Title of Invention	PROCESS FOR PREPARATION OF PANTOPRAZOLE SODIUM POLYMORPHS
Abstract	The present invention relates to novel polymorphs of pantoprazole sodium, to processes for their preparation and to pharmaceutical compositions containing them.

Full Text

The present invention relates to novel polymorphs of pantoprazole sodium, to processes for their preparation and to pharmaceutical compositions containing them. BACKGROUND OF THE INVENTION Pantoprazole sodium, chemically 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt, is represented by the following structure: Pantoprazole sodium is an antiulcerative, which is disclosed and claimed in US 4,758,579. A crystalline form of pantoprazole sodium is mentioned in Analytical Profiles of Drug Substances and Excipients - volume 29, year 2002, page no. 213-259. We have discovered two stable novel crystalline forms and these forms are at least as stable as the reported form. The novel crystalline forms are stable over the time. We have also discovered a sufficiently stable amorphous form of pantoprazole sodium. So, these forms can be utilized to prepare stable pharmaceutical dosage forms. The object of the present invention is to provide stable polymorphs of pantoprazole sodium, processes for preparing these forms and pharmaceutical compositions containing them. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a novel crystalline form of pantoprazole sodium, designated as form I, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 5.3, 13.1, 13.5, 14.8, 20.7, 21.8 and 25.6 degrees. Figure 1 shows typical form I x-ray powder diffraction spectrum. In accordance with the present invention, a process is provided for preparation of pantoprazole sodium form I. Pantoprazole sodium form I is prepared by dissolving pantoprazole sodium in a suitable solvent and isolating pantoprazole sodium form I from the solution by adding an anti-solvent. Pantoprazole sodium in any crystalline or amorphous form may be used in the process. The quantity of the anti-solvent should be at least sufficient to precipitate pantoprazole sodium from the solution. In accordance with the present invention, an another process is provided for preparation of pantoprazole sodium form I. Pantoprazole sodium form I is prepared by dissolving pantoprazole in a suitable solvent, adding sodium hydroxide to the solution and then isolating pantoprazole sodium form I from the solution by adding an anti-solvent. The quantity of sodium hydroxide to pantoprazole is not limiting, but 0.5 to 2.0 moles of sodium hydroxide per mole of pantoprazole is preferable. The quantity of the anti-solvent should be at least sufficient to precipitate pantoprazole sodium from the solution. In accordance with the present invention, there is provided a novel crystalline form of pantoprazole sodium, designated as form II, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 5.4, 8.7, 14.0, 15.1, 15.4, 16.2, 18.3, 18.9, 19.6, 19.9, 20.8, 21.3, 22.1, 23.1, 25.6, 28.2 and 28.6 degrees. Figure 2 shows typical form II x-ray powder diffraction spectrum. In accordance with the present invention, a process is provided for preparation of pantoprazole sodium form II. Pantoprazole sodium form II prepared by dissolving pantoprazole sodium in acetonitrile and isolating pantoprazole sodium form II from the solution by adding an anti-solvent. Pantoprazole sodium in any crystalline or amorphous form may be used in the process. The quantity of the anti-solvent should be at least sufficient to precipitate pantoprazole sodium from the solution. In accordance with the present invention, an another process is provided for preparation of pantoprazole sodium form II. Pantoprazole sodium form II is prepared by dissolving pantoprazole in acetonitrile, adding sodium hydroxide and isolating pantoprazole sodium form II from the solution by adding an anti-solvent. The quantity of sodium hydroxide to pantoprazole is not limiting, but 0.5 to 2.0 moles of sodium hydroxide per mole of pantoprazole is preferable. The quantity of the anti-solvent should be at least sufficient to precipitate pantoprazole sodium from the solution. In accordance with the present invention, there is provided a novel amorphous form of pantoprazole sodium, designated as amorphous pantoprazole sodium, characterized by having broad x-ray diffraction spectrum as in figure 3. In accordance with the present invention, a process is provided for preparation of amorphous pantoprazole sodium. Amorphous pantoprazole sodium is prepared by dissolving pantoprazole sodium in an alcohol or a mixture of alcohols and removing the solvents from the solution. Pantoprazole sodium in any crystalline or amorphous form may be used in the process. The alcohol is selected from the group consisting of methanol, ethanol and isopropyl alcohol. The solvent may be removed from the solution by vacuum drying or spray drying. The 'suitable solvents1 used in the above processes are methanol, ethanol, isopropyl alcohol and acetone; and a mixture thereof. Preferable 'anti-solvent1 is diisopropyl ether or toluene; or a mixture thereof. In accordance with the present invention, there is provided a pharmaceutical composition comprising pantoprazole sodium form I and a pharmaceutically acceptable carrier or diluent. In accordance with the present invention, there is provided a pharmaceutical composition comprising pantoprazole sodium form II and a pharmaceutically acceptable carrier or diluent. In accordance with the present invention, there is provided a pharmaceutical composition comprising amorphous pantoprazole sodium and a pharmaceutically acceptable carrier or diluent. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of pantoprazole sodium form I. Figure 2 is a x-ray powder diffraction spectrum of pantoprazole sodium form II. Figure 3 is a x-ray powder diffraction spectrum of amorphous pantoprazole sodium. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-Ka radiation. The invention will now be further described by the following examples, which are illustrative rather than limiting. Pantoprazole and pantoprazole sodium used in the following examples are obtained from the previously known methods. Example 1 Pantoprazole sodium (5.0 gm) is dissolved in methanol (15 ml) at 3O°C and then diisopropyl ether (250 ml) is added. The contents are stirred for 24 hours at 25°C to 3O°C and filtered to give 4.8 gm of pantoprazole sodium form I. Example 2 Pantoprazole (10.0 gm) is dissolved in methanol (30 ml), sodium hydroxide (1.1 gm) is added at 25°C and stirred for 2 hours at 25°C to 3O°C. Then diisopropyl ether (250 ml) is added to the solution and stirred for 1 hour at 25°C to 28°C. The separated solid is filtered to give 9.0 gm of pantoprazole sodium form I. Example 3 Pantoprazole sodium (10.0 gm) is dissolved in acetonitrile (50 ml) at 3O°C and then diisopropyl ether (300 ml) is added. The contents are stirred for 6 hours at 25°C to 3O°C and filtered to give 4.5 gm of pantoprazole sodium form II. Example 4 Pantoprazole (10.0 gm) is dissolved in acetonitrile (50 ml), sodium hydroxide (1.1 gm) is added slowly at 25°C to the clear solution. The contents are stirred for 3 hours at 25°C to 3O°C. Then diisopropyl ether (300 ml) is added to the solution and stirred for 2 hours at 25°C to 3O°C. The separated solid is filtered to give 9.1 gm of pantoprazole sodium form II. Example 5 Pantoprazole sodium (5.0 gm) is mixed with toluene (100 ml), heated to 7O°C and then acetonitirile (50 ml) is added to form a clear solution. The solution is cooled to 3O°C, stirred for 20 hours at 25°C to 3O°C and the separated solid is filtered to give 4.3 gm of pantoprazole sodium form II. Example 6 Example 3 is repeated using pantoprazole sodium form I instead of pantoprazole sodium. The yield of pantoprazole sodium form II is 4.1 gm. Example 7 Example 1 is repeated using pantoprazole sodium form II instead of pantoprazole sodium. The yield of pantoprazole sodium form I is 4.6 gm. Example 8 Pantoprazole sodium (5.0 gm) is dissolved in methanol (50 ml) at 25°C. The solution is subjected to vacuum drying at about 5O°C for 7 hours to give amorphous pantoprazole sodium in near quantitative yield. Example 9 Example 8 is repeated by subjecting the solution to spray drying instead of vacuum drying to give amorphous pantoprazole sodium. We claim: 1. A process for the preparation of pantoprazole sodium polymorph, crystalline form I, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 5.3, 13.1, 13.5, 14.8, 20.7, 21.8 and 25.6 degrees as shown in figure 1; crystalline form II, characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 5.4, 8.7, 14.0, 15.1, 15.4, 16.2, 18.3,18.9,19.6,19.9, 20.8, 21.3, 22.1, 23.1, 25.6, 28.2 and 28.6 degrees as shown in figure 2; amorphous form, characterized by an x- ray powder diffraction spectrum as shown in figure 3; as herein described comprising either; i) dissolving pantoprazole sodium in a suitable solvent and isolating pantoprazole sodium crystalline polymorphs, form I and form II, from the solution by adding an anti-solvent, or removing the solvents from the solution either by vacuum drying or by spray drying to form pantoprazole sodium amorphous form; or ii) dissolving pantoprazole in a suitable solvent, adding sodium hydroxide to the solution and isolating pantoprazole sodium crystalline polymorphs, form I and form II, from the solution by adding an anti-solvent; wherein the suitable solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile and mixture thereof. 2. The process as claimed in claim 1, wherein the anti-solvent is diisopropyl ether or toluene. 3. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving pantoprazole sodium in methanol, ethanol, isopropyl alcohol or acetone; and b) isolating pantoprazole sodium form I from the solution formed in step (a) by adding diisopropyl ether as an anti-solvent. 4. The process as claimed in claim 3, wherein the pantoprazole sodium in step (a) is dissolved in methanol. 5. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving pantoprazole in methanol, ethanol, isopropyl alcohol or acetone; b) adding sodium hydroxide; and c) isolating pantoprazole sodium form I from the solution formed in step (b) by adding toluene as an anti-solvent. 6. The process as claimed in claim 5, wherein the pantoprazole is dissolved in methanol or ethanol. 7. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving pantoprazole sodium in acetonitrile; and b) isolating pantoprazole sodium crystalline form II from the solution formed in step (a) by adding diisopropyl ether as an anti-solvent. 8. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving pantoprazole in acetonitrile; b) adding sodium hydroxide; and c) isolating pantoprazole sodium crystalline form II from the solution formed in step (b) by adding diisopropyl ether as an anti-solvent. 9. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving pantoprazole sodium in methanol, ethanol or isopropyl alcohol; and b) removing the solvents from the solution formed in step (a) either by vacuum drying or by spray drying to form pantoprazole sodium amorphous form. 10. The process as claimed in claim 9, wherein the solvent is removed by vacuum drying. 11. The process as claimed in claim 9, wherein the solvent is removed by spray drying. DATED: 05 May 2003

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