This application claims priority to Indian patent application No. 2745/CHE/2011 filed on Aug 10, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Pantoprazole magnesium hemipentahydrate, pharmaceutical compositions comprising the same.

BACK GROUND OF THE INVENTION

Pantoprazole magnesium salt ("PNT-Mg") has the chemical name 5-difluoromethoxy-2-[[3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole magnesium and the following chemical structure:
PNT-Mg is an inhibitor of gastric acid secretion. This class of compounds is known as proton pump inhibitors or H+K+ATPase inhibitors.

US 4758579 ("US'579 patent"), discloses the class of fluoroalkoxy-substituted benzimidazoles, which
includes pantoprazole and salts thereof. The US'579 patent states that preferred salts of sulfoxide compounds falling within the class of fluoroalkoxy-substituted benzimidazoles, such as Pantoprazole or its basic salts including sodium, potassium, calcium, and aluminum salts.

US 6124464 ("US'464 patent") discloses the magnesium salts of substituted sulfinyl heterocyclic compounds, which includes Pantoprazole magnesium. The US'464 patent is exemplified process for preparing the Pantoprazole magnesium in example 10, in which Pantoprazole free acid is reacted with magnesium sulfate heptahydrate in presence of an aqueous ammonia in methanol. The product is crystallized from methanol/water to obtain Pantoprazole magnesium salt.

US 6410569 ("US'569 patent") discloses Pantoprazole magnesium dihydrate and processes for its preparation. Wherein, Pantoprazole sodium sesquihydrate is reacted with magnesium chloride

hexahydrate in water. This patent also discloses that the product obtained according to the process of US '464 patent is anhydrous Pantoprazole magnesium.

US2008/0139623A1 (US'623) discloses Pantoprazole magnesium hemipentahydrate (Forms G & E), Pantoprazole magnesium tetrahydrate (Form H), Pantoprazole magnesium dimethanolate (Form F), pantoprazole magnesium dihydrate (Form C) and amorphous Pantoprazole magnesium. According to US'623 application the polymorphic form is obtained as per the process disclosed in US'464 is characterized as Pantoprazole magnesium dihydrate (referred as Form A). Pantoprazole magnesium hemipentahydrate (Form E) prepared as per the process of US'623 is not consistent, not reproducible in large scale. Moreover, the process involves the reflux temperature of methanol; at this temperature the compound degradation and impurity formation is more.

The present invention provides an improved process for the preparation of Pantoprazole magnesium hemipentahydrate (Form E) with consistent high yield and purity in large scale production.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of Pantoprazole magnesium hemipentahydrate with high yield and purity.

In one aspect, the present invention encompasses a process for preparing the crystalline Pantoprazole magnesium hemipentahydrate comprising the steps of a) suspending Pantoprazole in a solvent, b) treating with magnesium source, b) adding hydrocarbon solvent, and c) isolating Pantoprazole magnesium hemipentahydrate.

Another aspect, the present invention encompasses a process for preparing the crystalline Pantoprazole magnesium hemipentahydrate (Form E) comprising the steps of; a) suspending Pantoprazole in alcoholic solvent, b) treating with magnesium alkoxide, c) optionally heating to 50-55°C to get clear solution, d) optionally seeding with Pantoprazole magnesium hemipentahydrate (Form E) e) cooling to the room temperature, f) adding hydrocarbon solvent, and e) isolating Pantoprazole magnesium hemipentahydrate (Form E).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Pantoprazole magnesium hemipentahydrate, wherein the said process comprising reacting Pantoprazole with a source of magnesium in a solvent, adding hydrocarbon solvent and isolating Pantoprazole magnesium hemipentahydrate.

In one embodiment, the present invention encompasses a process for preparing the crystalline Pantoprazole magnesium hemipentahydrate comprising the steps of

a) suspending Pantoprazole in a solvent,
b) treating with magnesium source,
c) adding hydrocarbon solvent, and
d) isolating Pantoprazole magnesium hemipentahydrate.

According to the present invention Pantoprazole is suspended in a solvent at ambient temperature, magnesium source is added at same temperature. The suspension is optionally heated to get clear solution. The solution is slowly cooled to ambient temperature and allowed to stir for another 10 to 25 hrs at the same temperature. To the resulting mixture hydrocarbon solvent is added, stirred for 2-4hrs and the obtained solid is filtered to get Pantoprazole magnesium hemipentahydrate.

According to the embodiment, the solvent is selected from the group comprising alcohols, esters, ethers, ketones, chlorinated solvents, nitrile solvent or mixtures thereof. The alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol or butanol; the ester solvent selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate or isopropyl acetate; the ether solvent selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether or diisopropyl ether; the ketone solvent selected from acetone, methylethylketone or methylisobutylketone; the chlorinated solvent selected from methylene dichloride, ethylene dichloride, carbontetrachloride or chloroform; the nitrile solvent selected from acetonitrile or propionitrile.

According to the embodiment, the hydrocarbon solvent refers to aliphatic or aromatic hydrocarbon solvent. The aromatic hydrocarbon solvent is selected from toluene or xylene. The aliphatic hydrocarbon solvent is selected from cyclohexane, hexane, pentane or heptane.

According to the present invention, the magnesium source is selected from magnesium ethoxide, magnesium methoxide, magnesium acetate tetrahydrate, magnesium chloride or magnesium sulfate heptahydrate According to the embodiment, the obtained Pantoprazole magnesium hemipentahydrate is crystalline polymorphic Form E.

In another embodiment, the present invention encompasses a process for preparing the crystalline Pantoprazole magnesium hemipentahydrate (Form E) comprising the steps of

a) suspending Pantoprazole in alcohol solvent,
b) treating with magnesium alkoxide,
c) optionally heating to 50-55°C to get clear solution,
d) optionally seeding with Pantoprazole magnesium hemipentahydrate (Form E),
e) cooling to the room temperature,
f) adding toluene, and
g) isolating Pantoprazole magnesium hemipentahydrate (Form E).

According to the present invention Pantoprazole is suspended in alcohol solvent selected form methanol, ethanol, propanol, isopropanol or butanoi at ambient temperature, magnesium alkoxide selected from magnesium methoxide, magnesium ethoxide or magnesium isopropoxide is added at same temperature. The suspension is optionally heated to 50-55°C to get clear solution, further it seeded with pantoprazole magnesium hemipentahydrate (Form E). The reaction is maintained at same temperature for about 2-4hrs and the mixture is cooled to room temperature slowly at the rate of 10°C/hr, stirred for about 15-25 hrs. Toluene is added and stirred for 20-60 min. The resulting mixture is further cooled to 5 -10 °C and the obtained solid is filtered to get Pantoprazole magnesium hemipentahydrate.

According to the present invention, the magnesium alkoxide is selected from magnesium ethoxide, magnesium methoxide, magnesium or magnesium isopropoxide.

The rate of cooling in step e) is slow, consisting to avoid any formation of other polymorphic forms and the optimized cooling rate is 10°C/hr.

According to the present invention the word "suspending" means slurring, treating or contacting.

According to the present invention pantoprazole magnesium hemipentahydrate (Form E) is having water content of about 5.0-6.5% by weight.

The precipitated crystalline Pantoprazole magnesium hemipentahydrate (Form E) may be isolated from the mixture by any method refers to filtration, decantation, evaporation and the like. Preferably, the precipitated crystalline Pantoprazole magnesium hemipentahydrate (Form E) is isolated from the mixture by filtration. Optionally, the isolated crystalline pantoprazole magnesium hemipentahydrate (Form E) may be further purified by washing and drying. Preferably, the isolated crystalline Pantoprazole magnesium hemipentahydrate (Form E) is washed with hydrocarbon solvents. Preferably, the isolated crystalline Pantoprazole magnesium hemipentahydrate (Form E) is dried at a temperature of about 40°C to about 60°C, and more preferably at a temperature of about 45°C to 50°C under reduced pressure.

According to the embodiment, the present invention also encompasses the use of crystalline pantoprazole magnesium hemipentahydrate (FormE) in the manufacture of a pharmaceutical composition for inhibiting gastric acid secretion.

Advantages of the present invention

i) the present process provides Pantoprazole magnesium hemipentahydrate (Form E) in with high purity, ii) formation of mercaptobenzimidazole impurity is minimized in this process, iii) this process feasible at large scale production with consisting yield.

The following examples are provided to illustrate the process of the present invention. However, they are not intended to limit the scope of an invention.

Examples:

Example 1: Preparation of Pantoprazole Magnesium hemipentahydrate (Form E) Pantoprazole (100gm) was suspended in methanol (200ml) at 22-32°C. The mixture was stirred at room temperature, Magnesium methoxide (117.3 g of 11.14% in methanol solution) was added to the solution and the resulting mixture was heated to reflux for 3 to 4 Hrs. The mixture was then allowed to cool at 22°C-32°C, further it was stirred at same temperature for 18 to 22 Hrs. Toluene(200ml) was added to the resulting mixture and it was stirred for 2-3 Hrs. The obtained solid was filtered and washed with toluene (200ml) under nitrogen atmosphere and dried the wet product at 45°C-50°C under reduced pressure (50-100mm Hg) to obtain crystalline Pantoprazole magnesium hemipentahydrate. (Yield: 66.2%; Moisture content: 5.1-6.2%)

Example 2: Preparation of Pantoprazole Magnesium hemipentahydrate (Form E)
Pantoprazole (100gm) was suspended in methanol (200ml) at 22-32°C. The mixture was stirred at room temperature, Magnesium methoxide (117.3 g of 11.14% in methanol solution) was added to the solution and the resulting mixture was heated to 45°C-50°C for 3 to 4 Hrs. The mixture was then allowed to cool at 22°C-32°C, further it was stirred at same temperature for 18 to 22 Hrs.

Toluene(200ml) was added to the mixture and it was stirred for 2-3 Hrs. The resulting solid was filtered, washed with toluene (200ml) under nitrogen atmosphere and dried the wet product at 45°C-50°C under reduced pressure (50-100mm Hg) to obtain crystalline Pantoprazole magnesium hemipentahydrate. (Yield: 66.2%; Moisture content: 5.1- 6.2%)

Example 3: Preparation of Pantoprazole Magnesium hemipentahydrate (Form E)
Pantoprazole (100gm) was suspended in methanol (200ml) at 22-32°C. The mixture was stirred at room temperature, Magnesium methoxide (117.3 g of 11.14% in methanol solution) was added to the solution and the resulting mixture was stirred at 22-32°C for 3 to 4 Hrs. The mixture was then allowed to stir for another 18 to 22 Hrs at the same temperature. Toluene (200ml) was added to the mixture and it was stirred for 2-3 Hrs. The resulting solid was filtered and washed with toluene (200ml) under nitrogen atmosphere and dried the wet product at 45°C-50°C under reduced pressure (50-100mm Hg) to obtain crystalline Pantoprazole magnesium hemipentahydrate. (Yield: 66.2%; Moisture content: 5.1- 6.2%)

Example 4: Preparation of Pantoprazole Magnesium hemipentahydrate (Form E)
Pantoprazole (100gm) was suspended in methanol (300ml) at 22°C-32°C. The mixture was stirred at room temperature, Magnesium methoxide (117.3 g of 11.14% in methanol solution) was added to the solution and the resulting mixture was heated to 52°C-55°C to get a clear solution, followed by seeding with pure pantoprazole magnesium hemipentahydrate (E) (0.5gm) and it was stirred for 2 Hrs at 52°C-55°C. The mixture was then allowed to cool at 22°C-32°C, further it was stirred at same temperature for 17 to 20 Hrs. Toluene(100ml) was added to the mixture and it was stirred for 30 minutes. Cool the reaction mass at 5°C to 10°C and allowed to stir for I hr at same temperature. The resulting solid was filtered and washed with toluene (200ml) under nitrogen atmosphere and dried the wet product at 45°C-50°C under reduced pressure (50-100mm Hg) to obtain crystalline Pantoprazole magnesium hemipentahydrate. (Yield:74%; Moisture content: 5.1- 6.2%).

WE CLAIM:
1. A process for preparing the crystalline Pantoprazole magnesium hemipentahydrate comprising the steps of,

a) suspending Pantoprazole in a solvent,
b) treating with magnesium source,
c) adding hydrocarbon solvent, and
d) isolating Pantoprazole magnesium hemipentahydrate.

2. The process according to claim 1, wherein the solvent is used in step a) is selected from alcohols, ethers, ketones, chlorinated solvents, nitrile solvent or mixtures thereof.

3. The process according to claim 1, wherein the magnesium source is selected from magnesium ethoxide, magnesium methoxide, magnesium acetate tetrahydrate, magnesium chloride or magnesium sulfate heptahydrate.

4. The process according to claims 1, wherein the hydrocarbon solvent used in step c) is toluene, cyclohexane, hexane, pentane or heptane.

5. The process according to claims 1, wherein Pantoprazole magnesium hemipentahydrate is crystalline polymorphic Form E.

6. A process for preparing the crystalline Pantoprazole magnesium hemipentahydrate (Form E) comprising the steps of

a) suspending Pantoprazole in alcohol solvent,
b) treating with magnesium alkoxide,
c) optionally heating to 50-55°C to get clear solution,
d) optionally seeding with Pantoprazole magnesium hemipentahydrate (Form E),
e) cooling to the room temperature,
f) adding toluene, and
g) isolating Pantoprazole magnesium hemipentahydrate (Form E).

7. The process according to claim 6, wherein the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol.

8. The process according to claim 6, wherein the magnesium alkoxide is selected from magnesium methoxide, magnesium ethoxide or magnesium isopropoxide.