Field of the Invention
The present invention relates to a novel polymorphic Form of esomeprazole sodium, designated as Form-P and process for the preparation thereof.
Background of the Invention
Esomeprazole is a proton pump inhibitor which reduces gastric acid secretion through inhibition of H+/K+-ATPase in gastric parietal cells. Esomeprazole inhibits the functioning of this enzyme to prevent gastric acid secretion. Esomeprazole is administered as the magnesium salt and is available in the market under the brand name NEXIUM ™.
Esomeprazole is chemically known as (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole and having the following chemical structure.
U.S. Patent No 6,875,872 discloses optical purity of esomeprazole magnesium at least about 94% enantiomeric excess. This patent discloses preparation of esomeprazole magnesium by dissolving esomeprazole sodium in water followed by addition of aqueous solution of magnesium chloride to give esomeprazole magnesium salt. This patent does not disclose any polymorphic Form of esomeprazole sodium.
US application No. 2007/0259921 discloses different crystalline, amorphous Forms of esomeprazole sodium, which are designated J, K, L, M, N and amorphous. This application also mentioned process for the preparation said polymorphic Forms.

US application No. 2008/0039503 assigned to AstraZeneca, which discloses the process for the preparation of esomeprazole polymorphic Form C, E and H. According to this application esomeprazole potassium is dissolved in a mixture of water and toluene. The resulting solution pH is adjusted to 7.0 with acetic acid to liberate esomeprazole free base, separate the toluene layer which is in-situ treated with sodium hydroxide in respective crystallizing solvents methanol, ethanol, 2-propanol followed by seeding with esomeprazole sodium to give esomeprazole polymorphic Form C, E, H respectively.
WO 2006/001755 publication discloses crystalline esomeprazole sodium Form- B and process for the preparation thereof, wherein esomeprazole sodium is treated with water in a vial, further stirred and left over night to isolate crystalline esomeprazole sodium polymorphic Form-B
Object of the Invention
The main object of the present invention is to provide novel crystalline esomeprazole sodium polymorphic Form-P and process for the preparation thereof.
Yet another object of the present invention is the process for preparation of esomeprazole magnesium from crystalline esomeprazole sodium polymorphic Form-P.
Summary of the Invention
The present invention provides crystalline esomeprazole sodium polymorphic Form-P and process for the preparation of the same. The present invention also provides a process for the preparation of esomeprazole magnesium from crystalline esomeprazole sodium polymorphic Form-P.
Brief Description of the Figures
Figure 1 is a powder X-ray diffractogram (PXRD) of crystalline esomeprazole sodium
polymorphic Form-P.
Figure 2 is a TGA of crystalline esomeprazole sodium polymorphic Form-P.

Figure 3 is a DSC of crystalline esomeprazole sodium polymorphic Form-P.
Figure 4 is a FTIR spectrum of crystalline esomeprazole sodium polymorphic Form-P.
Detailed Description of the Invention
The present invention recites crystalline esomeprazole sodium polymorphic Form-P and process for the preparation of the same. Crystalline esomeprazole sodium polymorphic Form-P is characterized by its physical properties as well as by spectral data which includes X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), and FTIR absorption spectrum (FTIR).
Powder X-rav Diffraction (PXRD)
The said polymorph of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorph of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 9/ 9 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40 KV and 30 mA. The experiments were conducted over the 2 9 range of 2.0°-5.0°, 0.030° step size and 50 seconds step time.
Differential Scanning Calorimetry (DSC)
The DSC experiments were carried out on Mettler Toledo 822 Star and TA Q1000 of TA instruments. The experiments were perFormed at a heating rate of 10.0 ° C/min over a temperature range of 30° C-300° C purging with nitrogen at a flow rate of 150 ml/min and 5Oml/min.Standard aluminum crucibles covered by lids with three pin holes were used.
Thermo Gravimetric Analysis (TGA)
TGA was recorded using the instrument Mettler Toledo TGA/SDTA 85le and TA Q 5000 of TA instruments. The experiments were perFormed at a heating rate of 10.0 ° C/min over a temperature range of 30-300° C purging with nitrogen at a flow rate of 20ml/min and 25ml/min.

Fourier TransForm Infrared spectroscopy (FTIR)
Fourier transForm infrared (FTIR) spectra were recorded with a Perkin-Elmer spectrum one spectrophotometer. The samples were prepared as 13mm thickness potassium bromide discs by triturating 1 to 2mg of sample with 300mg to 400mg of KBR by applying pressure of about 1000 lbs/sq inch. Then theses discs were scanned in the spectral range of 4000 to 650 cm"1 with a resolution of 4 cm'1.
According to our present invention, crystalline esomeprazole sodium polymorphic Form-P is having substantially PXRD pattern as provided in figure 1. The PXRD pattern of crystalline esomeprazole sodium polymorphic Form-P is characterized by peaks at 6.51, 8.83, 11.2, 15.8, 18.19 and 19.6 ± 0.2 26 values. It is further characterized by additional peaks at 20 values at 21.37,22.29,22.69, 23.85,26.72 and 30.85 ± 0.2.
Another aspect of the present invention provides process for the preparation of Form-P of esomeprazole sodium which comprises,
a) dissolving esomeprazole sodium in solvent,
b) removing solvent from the mixture to get residue,
c) treating the residue with an anti-solvent,
d) isolating crystalline esomeprazole sodium Form-P and
e) optionally purifying in ketone solvent.
According to the above mentioned process esomeprazole sodium is dissolved in a solvent and filtered. The clear filtrate is subjected to distillation under reduced pressure to give residue, followed by treatment with anti-solvent. The solvent used herein is selected from the group consisting of but not limited to alcohol such as C1-C5 alcohol like methanol, ethanol, propanol, isopropanol, n-butanol, iso-butanol, tert-butanol; water or mixture thereof. The anti-solvent used herein is selected from the group consisting of but not limited to nitrile such as acetonitrile; polar aprotic such as tetrahydrofuran; ester such as ethyl acetate, aliphatic and aromatic hydrocarbon such as n-pentane, n-hexane, n-heptane, cyclohexane, toluene and ether such as isopropyl ether.

The above separated solid is filtered and dried at 50-55°C for 6-8 hours to give crystalline esomeprazole sodium polymorphic Form-P. Crystalline esomeprazole sodium polymorphic Form-P is optionally subjected to purification by treatment with a ketone solvent such as acetone, and the resulting suspension is heated to reflux, followed by cooling at 25-35°C. The obtained solid is filtered and wash with a solvent such as acetone and dry the compound to give pure crystalline esomeprazole sodium polymorphic Form-P. The esomeprazole sodium used as a starting material herein can be prepared by the methods known in the prior art.
In yet another aspect of the present invention provides the process for the preparation of esomeprazole magnesium from crystalline esomeprazole sodium polymorphic Form-P by dissolving esomeprazole sodium polymorphic Form-P in a solvent such as water, methanol, ethanol, propanol or mixtures thereof followed by salt Formation with magnesium ion source such as MgCl2 .6H2O to give esomeprazole magnesium.

EXAMPLES
Example-01: Preparation of esomeprazole sodium
Omeprazole sulphide (100 g) was added to the ethyl acetate (500 ml) to Form a suspension under nitrogen atmosphere. Water (0.7 g), (-)-diethyl-D-tartrate (37.5 g) and titanium(IV)isopropoxide (25.5 g) were added with stirring and then mixture was stirred at 60-65°C for 15 minutes. Reaction mixture was cooled to 50-5 5°C and maintained for 15 minutes. N,N-diisopropylethylamine (11.5 g) followed by cumene hydroperoxide (55 g) was added to the reaction mixture at 25-30°C and maintained for 15-60 minutes up to completion of the reaction. The solution was extracted three times with aqueous ammonia solution 12.5% (330 ml ><3). To the combined aqueous ammonia layers was added ethyl acetate. The reaction mass was cooled to 15-25°C. The aqueous layer was pH adjusted to 7-7.5 with acetic acid. The reaction mixture temperature was raised to 25-30°C and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with an additional portion of ethyl acetate (300 ml). Sodium methoxide solution was added to the ethyl acetate layer and stirred for 15 minutes. Reaction mass was distilled completely under vacuum followed by traces of methanol solvent was distilled with addition of ethyl acetate. Ethyl acetate (500 ml) was added to the residue and stirred for 30 minutes at 25-30°C. Additional amount of ethyl acetate of 500 ml was added to the reaction mass and stirred for 4 hours. Crystallized compound is filtered, washed with ethyl acetate and dried at 30-35°C for 12 hours to give esomeprazole sodium polymorphic Form-P.
Example-02: Preparation of crystalline esomeprazole sodium Form-P;
A mixture of esomeprazole sodium obtained as prepared in example 1 (100 g) in acetone was stirred at 25-35°C for 10-15 minutes. The reaction mass was stirred at 50-55°C for 60 minutes and cooled to 25-35°C, stirred for 60 minutes. Crystals Formed were filtered, washed with acetone and dried at 50-55°C for 6-8 hours to give required Form-P.

Example-03: Preparation of crystalline esomeprazole sodium Form-P;
Esomeprazole sodium crude (100 g) obtained in example-01 was dissolved in methanol (1000 ml) and stirred at 25-35°C for 10-15 minutes. Reaction mass was filtered to remove any undeserved compound. The filtrate was distilled completely under vacuum at 35-40°C followed by traces of methanol was removed by distillation in presence of ethyl acetate. Ethyl acetate (500 ml) was added to the residue at 35-40°C and stirred for 60 minutes at 25-35°C. Reaction mass is filtered, washed with ethyl acetate (100 ml) and dried at 50-55°C for 6-8 hours to give esomeprazole sodium polymorphic Form-P.
Esomeprazole sodium (100 g) Form-P obtained above was suspending in acetone (1000 ml) and stirred for 10-15 minutes at 25-35°C. Reaction mass was stirred for 60 minutes at 50-55°C. The reaction mixture was cooled to 25-35°C and maintained for 60 minutes. The reaction mass is filtered, washed with acetone and dried at 50-55°C for 6-8 hours to give pure esomeprazole sodium polymorphic Form-P.
Example-04; Preparation of crystalline esomeprazole sodium Form-P:
Esomeprazole sodium crude (100 g) obtained in example-01 was dissolved in methanol (1000 ml) and stirred at 25-35°C for 10-15 minutes. Reaction mass was filtered to remove any undeserved compound. The filtrate was distilled completely under vacuum at 35-40°C followed by traces of methanol was removed by distillation in presence of tetrahydrofuran (100 ml). Tetrahydrofuran (500 ml) was added to the residue at 35-40°C and stirred for 60 minutes at 25-35°C. Reaction mass was filtered, washed with tetrahydrofuran (100 ml) and dried at 50-55°C for 6-8 hours to give esomeprazole sodium polymorphic Form-P.
Esomeprazole sodium (100 g) Form-P obtained above was suspended in acetone (1000 ml) and stirred for 10-15 minutes at 25-35°C. Reaction mass was stirred for 60 minutes at 50-55°C. The reaction mixture was cooled to 25-35°C and maintained for 60 minutes. The reaction mass is filtered, washed with acetone and dried at 50-55°C for 6-8 hours to give pure esomeprazole sodium polymorphic Form-P.

Example-05: Preparation of crystalline esomeprazole sodium Form-P:
Esomeprazole sodium crude (100 g) obtained in example-01 was dissolved in methanol (1000 ml) and stirred at 25-35°C for 10-15 minutes. Reaction mass was filtered to remove any undeserved compound. The filtrate was distilled completely under vacuum at 35-40°C followed by traces of methanol was removed by distillation in presence of acetonitrile (100 ml). Acetonitrile (500 ml) was added to the residue at 35-40°C and stirred for 60 minutes at 25-35°C. Reaction mass was filtered, washed with acetonitrile (100 ml) and dried at 50-55°C for 6-8 hours to give esomeprazole sodium polymorphic Form-P.
Esomeprazole sodium (100 g) Form-P obtained above was suspended in acetone (1000 ml) and stirred for 10-15 minutes at 25-35°C. Reaction mass was stirred for 60 minutes at 50-55°C. The reaction mixture was cooled to 25-35°C and maintained for 60 minutes. The reaction mass was filtered, washed with acetone and dried at 50-55°C for 6-8 hours to give pure esomeprazole sodium polymorphic Form-P.
Example-06: Preparation of amorphous esomeprazole magnesium salt
Esomeprazole sodium Form-P (100 g) obtained by any of the above examples was
dissolved in DM water under nitrogen atmosphere and stirred for 10 minutes at 25-35°C. Reaction mixture was filtered through a micron filter paper. Aqueous MgCl2.6H20 (28 g) was added to the above filtrate at 25-35°C over a period of 30-45 minutes. Slurry was stirred for 30 minutes at 25-35°C and filtered the compound. The wet cake was slurried with water, filtered twice and dried at 30-3 5°C for 12 hours to give amorphous esomeprazole magnesium salt.

We Claim:
1. Crystalline esomeprazole sodium polymorphic Form-P.
2. Crystalline esomeprazole sodium polymorphic Form-P having the PXRD pattern as shown in figure-1.
3. The crystalline esomeprazole sodium polymorphic Form-P according to claim 2, where in crystalline Form-P is having 26 values 6.51, 8.83, 11.2, 15.8,19.6 ± 0.2.
4. A process for the preparation of crystalline esomeprazole sodium polymorphic Form-P, which comprising the steps of:

a) dissolving esomeprazole sodium in solvent,
b) removing solvent from the mixture,
c) treating the residue with an anti-solvent,
d) isolating crystalline esomeprazole sodium Form-P and
e) optionally purifying in ketone solvent.

5. The process according to the claim 4a, wherein solvent used is selected from methanol, ethanol, isopropyl alcohol, butanol, water or mixture thereof.
6. The process according to the claim 4c, wherein the anti-solvent is selected from nitrile such as acetonitrile; polar aprotic such as tetrahydrofuran; ester such as ethyl acetate, aliphatic and aromatic hydrocarbon such as n-pentane, n-hexane, n-heptane, cyclohexane, toluene and ether such as isopropyl ether.
7. The process according to claim 4e, ketone solvent is acetone.
8. A process for the preparation of esomeprazole magnesium which comprising the steps of:

a) dissolving esomeprazole sodium polymorphic Form-P in solvent,
b) treating with magnesium ion source, and
c) isolating esomeprazole magnesium.

9. The process according to claim 8a, wherein solvent is selected from water,
methanol, ethanol, propanol or mixtures thereof.
10. The process according to claim 8b, wherein magnesium ion source is magnesium
chloride.