FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION:
"CRYSTALLINE POLYMORPH OF ESOMEPRAZOLE POTASSIUM AND PROCESS FOR PREPARATION THEREOF"

2. APPLICANT:
(a) NAME: CIPLA LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

FIELD OF THE INVENTION:
The present invention relates to a new crystalline form of (S)-6-methoxy-2-((4-methoxy-3,5-dimethylpyridm-2-yl)methylsulfinyl)-lH-berizo[dimidazole potassium, also known as esomeprazole potassium, a process for its preparation and pharmaceutical formulations thereof.
BACKGROUND OF INVENTION:
Omeprazole, chemically known as 6-methoxy-2-((4-methoxy-3,5-dimethy]pyridin-2-y]) methylsulfinyl) -lH-benzo[d]imidazole, is a proton pump inhibitor and exists as a racemic mixture containing equal amounts of both (R) and (S)-enantiomers. As compared to racemic mixture, (S)-enantiomer of omeprazole has shown to possess improved efficacy and hence is mostly used in pharmaceutical compositions,
US5948789 and US5693818 disclose the process for resolving enantiomers of omeprazole from its racemic mixture.
W0199828294 claims esomeprazole in substantially crystalline form.
WO200523797 claims preparation of novel salts of R and S - enantiomer of omeprazole.
Certain salts of (S)-enantiomer of omeprazole and their preparation is disclosed in EP0897386, EP2000468, EP1919897, EP1885711, EP1801110, WO2005082888 and WO2007142580.
WO1998054171 discloses synthesis of magnesium salt of esomeprazole trihydrate, wherein the potassium salt of esomeprazole is used as an intermediate. The potassium salt of esomeprazole of this application is designated as Form A which is a methanol solvate.
WO20004474 claims the Form B of potassium salt of esomeprazole, processes for its preparation and pharmaceutical compositions thereof.

WO2007148213 claims the Form X of esomeprazole potassium which is crystallised using dichloromethane as solvent.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a new stable crystalline form of esomeprazole potassium.
Another object of the present invention is to provide a highly reproducible process for preparing the new crystalline polymorph of esomeprazole potassium.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Powder X-ray diffractogram (XRD) of crystalline Form C of esomeprazole potassium. Figure 2: Infra-Red (IR) absorption spectra of crystalline Form C of esomeprazole potassium. Figure3: Differential Scanning Calorimetry (DSC) thermogram of crystalline Form C of esomeprazole potassium.
DETAILED DESCRIPTION OF INVENTION:
In one aspect, the present invention provides a stable crystalline polymorph of esomeprazole potassium which is substantially non-hygroscopic and has good flow characteristics.
In another aspect, the present invention provides a process for preparing the novel form of esomeprazole potassium hereinafter designated as Form C in high yield and purity.
The crystalline nature of polymorph Form C of esomeprazole potassium is analysed, characterized and differentiated by X-ray diffractogram, Infrared spectrum and Differential scanning calorimetry thermogram techniques, known per se.

The X-ray powder diffraction pattern of crystalline polymorph Form C of esomeprazole potassium was measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a copper-K-a radiation source.
In an embodiment, the crystalline polymorph Form C of potassium salt of esomeprazole has an XRD pattern with peaks at d-values as listed in Table 1.
Table 1: XRD values of Form C

Diffraction angles (d-value) Relative Intensity
13.97 100
11.06 7
7.96 11
6.94 9
6.77 11
6.33 15
5.98 41
5.54 24
5.44 24
4.92 27
4.71 14
4.54 11
4.44 28
4.01 19
3.96 14
3.87 33
3.72 46
3.64 39
3.55 24

Diffraction angles (d-value) Relative Intensity
3.46 31
3.37 18
3.30 45
3.15 29
3.09 16
3.00 24
2.94 25
2.90 10
2.80 13
2.76 19
2.73 12
2.63 16
2.60 18
2.57 21
2.50 16
2.45 16
2.38 12
2.32 13
2.30 10

In another embodiment, the X-ray powder diffraction spectrum of crystalline polymorph Form C of esomeprazole potassium is depicted in Figure 1.
Infrared (FT-IR) spectra were obtained in a KBr disk using a Perkin Elmer FT-IR spectrophotometer Spectrum 1000 at resolution 4 cm'1. The characteristic absorption bands are expressed in cm"1.

In an embodiment, Form C of esomeprazole potassium of the present invention is characterized by having characteristic IR spectra peaks at about 3397 cm"1, 2937 cm"1, 1611 cm"1, 1563 cm"1, 1476 cm"1, 1439 cm"1, 1378 cm"1, 1358 cm"1, 1296 cm"', 1267 cm"1, 1224 cm"1, 1198 cm"1, 1151 cm'1, 1074 cm"1, 1033 cm"1, 1000 cm"1, 949 cm"1, 872 cm"1, 836 cm"1, 817 cm"1, 801 cm"', as shown in Figure 2.
In an embodiment, the Form C of esomeprazole potassium of present invention is characterized as having a DSC, exhibiting a significant exothermic peak at 112.71°C and endothermic peak at 206.99°C. The DSC of Form C of esomeprazole potassium of the present invention is shown in Figure 3.
Still another embodiment of the present invention provides a process for preparing the novel form of potassium salt of esomeprazole, designated as Form C. The process comprises -
a) preparing potassium salt of esomeprazole by treating esomeprazole with a potassium source;
b) dissolving esomeprazole potassium in a solvent and concentrating to obtain a residue;
c) stirring the residue in another solvent;
d) cooling and then isolating esomeprazole potassium Form C.
The potassium source for preparing the esomeprazole potassium salt is selected from methanolic potassium hydroxide, ethanolic potassium hydroxide or methanolic potassium methoxide.
In an embodiment, esomeprazole potassium is dissolved in a solvent which may be a polar aprotic solvent selected from dichloromethane, THF, acetonitrile, acetone, methyl isobutyl ketone and methyl ethyl ketone but preferably acetone is used. The solution of esomeprazole potassium is then concentrated under vacuum to yield the residue.
The residue from the preceding step is then stirred at room temperature alongwith another solvent which may be selected from methanol, ethanol, isopropyl alcohol and n-butanol but preferably ethanol.

The solution obtained from the above step is then cooled to 0-lO°C, more preferably at 0-5°C. The solid thus obtained is dried under vacuum at 35 to 50 °C but preferably at 40 - 45°C to obtain esomeprazole potassium Form C.
The simple, economical and highly reproducible process of the present invention advantageously provides esomeprazole potassium polymorph Form C in relatively high purity of greater than or equal to about 99.8%.
Further the present invention relates to pharmaceutical compositions comprising Form C of esomeprazole potassium admixed with one or more pharmaceutical carriers.
The following examples will further illustrate the preparation of potassium salt of esomeprazole Form C, but are not intended to limit the scope of the invention as defined hereinabove or as claimed.
EXAMPLES:
Example 1 - Preparation of Potassium salt of Esomeprazole Form C:
Toluene (250 ml) was charged followed by D-(-)-diethyl tartrate (9.5 g), titanium (IV) isopropoxide (6.5 g) and stirred for 15 minutes. To this water was charged up to 0.4% based on the moisture content of reaction mass. The reaction mass was stirred for 30 minutes at 25-30°C to form a chiral titanium complex. Further, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyI)methyI]thio]-lH-benzimidazoIe (50 g) was charged to the complex and the contents were heated to 70°C over a period of 1 hour and maintained at 70-75°C for V% hour. The reaction mass was then cooled to 10 - 15°C, cumene hydroperoxide (57 g) was slowly added at 10 - 15°C over a period of 3 hours. After reaction completion methanolic potassium hydroxide solution (10 g of potassium hydroxide dissolved in 100 ml of methanol) was added to the reaction mass at 10 - 15°C, the contents were stirred at 25 - 30°C for 2 hours and chilled to 10°C. The precipitated product was filtered under nitrogen atmosphere, washed with toluene (75 ml). The crude esomeprazole potassium was purified by dissolving in acetone (1000 ml) and then displacing off the solvent with methanol (82 ml) to obtain pure potassium salt of esomeprazole (33.3 g, 63% yield and 99.0% purity).

25 g of pure esomeprazole potassium was dissolved in 250 ml acetone, concentrated at 55-60°C and then solvent was distilled off completely under vacuum. To this 25 ml of ethanol was added and solution was stirred at 25-30°C for 1 hour. The solution was cooled to 0-5°C, filtered and then dried under vacuum at 40 - 45°C to obtain esomeprazole potassium Form C (19.5 g, 78% yield and 99.8% purity).
Example 2 - Preparation of Esomeprazole Potassium Form C:
20 g of esomeprazole potassium was dissolved in 200 ml acetone, concentrated at 55-60°C and then solvent was distilled off completely under vacuum. To this 20 ml of ethanol was added and solution was stirred at 25-30°C for 1 hour. The solution was cooled to 0-5°C, filtered and then dried under vacuum at 40 - 45°C to obtain esomeprazole potassium Form C (15.2 g, 76% yield and 99.7% purity).
Example 3 - Preparation of Esomeprazole potassium Form C:
Toluene (125 ml) was charged followed by D-(-)-diethyl tartrate (4.75 g), titanium (IV) isopropoxide (3.25 g) and stirred for 15 minutes. To this water was charged up to 0.4% based on the moisture content of reaction mass. The reaction mass was stirred for 30 minutes at 25-30°C to form a chiral titanium complex. Further, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-lH-benzimidazole (25 g) was charged to the complex and the contents were heated to 70°C over a period of 1 hour and maintained at 70-75°C for 14 hour. The reaction mass was then cooled to 10 - 15°C, cumene hydroperoxide (28.5 g) was slowly added at 10 -15°C over a period of 3 hours. After reaction completion methanolic potassium hydroxide solution (5 g of potassium hydroxide dissolved in 50 ml of methanol) was added to the reaction mass at 10 - 15°C, the contents were stirred at 25 - 30°C for 2 hours and chilled to 10°C. The precipitated product was filtered under nitrogen atmosphere, washed with toluene (40 ml). The precipitated esomeprazole potassium was dissolved in 125 ml acetone at 50-55°C, clarified, and distilled off solvent completely under vacuum. To this 25 ml of ethanol was added and solution was stirred at 25-30°C for 1 hour. The solution was cooled to 0-5°C, filtered and then dried under vacuum to obtain esomeprazole potassium Form C (18 g, 68% yield and 99.4% purity).

Example 4 - Preparation of Esomeprazole potassium Form C:
Toluene (125 ml), D-(-)-diethyl tartrate (4.7 g) and titanium (IV) isopropoxide (3.2 g) were charged in reaction vessel and stirred for 15 minutes. To this up to 0.4% water based on the moisture content was added and stirring continued for 30 minutes at 25-30°C to form a chiral titanium complex. Further, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-lH-benzimidazole (25 g) was added to the mass and contents were heated to 70°C over a period of 1 hour and maintained at 70-75°C for Vi hour. After cooling the reaction mass to 10 - 15°C, cumene hydroperoxide (28.5 g) was slowly added at 10 - 15°C over a period of 3 hours. After reaction completion, an ethanolic solution of potassium hydroxide (5 g of potassium hydroxide dissolved in 50 ml of ethanol) was added to the reaction mass at 10 - 15°C, content was stirred at 25 - 30°C for 2 hours and chilled to 10°C. The precipitated product was filtered and dissolved in 125 ml acetone at 50-55oC, clarified, and the solvent was distilled off completely under vacuum. To this 25 ml of ethanol was added and solution was stirred at 25-30°C for 1 hour. The solution was cooled to 0-5°C, filtered and then dried under vacuum to obtain esomeprazole potassium Form C (18.2 g, 69% yield and 99.7% purity).
Dated this 24th day of February, 2009