Title of Invention	AN IMPROVED PROCESS FOR PREPARATION OF CRYSTALLINE FORM-I OF PANTOPRAZOLE SODIUM SESQUIHYDRATE
Abstract	The present invention relates to an improved process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate, chemically known as 5-(Difluoromethoxy)-2-[[C3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazo!e sodium sesquihydrate. The Pantoprazole sodium sesquihydrate of the present invention can be depicted as Formula (1). The process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate comprises dissolution of Pantoprazole free base in which it substantially dissolves at an ambient temperature containing a stoechiometric quantity of sodium hydroxide, filtration of the clear solution and followed by addition of anti-solvent in which the product is insoluble to isolate the desired crystalline compound. The process of the present invention is cost effective and eco-friendly over prior art procedures.

Title of Invention

AN IMPROVED PROCESS FOR PREPARATION OF CRYSTALLINE FORM-I OF PANTOPRAZOLE SODIUM SESQUIHYDRATE

Abstract

The present invention relates to an improved process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate, chemically known as 5-(Difluoromethoxy)-2-[[C3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazo!e sodium sesquihydrate. The Pantoprazole sodium sesquihydrate of the present invention can be depicted as Formula (1). The process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate comprises dissolution of Pantoprazole free base in which it substantially dissolves at an ambient temperature containing a stoechiometric quantity of sodium hydroxide, filtration of the clear solution and followed by addition of anti-solvent in which the product is insoluble to isolate the desired crystalline compound. The process of the present invention is cost effective and eco-friendly over prior art procedures.

Full Text	FIELD OF THE INVENTION: The present invention relates to an improved process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate, chemically known as 5-(Difiuoromethoxy)2-[[(3,4-dimelhoxy-2-pyridinyl) methyl ] sulfinyl]-lH-benzimidazole sodium sesquihydrate. The Pantoprazole sodium sesquihydrate of the present invention can be depicted as Formula (1). Formula (1) BACK GROUND OF THE INVENTION: Pantoprazole sodium sesquihydrate is a known Anti-ulcerative drug, gastric acid secretion inhibitor and has been used for the treatment of ulcer patients. USP 4,758,79 specifically claimed the Pantoprazole and its pharmaceutically acceptable salts. The patent also described the process for the preparation of pantoprazole and its related compounds. The process for the preparation of pantoprazole sodium sesquihydrate is not described specifically in '579 patent, but disclosed in the summary of the invention that "the salts are obtained by dissolving five base in a suitable solvent, for example in a suitable halo hydrocarbon solvent such as methylene chloride or chloroform or a low molecular weight aliphatic alcohol such as ethanol or iso propanol or a ketone like acetone or water, which contains the desired acid or base, or to which the desired acid or base is added (if necessary) in the precisely calculated stochiometric amount accompanied by filtering, evaporating the solvent yielded the corresponding salt of Pantoprazole. The process disclosed in the above '579 patent suffers from the draw back that more number of stages and high volume of solvents are involved in the salt preparation. J.Med.Chem. 35,1049-1057 (1992) described the process for the preparation of Pantoprazole sodium sesquihydrate, which comprises the dissolution of pantoprazole freebase in a mixture of ethanol and dichloromethane followed by addition of stoichiometric amount of sodium hydroxide solution and further reaction wort: up resulted the Pantoprazole sodium sesquihydrate with a melting point of 130 c. The process of said journal also suffers from the draw back ofusing mixture of solvents in a high volume, which in turn the desired product was not isolated, hence the volume of ethanol was reduced to isolate the product. The crystalline forms of Pantaprazole sodium sesquihydrate were not reported in any of the relevant references known in the art till date. The inventors of the present invention have prepared the crystalline form of pantoprazole sodium sesquihydrate according to the process disclosed in J.Med.ChenL 35, 1049-1057 (1992) with less volume of ethanol and analyzed the crystalline structure by X-ray diffractogram and hereinafter it is referred as prior art crystallne Form-I of Pantoprazole sodium sesqui hydrate for convenience. Many attempts have been done to provide the novel crystalline form of Pantaprazole sodium sesquihydrate but in all the cases the crystalline structure of product is substantially similar to that of prior art crystalline Form-I of Pantoprazole sodium sesqui hydrate. Since polymorphic fonns of drug substances are known to differ in their physical properties such as melting point, solubility, chemical reactivity etc., they can appreciably influence the phannaceutical properties such as dissolution rate and bioavailability and pentaprazole sodium sesqui hydrate is being a known anti ulcerative drug, it is important to further evaluate the polymorphism to obtain newer polymorphs or to provide an altemate process in a cost-effective, non-hazardous and commercially viable for existing polymorphs. The main aspect of the present invention is to provide an improved process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate. The improved process of the present invention is simple, cost effective, non-hazardous and industrially scalable. The crystalline nature of the pantoprazole sodium sesquihydrate of the present invention has been analyzed by XRD and found that the crystalline stmcture is identical to that of prior art crystalline Form-I of Pantoprazole sodiimi sesqui hydrate. SUMMARY OF THE INVENTION: The present invention is related to an improved process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate. The process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate comprises dissolution of Pantoprazole free base in which it substantially dissolves at an ambient temperature containing a stoichiometric quantity of sodium hydroxide, filtration of the clear solution and followed by addition of anti-solvent in which the product is insoluble to isolate the desired crystalline compound. The solvents for dissolution are selected from C1-C4 straight or branched chain alcohols, tetrahydrofuran, ethyl acetate and the solvents for isolation are selected from a group of aliphatic or alicyclic hydrocarbon solvents, such as petroleum ether, hexane, n-heptane, cyclohexane, cycloheptane or chlorinated solvents such as dichloromethane or chloroform or ethereal solvents, such as diisopropyl ether or methyl-tertiary butyl ether. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING: Fig. 1 is characteristic XRD of prior art crystalline Form-I of Pantoprazole sodium sesquihydrate. Fig. 2 is characteristic XRD of crystalline Form-I of Pantoprazole sodium sesquihydrate obtained as per the process of the present invention. DETAILED DESCRIPTION OF THE INVENTION: The present invention relates to an improved process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate. The crystalline Form-I of Pantoprazole sodium sesquihydrate of the present invention is characterized by X-ray Powder diffractogam, Differential Scanning Colorimetry thermogram and Infra red spectra. The X-ray powder diffractogram of the crystalline Form-I of pantoprazole sodium sesquihydrate of the present invention and the prior art crystalline Form-I of Pantoprazole sodium sesqui hydrate are measured on a Bniker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source. The pattern of X-ray dif&actogram of these two compounds is found to be identical. The X-ray powder diffractogram of prior art crystalline Form-I of Pantoprazole sodium sesqui hydrate is substantially as depicted in Figure (1). The X-ray powder diffractogram of the crystalline Fonn-I of pantoprazole sodium sesquihydrate obtained in the present inventive process is substantially as depicted in Figure (2). The characteristic peaks (in 2-theta values) and their relative intensities (in percentage) of crystalline Form-I of pantoprazole sodium sesquihydrate are shown in the following table (1). The crystalline Form-I of pantoprazole sodium sesquihydrate of the present invention is fiuther characterized by Infrared spectrum, which is measured by KBr-transmission method. The identified significant IR bands are observed around 456, 477, 500.7, 532.3, 575.2, 397.3, 643.9, 685.6. 719.8, 764.4, 804.3, 860.4, 909.1, 922.8, 986.6, 1028.1. 1065.0, 1087.7, 1113.0, 1139.9, 1171.5, 1293.0, 1319.6, 1365.3.1383.7, 1401.3, 1467.9, 1490.3, 1572.3, 2059.8, 2600.5, 2639.0, 2666.5, 2697.2, 2741.5, 2794.9, 2867.9, 3030.0. 3061.0, 3290.6. Another aspect of the present invention is to provide an improved process for the preparation of ctystalline Form-I of Pantoprazole sodiiun sesquihydrate. Accordmgty, an improved process for the preparation of cr>«talline Form-I of Pantoprazole sodium sesquihydrate, which comprises; i. dissolving Pantoprazole free base in a solvent in which it dissolves at a temperature of 25-50°C containing the stoichiometric amount of aqueous sodium hydroxide solution or by adding if necessary, ii. optionally filtering the clear solution obtained in step (i); iii. adding the solvent in which the Pantoprazole sodium is insoluble, accompanied by optionally cooling the mass to -10 to +20*^C and accompanied by stirring till the compound substantially crystallizes; iv. filtering the crystallized solid in step (iii) by conventional methods; v. drying of the soUd obtained in step (iv) at a temperature of 40-90°C, preferably 40-50'^C under vacuimi to a constant weight to afford the desired crystalline Form-I of Pantoprazole sodiiun sesqui hydrate. The solvents for dissolving Pantoprazole freebase are selected fom the group comprising of CI-C4 straight or branched alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol or tertiary butanol or other solvents such as tetrahydro furan or acetonitrile or ethylacetate containing stoichiometric amount of aqueous sodium hydroxide solution. The preferred solvent for dissolution is tetrahydrofuran, acetonitrile or ethyl acetate. The solvents for isolating the desired crystalline Form-I of Pantoprazole sodium sesqui hydrate as an anti solvent are selected from a group of aliphatic or alicyclic hydrocarbon solvents comprising of petroleum ether, hexane, n-heptane, cyclohexane or cyclo heptane, or chlorinated solvents such as dichloromethane or chloroform or ethers having C1-C4 carbon atoms in straight or branched chain such as dimethyl ether, diethyl ether, di isopropyl ether, di butyl ether or methyl tertiary butyl ether. The preferred anti solvents are dichloromethane or diisopropylether or methyl-tertiary butyl ether. The inventors of the present invention were prepared the desired crystalline Form-I of Pantoprazole sodium sesquihydrate from various solvents and analyzed the crystalline stmcture by X-ray diffractogram, which are substantially identical. The laboratory findings are tabulated in the following table (2). The crystalline Form-I of pantoprazole sodium sesquihydrate obtained as per the above processes is observed as free flowing, non-solvated crystalline solid which is well suited for pharmaceutical applications. The process of the present invention is simple, non-hazardous and well suited for commercial production. It is noteworthy to mention that the Pantoprazole free base used as the starting material for the present invention is prepared as per the process disclosed in USP '579. The following examples illustrate the invention but don not limit the scope of further invention. Preparation of Crystalline Form-I of Pantoprazole sodium sesquihydrate: EXAMPLE-1: To a stirred solution of tetrahydrofiiran (350 ml), aqueous sodium hydroxide solution (5.4 grams dissolved in 10 ml of water), Pantoprazole free base (50 grams) was added and stirred at a temperature of 25-35 " C till the clear solution results. The reaction solution was filtered through hyflow and washed the bed with tetrahydrofiiran (2x25 m!). Dichloromethane (400 ml) was added slowly to the filtrate in over a period of 1 hour and stirred for 5-6 hours to separate the solid mass. The separated solid mass was cooled to a temperature of 5-10 " C and fiirtfier stirred for 2-3 hours. The solid was filtered, washed with dichloromethane (2x25 ml) and suck dried under vacuum. The wet solid is susp^ided in dichloromethane (250 ml) and stirred for 15-30 minutes. Then the solid was filtered and suck dried under vacuum and further dried at a temperature of 40-50°C to obtain crystalline Form-I of Pantoprazole sodium sesquihydrate. (Weight: 50.4 grams, MC: 6.49% w/w) EXAMPLE-2: Pantoprazole free base (25 grams) was added to the stirred mixture of acetonitrile (!75 ml), aqueous sodium hydroxide solution (2.7 grams in 5 ml of water) and stirred at a temperature of 25-35 c the clear solution results. The reaction solution was filtered through hyflow and washed the bed with acetonitrile (25 ml). Isopropyl ether (225 ml) was added slowly to the filtrate in over a period of 1/2 hour and stirred for 1-2 hours to separate the solid mass. The sc^iarated solid mass was cooled to a ten^erature of 5-10 ° C and further stirred for 3-4 hours. The solid was filtered, washed with Isopropyl ether (25 ml) and suck dried under vacuum. The wet solid is further dried at a temperature of 40-50°C to obtain crystalline Form-I of Pantoprazole sodium sesquihydrate. (Weight: 25.4 grams, MC: 6.55% w/w) EXAMPLE-3: Pantoprazole freebase (25 grams) was added to the stirred mixture of ethyl acetate (50 ml), aqueous sodiiun hydroxide solution (2.7 grams in 5 ml of water) and stirred at a temperature of 40-50 " C till the clear solution results. Methyl tertiary butyl ether (250 ml) was added and stirred for 3-4 hours to separate the solid mass. The separated solid mass was fihered, washed with methyl tertiary butyl ether (50 ml) and suck dried under vacuum. The wet solid is fiirther dried at a temperature of 40-50°C to obtain crystalline Form-I of Pantoprazole sodium sesquihydrate. (Weight: 15.6 grams, MC: 7.07% w/w) DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWINGS: Fig-1. is characteristic X-ray powder diffraction pattern of crystalline Form-I of Pantoprazole sodium sesquihydrate (according to process disclosed in J.Med.Chem.,1992,35,lO49-1057). Vertical axis: Intensity (CPS); Horizontal axis\| Two Theta (degrees). The significant two-theta values obtained are 5.238,7.294,10.523,11.428,12.345, 13.024,13.30,14.459,15.207,15.844,16.15,16.653,17.527,17.884,18.404,19.97, 20.486,21.214.22.148, 22.812, 23.26,24.002, 24.497,24.957, 25.32, 26.278,27.037, 27.798,28.737,28.383. 30.18. 30.861, 32.652,33.647, 34.671 and 37.572 degrees two- theta. Fig-2. is characteristic X-ray powder diffraction pattern of crystalline form-I of Pantoprazole sodium sesquihydrate. Vertical axis: Intensity (CPS); Horizontal axis: 2 Theta (degrees). Thesignificant two-thetavaluesobtained are 5.326, 7.385, 9.868,10.63,11.531,12.472, 13.102,13.366,14.543,15.317,15.92,16.207,16.687,16.836,17.62,17.966,18.498, 20.061,20.581,21.271,21.621,22.254, 22.886,23.33, 24.122, 24.587,25.026,25.405, 26.353, 26.803, 27.147, 27.887,28.842, 29.487, 30.926, 31.878, 32.708, 33.694,34.748 and 37.642 degrees two-theta. We claim: 1. An improved process for the preparation of crystalline Fonn-I of Pantoprazole sodium sesquihydrate comprises of: i. dissolving Pantoprazole free base in a solvent in which it dissolves at a temperature of 25-50°C containing the stoichiometric amount of aqueous sodium hydroxide solution or by adding if necessary, ii. optionally filtering the clear solution obtained in step (i); iii. adding the solvent in which the Pantoprazole sodium is insoluble, accompanied by optionally cooling the mass to -10 to +20°C and accompanied by stirring till the compound substantially crystallizes; iv. filtering the crystallized solid in step (iii) by conventional methods; V. drying of the solid obtained in step (iv) at a temperature of 40-90°C, preferably 40-50°C under vacuum to a constant weight to afford the desired crystalline Form-I of Pantoprazole sodium sesqui hydrate. 2. The process according to claim (I) of step (1), wherein the solvents are selected from a group comprising of C1-C4 straight or branched alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol or tertiary butanol or tetrahydrofuran or acetonitrile or ethylacetate. 3. The process according to claim (2), wherein the solvent is tetrahydrofuran. 4. The process according to claim (1) of step (3), wherein the solvents are selected from a group comprising of aliphatic or alicyclic hydrocarbon solvents such as petroleum ether, hexane, n-heptane, cyclohexane or cyclo heptane or chlorinated solvents such as dichloromethane or chloroform or ethers having C1-C4 carbon atoms in straight or branched chain such as dimethyl ether, diethyl ether, di isopropyl ether, di butyl ether, methyl ethyl ether or methyl tertiary butyl ether. 5. The process according to claim (4), wherein the solvent is dichloromethane. 6. The process according to claim (4), wherein the solvent is di isopropyl ether. 7. The process according to claim (4), wherein the solvent is methyl tertiary butyl

Full Text

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate, chemically known as 5-(Difiuoromethoxy)2-[[(3,4-dimelhoxy-2-pyridinyl) methyl ] sulfinyl]-lH-benzimidazole sodium sesquihydrate. The Pantoprazole sodium sesquihydrate of the present invention can be depicted as Formula (1).

Formula (1) BACK GROUND OF THE INVENTION:
Pantoprazole sodium sesquihydrate is a known Anti-ulcerative drug, gastric acid
secretion inhibitor and has been used for the treatment of ulcer patients.
USP 4,758,79 specifically claimed the Pantoprazole and its pharmaceutically acceptable
salts. The patent also described the process for the preparation of pantoprazole and its
related compounds.
The process for the preparation of pantoprazole sodium sesquihydrate is not described
specifically in '579 patent, but disclosed in the summary of the invention that "the salts
are obtained by dissolving five base in a suitable solvent, for example in a suitable halo
hydrocarbon solvent such as methylene chloride or chloroform or a low molecular weight
aliphatic alcohol such as ethanol or iso propanol or a ketone like acetone or water, which
contains the desired acid or base, or to which the desired acid or base is added (if

necessary) in the precisely calculated stochiometric amount accompanied by filtering,
evaporating the solvent yielded the corresponding salt of Pantoprazole.
The process disclosed in the above '579 patent suffers from the draw back that more
number of stages and high volume of solvents are involved in the salt preparation.
J.Med.Chem. 35,1049-1057 (1992) described the process for the preparation of
Pantoprazole sodium sesquihydrate, which comprises the dissolution of pantoprazole
freebase in a mixture of ethanol and dichloromethane followed by addition of
stoichiometric amount of sodium hydroxide solution and further reaction wort: up
resulted the Pantoprazole sodium sesquihydrate with a melting point of 130 c.
The process of said journal also suffers from the draw back ofusing mixture of solvents
in a high volume, which in turn the desired product was not isolated, hence the volume of
ethanol was reduced to isolate the product.
The crystalline forms of Pantaprazole sodium sesquihydrate were not reported in any of
the relevant references known in the art till date.
The inventors of the present invention have prepared the crystalline form of pantoprazole
sodium sesquihydrate according to the process disclosed in J.Med.ChenL 35, 1049-1057
(1992) with less volume of ethanol and analyzed the crystalline structure by X-ray
diffractogram and hereinafter it is referred as prior art crystallne Form-I of Pantoprazole
sodium sesqui hydrate for convenience.
Many attempts have been done to provide the novel crystalline form of Pantaprazole
sodium sesquihydrate but in all the cases the crystalline structure of product is
substantially similar to that of prior art crystalline Form-I of Pantoprazole sodium sesqui
hydrate.

Since polymorphic fonns of drug substances are known to differ in their physical
properties such as melting point, solubility, chemical reactivity etc., they can appreciably
influence the phannaceutical properties such as dissolution rate and bioavailability and
pentaprazole sodium sesqui hydrate is being a known anti ulcerative drug, it is important
to further evaluate the polymorphism to obtain newer polymorphs or to provide an
altemate process in a cost-effective, non-hazardous and commercially viable for existing
polymorphs.
The main aspect of the present invention is to provide an improved process for the
preparation of crystalline Form-I of Pantoprazole sodium sesquihydrate. The improved
process of the present invention is simple, cost effective, non-hazardous and industrially
scalable.
The crystalline nature of the pantoprazole sodium sesquihydrate of the present invention
has been analyzed by XRD and found that the crystalline stmcture is identical to that of
prior art crystalline Form-I of Pantoprazole sodiimi sesqui hydrate.
SUMMARY OF THE INVENTION:
The present invention is related to an improved process for the preparation of crystalline
Form-I of Pantoprazole sodium sesquihydrate.
The process for the preparation of crystalline Form-I of Pantoprazole sodium
sesquihydrate comprises dissolution of Pantoprazole free base in which it substantially
dissolves at an ambient temperature containing a stoichiometric quantity of sodium
hydroxide, filtration of the clear solution and followed by addition of anti-solvent in
which the product is insoluble to isolate the desired crystalline compound. The solvents
for dissolution are selected from C1-C4 straight or branched chain alcohols,

tetrahydrofuran, ethyl acetate and the solvents for isolation are selected from a group of
aliphatic or alicyclic hydrocarbon solvents, such as petroleum ether, hexane, n-heptane,
cyclohexane, cycloheptane or chlorinated solvents such as dichloromethane or
chloroform or ethereal solvents, such as diisopropyl ether or methyl-tertiary butyl ether.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING:
Fig. 1 is characteristic XRD of prior art crystalline Form-I of Pantoprazole sodium
sesquihydrate.
Fig. 2 is characteristic XRD of crystalline Form-I of Pantoprazole sodium sesquihydrate
obtained as per the process of the present invention.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for the preparation of crystalline
Form-I of Pantoprazole sodium sesquihydrate.
The crystalline Form-I of Pantoprazole sodium sesquihydrate of the present invention is
characterized by X-ray Powder diffractogam, Differential Scanning Colorimetry
thermogram and Infra red spectra.
The X-ray powder diffractogram of the crystalline Form-I of pantoprazole sodium
sesquihydrate of the present invention and the prior art crystalline Form-I of Pantoprazole
sodium sesqui hydrate are measured on a Bniker Axs, D8 Advance Powder X-ray
Diffractometer with Cu K alpha-1 Radiation source. The pattern of X-ray dif&actogram
of these two compounds is found to be identical.
The X-ray powder diffractogram of prior art crystalline Form-I of Pantoprazole sodium
sesqui hydrate is substantially as depicted in Figure (1).

The X-ray powder diffractogram of the crystalline Fonn-I of pantoprazole sodium sesquihydrate obtained in the present inventive process is substantially as depicted in Figure (2).
The characteristic peaks (in 2-theta values) and their relative intensities (in percentage) of crystalline Form-I of pantoprazole sodium sesquihydrate are shown in the following table (1).

The crystalline Form-I of pantoprazole sodium sesquihydrate of the present invention is
fiuther characterized by Infrared spectrum, which is measured by KBr-transmission
method.
The identified significant IR bands are observed around 456, 477, 500.7, 532.3, 575.2,
397.3, 643.9, 685.6. 719.8, 764.4, 804.3, 860.4, 909.1, 922.8, 986.6, 1028.1. 1065.0,
1087.7, 1113.0, 1139.9, 1171.5, 1293.0, 1319.6, 1365.3.1383.7, 1401.3, 1467.9, 1490.3,
1572.3, 2059.8, 2600.5, 2639.0, 2666.5, 2697.2, 2741.5, 2794.9, 2867.9, 3030.0. 3061.0,
3290.6.
Another aspect of the present invention is to provide an improved process for the
preparation of ctystalline Form-I of Pantoprazole sodiiun sesquihydrate.
Accordmgty, an improved process for the preparation of cr>«talline Form-I of
Pantoprazole sodium sesquihydrate, which comprises;
i. dissolving Pantoprazole free base in a solvent in which it dissolves at a
temperature of 25-50°C containing the stoichiometric amount of aqueous sodium hydroxide solution or by adding if necessary, ii. optionally filtering the clear solution obtained in step (i); iii. adding the solvent in which the Pantoprazole sodium is insoluble, accompanied by optionally cooling the mass to -10 to +20*^C and accompanied by stirring till the compound substantially crystallizes; iv. filtering the crystallized solid in step (iii) by conventional methods; v. drying of the soUd obtained in step (iv) at a temperature of 40-90°C,
preferably 40-50'^C under vacuimi to a constant weight to afford the desired crystalline Form-I of Pantoprazole sodiiun sesqui hydrate.

The solvents for dissolving Pantoprazole freebase are selected fom the group comprising of CI-C4 straight or branched alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol or tertiary butanol or other solvents such as tetrahydro furan or acetonitrile or ethylacetate containing stoichiometric amount of aqueous sodium hydroxide solution. The preferred solvent for dissolution is tetrahydrofuran, acetonitrile or ethyl acetate.
The solvents for isolating the desired crystalline Form-I of Pantoprazole sodium sesqui hydrate as an anti solvent are selected from a group of aliphatic or alicyclic hydrocarbon solvents comprising of petroleum ether, hexane, n-heptane, cyclohexane or cyclo heptane, or chlorinated solvents such as dichloromethane or chloroform or ethers having C1-C4 carbon atoms in straight or branched chain such as dimethyl ether, diethyl ether, di isopropyl ether, di butyl ether or methyl tertiary butyl ether. The preferred anti solvents are dichloromethane or diisopropylether or methyl-tertiary butyl ether. The inventors of the present invention were prepared the desired crystalline Form-I of Pantoprazole sodium sesquihydrate from various solvents and analyzed the crystalline stmcture by X-ray diffractogram, which are substantially identical. The laboratory findings are tabulated in the following table (2).

The crystalline Form-I of pantoprazole sodium sesquihydrate obtained as per the above
processes is observed as free flowing, non-solvated crystalline solid which is well suited
for pharmaceutical applications.
The process of the present invention is simple, non-hazardous and well suited for
commercial production.
It is noteworthy to mention that the Pantoprazole free base used as the starting material
for the present invention is prepared as per the process disclosed in USP '579.
The following examples illustrate the invention but don not limit the scope of further
invention.

Preparation of Crystalline Form-I of Pantoprazole sodium sesquihydrate:
EXAMPLE-1:
To a stirred solution of tetrahydrofiiran (350 ml), aqueous sodium hydroxide solution (5.4
grams dissolved in 10 ml of water), Pantoprazole free base (50 grams) was added and stirred at a temperature of 25-35 " C till the clear solution results. The reaction solution was filtered through hyflow and washed the bed with tetrahydrofiiran (2x25 m!). Dichloromethane (400 ml) was added slowly to the filtrate in over a period of 1 hour and stirred for 5-6 hours to separate the solid mass. The separated solid mass was cooled to a temperature of 5-10 " C and fiirtfier stirred for 2-3 hours. The solid was filtered, washed with dichloromethane (2x25 ml) and suck dried under vacuum. The wet solid is susp^ided in dichloromethane (250 ml) and stirred for 15-30 minutes. Then the solid was filtered and suck dried under vacuum and further dried at a temperature of 40-50°C to obtain crystalline Form-I of Pantoprazole sodium sesquihydrate. (Weight: 50.4 grams, MC: 6.49% w/w) EXAMPLE-2:
Pantoprazole free base (25 grams) was added to the stirred mixture of acetonitrile (!75 ml), aqueous sodium hydroxide solution (2.7 grams in 5 ml of water) and stirred at a temperature of 25-35 c the clear solution results. The reaction solution was filtered through hyflow and washed the bed with acetonitrile (25 ml). Isopropyl ether (225 ml) was added slowly to the filtrate in over a period of 1/2 hour and stirred for 1-2 hours to separate the solid mass. The sc^iarated solid mass was cooled to a ten^erature of 5-10 ° C and further stirred for 3-4 hours. The solid was filtered, washed with Isopropyl ether (25 ml) and suck dried under vacuum.

The wet solid is further dried at a temperature of 40-50°C to obtain crystalline Form-I of
Pantoprazole sodium sesquihydrate.
(Weight: 25.4 grams, MC: 6.55% w/w)
EXAMPLE-3:
Pantoprazole freebase (25 grams) was added to the stirred mixture of ethyl acetate (50
ml), aqueous sodiiun hydroxide solution (2.7 grams in 5 ml of water) and stirred at a
temperature of 40-50 " C till the clear solution results. Methyl tertiary butyl ether (250
ml) was added and stirred for 3-4 hours to separate the solid mass. The separated solid
mass was fihered, washed with methyl tertiary butyl ether (50 ml) and suck dried under
vacuum. The wet solid is fiirther dried at a temperature of 40-50°C to obtain crystalline
Form-I of Pantoprazole sodium sesquihydrate.
(Weight: 15.6 grams, MC: 7.07% w/w)
DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig-1. is characteristic X-ray powder diffraction pattern of crystalline Form-I of
Pantoprazole sodium sesquihydrate (according to process disclosed in
J.Med.Chem.,1992,35,lO49-1057).
Vertical axis: Intensity (CPS); Horizontal axis| Two Theta (degrees).
The significant two-theta values obtained are 5.238,7.294,10.523,11.428,12.345,
13.024,13.30,14.459,15.207,15.844,16.15,16.653,17.527,17.884,18.404,19.97,
20.486,21.214.22.148, 22.812, 23.26,24.002, 24.497,24.957, 25.32, 26.278,27.037,
27.798,28.737,28.383. 30.18. 30.861, 32.652,33.647, 34.671 and 37.572 degrees two-
theta.

Fig-2. is characteristic X-ray powder diffraction pattern of crystalline form-I of Pantoprazole sodium sesquihydrate.
Vertical axis: Intensity (CPS); Horizontal axis: 2 Theta (degrees). Thesignificant two-thetavaluesobtained are 5.326, 7.385, 9.868,10.63,11.531,12.472, 13.102,13.366,14.543,15.317,15.92,16.207,16.687,16.836,17.62,17.966,18.498, 20.061,20.581,21.271,21.621,22.254, 22.886,23.33, 24.122, 24.587,25.026,25.405, 26.353, 26.803, 27.147, 27.887,28.842, 29.487, 30.926, 31.878, 32.708, 33.694,34.748 and 37.642 degrees two-theta.

We claim:
1. An improved process for the preparation of crystalline Fonn-I of Pantoprazole
sodium sesquihydrate comprises of:
i. dissolving Pantoprazole free base in a solvent in which it dissolves at a temperature of 25-50°C containing the stoichiometric amount of aqueous sodium hydroxide solution or by adding if necessary, ii. optionally filtering the clear solution obtained in step (i); iii. adding the solvent in which the Pantoprazole sodium is insoluble, accompanied by optionally cooling the mass to -10 to +20°C and accompanied by stirring till the compound substantially crystallizes; iv. filtering the crystallized solid in step (iii) by conventional methods; V. drying of the solid obtained in step (iv) at a temperature of 40-90°C, preferably 40-50°C under vacuum to a constant weight to afford the desired crystalline Form-I of Pantoprazole sodium sesqui hydrate.
2. The process according to claim (I) of step (1), wherein the solvents are selected from a group comprising of C1-C4 straight or branched alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol or tertiary butanol or tetrahydrofuran or acetonitrile or ethylacetate.
3. The process according to claim (2), wherein the solvent is tetrahydrofuran.
4. The process according to claim (1) of step (3), wherein the solvents are selected from a group comprising of aliphatic or alicyclic hydrocarbon solvents such as petroleum ether, hexane, n-heptane, cyclohexane or cyclo heptane or chlorinated solvents such as dichloromethane or chloroform or ethers having C1-C4 carbon

atoms in straight or branched chain such as dimethyl ether, diethyl ether, di isopropyl ether, di butyl ether, methyl ethyl ether or methyl tertiary butyl ether.
5. The process according to claim (4), wherein the solvent is dichloromethane.
6. The process according to claim (4), wherein the solvent is di isopropyl ether.
7. The process according to claim (4), wherein the solvent is methyl tertiary butyl

Documents:

0648-mas-2002 complete specification as granted.pdf

648-mas-2002 abstract.pdf

648-mas-2002 claims.pdf

648-mas-2002 correspondence others.pdf

648-mas-2002 description (complete).pdf

648-mas-2002 drawings.pdf

648-mas-2002 form-1.pdf

648-mas-2002 form-18.pdf

648-mas-2002.tif

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Patent Number

235251

Indian Patent Application Number

648/MAS/2002

PG Journal Number

29/2009

Publication Date

17-Jul-2009

Grant Date

29-Jun-2009

Date of Filing

02-Sep-2002

Name of Patentee

DR. REDDY'S LABORATORIES LIMITED

Applicant Address

7-1-27,AMEERPET HYDERABAD 500 016

Inventors:

#	Inventor's Name	Inventor's Address
1	MANNE SATYANARAYANA REDDY	Dr.REDDY'S LABORATORIES LTD 7-1-27,AMEERPET HYDERABAD 500 016
2	SAJJA ESWARAIAH	Dr.REDDY'S LABORATORIES LTD 7-1-27,AMEERPET HYDERABAD 500 016
3	VIJAYAVITTHAL THIPPANNACHAR MATHAD	Dr.REDDY'S LABORATORIES LTD 7-1-27,AMEERPET HYDERABAD 500 016
4	GOVINDAN SHANMUGAM	Dr.REDDY'S LABORATORIES LTD 7-1-27,AMEERPET HYDERABAD 500 016
5	PONDICHETTY ANILKUMAR	Dr.REDDY'S LABORATORIES LTD 7-1-27,AMEERPET HYDERABAD 500 016
6	ELATI RAVI RAM CHANDRASHEKAR	Dr.REDDY'S LABORATORIES LTD 7-1-27,AMEERPET HYDERABAD 500 016

PCT International Classification Number

C07D235/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA