FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. "METHOD FOR PREPARATION OF AMORPHOUS RABEPRAZOLE SODIUM"
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS” , SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJAR4 T, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TITLE : Method of preparation of amorphous Rabeprazole sodium

1

FIELD OF INVENTION :
The present invention relates to an improved method of preparation of amorphous Rabeprazole sodium.
2

BACKGROUND OF INVENTION:
Rabeprazole sodium of formula-1 is referred to by the chemical name 2-[[[4—(3-methoxypropoxy)-3- methyl-2-pyridinyl]-methyl]sulfinyl]-1 H-benzimidazole sodium which is a proton pump inhibitor and is useful as an antiulcer agent.

WO 03/082858A, discloses a process for the preparation of crystalline form X of rabeprazole sodium, by dissolving crude Rabeprazole sodium in a chlorinated aliphatic hydrocarbon and adding to it an anti-solvent alkane. When aliphatic alcoholic solvent is used , in combination with ethereal solvent as an anti-solvent, crystalline form Y of Rabeprazole sodium is formed.
US 2004/0180935A1 discloses preparation of form Z of Rabeprazole sodium directly from crude Rabeprazole sodium or amorphous or other crystalline forms of Rabeprazole sodium. Rabeprazole sodium prepared by the reaction can be used for the preparation process of crystalline form Z without purification steps. Also amorphous form or other crystalline forms of Rabeprazole sodium such as Form II,X or Y can be conveniently converted to crystalline form Z by the process disclosed in US 2004/0180935A1 .
US Patent 5045552 and its equivalent European patent No. 268956 describe the preparation of crystalline Rabeprazole sodium from Rabeprazole using aqueous alcoholic alkali to convert into its sodium salt and an ether solvent for crystallization.
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PCT publication WO03/01452 A describes preparation of powder Rabeprazole sodium from Rabeprazole by contacting with aqueous alkaline solution followed by freeze drying. Freeze drying process is tedious , commercially difficult and expensive.
PCT publication WO 2006024890 A1 describes a process for the preparation of amorphous Rabeprazole sodium in non aqueous medium by oxidation of Rabeprazole sulfide , followed by preparation of sodium salt of oxidized product by contacting with alcoholic alkali solution , evaporating to obtain a residue , dissolving the residue in aliphatic halogenated hydrocarbon solvent, adding the solution on to alkane or ether solvent to obtain amorphous powder of Rabeprazole sodium, the invention also relates to adding an alkane or ether solvent to the residue to obtain amorphous powder of Rabeprazole sodium.
US20060135565 Al discloses Rabeprazole sodium in crystalline hydrate form ( form a )
having water content approximately ranging from 2.2 to 3 % by weight having 29 peak
values in XRD as 3.8 ; 5.1; 7.1; 16.9; 17.6; 18.8 and 19.9± 0.2° . Also disclosed is
Rabeprazole sodium form |3 having a water content ranging between 6.0 and 7.2 % by
wt. and having more intense diffraction peaks observed at 4.7,9.4,13.2,16.8,22.2,±0.2
in 2θ.
In summary , the known prior art processes involve :
[1] Use of halogenated solvents such as carbon tetrachloride, chloroform,
dichloromethane, for dissolving crude Rabeprazole sodium for isolation of Rabeprazole
sodium, or
[2] Processes which give crystalline forms of Rabeprazole sodium, or
[3] Use of freeze drying as a process for getting Rabeprazole sodium, requiring long
reaction hours, or
[4] Use of aqueous alkali for preparing sodium salt of Rabeprazole, or
[5] Use of NaOH in alcohol, especially , methanol to give Rabeprazole sodium salt,
generating a molecule of water.
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It is therefore a long-felt need for the industry to develop a commercially feasible process for preparing amorphous Rabeprazole sodium, avoiding use of halogenated solvents , aqueous / nonaqueous sodium hydroxide, and freeze drying.
5

SUMMARY OF INVENTION :
The main object of this invention is to develop a process for the preparation of Rabeprazole sodium in amorphous form.
Another object of this invention is to avoid use of halogenated solvents for isolation of Rabeprazole sodium
Yet another object of this invention is to avoid use of freeze drying as a process for
getting Rabeprazole sodium.
Yet another object of this invention is to avoid use of aqueous sodium hydroxide or
sodium hydroxide in alcohol for the preparation Rabeprazole sodium, which requires
azeotropic removal of water.
The present invention involves preparation of Rabeprazole sodium using sodium tert.
butoxide in anhydrous tert. butanol which does not require azeotropic water removal.
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DETAILED DESCRIPTION:
In accordance with the present invention, Rabeprazole sodium amorphous form is prepared using sodium tertiary butoxide in tert. butyl alcohol, preferably under nitrogen atmosphere.
Rabeprazole is added to sodium tert. butoxide in tert. butanol and stirred at about 27-30°C for about one hour. The reaction mass is treated with activated charcoal for one hour and filtered over hyflo bed , hyflo bed is washed with tert. butyl alcohol and filtrate is evaporated in vacuo , and finally traces of tert. butyl alcohol are removed using high vacuum at 50°C for about 30 minutes to give brown viscous mass. To the viscous mass diisopropyl ether is added and stirred under nitrogen at 27-30 C for one hour. Off-white ,amorphous powder of Rabeprazole-Na salt is obtained, which is filtered under nitrogen and washed with diisopropyl ether. The product is dried under vacuum at 50°C for about 24 hours to give Rabeprazole sodium which is characterized as amorphous by X-ray diffraction spectra.
The present invention is illustrated by following example which does not limit the scope of invention.
Preparation of Rabeprazole sodium from Rabeprazole:
0.64 gm of freshly cut clean sodium metal was dissolved in 100 ml of tert. butyl alcohol under nitrogen atmosphere by refluxing to give a clear solution which was cooled to about 30°C. Rabeprazole (10 gm) was added to it at about 30°C and stirred for about one hour to give an orange brown solution. The reaction mass was treated with about 1 gm of activated charcoal and stirred at 27-3 0°C for about one hour. The reaction mass was filtered using hyflo bed and washed with about 10 ml of tert. butyl alcohol. The filtered solution was distilled under vacuum at 40-50°C to remove tert. butyl alcohol and high vacuum was applied for about 30 min to remove traces of tert. butyl alcohol. 150 ml of diisopropyl ether were added to the viscous mass, and stirred under nitrogen at 27-30°C for about one hour. Off-white ,amorphous powder of Rabeprazole-Na salt was obtained, which was filtered under nitrogen and washed with 10 ml of diisopropyl ether. The
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product was dried under vacuum at 50 C for about 24 hours to give amorphous Rabeprazole sodium which was characterized by X-ray diffraction spectra.
Wt. of Rabeprazole sodium was 9.60 gms % yield is 90 % having purity of ≥ 99 % % water by K.F. ≤ 4 %
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