Indian Patents. 238641:PROCESS FOR PREPARATION OF PANTOPRAZOLE SODIUM SESQUIHYDRATE

Title of Invention	PROCESS FOR PREPARATION OF PANTOPRAZOLE SODIUM SESQUIHYDRATE
Abstract	The present invention relates to the process of pantoprazole sodium sesquihydrate Form I having following 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.

Full Text	COMPLETE AFTER PROVISIONAL LEFT ON ^ 2MAY 2006 FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See Section 10 and Rule 13) 1. Title of the Invention: - Process for Preparation of Pantoprazole Sodium Sesquihydrate and Product Prepared Thereby 2. Applicants:- (a) Name : RPG LIFE SCIENCES LIMITED (b) Nationality : An Indian Company (c) Address : Ceat Mahal, 463, Dr. Annie Besant Road, Worli, MUMBAI - 400 030, Maharashtra, INDIA 3. Preamble to the Description:- Complete Specification: The following specification particularly describes the Invention and the manner in which it is to be performed. ORGN 551/MUM/2005 4.5.2005 RPG/PSQH 10 15 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]sulfinyl]-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 Due to its suitability as pharmaceutically active gastric acid secretion inhibitor, pantoprazole sodium sesquihydrate Form - I finds its 25 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 2 RPG/PSQH 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 5 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]. 10 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 15 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)]. 20 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 25 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 30 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 RPG/PSQH 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 5 [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 10 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 15 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 20 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 25 successful in avoiding use of excess number of solvents and an ti-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 30 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 RPG/PSQH 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. 5 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 10 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 15 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 20 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 25 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 30 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, RPG/PSQH 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 5 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 10 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 15 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 20 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 25 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. 30 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 RPG/PSQH 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 5 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 j 10 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 15 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. 20 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 25 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- 30 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 7 RPG/PSQH 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 5 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- 10 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- 15 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 20 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 25 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 30 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 8 RPG/PSQH 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 5 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 10 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 15 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 20 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. 25 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. 30 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 9 RPG/PSQH 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 5 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 10 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. 15 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. 20 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%. 25 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 30 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 10 RPG/PSQH 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 5 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 10 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 15 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 20 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 25 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 30 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 11 RPG/PSQH 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 5 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 10 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 15 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 20 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 25 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 30 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. 12 RPG/PSQH Accordingly, the present invention relates to a process for preparation of pantoprazole sodium sesquihydrate having following Formula-I. 5 from pantoprazole sodium comprising formation of a suspension of pantoprazole sodium in a solvent mixture and directly recovering the 10 pantoprazole sodium sesquihydrate Form - I 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 15 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 20 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 25 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. 13 RPG/PSQH 15 20 BRIEF DESCRIPTION OF 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 25 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. 14

Full Text

COMPLETE AFTER PROVISIONAL
LEFT ON ^
2MAY 2006
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
1. Title of the Invention: -
Process for Preparation of Pantoprazole Sodium Sesquihydrate and Product Prepared Thereby
2. Applicants:-
(a) Name : RPG LIFE SCIENCES LIMITED
(b) Nationality : An Indian Company
(c) Address : Ceat Mahal, 463, Dr. Annie Besant Road, Worli,
MUMBAI - 400 030, Maharashtra, INDIA
3. Preamble to the Description:-
Complete Specification:
The following specification particularly describes the Invention and the manner in which it is to be performed.

ORGN
551/MUM/2005
4.5.2005

RPG/PSQH

10
15

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]sulfinyl]-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

Due to its suitability as pharmaceutically active gastric acid
secretion inhibitor, pantoprazole sodium sesquihydrate Form - I finds its
25 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
2

RPG/PSQH
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
5 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].
10 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
15 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)].
20 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
25 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
30 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

RPG/PSQH
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
5 [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
10 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
15 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
20 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
25 successful in avoiding use of excess number of solvents and an ti-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
30 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

RPG/PSQH
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.
5 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
10 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
15 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
20 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
25 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
30 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,

RPG/PSQH
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
5 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
10 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
15 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
20 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
25 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.
30 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

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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
5 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 j
10 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
15 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.
20 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
25 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-
30 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
7

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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
5 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-
10 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-
15 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
20 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
25 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
30 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
8

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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
5 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
10 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
15 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
20 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.
25 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.
30 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
9

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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
5 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
10 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.
15 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.
20 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%.
25 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
30 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
10

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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
5 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
10 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
15 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
20 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
25 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
30 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
11

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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
5 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
10 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
15 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
20 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
25 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
30 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.
12

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

5

from pantoprazole sodium comprising formation of a suspension of pantoprazole sodium in a solvent mixture and directly recovering the
10 pantoprazole sodium sesquihydrate Form - I 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
15 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
20 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
25 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.
13

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15
20

BRIEF DESCRIPTION OF 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

25 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.
14

PROCESS FOR PREPARATION OF PANTOPRAZOLE SODIUM SESQUIHYDRATE

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