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Title:
PROCESS FOR PREPARATION OF PANTOPRAZOLE SODIUM SESQUIHYDRATE AND PRODUCT PREPARED THERBY
Document Type and Number:
WIPO Patent Application WO/2007/017890
Kind Code:
A3
Abstract:
The process for preparation of pantoprazole sodium sesquihydrate Form I having Formula (I), from pantoprazole sodium comprising formation of a suspension of pantoprazole sodium in a solvent mixture and directly recovering the pantoprazole sodium sesquihydrate Form-I by filtration and pantoprazole sodium sesquihydrate Form-I produced from said process are disclosed.

Inventors:
SRIVASTAVA, Ranjan, Prasad (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
MISHRA, Vinodkumar, Deonayak (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
KADAM, Ajit, Arjun (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
DALVI, Rajiv, Ramchandra (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
Application Number:
IN2006/000150
Publication Date:
October 25, 2007
Filing Date:
April 28, 2006
Export Citation:
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Assignee:
RPG LIFE SCIENCES LIMITED (Ceat Mahal, 463 Dr. Annie Besant Road,Worli,Mumbai 0, Maharashtra, 400 03, IN)
SRIVASTAVA, Ranjan, Prasad (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
MISHRA, Vinodkumar, Deonayak (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
KADAM, Ajit, Arjun (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
DALVI, Rajiv, Ramchandra (RPG LIFE SCIENCES LIMITED, Ceat Mahal 463, Dr. Annie Besant Road, Worli, Mumbai 0, 400 03, IN)
International Classes:
C07D403/12; A61K31/4439
Foreign References:
US20040186139A12004-09-23
Other References:
KOHL B. ET AL.: "(H+,K+)-ATPase Inhibiting 2[(2-Pyridylmethyl)sulfinyl]benzimidazoles. 4. A Novel Series of Dimethoxypyridyl-Substituted Inhibitors with Enhanced Selectivity. The Selection of Pantoprazole as a Clinical Candidate", J. MED. CHEM., vol. 35, 1992, pages 1049 - 1057, XP002291720, DOI: doi:10.1021/jm00084a010
ZUPANCIC V. ET AL.: "Physical characterization of pantoprazole sodium hydrates", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 291, 29 December 2004 (2004-12-29), pages 59 - 68, XP027624280
Attorney, Agent or Firm:
MEHTA, Ramesh, Kumar et al. (Mehta & Mehta Associates, Mehta HouseB-474, Sushant Lok-I,Sector 27, Gurgaon 2 NCR, 122 02, IN)
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Claims:

Claims

The process for preparation of pantoprazole sodium sesquihydrate Form I having following Formula -I.

-3/2H 2 O

Formula -I

from pantoprazole sodium comprising formation of a suspension of pantoprazole sodium in a solvent mixture and directly recovering the pantoprazole sodium sesquihydrate Form-I by filtration.

A process as claimed in claim 1, wherein said solvent mixture is mixture of water and an ether.

A process as claimed in claim 1 or 2, wherein said ether is selected from diisopropyl ether [DIPE], diethyl ether and methyl fert-butyl ether [MBTE].

A process as claimed in any one of the preceding claims, wherein said ether is diisopropryl ether.

A process as claimed in any one of the preceding claims, wherein the water content in said solvent mixture is varied from about 0.3 to about 1.2% (V /V) of the volume of ether.

A process as claimed in any one of the preceding claims, wherein the water content in said solvent mixture is varied from about 0.6 to about 1.2% (V/ V) of the volume of ether.

A process as claimed in any one of the preceding claims, wherein the water content in said solvent mixture is varied from about 0.6 to about 0.8% (V /V) of the volume of ether.

8. A process as claimed in any one of the preceding claims, wherein pantoprazole sodium and said solvent mixture are taken in a ratio varying from about 1:8 to about 1:12.

9. A process as claimed in any one of the preceding claims, wherein pantoprazole sodium and said solvent mixture are taken in a ratio varying from about 1:9 to about 1:11, preferably varying from about 1:10 (W /V).

10. A process as claimed in any one of the preceding claims, wherein said pantoprazole sodium is characterized by having a PXRD shown in Figure II.

11. A process as claimed in any one of the preceding claims, wherein said pantoprazole sodium is characterized by having a DSC scan shown in Figure III.

12. A process as claimed in any one of the preceding claims, wherein said step of stirring is carried out at room temperature of about 25-30 0 C for about 1 to 12 hours.

13. Pantoprazole sodium sesquihydrate Form I produced by process claimed in any one of the preceding claims.

14. Pantoprazole sodium sesquihydrate Form I characterized by PXRD shown in Figure IV.

15. Pantoprazole sodium sesquihydrate Form I characterized by DSC shown in Figure V.

16. Pantoprazole sodium sesquihydrate Form I characterized by IR spectra shown in Figure VI. 17. Pharmaceutical compositions comprising pantoprazole sodium sesquihydrate Form-I of any one of preceding claims 13-16.

18. A method for treatment of stomach disorder or gastroesophageal reflux disease by way of administration of pantoprazole sodium sesquihydrate Form-I of any one of preceding claims 13-16 or by administration of Pharmaceutical composition of claim 17.

19. Use of pantoprazole sodium sesquihydrate Form-I of any one of preceding claims 13-16 or of Pharmaceutical composition of claim 17 as suitable pharmaceutically active gastric acid secretion inhibitor.

20. The process for preparation of pantoprazole sodium sesquihydrate Form I substantially as herein described with the help of forgoing examples and as illustrated in the accompanying drawings.

21. Pantoprazole sodium sesquihydrate Form I substantially as herein described with the help of forgoing examples and as illustrated in the accompanying drawings.

Description:

TITLE OF THE INVENTION

Process for preparation of pantoprazole sodium sesquihydrate and product prepared thereby. TECHNICAL FIELD OF THE INVENTION

The present invention relates to a process for preparation of pantoprazole sodium sesquihydrate and product prepared thereby and to pharmaceutical compositions containing the same. Particularly, it relates to a process for preparation of pantoprazole sodium sesquihydrate, which has been designated as Form I and Form I of pantoprazole sodium sesquihydrate produced thereby and to pharmaceutical compositions containing the same. BACKGROUND OF THE INVENTION

Pantoprazole sodium sesquihydrate is chemically known as 5- (Difluoromethoxy)-2-[[(3,4-di-methoxy-2-pyridinyl)methyl]sul finyl]-lH- benzimidazole sodium sesquihydrate and has been found to be more suitable pharmaceutically active gastric acid secretion inhibitor.

Pantoprazole sodium sesquihydrate Form - I has following Formula-I

3/2 H 2 O

Formula-I

Due to its suitability as pharmaceutically active gastric acid secretion inhibitor, pantoprazole sodium sesquihydrate Form - I finds its application as an active ingredient of pharmaceutical product, which is in solid state and more of crystalline Form having unique physical properties, so that it can be used for pharmaceutical composition meant for

gastroesophageal reflux disease. Therefore, a constant research is going on to find out more and more economical and environment friendly method for its preparation.

The pantoprazole sodium sesquihydrate has been prepared from pantoprazole free base by drop wise addition of sodium hydroxide in a solution of pantoprazole free base in the mixture of ethanol and dichloromethane followed by addition of diisopropryl ether as an anti solvent (hereinafter referred to as first known method) [J. Medicinal Chemistry, 1992, Vol. 35, page 1049-1057, No.6]. The major drawback of above first known method is that it employs two solvents - ethanol and dichloromethane, and one anti solvent - diisopropryl ether in-addition to sodium hydroxide and is two steps process.

As the above first known method employs large amount of ethanol, not only the isolation of pantoprazole sodium sesquihydrate is problematic, but even its yield is low.

Further, this first known method employs dichloromethane, which is known to cause carcinogenicity, hazard and toxic pollution in the environment being chlorinated solvent [National Institute for Occupational Safety and Health Doc. No. 76-138 (1976)]. Therefore, the above first known method is highly uneconomical not only on small scale production, but also on large scale production and is also more time consuming and less environment friendly.

To overcome the disadvantages of above first known method, an alternative process for preparation of pantoprazole sodium sesquihydrate from pantoprazole free base has been reported (US2004/0186139 Al). This method [hereinafter referred to as second known method) comprises dissolving pantoprazole free base in sodium hydroxide solution in a suitable solvent followed by filtration to have a clear solution and then followed by adding an anti solvent to the filtrate produced thereby to isolate pantoprazole sodium sesquihydrate.

In accordance with above second known method, the suitable solvent to dissolve pantoprazole free base to have a clear solution is selected from C1-C4 straight or branched chain alcohols, tetrahydrofuran and ethyl

acetate, and the suitable anti-solvent employed in this process is selected from petroleum ether, hexane, n-heptane, cyclohexane, cycloheptane or chlorinated solvents such as dichloromethane or chloroform or ethereal solvents, such as diisopropryl ether [DIPE] or methyl-tertiary butyl ether [MTBE].

The main object of the above second known method was to overcome disadvantages, drawbacks and limitations of the above first known method by avoiding use of excess volumes of the solvents and to avoid large number of solvents to have cost-effective, substantially pure, easily scalable and environment friendly process.

However, even the second known method to prepare pantoprazole sodium sesquihydrate from pantoprazole free base has not been successful to overcome disadvantages, drawbacks and limitations of the first known method, because second known method also involves more than one solvent in-addition to employing sodium hydroxide solution, and also requires formation of a clear solution before isolating pantoprazole sodium sesquihydrate from reaction mixture meaning thereby the second known method is also a two step process.

Further, disadvantage of the second known method is that it not only involves two solvents in-addition to sodium hydroxide, but it also employs the solvents in sufficiently large quantities.

Accordingly, even the second known method could not overcome main drawbacks of the first known method to prepare pantoprazole sodium sesquihydrate from pantoprazole free base, that is, it could not be successful in avoiding use of excess number of solvents and anti-solvents, and excess volume of solvents and anti-solvents, and could not overcome problem of two step process, that is, the problems of time consuming, poor yield and poor purity.

The another object of the second known method was to avoid use of large amounts of ethanol to have better yield and better purity of pantoprazole sodium sesquihydrate and ease of isolation.

In accordance with the second known method, as stated hereinabove, the suitable solvent to dissolve pantoprazole free base includes

alcohols, including ethanol. Accordingly, this method might have been successful to avoid excess volume of ethanol as solvent, but it could not avoid use of ethanol to have better yield and better purity of pantoprazole sodium sesquihydrate and ease of isolation. Further, as stated hereinabove, even the second known method is also two steps process. It is well known that processes involving more than one process step are known to give poor yield and low purity of the end product, particularly during the large scale production. To have a process commercially successful, it is most desirable to have minimum number of process steps and minimum number of solvent mediums, because this will result in minimum amount of efforts for removal of solvents and isolation of the desired end product.

Accordingly, even the second known method for preparing pantoprazole sodium sesquihydrate cannot be considered, at least, to be cost-effective, less time consuming, less hazardous and environment friendly process.

It is clear that the above processes - the first known method and the second known method require in first step to react with or to dissolve pantoprazole free base in solution of sodium hydroxide in a solvent or mixture of solvents to give a clear solution, and in second step the clear solution of pantoprazole free base in solution of sodium hydroxide in a solvent or mixture of solvents is then treated with an anti-solvent to precipitate pantoprazole sodium sesquihydrate from such clear solution thereby making the overall process two step process. Further, the above known processes are not only more time consuming but also more energy consuming thereby making the overall processes further uneconomical, less productive, more time consuming, particularly on large scale production.

Yet another known method for preparation of pantoprazole sodium sesquihydrate from pantoprazole free base (hereinafter referred to as third known method) comprises reacting pantoprazole free base with solution of sodium hydroxide in a selected diluent (US 2004/0177804A1). In this method, the diluent is selected from 2-propanol, tetrahydrofuran,

acetonitrile, methanol, ethanol, water, mixtures of sec-butanol and dichloromethane and ethyl acetate.

The main drawback of the above third known method is that in accordance with this method also the resulted mixture of pantoprazole free base in solution of sodium hydroxide in a selected diluent is treated to obtain clear solution which is then subjected to a step of crystallization to produce pantoprazole sodium sesquihydrate either by cessation of heating or by adding an anti-solvent selected from MTBE and heptane.

Further disadvantage of the above third known method is that it also employs alcohols, particularly ethanol as solvent, which as stated hereinabove has associated disadvantages of resulting in poor yield and low purity of the desired product.

Still another drawback of the above third known method is that it requires a step of heating to reflux the solution of pantoprazole free base in sodium hydroxide in a selected diluent to obtain clear solution before the pantoprazole sodium sesquihydrate is precipitated and isolated, and hence, it is also more time consuming and more energy consuming.

Accordingly, the above third known method also teaches that first the pantoprazole free base is dissolved in a solution of sodium hydroxide in suitable solvent to have a clear solution, even if required, by heating to reflux to have a clear solution. The clear solution is then subjected to treatment with another solvent to precipitate pantoprazole sodium sesquihydrate, which in- turn is isolated from the reaction mixture. For all practical purposes this process is also two steps process in-addition to requiring a step of heating.

It has been observed that in case the step of heating is avoided, then the yield of the end product is not commercially viable to make the process economical, and hence, the energy can be saved but at the cost of loss in yield of the end product. Therefore, even the above third known method is also a two steps process requiring the reaction mixture of pantoprazole free base in solution of sodium hydroxide in a selected diluent to be heated to reflux to obtain a clear solution which is then subjected to a step of crystallization to obtain

pantoprazole sodium sesquihydrate, and hence, the overall process still suffers from drawbacks of two step process, and being more time consuming and more energy consuming thereby making the overall process further uneconomical and less productive, particularly on large scale production In all, the above three known methods involve use of solution of sodium hydroxide if pantoprazole sodium sesquihydrate is prepared from pantoprazole free base, and of solvents like ethanol and chlorinated solvents, and require formation of a clear solution as pre-condition before precipitating pantoprazole sodium sesquihydrate, and hence, the above three methods are neither environment friendly nor are suitable for economical production.

The other known method (hereinafter referred to as fourth known method) for preparing pentoprazole sodium sesquihydrate (US 2004/0177804A1) comprises forming heterogeneous mixture of pantoprazole sodium Form II identified by PXRD shown in accompanying Figure-I with a diluent selected from ethyl acetate, dichloromethane, water, dimethylcarbonate and 2-propanol.

In accordance with some of the preferred embodiments, the above fourth known method does overcome problem of large volume of solvents. However, it has been observed that due to very low amount of solvent(s), this process results in very poor mixing, particularly on large scale production thereby rendering the process more or less solid ageing process which is not advisable in the pharma production which requires homogeneous mixing and not the heterogeneous mixing for better yield and better purity of the end product. Therefore, the reaction mixture is required to have proper slurry in the solvent medium for getting homogeneous mixture to obtain better yield and better purity of the end product. The solid ageing process, that is a process comprising heterogeneous mixing does not result in completion of a reaction, and hence, the end product may comprise un- reacted pantoprazole sodium thereby rendering the end product unsuitable for pharmaceutical applications.

The another drawback of above fourth known method is that in accordance with some preferred embodiments, it employs 2-propanol as a

solvent, which, as per International Conference of Harmonization [ICH] guidelines, is Class 3 solvent and its permissible limit is 5000 ppm, that is 0.5% w/w. However, as per the above fourth known method, the 2-propanol is used in an amount of about 4% w/v, which is equivalent to 3.16% w/w which is obviously very higher than the permissible limit of 0.5% w/w. Accordingly, the above fourth process is not acceptable for the production of a pharmaceutical substance. Further, if no drying is involved, the end product may very likely fail in residual solvent content at production scale. Still further, the process may also fail with respect to the odour because 2- propanol has a peculiar and irritant smell, and hence, is not advisable as a solvent in pharmaceutical productions.

Further, it has also been observed that according to some of the preferred embodiments, the preparation of pantoprazole sodium sequihydrate from said pantoprazole sodium, in case the diluent is 2- propanol or tetrahydrofuran or acetonitrile or ethanol or water or ethyl acetate, requires that said pantoprazole sodium is first dissolved in the diluent by heating to reflux to obtain clear solution followed by either evaporating the diluent or concentrating the reaction mixture to obtain pantoprazole sodium sesquihydrate. Accordingly, these processes are also two steps processes, and require heating to reflux and hence, are highly time consuming as the reaction is carried out for about two or more nights and highly energy consuming as the reaction mixture is heated to obtain the clear solution.

Further, it has also been observed that even the above fourth known method cannot be scaled up on large scale production and hence, is not economical and in view of use of hazardous solvents, it is also not environment friendly.

It has also been observed that pantoprazole sodium employed in the present invention is distinctively different from pantoprazole sodium employed in above fourth known method as can be visualized from PXRD shown in Figures I and II, which respectively show PXRD of pantoprazole sodium employed in US 2004/0177804A1 as starting material and PXRD of

pantoprazole sodium employed in present invention as starting material for preparing pantoprazole sodium sesquihydrate of Form I. NEED OF THE INVENTION

Accordingly, there is still a need to develop a suitable process for preparing pantoprazole sodium sesquihydrate Form I from pantoprazole sodium, which is not only economical, but can also be scaled up for commercial production on large scales, and can also avoid use of hazardous solvents to make the developed process more environment friendly, and at the same time, the developed process should be simple and fast, that is one step process and less time consuming and less energy consuming, and should result in higher yields of pantoprazole sodium sesquihydrate Form I having higher purity. OBJECTS OF THE INVENTION

The main object of the present invention is to provide an improved process for preparation of pantoprazole sodium sesquihydrate Form I employing pantoprazole sodium as a starting material.

The another main object of the present invention is to provide an improved process for preparation of pantoprazole sodium sesquihydrate Form I employing pantoprazole sodium as a starting material, and still being less time consuming and less energy consuming, that is which neither requires preparation of a clear solution as a pre-condition for isolation of pantoprazole sodium sesquihydrate Form I thereby resulting the process one step process and less time consuming process nor requires a step of heating to reflux thereby resulting the process energy saving process. The another object of this invention is to provide a process for preparation of pantoprazole sodium sesquihydrate Form I employing pantoprazole sodium as a starting material, wherein the pantoprazole sodium sesquihydrate Form I is directly produced from pantoprazole sodium. Still another object of this invention is to provide a process for preparation of pantoprazole sodium sesquihydrate Form I which neither employs undesirable and hazardous solvents, like alcohols and chlorinated

solvents nor sodium hydroxide nor demands anhydrous conditions and is simple, convenient and safe even on large scale productions.

Yet another object of this invention is to provide a process for preparation of pantoprazole sodium sesquihydrate Form I which neither employs large number of solvents nor employs large amount of solvents and still results in higher yield of pantoprazole sodium sesquihydrate Form I.

This is another object of this invention to provide a process for preparation of pantoprazole sodium sesquihydrate Form I, which is not only highly economical on large scale production but is also environment friendly.

This is still another object of the present invention to provide a process for preparation of pantoprazole sodium sesquihydrate Form I, which is not only one step process, but can also be easily scaled up for large scale productions without effecting the overall yield of the process. This is yet an object of this invention to provide a process for preparation of pantoprazole sodium sesquihydrate Form I, where not only isolation of pantoprazole sodium sesquihydrate Form I is easier, but the purity of the pantoprazole sodium sesquihydrate Form I produced is also quite high. This is still an object of the present invention to provide a process for preparation of pantoprazole sodium sesquihydrate Form I which is suitable to produce pantoprazole sodium sesquihydrate Form I having moisture content varying within the permissible limits, that is between about 6.2 to about 7.1%. BRIEF DESCRIPTION OF THE INVENTION

It has been observed that the methods known in the prior art for preparation of pantoprazole sodium sesquihydrate primarily suffer from the problem of requirement of preparation of clear solution of pantoprazole free base or of pantoprazole sodium, as the case may be, as a pre-condition for isolating pantoprazole sodium sesquihydrate and the requirement of heating to reflux to obtain a clear solution of pantoprazole free base or of pantoprazole sodium, as the case may be, because the selection of starting material, that is pantoprazole free base or pantoprazole sodium and of

solvent medium is such that it cannot result in direct preparation of pantoprazole sodium sesquihydrate. Therefore, the main object of the inventors of the present invention is to provide a method which is not only one step process, but also avoids heating to reflux, that is which does not require formation of a clear solution as a precondition.

It has been surprisingly observed that if pantoprazole sodium is treated with a solvent mixture of water and ether taken in such a ratio so as to have water content varying from about 0.3% to about 1.2% v/v of the volume of ether it directly results in preparation of pantoprazole sodium sesquihydrate thereby avoiding preparation of a clear solution of pantoprazole sodium and solvent mixture as a precondition, and hence, provides a one step process which is less time consuming.

It has also been surprisingly observed that if pantoprazole sodium is treated with above solvent mixture of water and ether taken in above ratio so as to have water content varying from about 0.3% to about 1.2% v/v of the volume of ether at room temperature it still results in direct preparation of pantoprazole sodium sesquihydrate thereby avoiding a step of heating to reflux to obtain a clear solution of pantoprazole sodium and solvent mixture as a precondition, and hence, provides a one step process which is less energy consuming.

The present process, in-addition to avoiding pre-condition of preparation of a clear solution of pantoprazole sodium and solvent, and avoiding a step of heating to reflux to obtain clear solution of pantoprazole sodium and solvent as a pre-condition before isolation of pantoprazole sodium sesquihydrate, has also been observed to avoid chances of formation of side products thereby making the process more productive to produce pantoprazole sodium sesquihydrate in higher yield having higher purity.

In accordance with the present invention, the pantoprazole sodium and solvent mixture are taken in a ratio varying from about 1 :8 to about 1 : 12 w/v which has been surprisingly observed to allow very good mixing of pantoprazole sodium and solvent mixture even on large scale production thereby making the process a wet blending process which is more desirable in the pharma production which produces required

homogeneous mixing for better yield and better purity of the end product, that is of pantoprazole sodium sesquihydrate. The reaction mixture produced in accordance with present method has also been observed to have proper slurry in the solvent medium which results in formation of a homogeneous mixture to obtain better yield and better purity of the end product, that is of pantoprazole sodium sesquihydrate, and hence, it has been observed to result in completion of a reaction by converting pantoprazole sodium to pantoprazole sodium sesquihydrate. It has been observed that the end product does not comprise un-reacted pantoprazole sodium thereby makes the end product more suitable for pharmaceutical applications, and the present method still avoids preparation of clear solution and/ or heating to reflux to obtain clear solution as a pre-condition to isolate pantoprazole sodium sesquihydrate.

The above solvent mixture of water and ether used in above ratio of the present invention has also been observed to be safer solvent medium thereby making the present process more environment friendly and less hazardous.

Accordingly, the present invention provides an economical and easily scalable to large scale production, and environment friendly, and one step, one pot, simple, convenient and safe process for preparation of pantoprazole sodium sesquihydrate Form-I from pantoprazole sodium by forming a suspension of pantoprazole sodium in a mixture of selected solvents and directly recovering the pantoprazole sodium sesquihydrate Form - I by filtration in better yield and high purity, thereby avoiding not only use of undesirable and hazardous solvents and anhydrous conditions, but also avoiding the step of forming a clear solution as a pre-condition to isolate pantoprazole sesquihydrate Form I or avoiding the step of heating to reflux to form a clear solution as a pre-condition to isolate pantoprazole sesquihydrate Form I, and at the same time being less time consuming and less energy consuming.

In accordance with the present invention the pantoprazole sodium sesquihydrate Form-I is recovered directly from the suspension by way of filtration, thereby making its isolation easier.

Accordingly, the present invention relates to a process for preparation of pantoprazole sodium sesquihydrate having following Formula-I.

-3/2H 2 O

Formula -I

from pantoprazole sodium comprising formation of a suspension of pantoprazole sodium in a solvent mixture and directly recovering the pantoprazole sodium sesquihydrate Form - 1 by filtration.

In another aspect the present invention provides a pantoprazole sodium sesquihydrate Form-I which has been characterized by PXRD, IR, DSC, and C, H, N analysis and moisture content (MC).

In still another aspect the present invention also provides pharmaceutical compositions comprising pantoprazole sodium sesquihydrate Form-I produced by the present process.

In yet another aspect the present invention also provides a method for treatment of stomach disorder or gastroesophageal reflux disease by way of administration of pantoprazole sodium sesquihydrate Form-I produced by the present process.

In still another aspect the present invention also provides use of pantoprazole sodium sesquihydrate Form-I produced by the present process as suitable pharmaceutically active gastric acid secretion inhibitor.

The other objects and advantages of the present invention will be more apparent after referring to the following description when read in conjunction with the accompanying figures, which are not intended to limit scope of the present invention.

BRIEF DESCRIPTION QF THE ACCOMPANYING FIGURES

Figure - I shows PXRD of pantoprazole sodium employed as starting material in the prior art.

Figure - II shows PXRD of pantoprazole sodium employed as starting material in the present invention.

Figure - III shows DSC scan of pantoprazole sodium employed as starting material in the present invention.

Figure - IV shows PXRD of pantoprazole sodium sesquihydrate Form I prepared in accordance with one embodiment of the present invention.

Figure - V shows DSC scan of pantoprazole sodium sesquihydrate Form I prepared in accordance with one embodiment of the present invention the PXRD of which has been shown in Figure IV.

Figure - VI shows IR of pantoprazole sodium sesquihydrate Form I prepared in accordance with one embodiment of the present invention the PXRD of which has been shown in Figure IV. DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides an economical and easily scalable to large scale production, and environment friendly, and one step, one pot, simple, convenient and safe process for preparation of pantoprazole sodium sesquihydrate Form-I having a following Formula -I

-3/2H 2 O Formula -I from pantoprazole sodium by forming a suspension of pantoprazole sodium in a solvent mixture and directly recovering the pantoprazole sodium sesquihydrate Form - I by filtration in better yield and high purity.

In accordance with the present invention, the solvent mixture is mixture of water and ether. The ether is selected from diisopropyl ether [DIPE], diethyl ether and methyl tert-butyl ether [MBTE], preferably the ether is diisopropryl ether. The water content in the solvent mixture is varied from about 0.3 to about 1.2% (V/V) of the volume of ether, preferably varied from about 0.6 to about 1.2% (V/V) of the volume of ether, more preferably varied from about 0.6 to about 0.8% (V/V) of the volume of ether.

It has been observed that when water content is taken in higher amount than 1.2% (V/V) of the volume of ether, the pantoprazole sodium forms a clear solution thereby making recovery of pantoprazole sodium sesquihydrate Form I very difficult.

However, when the water content in solvent mixture consisting of water and ether varies between about 0.3 to about 1.2% (V/V) of the volume of ether, it has been observed that the pantoprazole sodium does not form clear solution and gets completely converted to pantoprazole sodium sesquihydrate Form-I thereby making the recovery of pantoprazole sodium sesquihydrate Form-I not only easier, but also in higher yield having higher purity.

It has also been observed that when water content in the solvent mixture consisting of water and ether is taken in an amount lower than

0.3% (V/V) of the volume of ether, the pantoprazole sodium forms heterogeneous mixture and such heterogeneous mixture has been observed to result in incomplete conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate. Further, it has been observed that the end product from the heterogeneous mixture comprises un-reacted pantoprazole sodium thereby renders the end product unsuitable for pharmaceutical applications.

In accordance with the present invention, pantoprazole sodium and the solvent mixture are taken in a ratio varying from about 1:8 to about 1: 12, preferably varying from about 1 :9 to about 1 : 1 1, more preferably in a ratio of about 1: 10 (W/ V).

It has been surprisingly found that when pantoprazole sodium of the present invention is mixed in accordance with present invention in a solvent mixture consisting of water and ether present in above ratio, it forms

a homogenous suspension and not a clear solution, which on stirring just for few hours directly results in formation of crystalline form of pantoprazole sodium sesquihydrate Form I in higher yield having better purity thereby making the present process one step process which has been observed to be highly economical and environment friendly, and highly time saving and energy saving process due to avoidance of formation of a clear solution as precondition and avoidance of step of heating to reflux to obtain a clear solution as a precondition.

It has also been observed that no side products or impurities are formed in the present process thereby avoids loss on yield and purity of the end product - pantoprazole sodium sesquihydrate Form I, and therefore, it has been observed that the desired end product is obtained in higher yields varying from about 90 to about 95%, preferably more than about 91% having higher purity of about >99 %. The pantoprazole sodium employed in the present invention can be prepared by any known method or obtained from the commercially available pantoprazole sodium. However, it should be characterized by the PXRD shown in accompanying Figure II, which is significantly different from the pantoprazole sodium employed in US 2004/0177804A1 having PXRD shown in accompanying Figure I.

In accordance with the present invention, the process comprises formation of a suspension of pantoprazole sodium having a PXRD shown in Figure II and DSC scan shown in Figure III in a solvent mixture consisting of water and ether, wherein ether is selected from diisopropyl ether [DIPE], diethyl ether and methyl fert-butyl ether [MBTE], preferably the ether is diisopropryl ether, and water and ether are taken in such a ratio so as to have water content in the solvent mixture varying from about 0.3 to about 1.2% (V/V) of the volume of ether, preferably varying from about 0.6 to about 1.2% (V/V) of the volume of ether, more preferably varying from about 0.6 to about 0.8% (V/V) of the volume of ether, and the pantoprazole sodium and the solvent mixture are taken in a ratio varying from about 1:8 to about 1: 12 (W/V), preferably varying from about 1:9 to about 1 :11 (W/V), more preferably in a ratio of about 1: 10 (W/V), which is stirred at room

temperature of about 25-30 0 C for about 1 to 12 hours depending on the batch size to directly result in formation of pantoprazole sodium sesquihydrate Form I, which can be isolated by any known means, for example by filtration. It has been surprisingly observed that when a suspension of pantoprazole sodium in solvent mixture of the present invention is stirred, the time required for higher batch size is relative lower than what is expected to be in ordinary case thereby making the present process less time consuming and more and more economical with increase in batch size. This in-turn results in process being easily scalable for large-scale productions and still being economical. The mechanism for this surprised finding is expected to involve good and easy interaction, with the increase in overall weight by volume of the suspension, of the particles of the pantoprazole sodium with the molecules of water in solvent mixture of the present invention to have the desired moisture content in the pantoprazole sodium sesquihydrate Form I, which in-turn does not go into solution form, but remains suspended and is easily isolated from the reacted mass in higher yield having higher purity.

The present invention uses benefit of formation of suspension of pantoprazole sodium in the solvent mixture of water and ether when present in ratio disclosed in present invention. It has been surprisingly observed that solvent mixture of water and ether in above ratio, when taken in above- described ratio with respect to pantoprazole sodium, not only provides the adequate volume to pantoprazole sodium to form homogeneous suspension under stirring but also results in higher yield of pantoprazole sodium sesquihydrate Form I of higher purity, that is there is no loss of overall yield due to completion of desired reaction and there is no loss of purity due to no formation of side products.

Accordingly, the present invention discloses a process which neither employs large number of solvents nor large amount of solvents. Further, the disclosed process has been observed to be safe, eco-friendly, economical, simple and convenient process even on large scale productions, because it neither demands any anhydrous medium nor requires use of any

undesired or hazardous or expensive reagents or solvents like, alcohols, chlorinated solvents, sodium hydroxide, methylene dichloride, chloroform, carbon tetrachloride etc.

Further, as the process is carried out in presence of water, hence no extra care is required to make the process inert by using nitrogen gas or carrying out process in a moisture free environment.

The still another advantage of the present process is that it is carried out at room temperature neither requiring step of heating to reflux nor a pre-condition to form a clear solution of pantoprazole sodium in solvent mixture. This not only results in savings of energy, but also results in end product in higher yield having higher purity even on prolonged reaction time, which in present invention varies up to 12 hrs. Accordingly, the present process has also been observed to be commercially feasible on industrial scale productions. In another aspect the present invention provides a pantoprazole sodium sesquihydrate Form-I which has been characterized by PXRD, IR, DSC, and C, H, N analysis and moisture content (MC).

In still another aspect the present invention also provides pharmaceutical compositions comprising pantoprazole sodium sesquihydrate Form-I produced by the present process.

In yet 'another aspect the present invention also provides a method for treatment of stomach disorder or gastroesophageal reflux disease by way of administration of pantoprazole sodium sesquihydrate Form-I produced by the present process. In still another aspect the present invention also provides use of pantoprazole sodium sesquihydrate Form-I produced by the present process as suitable pharmaceutically active gastric acid secretion inhibitor.

In accordance with the present invention, the pantoprazole sodium used as starting material for preparation of pantoprazole sodium sesquihydrate Form-I has been characterized by Powder X-ray diffractogram

(PXRD) [Figure-II] and Differential Scanning Calorimetry thermogram (DSC)

[Figure-Ill].

A PXRD pattern of pantoprazole sodium shown in Figure-II having significant two-theta values shows following peaks:

5.325, 21.722, 14.823, 21.394, 20.65, 15.987, 18.981, 25.471, 23.271, 13.058, 13.493, 26.414, 26.81, 25.924, 11.579, 31.666, 28.529, 43.541, 37.09, 27.279, 12.314, 33.417, 23.656, 35.363, 29.159, 37.946, 17.811, 16.701, 36.236, 15.294, 34.676, 47.23, 39.299, 41.809, 44.61, 50.561, 61.366, 10.723, 57.547, 52.269, 46.146, 30.232.

The values of characteristic peaks [in 2-theta (2θ) values] and their relative intensities (I /Io in percentage) of pantoprazole sodium, a PXRD pattern of which has been shown in Figure-II, are as shown in Table - 1.

Table - 1

The pantoprazole sodium sesquihydrate Form-I prepared in accordance with the present invention has been characterized by Powder X- ray diffractogram (PXRD) [Figure-IV], Differential Scanning Calorimetry thermogram (DSC) [Figure-V], Infrared spectrum (IR) [Figure-VI], and C,H,N analysis and moisture content (MC).

The X-ray powder diffractogram of the crystalline Form-I of pantoprazole sodium sesquihydrate Form I is measured on a Philips X' pert CUU3040/60 advance powder X-ray Diffractometer with Cu k alpha- 1 Radiation source and the diffractogram has been shown accompanying in Figure-IV.

A PXRD pattern shown in Figure-IV having significant two-theta values shows following peaks:

5.303, 7.355, 10.569, 1 1.462, 12.080, 12.454, 13.056, 13.317, 14.501, 15.280, 15.892, 16.145, 16.632, 16.814, 17.576, 17.916, 18.443, 18.702, 19.293, 20.03, 20.535, 20.972, 21.215, 21.560, 22.204, 22.866, 23.335, 24.070, 24.422, 24.548, 24.993, 25.348, 26.306, 26.711, 27.101, 27.394, 27.853, 28.760,29.442, 29.719, 30.241, 30.917, 31.839, 32.717, 33.587, 34.216, 34.758,35.431, 36.681 and 37.621 degrees two-theta. The values of characteristic peaks [in 2-theta (2θ) values] and their relative intensities (I/Io in percentage) of crystalline Form-I of pantoprazole sodium sesquihydrate, a PXRD pattern of which has been shown in Figure-IV, are as shown in Table - 2.

The above crystalline pantoprazole sodium sesquihydrate Form - I has also been characterized by Differential Scanning Calorimetry thermogram (DSC) which exhibits a significant endo peak about 138.38°C, the thermogram of which has been shown in Figure-V.

The above crystalline pantoprazole sodium sesquihydrate Form - I has further been characterized by the infrared (IR) spectrum, which is

measured by KBr transmission method and shown in Figure - VI. It shows following significant I. R. bands:

523.6, 554.6, 583.7, 629.8, 643.9, 678.4, 710.4, 754.8, 796.6, 815.7, 837.7, 938, 960.1 , 985.2, 1041.8, 1073.1, 1089.3, 1120.0,

1170.7, 1235.7, 1277.2, 1305.6, 1362.5, 1376.6, 1427.8, 1449.9,

1465.6, 1491.7, 1589.9, 1653.9, 1905.1, 2280.7, 2603.5, 2846.3,

2942.4, 2997.5, 3190.1, 3363.4, 3488.4, 3552.2.

The C, H, N analysis of above crystalline form of pantoprazole sodium sesquihydrate Form I has further established that the present invention results in formation of crystalline form of pantoprazole sodium sesquihydrate Form I.

The moisture content (MC) of above crystalline form of pantoprazole sodium sesquihydrate Form I has been found to be in the range of about 6.2 to about 7.1% further establishing that the present invention results in formation of crystalline form of pantoprazole sodium sesquihydrate Form I.

As evident from above Table 1 and Table 2 and accompanied PXRDs shown in figures II and IV for pantoprazole sodium and pantoprazole sodium sesquihydrate Form I respectively, the characteristic peak at about 22.204 [2-theta (2θ) angle] for pantoprazole sodium sesquihydrate Form I is absent in PXRD of pantoprazole sodium, and the characteristic peak at about 21.722 [2-theta (2θ)] for pantoprazole sodium is absent in PXRD of pantoprazole sodium sesquihydrate Form I confirming thereby conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate Form I when the same is prepared in accordance with method of the present invention.

As also evident from above data and accompanied DSC scans shown in figures III and V for pantoprazole sodium and pantoprazole sodium sesquihydrate Form I respectively, the DSC scan of pantoprazole sodium is characterized by a significant endothermic peak at about 153.15 0 C [Figure- Ill] and the DSC scan of pantoprazole sodium sesquihydrate Form I is characterized by a significant endothermic peak at about 138.38 0 C [Figure-

V] confirming thereby conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate Form I when the same is prepared in accordance with method of the present invention.

Accordingly, the end product of the process of present invention is pantoprazole sodium sesquihydrate Form I and not pantoprazole sodium meaning thereby the pantoprazole sodium sesquihydrate Form I is obtained in higher yield and having higher purity.

The present invention will be more clear from the following examples, which are provided only for the illustrations and are not intended to limit scope of the invention. EXAMPLES

EXAMPLE-I : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-

2 -pyridinyl) methyl] sulfinyl]- lH-benzimidazole sodium sesquihydrate Form-I (Pantoprazole sodium sesquihydrate Form-I)

To a suspension of diisopropyl ether (0.2L) and distilled water

(0.0024L) was added Pantoprazole sodium (0.02K) in one lot at room temperature. The suspension was stirred at room temperature (25-30 0 C) for lhr to directly result in preparation of pantoprazole sodium sesquihydrate Form-I. The white solid was Filtered and dried at 40-45°C for 3 to 3.5hrs. under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has been observed to have PXRD, DSC scan and IR spectra shown in Figures IV, V and VI respectively, and expected C,

H and N. Yield of end product has been found to be 93.7% and MC 7.01%. EXAMPLE-2 : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-

2-pyridinyl)methyl] sulfinyl] - 1 H-benzimidazole sodium sesquihydrate Form-I (Pantoprazole sodium sesquihydrate Form-I)

To a suspension of diisopropylether (5.0L) and pantoprazole sodium (0.5k) was added distilled water (0.03L) in one lot at room temperature. The suspension was stirred at room temperature (25-30 0 C) for 12hrs to directly result in preparation of pantoprazole sodium sesquihydrate

Form-I. The white solid was filtered and dried at 40-45 0 C under 700mm vacuum for 3 to 3.5hrs to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 93% and MC 6.59%.

EXAMPLES : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-

2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium sesquihydrate Form-I (Pantoprazole sodium sesquihydrate Form-I)

To a suspension of diisopropylether (0.1L) and distilled water

(0.0003L) was added pantoprazole sodium (0.01k) in one lot at room temperature. The suspension was stirred at room temperature (25-30 0 C) for

12hrs to directly result in preparation of pantoprazole sodium sesquihydrate Form-I. The white solid was filtered and dried at 40-45 0 C for 3 to 3.5hrs under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 91.93% and MC 6.65%.

EXAMPLE-4 : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-

2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium sesquihydrate Form-I (Pantoprazole sodium sesquihydrate Form-I) To a suspension of diethyl ether (0.1L) and distilled water

(0.0006L) was added pantoprazole sodium (0.01k) in one lot at room temperature. The suspension was stirred at room temperature (25-30 0 C) for 12hrs to directly result in preparation of pantoprazole sodium sesquihydrate Form-I. The white solid was filtered and dried at 40-45 0 C for 3 to 3.5hrs under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI

respectively, and expected C, H and N. Yield of end product has been found to be 91.93% and MC 6.75%.

EXAMPLES : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-

2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium sesquihydrate Form-I (Pantoprazole sodium sesquihydrate Form-I)

To a suspension of methyl tert-butyl ether (0.1L) and distilled water (0.0006L) was added pantoprazole sodium (0.01k) in one lot at room temperature. The suspension was stirred at room temperature (25-30 0 C) for 12hrs to directly result in preparation of pantoprazole sodium sesquihydrate

Form-I. The white solid was filtered and dried at 40-45 0 C for 3 to 3.5hrs under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 92.4% and MC 6.69%.

The word "about" incorporated hereinbefore is intended to include permissible practical errors for each parameter referred therein.

The range of a parameter includes both values of the range, for example range "about 90 to about 95%" includes both values 90 and 95.

It may be noted that various modifications of the present invention are possible without deviating from the intended scope of this invention, which are also intended to be included within the scope of the present invention. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purpose of limitation.