FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
PROVISIONAL SPECIFICATION (See section 10)
PROCESS FOR THE PREPARATION OF AMORPHOUS RABEPRAZOLE SODIUM
SUN PHARMACEUTICAL INDUSTRIES LIMITED
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA
The following specification describes the nature of this invention.

The present invention relates to a novel process for the preparation of amorphous form of rabeprazole sodium.
Rabeprazole sodium, chemically known as (±) sodium-2-[[[4-(3-methoxypropoxy)-3-methyl-pyridinyl]methyl]sulfinyl]-lH-benzimidazole, is commercially available as Aciphex® tablets, approved for healing of erosive or ulcerative gastroesophageal reflux disease, and maintenance of the healing, treatment of duodenal ulcers and treatment of symptomatic gastroesophageal reflux disease.
United States Patent 5,045,552, which covers rabeprazole and its salts, exemplifies the preparation of rabeprazole sodium (example 33), wherein crude rabeprazole obtained by conventional process is dissolved in 0.1N aqueous sodium hydroxide to obtain a solution. This solution is distilled with ethanol thrice to remove the water as an azeotropic mixture with ethanol and dried in vacuum. Ether is added to the obtained residue to precipitate a white crystal, which is washed with ether and then dried to obtain rabeprazole sodium crystals. The patent also discloses preparation of amorphous rabeprazole sodium by freeze-drying a mixture of rabeprazole and aqueous sodium hydroxide.
United States patent application 20060178406 claims a method of preparing amorphous rabeprazole sodium by heat drying a solvated crystal of the benzimidazole. Typically, the application discloses heat drying of an acetone or acetonitrile complex of the sodium salt of rabeprazole under reduced pressure.
PCT application WO 2006024890 claims a process for preparation of amorphous rabeprazole sodium wherein the process involves dissolving rabeprazole in an alcoholic alkali solution at a temperature of 40-50°C for a period of 4-6 hours, charcolising the solution and filtering it, removal of the alcoholic solvent from the filtrate under vacuum at a temperature of 50-55°C to obtain a residue, dissolving the residue in an aliphatic halogenated hydrocarbon at a temperature of 20-25°C to obtain a solution, adding this solution to an alkane or ether solvent with stirring in an inert atmosphere to obtain a precipitate, separating the precipitate by filtering and drying under vacuum at a temperature ranging between 40-50°C for a time period of about 10 hours to 30 hours to obtain amorphous rabeprazole sodium.


United States Patent application 20080071089 claims a process for the manufacture of amorphous rabeprazole sodium with mean particle diameter between 10 to 55 microns, said process comprising (a) addition of rabeprazole to an aqueous sodium hydroxide, (b) addition of ethyl alcohol to the solution, (c) distillation of solvents from the solution obtained till a thick mass is obtained, (d) addition of an organic solvent selected from C3 to C8 straight chain or branched aliphatic ester, chlorinated aliphatic hydrocarbon, cycllic ethers and mixtures thereof to the residue to obtain a clear solution, (e) addition of this clear solution to an anti-solvent under agitation, and (f) isolation of the product.
PCT application WO 2008035192 claims a process for the preparation of amorphous rabeprazole sodium comprising (a) reacting rabeprazole with a solution of sodium tertiary butoxide in tertiary butyl alcohol, (b) removing tertiary butyl alcohol, after charcoal treatment and filtration, to give a residue, (c) adding diisopropyl ether, stirring, followed by separating amorphous rabeprazole sodium.
We have now found a novel process for the preparation of amorphous rabeprazole sodium that is an industrially and commercially feasible process, and which process provides a product with low impurity.
Rabeprazole sodium is a hygroscopic compound, and in our experience extended, contact with protic solvents, incuding water, leads to degradation and/or discoloration of the product. One of the noticeable impacts is formation of the sulfone impurity (I).

CH3
(I) Hence, in order to obtain rabeprazole sodium with low levels of impurity, it is important to ensure that the process involves minimal use of protic solvents, and the final product has low residual content of the protic solvent(s), if any.


Accordingly, the present invention provides a process for the preparation of amorphous rabeprazole sodium having the corresponding sulfone impurity less than 0.5%, the said process comprising -
(a) suspending rabeprazole in an organic solvent having dielectric constant ranging between 1.8 to 21, wherein at least 80% of the organic solvent is a ketonic solvent having dielectric constant ranging between 13 to 21,
(b) adding aqueous sodium hydroxide,
(c) azeotropically distilling out water from the above reaction system to obtain a residue,
(d) adding ketonic solvent having dielectric constant ranging between 13 to 21 to the residue of step (c) to obtain a solution, and
(e) quenching the solution obtained in step (d) into an organic solvent having a dielectric constant ranging between 1.8 to 21, wherein at least 80% of the organic solvent is an ethereal solvent having dielectric constant ranging between 1.8 to 5.
The amorphous rabeprazole sodium obtained by the process of the present invention has the corresponding sulfone impurity less than 0.5%. In preferred embodiments of the process of the present invention, the amorphous rabeprazole sodium obtained has sulfone impurity less than 0.3%, more preferably less than 0.15%.
The process of the present invention uses water-immiscible organic solvents that are easy to remove and/or isolate, and to recover and reuse, thereby making the process highly commercially feasible. Also, the organic solvents used in the process of the present invention are such that they can be analyzed for residual solvent content by conventional analytical methods.
The process of the present invention avoids use of aqueous sodium hydroxide alone, unlike prior art. Use of aqueous sodium hydroxide alone, or use along with solvents like ethanol, involves tedious processes to remove the solvent contained in the product formed. The residual solvent content is difficult to remove or reduce, most often requiring prolonged drying times and/or use of processes such as freeze-drying. As mentioned above, the residual water and/or solvent affects the quality of the product, since the product may discolor and/or the amount of the corresponding sulfone impurity may increase beyond acceptable limits. In the process of the present invention, the rabeprazole is first suspended in an organic solvent having dielectric constant ranging between 1.8 to 21. The term "organic solvent" as used herein includes one or more solvents, such that at least 80% is a ketonic solvent having dielectric constant ranging between 13 to 21. The


ketonic solvents used in the process of the present invention do not form complex with the rabeprazole sodium formed. Also, the organic solvent used in the process of the present invention is such that it is easily removed by conventional processes, without loss of time and effort.
In one preferred embodiment of the present invention, the ketonic solvent used in step (a) of the process is methyl isobutyl ketone. Use of methyl isobutyl ketone, along with the aqueous sodium hydroxide, is advantageous in that the water contained in the reaction system can be removed azeotropically, and the distillate can be "visually assesed" for the water content, owing to immiscibility of water with methyl isobutyl ketone, thereby ensuring near complete removal of the water from the reaction system. Methyl isobutyl ketone offers the additional advantage of having the ability to solubilise the rabeprazole sodium formed. Thus, if need be, the solution can be charcoalised to improve the color.
Aqueous sodium hydroxide is added to the suspension of crude rabeprazole in organic solvent having dielectric constant ranging between 1.8 to 21. This addition is carried out under stirring over a period of about ten minutes at ambient temperature, followed by further stirring until a biphasic reaction system is obtained. The water contained in the reaction system is then azeotropically distilled out to obtain a residual syrupy mass. A ketonic solvent having dielectric constant ranging between 13 to 21 may then be added to this syrupy mass, and the solution may be distilled to remove the solvent completely to obtain a residual mass.
The residual mass is dissolved in a ketonic solvent having dielectric constant ranging between 13 to 21 to obtain a clear solution. This solution is added dropwise with stirring to a mixture containing an organic solvent having dielectric constant ranging between 1.8 to 21, wherein at least 80% of the solvent is an ethereal solvent having dielectric constant ranging between 1.8 to 5. Examples of such organic solvents having dielectric constant ranging between 1.8 to 5 include, but are not limited to, ethers, aliphatic hydrocarbons, aromatic hydrocarbons and mixtures thereof, wherein at least 80% of the solvent is an ethereal solvent having dielectric constant ranging between 1.8 to 5. A preferred solvent with dielectric constant ranging between 1.8 to 5 is methyl t-butyl ether.
In one preferred embodiment of the present invention the solution of the residual mass in methyl isobutyl ketone is added with stirring to a mixture of methyl isobutyl ketone and methyl t-butyl ether. The reaction system is stirred for about 2 hours at room temperature, and then optionally


cooled to 0-5°C, to obtain the amorphous rabeprazole sodium. The product is filtered under nitrogen atmosphere and dried under vacuum.
The examples that follow do not limit the scope of the present invention and are merely added as illustrations.
Example 1
25g of cude rabeprazole is added to 125ml of methyl isobutyl ketone and stirred to obtain a homogenous suspension. Aqueous sodium hydroxide is then added to this suspension with stirring over a period of about 10 minutes. The reaction mixture is stirred at room temperature for another 15-30 minutes until a biphasic reaction mixture is obtained. This reaction mixture is then distilled at 45-50°C under vacuum to remove the solvents. The syrupy mass thus obtained is mixed with 50ml of methyl isobutyl ketone, distilled under vacuum at 45-50°C and degassed for 30 minutes to obtain a residual mass. This residual mass is dissolved in 50ml of methyl isobutyl ketone to obtain a clear solution. This clear solution is added dropwise, with stirring, to a mixture containing 375ml of methyl t-butyl ether and 12.5 ml of methyl isobutyl ketone. The mixture is stirred for about 1 to 2 hours at room temperature, followed by cooling to 0-5°C for about 1 to 2 hours. The product obtained is filtered under nitrogen atmosphere and dried under vacuum at 45-50°C for about 10 hours. The amorphous rabeprazole sodium thus obtained contains 0.05% of the corresponding sulfone impurity, when analyzed by HPLC.