosodium salt stable anhydrous form which comprises: (a)) Addition of 3 -pyridyl-1 -hydroxyethylidene-1,1-biphosphonic acid Monosodium salt Hemipentahydrate in water to a Polyethylene glycol at a temperature of about 70-85°C, then rising the temperature to about 95-110°C

(b) Agitating the reaction mass at 150-170 °C for 20-40 minutes.
(c) Cool the reaction mass to 20-40°C.
(d) Filter the so obtained crystals
(e) Washing with alcohols containing from C1 to C3 carbon atoms.
2. A process for the preparation of 3-pyridyl-l-hydroxyethylidene-l,l- biphosphonic acid monosodium salt stable anhydrous form which comprises:
a) 3-pyridyl-l-hydroxyethylidene-l, 1-biphosphonic acid in water is adjusted pH to 6-7 with a basic solution. After Filtering the unwanted yellow material filtrate is again adjusted to pH 4.4-4.6 with acetic acid and added to Polyethylene glycol and heated upto 170°C
(b) Agitating the reaction mass at 150-170 °C for 20-40 minutes.
(c) Cool the reaction mass to 20-40°C.
(d) Filter the so obtained crystals.
(e) Washing with alcohols containing from C1 to C3 carbon atoms.
3. The process of claim 1&2 where in the glycols are Monoglycols and polyethylene glycols are used as an anti solvating agents such as MEG, MMG PEG 200,400,600 upto 6000.
4. The process of claim 1 wherein said Step (a) the addition of PEG 200 is at a temperature range of about 70-85°C and preferably about 70-80°C and more preferably at 75°C.
5. The process of claim 1 wherein said Step (a) rising the temperature of the reaction mass is in the range of about 95-110°C and preferably to 105-110°C.
6. The process of claim 1 wherein said Step (b) agitating the reaction mass in the range of about 100-170 °C and preferably in the range of 100-165°C.

7. The process of claim 1&2 wherein said Step (c) cooling the reaction mass to a temperature in the range of about 20-40°C and more preferably at about 25-30°C.
8. The process of claim 1&2 wherein said Step (e) for washing the crystals obtained in step(d) alcohols containing from C1 to C3 carbon atoms and more preferably methanol.
9. The process of claim 2 where in said step (a) adjustment of pH of raw Risedronic Acid to pH 6-7 is by using alkaline solution preferably sodium hydroxide solution.

10. The process of claim 2 wherein said Step (a) rising the temperature of the reaction mass is in the range to about 170°C and preferably to 160°C.
11. The process of claim 1&2 wherein said Step (e) Risedronate Monosodium Salt obtained is stable anhydrous form.