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Field of the Invention:
The present invention relates to a process for preparation and purification of pantoprazole sodium sesquihydrate Form -I.
Background of the Invention:
Pantoprazole sodium sesquihydrate, 5-(Difluoromethoxy)-2-[[(3,4- dimethoxy-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazole sodium sesquihydrate has the following structural formula
O
Pantoprazole sodium sesquihydrate
Pantoprazole sodium sesquihydrate is used in the treatment of gastro oesophageal reflux disease, reflux esophagitis, gastric ulcers, duodenal ulcers and Zollinger-Ellison Syndrome. Pantoprazole is a proton pump inhibitor, accumulates in the acidic compartment of the parietal cells after absorption and is protonated by specific action on the proton pumps of the parietal cells. Pantoprazole inhibits specifically and dose proportionally H+, K+-AT-Pase, the enzyme, which is responsible for gastric acid secretion in the parietal cells of the stomach thereby acting as Q gastric acid secretion inhibitor.
U.S. Patent No.4,758,579 discloses pantoprazole and many other fluoroalkoxy substituted benzimidazoles as gastric acid secretion inhibitors and further discloses the process for preparation of pantoprazole by oxidation of sulfide analog (5-( Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl] thio]- lH-Benzimidazole) with m-chloro perbenzoic acid in methylene chloride followed by quenching with sodium thiosulfate and sodium carbonate. The product is isolated by extraction with methylene chloride, washing with water, drying the organic layer over magnesium sulphate, concentration, and crystallization from diisopropyl ether and recrystallization from a mixture of methylene chloride and diisopropyl ether. Although pantoprazole sodium is the subject of a claim in the U.S patent 4,758,579,.. a detailed procedure for converting pantoprazole to its sodium salt is not set forth in the patent.
J. Med. Chem, 35 (1992) 1049 - 57 describes the process for preparation of pantoprazole sodium sesquihydrate by oxidation of sulfide analog (5-(Difluoromethoxy)-2-[[(3, 4-dimethoxy-2- pyridinyl)methyl]thio]-lH-Benzimidazole) with m-chloro perbenzoic acid in methylene chloride at temperature of -30°C followed by
O quenching with sodium thiosulfate and sodium carbonate followed
by extracting with methylene dichloride, washing with water, drying over magnesium sulphate, concentrating and adding diisopropyl ether yielded the pantoprazole. Slowly adding the sodium hydroxide solution to a solution of pantoprazole in a mixture of ethanol: methylene dichloride (5:1) at temperature of 20°C, followed by addition of diisopropyl ether, isolation, washing with diisopropyl ether and drying at 40°C under vacuum. The alternate method reported by oxidation of sulfide analog with sodium hypochlorite in ethyl acetate in alkali medium.
PCT Publication WO 91/19710 discloses the monohydrate of pantoprazole sodium and a process for the preparation of the same. The disclosed process involves treating pantoprazole with
ff I
sodium hydroxide in acetone or in lower ketone solution or alternatively by recrystallization of pantoprazole sodium sesquihydrate from acetone or lower ketone.
PCT Publication WO 2004/056804 discloses the various crystalline forms of pantoprazole sodium (Form-II, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX and XX), solvates containing water, acetone, butanol, methyl ethyl ketone, dimethyl
PCT Publication WO 2004/056804 discloses the various crystalline forms of pantoprazole sodium (Form-II, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV, XV and XX), solvates containing water, acetone, butanol, methyl ethyl ketone, dimethyl carbonate, propanol and 2- methyl propanol along with amorphous form and the processes for their preparation starting with pantoprazole or pantoprazole sodium.
U.S. Patent Application US 2004/0186139 discloses the process for the preparation of pantoprazole sodium sesquihydrate Form-I by reacting pantoprazole with stoichiometric quantity of aq.sodium hydroxide in C1-C4 alcohol or THF or ethyl acetate or acetonitrile, optionally filtering the solution, adding the anti solvent such as dichloro methane, chloroform, ethers of Ci~ C4 straight or branched chains for isolation.
The prior reported methods involve the oxidation of sulfide analog either at low temperature (-30°C) or involves the usage of alkali medium (sodium hypochlorite in sodium hydroxide) with the solvent ethyl acetate. Ethyl acetate undergoes hydrolysis in alkali medium such as sodium hydroxide and liberates the acetic acid, ethanol that creates operational problems during • layer separation, extraction and isolation of product. Also prior art reported solvents gives color impurities
Another object of the present invention is to provide a process for recrystallization of pantoprazole sodium sesquihydrate Form-I
Accordingly in the present invention treating the sulfide analog (5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] thio] -lH-Benzimidazole) with sodium hypochlorite solution in presence of sodium hydroxide in methylene dichloride, and isolation in ethyl acetate affords pantoprazole.
Treatment of aqueous sodium hydroxide solution with pantoprazole solution in ethanol, removal of insolubles, concentration, addition of methylene chloride, removal of insolubles and addition of diisopropyl ether affords the pantoprazole sodium sesquihydrate. -Pantoprazole sodium sesquihydrate obtained is dissolved in an organic ester solvent, removal of insolubles if any, cooling to low temperature, addition of stoichiometric amount of aqueous sodium hydroxide solution followed by a small quantity water, optionally by dissolution of pantoprazole sodium sesquihydrate in mixture of Ethyl acetate,sodium hydroxide and water by heating, removal of insolubles(if any),cooling to room temperature and maintenance affords the pure pantoprazole sodium sesquihydrate Form-1.
Scheme-1
Detailed description of the invention:
Thus in accordance with the present invention preparation and purification of pantoprazole sodium sesquihydrate Form-I essentially comprises of the following steps
- Dissolving sulfide analog in methylene chloride
Treating ting with sodium hypochlorite solution in presence of sodium hydroxide
Quenching with sodium thiosulphate, addition of ammonium sulphate
Separating the layers and concentrating the organic solvent
- Adding ethyl acetate and isolation of pantoprazole
- Dissolving pantoprazole in a mixture of ethanol and methylene chloride
- Reacting with aqueous sodium hydroxide solution
Removal of insolubles (if any) and adding diisopropyl ether Isolating and drying the pantoprazole sodium sesquihydrate
- Dissolving pantoprazole sodium sesquihydrate in a mixture of organic ester solvent, sodium hydroxide solution and water
- Removing insolubles if any and cooling the solution (optionally) Isolating and drying pantoprazole sodium sesquihydrate Form-I
In the present invention Sulfide analog (5-(Difluoromethoxy)-2- [[(3,4-dimethoxy-2-pyridinyl) methyl] thio]-lH-Benzimidazole) is dissolved in methylene dichloride, cooled to a temperature below 10°C preferably -3°C to 3°C, sodium hydroxide solution is added,
stoichiometric amount of sodium hypochlorite solution is slowly added over 30 min to 6 hrs at temperature below 10°C preferably -3°C to 3°C, maintained for about 30 min to 4 hrs at temperature of below 10°C, sodium thiosulphate solution is added, raised temperature to about 15°C to 35°C, mixed for about 15 min to 2 hrs, aqueous ammonium sulphate solution is added, mixed for about 15 min to lhr, allowed to settle, organic layer is separated, washed with water and brine solution, dried the organic layer over sodium sulphate, treated with activated carbon, removed the insolubles, concentrated the organic layer below 45°C,ethyl acetate is added and cooled the reaction mass to temperature of 15°C to 0°C and maintaining at 15°C to 0°C for about 30 min to 6hrs,product is isolated, washed with ethyl acetate and dried at a temperature of 50°C to 75°C yielded pantoprazole.
Pantoprazole is dissolved in ethanol, stoichiometric amount of aqueous sodium hydroxide solution is added at temperature of 15°C to 35°C, mixed for about 1 hr to 4 hrs at temperature of 15°C to 35°C, removed the insolubles followed by treated with activated carbon, concentrated the reaction mass to about 40% to 75% of the original volume under vacuum at temperature of 35°C to 55°C, 2 to 5 volumes of methylene chloride is added (w.r.t to pantoprazole) to the reaction mass, maintained for about 15 min to 2hrs, filtered the insolubles, 12 volumes to 25 volumes diisopropyl ether is added (w.r.t to pantoprazole) at a temperature of 15°C to 35°C and mixed for about 2 hrs to 6 hrs. The precipitated product is isolated, washed with mixture of methylene dichloride and diisopropyl ether, dried at temperature of 35°C to 55°C afforded pantoprazole sodium having the water content about 6.8%.
The above obtained Pantoprazole sodium is dissolved in organic ester solvent (s) such as methyl acetate, isopropyl acetate, ethyl acetate and mixtures thereof, preferably ethyl acetate in volumes v ' of about 15 volumes to 30 volumes w.r.t to pantoprazole sodium at C'• a temperature of about 45°C to about 65°C.The insolubles are j
removed and cooled the clear solution to about 15°C to about 35°C. To the reaction mixture IN sodium hydroxide solution is added in stoichiometric amount of 0.02 - 0.10 mole equivalents followed by water. Reaction mixture is mixed for about 30 min to 6 hrs at temperature of 10°CJto 35°C, the product is isolated, washed with ethyl acetate and dried under vacuum at temperature of 35°C to 55°C afforded pantoprazole sodium sesquihydrate.
The prepared pantoprazole sodium, pantoprazole sodium sesquihydrate are identified as Form-I by the characteristic melting range, water content, DSC and XRD.
The required sulfide analog (5-(Difluoromethoxy)-2-[ [ (3,4- dimethoxy-2-pyridinyl)methyl] thio]-lH-Benzimidazole) is prepared according to the prior art methods.
The invention is further illustrated with non-limiting examples Example 1: Preparation of pantoprazole
Sulfide analog (50g) is dissolved in methylene dichloride (750ml), cooled the solution to -2°C and IN sodium hydroxide solution (50 ml) is added. 1% Sodium hypochlorite (1077g) is slowly added at temperature of -2°C to 2°C over 2hr 30 min and maintained at -2°C to 0°C for about 90 min. 10% Sodium thiosulphate solution (50 ml) is added, maintained at 0°C to 10°C for 30 min, temperature is raised to 20°C to 25°C, 50% ammonium sulphate solution (100 ml) is added and maintained at 25°C to 35°C for 30 min. Reaction mass is allowed to settle, layers are separated, organic layer is washed with water (3 x 250ml), followed by 5% sodium chloride solution (250ml) and water (250ml). Organic layer is dried over sodium sulphate (20g), treated with activated carbon (5g) at 25°C to 35°C for 30 min and filtered to get clear solution. Solvent is distilled off from the filtrate under vacuum at temperature below 45°C, ethyl acetate (100ml) is added, mixed for 10 min and again distilled off under vacuum at temperature below 45°C to 50°C. Ethyl acetate (150ml) is added to the reaction mass and maintained at temperature 25°C to 30°C for 30 min. Reaction mass is cooled and maintained at temperature of 0°C to 5°C for 1 hr. Product is filtered, washed with ethyl acetate (50ml) and dried at temperature of 50°C to 60°C till constant weight.
The dry weight of pantoprazole is 35 g (Yield: 67.1%)
Example-2: Preparation of pantoprazole sodium sesquihydrate
Pantoprazole (25g) is suspended in ethanol (50ml), 6N sodium hydroxide solution (11.2ml) is added at temperature of 25 - 28°C over 15 min. Ethanol (25ml) is added, maintained at temperature of 25°C to 32°C for 2 hrs, treated with carbon for 30 min and filtered off the carbon. The filtrate is concentrated to 60ml under vacuum at temperature below 50°C, Methylene dichloride (75ml) is added, maintained at 25°C to 30°C for 15 min and filtered the reaction mass. Diisopropyl ether (375ml) is added and maintained at 25°C to 30°C for 3 hrs. The precipitated product is filtered, washed with diisopropyl ether (50 ml) and dried at 40°C - 45°C till constant weight.
Dry weight of product is 25 g (yield: 88.68%).
The obtained product is identified as pantoprazole sodium sesquihydrate Form-1 based on the Water content (by KF: 6.56%), DSC and XRD
Example-3: Purification of pantoprazole sodium sesquihydrate.
Pantoprazole sodium (20g) is suspended in ethyl acetate (440 ml), temperature is raised and maintained at 55°C to 60°C for 30 min. Reaction mass is filtered while hot through hyflow and cooled the clear filtrate to 28°C to 35°C. IN sodium hydroxide solution (1.6 ml), water (1.0ml) is added to the reaction mass and maintained at temperature of 25°C to 28°C for 2hr 30 min.
The crystallized solid is filtered, washed with ethyl acetate (25 ml) and dried under vacuum at temperature of 40°C to 45°C till constant weight.
Dry weight of pantoprazole sodium sesquihydrate is 17.5 g (Yield: 87.5%)
The product is identical with the reported pantoprazole sodium sesquihydrate Form-I by its chemical analysis, XRD and DSC.

We claim:
1 . A process for the preparation of pantoprazole sodium sesquihydrate form-l essentially comprises of the following steps.
- Dissolving sulfide analog in methylene chloride
Treating with sodium hypochlorite solution in presence of sodium hydroxide
Quenching with sodium thiosulphate, addition of ammonium sulphate
Separating the layers and concentrating the organic solvent
- Adding ethyl acetate and isolation of pantoprazole Dissolving pantoprazole in a mixture of ethanol and methylene chloride
Reacting with aqueous sodium hydroxide solution Removing insolubles (if any) and adding diisopropyl ether Isolating and drying the pantoprazole sodium sesquihydrate Dissolving pantoprazole sodium sesquihydrate in organic ester solvent
Adding aqueous sodium hydroxide solution followed by water Removing insolubles if any and cooling the solution Isolating and drying pantoprazole sodium sesquihydrate Form-I
2. The process as claimed in claiml, wherein the reaction of sulfide analog with sodium hypochlorite solution is carried out at temperature of -3°C to 3°C in methylene dichloride
3. The process as claimed in claim 1, wherein the concentration of organic layer is carried out under vacuum at temperature of below 4 5°C
4. The process for the purification of pantoprazole sodium sesquihydrate prepared by the process as claimed in claim 1-3 essentially comprises of the following steps
Dissolving pantoprazole sodium sesquihydrate in organic ester solvent
Adding aqueous sodium hydroxide solution followed by water Removing insolubles if any !
Cooling the solution to temperature of 15°C to 35°C
Mixing the reaction mass at temperature of 10°C to 3 5°C for 3 0 min to 6hrs
Isolating and drying pantoprazole sodium sesquihydrate
5. The process as claimed in claim 6, wherein the organic ester solvent is methyl acetate, ethyl acetate, and isopropyl acetate
6. The process as claimed in claim 6 & 7, wherein the dissolution of pantoprazole sodium sesquihydrate in organic ester solvent is carried out by heating
7. The process as claimed in claim 6-8, wherein the volume of ^ organic ester solvent with respect to pantoprazole sodium \v/ sesquihydrate is in ratio of 15 volumes to 30 volumes
ft
8. The process as claimed in claim 6, wherein the addition of } sodium hydroxide solution and water is in stoichiometric quantity
9. The process as claimed in claim 6, wherein the drying temperature of pantoprazole sodium sesquihydrate Form-I is 35°C to 55°C under vacuum.