EP2294064A2 - Process for purification of rabeprazole sodium - Google Patents
Process for purification of rabeprazole sodiumInfo
- Publication number
- EP2294064A2 EP2294064A2 EP08808137A EP08808137A EP2294064A2 EP 2294064 A2 EP2294064 A2 EP 2294064A2 EP 08808137 A EP08808137 A EP 08808137A EP 08808137 A EP08808137 A EP 08808137A EP 2294064 A2 EP2294064 A2 EP 2294064A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- rabeprazole
- sodium
- stirred
- added
- rabeprazole sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a process for obtaining pure rabeprazole sodium.
- Xhe present invention also relates to a novel process for the preparation rabeprazole sodium amorphous form, and to a pharmaceutical composition comprising it.
- Rabeprazole sodium is an inhibitor of the gastric proton pump. It suppress gastric acid secretion by inhibiting the gastric H + , K + ATPase at the secretory surface of the gastric parital cell and blocks the final step of gastric acid secretion.
- Rabeprazole sodium is a sulfoxide compound have been prepared by oxidizing thioether compound with an oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, sodium hypochlorite, sodium hypobromite etc., as described in JP-A1-6270 (EP 268956), US 5045552). Rabeprazole represented by following structure:
- Japanese patent application JP2001039975 indicates that the product obtained by example 33 of U.S. patent No. 5045552 with a melting point of 140- 141 0 C corresponds to amorphous rabeprazole sodium.
- the X- ray powder diffraction pattern of the amorphous rabeprazole sodium is shown.
- U.S. patent No. 6180652 concerns process for the purification of rabeprazole and its pharmaceutically acceptable salts for its sulfone impurity, via: acetone complex of the rabeprazole or its pharmaceutically acceptable salts.
- rabeprazole sodium in amorphous form is obtained by lyophilizing an aqueous solution of rabeprazole sodium acetone complex.
- lyophilization is a technique which is not suitable for production at industrial scale because this process presents serious limitations on cost, time, equipment capability and environmental protection.
- WO 2004/085424 A1 refers to the conversion of the rabeprazole sodium acetone complex into amorphous rabeprazole sodium by heating at elevated temperatures, preferably between 100 and 110 0 C. It is well known that exposing rabeprazole-type compounds to high temperatures increases the risk of decomposition to form impurities and as such, heat treatment of rabeprazole sodium acetone complex into amorphous rabeprazole sodium is not adequate for the production of a rabeprazole which is suitable for pharmaceutical use.
- a process for preparing amorphous rabeprazole sodium comprises: a) Mixing a solution of rabeprazole sodium in a chlorinated solvent with cyclohexane, b) stirring the contents obtained in step (a) at 0-50 0 C for at least 15 minutes, and c) isolating amorphous rabeprazole sodium from the contents obtained in step (b).
- the solution of rabeprazole sodium in the chlorinated solvent may be obtained for example, by dissolving rabeprazole sodium in the chlorinated solvent or as a part of reaction mass obtained by reaction of rabeprazole with a base such as sodium hydroxide.
- the chlorinated solvent used in step (a) may preferably be methylene chloride, ethylene chloride or chloroform; or a mixture thereof.
- the more preferred chlorinated solvent is methylene chloride.
- the stirring in step (b) may preferably carried out at 20-35 0 C for 15 to 75 minutes, more preferably at 15 to
- Preparation of the amorphous rabeprazole sodium may occur during step (b).
- the precipitated solid may be isolated from the contents by methods such as filtration or ce ⁇ trifugation. If required the isolation of the amorphous rabeprazole sodium may be performed by the methods known in the art such as by cooling, using an antisolvent, by partial evaporation or a combination thereof followed by filtration or a centrifugation.
- the bottom organic layer was separated twice by treating with methylene chloride (2 x 250 L), stirred and allowed to settle for 15 minutes.
- Water (1300 L) and sodium hydroxide flakes (50 Kg) were added to the reactor, cooled to 20 - 25 0 C and then added the methylene chloride layer to the reactor.
- Sodium chloride (50 Kg) was added to the reaction mixture, stirred for 20 minutes and allowed to settle for 20 minutes.
- the bottom organic layer was separated.
- the pH of the aqueous layer was adjusted to 9.2 - 9.4 with ammonium acetate solution (ammonium acetate: 52 Kg + water: 200 L) and acetic acid solution (acetic acid: 65 L + water: 200 L).
- the bottom organic layer was separated twice by treating with methylene chloride (2 x 650 L), stirred and allowed to settle for 15 minutes.
- the organic layer was given carbon treatment, filtered and washed the filtrate with methylene chloride (50 L). Dried the total organic layers with sodium sulfate (20 Kg) and 2-Amino ethanol (1.8 L) was added. The organic layer was concentrated until the mass temperature reached to 40 - 45 0 C.
- Acetonitrile (50 L) was added to the reaction mass and acetonitrile was distilled off from the reaction mass until the mass temperature reached to 40 - 45 0 C.
- Acetonitrile (600 L) was added to the reaction mass, stirred for 2 hours at room temperature and cooled to 0 - 5 0 C.
- the total organic layer was washed with sodiumchloride solution (sodium chloride: 36 Kg, DM water: 140 L), given carbon treatment, filtered, washed the filtrate with methylenechloride (50 L) and 2-amino ethanol (0.54 L) was added.
- the organic layer was concentrated until the mass temperature reached to 35 - 40 0 C.
- Acetonitrile (90 L) was added to the reaction mass and acetonitrile was distilled off from the reaction mass until the mass temperature reached to 35 - 40 0 C.
- Acetonitrile (270 L) was added to the reaction mass, cooled to 25 - 35 0 C, stirred for 1 hour 30 minutes, cooled to 0 - 5 0 C and stirred for 1 hour.
- Rabeprazole was added to the solution and stirred at 25 - 35 0 C for 1 hour. Methanol was distilled off from the reaction mass, dichloromethane (150 L) was added to the residual mass and the contents were stirred to obtain solution. The solution was added to cyclohexane (1080 L). The contents were stirred at 25 - 35 0 C for 30 minutes, centrifuged the material and washed at 60 - 65 0 C to obtain 69 Kg of amorphous rabeprazole sodium.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
There is provided a process for preparing amorphous rabeprazole sodium. Thus, for example, sodium hydroxide was dissolved in methanol. Rabeprazole was added to the solution and stirred at 25 - 35°C for 1 hour. Methanol was distilled off from the reaction mass, dichloromethane was added to the residual mass and the contents were stirred to obtain solution. The solution was added to cyclohexane. The contents were stirred at 25 - 35°C for 30 minutes, centrifuged the material and washed at 60 - 65°C to obtain amorphous rabeprazole sodium.
Description
PROCESS FOR PURIFICATION OF RABEPRAZOLE SODIUM
FIELD OF THE INVENTION
The present invention relates to a process for obtaining pure rabeprazole sodium. Xhe present invention also relates to a novel process for the preparation rabeprazole sodium amorphous form, and to a pharmaceutical composition comprising it.
BACKGROUND OF THE INVENTION
Rabeprazole sodium is an inhibitor of the gastric proton pump. It suppress gastric acid secretion by inhibiting the gastric H+, K+ ATPase at the secretory surface of the gastric parital cell and blocks the final step of gastric acid secretion. Rabeprazole sodium is a sulfoxide compound have been prepared by oxidizing thioether compound with an oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, sodium hypochlorite, sodium hypobromite etc., as described in JP-A1-6270 (EP 268956), US 5045552). Rabeprazole represented by following structure:
Japanese patent application JP2001039975 indicates that the product obtained by example 33 of U.S. patent No. 5045552 with a melting point of 140- 1410C corresponds to amorphous rabeprazole sodium. In this application, the X- ray powder diffraction pattern of the amorphous rabeprazole sodium is shown.
The process referred in example 33 of U.S. Patent No. 5045552 is that during the oxidation of the rabeprazole thioether compound, the obtained sulfoxide compound suffers a further oxidation generating the undesired sulfone (2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfonyl]-1H- benzimidazole) impurity.
U.S. patent No. 6180652 concerns process for the purification of rabeprazole and its pharmaceutically acceptable salts for its sulfone impurity, via: acetone complex of the rabeprazole or its pharmaceutically acceptable salts.
In the reference example 1 of U.S. patent 6180652 rabeprazole sodium in amorphous form is obtained by lyophilizing an aqueous solution of rabeprazole sodium acetone complex.
However, lyophilization is a technique which is not suitable for production at industrial scale because this process presents serious limitations on cost, time, equipment capability and environmental protection.
WO 2004/085424 A1 refers to the conversion of the rabeprazole sodium acetone complex into amorphous rabeprazole sodium by heating at elevated temperatures, preferably between 100 and 1100C. It is well known that exposing rabeprazole-type compounds to high temperatures increases the risk of decomposition to form impurities and as such, heat treatment of rabeprazole sodium acetone complex into amorphous rabeprazole sodium is not adequate for the production of a rabeprazole which is suitable for pharmaceutical use.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention there is provided a process for preparing amorphous rabeprazole sodium the said process comprises: a) Mixing a solution of rabeprazole sodium in a chlorinated solvent with cyclohexane, b) stirring the contents obtained in step (a) at 0-500C for at least 15 minutes, and c) isolating amorphous rabeprazole sodium from the contents obtained in step (b).
The solution of rabeprazole sodium in the chlorinated solvent may be obtained for example, by dissolving rabeprazole sodium in the chlorinated solvent or as a part of reaction mass obtained by reaction of rabeprazole with a base such as sodium hydroxide.
The chlorinated solvent used in step (a) may preferably be methylene chloride, ethylene chloride or chloroform; or a mixture thereof. The more preferred chlorinated solvent is methylene chloride. The stirring in step (b) may preferably carried out at 20-350C for 15 to 75 minutes, more preferably at 15 to
60 minutes.
Preparation of the amorphous rabeprazole sodium may occur during step (b). The precipitated solid may be isolated from the contents by methods such as
filtration or ceπtrifugation. If required the isolation of the amorphous rabeprazole sodium may be performed by the methods known in the art such as by cooling, using an antisolvent, by partial evaporation or a combination thereof followed by filtration or a centrifugation.
Examples Example 1
2-[[[4-(3-Methoxypropoxy)~3-methyl-2-pyridinyl]methyl]thio]-1H- benzimidazole (130 Kg) was dissolved in methylene chloride(780 L)1 stirred at 25 - 350C and cooled the reaction mass to 0 - 50C. Sodium hypochlorite solution (2%, 975 L) was added to the reaction mass for 1 hour 30 minutes at 0 - 50C and stirred. Ammonium sulphate (122 Kg), water (1000 L), methylene chloride (250 L) and sodium chloride (130 Kg) were added to the reaction mass, stirred for 30 minutes at 5 - 100C and allowed to settle for 15 minutes. The bottom organic layer was separated twice by treating with methylene chloride (2 x 250 L), stirred and allowed to settle for 15 minutes. Water (1300 L) and sodium hydroxide flakes (50 Kg) were added to the reactor, cooled to 20 - 250C and then added the methylene chloride layer to the reactor. Sodium chloride (50 Kg) was added to the reaction mixture, stirred for 20 minutes and allowed to settle for 20 minutes. The bottom organic layer was separated. The pH of the aqueous layer was adjusted to 9.2 - 9.4 with ammonium acetate solution (ammonium acetate: 52 Kg + water: 200 L) and acetic acid solution (acetic acid: 65 L + water: 200 L). The bottom organic layer was separated twice by treating with methylene chloride (2 x 650 L), stirred and allowed to settle for 15 minutes. The organic layer was given carbon treatment, filtered and washed the filtrate with methylene chloride (50 L). Dried the total organic layers with sodium sulfate (20 Kg) and 2-Amino ethanol (1.8 L) was added. The organic layer was concentrated until the mass temperature reached to 40 - 450C. Acetonitrile (50 L) was added to the reaction mass and acetonitrile was distilled off from the reaction mass until the mass temperature reached to 40 - 450C. Acetonitrile (600 L) was added to the reaction mass, stirred for 2 hours at room temperature and cooled to 0 - 50C. Centrifuged the material twice, washed with acetonitrile (2 x 50 L) and dried to give 90 Kg of crude rabeprazole. Taken Monomethylamine (135 L) in water (765 L), cooled to 10 - 200C, added crude rabeprazole and stirred for dissolution. The bottom organic layer was separated
twice by treating with methylene chloride (2 x 180 L), stirred and allowed to settle for 15 minutes. The pH of the aqueous layer was adjusted to 9.6 - 9.8 with ammonium acetate solution (ammonium acetate: 36 Kg + DM water: 140 L). The bottom organic layer was separated twice by treating with methylene chloride (2 x 450 L), stirred and allowed to settle for 15 minutes. The total organic layer was washed with sodiumchloride solution (sodium chloride: 36 Kg, DM water: 140 L), given carbon treatment, filtered, washed the filtrate with methylenechloride (50 L) and 2-amino ethanol (0.54 L) was added. The organic layer was concentrated until the mass temperature reached to 35 - 400C. Acetonitrile (90 L) was added to the reaction mass and acetonitrile was distilled off from the reaction mass until the mass temperature reached to 35 - 400C. Acetonitrile (270 L) was added to the reaction mass, cooled to 25 - 350C, stirred for 1 hour 30 minutes, cooled to 0 - 50C and stirred for 1 hour. Centrifuged the material, washed with acetonitrile (50 L) and dried the material to give 72 Kg of rabeprazole (HPLC purity: 99.8%). Sodium hydroxide (8.2 Kg) was dissolved in methanol (360 L).
Rabeprazole was added to the solution and stirred at 25 - 350C for 1 hour. Methanol was distilled off from the reaction mass, dichloromethane (150 L) was added to the residual mass and the contents were stirred to obtain solution. The solution was added to cyclohexane (1080 L). The contents were stirred at 25 - 350C for 30 minutes, centrifuged the material and washed at 60 - 650C to obtain 69 Kg of amorphous rabeprazole sodium.
Claims
We claim
1) A process for preparing amorphous rabeprazole sodium the said process comprises: a) Mixing a solution of rabeprazole sodium in a chlorinated solvent with cyclohexane, b) stirring the contents obtained in step (a) at 0-500C for at least 15 minutes, and c) isolating amorphous rabeprazole sodium from the contents obtained in step (b). 2) The process according to claim 1, wherein the solvent used in step (a) is methylene chloride.
3) The process according to claim 1 , wherein the step (b) is carried out at 20 - 350C for 15 to 75 minutes.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2008/000433 WO2010004571A2 (en) | 2008-07-07 | 2008-07-07 | Process for purification of rabeprazole sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP2294064A2 true EP2294064A2 (en) | 2011-03-16 |
| EP2294064A4 EP2294064A4 (en) | 2011-10-05 |
Family
ID=41507511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP08808137A Withdrawn EP2294064A4 (en) | 2008-07-07 | 2008-07-07 | Process for purification of rabeprazole sodium |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP2294064A4 (en) |
| WO (1) | WO2010004571A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2391197B1 (en) * | 2011-04-27 | 2013-07-16 | Moehs Ibérica S.L. | PROCEDURE FOR OBTAINING RABEPRAZOL SODIUM AMORFO. |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005016917A1 (en) * | 2003-07-15 | 2005-02-24 | Allergan, Inc. | Process for preparing isomerically pure prodrugs of proton pump inhibitors |
| WO2006024890A1 (en) * | 2004-08-30 | 2006-03-09 | Apollo International Limited | Improved process for rabeprazole sodium in amorphous form |
| ATE495166T1 (en) * | 2005-03-30 | 2011-01-15 | Lupin Ltd | IMPROVED METHOD FOR PREPARING RABEPRAZOLE SODIUM |
| AR058440A1 (en) * | 2005-08-02 | 2008-02-06 | Medichem Sa | PROCESSES FOR THE PRODUCTION OF RABEPRAZOL SODICO AMORFO |
| EP2162449A4 (en) * | 2007-05-25 | 2011-07-13 | Hetero Drugs Ltd | Improved process for amorphous rabeprazole sodium |
-
2008
- 2008-07-07 WO PCT/IN2008/000433 patent/WO2010004571A2/en not_active Ceased
- 2008-07-07 EP EP08808137A patent/EP2294064A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010004571A2 (en) | 2010-01-14 |
| EP2294064A4 (en) | 2011-10-05 |
| WO2010004571A3 (en) | 2010-12-29 |
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Legal Events
| Date | Code | Title | Description |
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| 17P | Request for examination filed |
Effective date: 20100513 |
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| AX | Request for extension of the european patent |
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| A4 | Supplementary search report drawn up and despatched |
Effective date: 20110901 |
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| RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07D 401/12 20060101AFI20110826BHEP |
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| DAX | Request for extension of the european patent (deleted) | ||
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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| 18D | Application deemed to be withdrawn |
Effective date: 20140201 |