WO2011004281A1

WO2011004281A1 - A process for the preparation of amorphous form of rabeprazole sodium

Info

Publication number: WO2011004281A1
Application number: PCT/IB2010/052819
Authority: WO
Inventors: Ravi Ponnaiah; Sanjay Desai; Dhiraj Rathod; Lalit Katariya; Nilesh Bhimani; Viral Modi
Original assignee: Alembic Limited
Priority date: 2009-07-09
Filing date: 2010-06-22
Publication date: 2011-01-13

Abstract

The present invention relates to a process for the preparation of amorphous form of Rabeprazole sodium of formula (I).

Description

Title of Invention: A PROCESS FOR THE PREPARATION OF

AMORPHOUS FORM OF RABEPRAZOLE SODIUM

Field of invention

[1] The present invention relates to a process for the preparation of amorphous form of

Rabeprazole sodium of formula (I).

(I)

[3]

Background of the invention

[4] Rabeprazole belongs to class of proton pump inhibitors. It is an antiulcer agent. It is useful for the treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease. It is marketed by Eisai in USA under brand name ACHIPHX^®.

[5]

[6] Rabeprazole was first disclosed in US patent no. 5045552. The process for preparing

Rabeprazole involves dissolving Rabeprazole base in aqueous solution of sodium hydroxide. Further water was removed from azeotropically from the reaction mixture using ethanol to obtain residue. Ether was added to the residue to obtain precipitate of the product. The form obtained by following the process disclosed in US patent no. 5045552 is amorphous form. The major drawback of this process is that when it is practiced on commercial scale the product obtained is sticky and not easily filterable. Moreover, azeotropic distillation is not economically viable process.

[7]

[8] It is disclosed in US patent no. 6180652 that by lyophilizing acetone complex of

Rabeprazole sodium salt in distilled water for 48 hours results in amorphous form of Rabeprazole sodium. WO 03101452 discloses process for preparation of amorphous form of Rabeprazole sodium which involves dissolution of Rabeprazole base in aqueous sodium hydroxide and lyophilizing the solution. Lyophilization technique involves large production capital. Therefore, these processes are also not commercially useful.

[9]

[10] The inventors of present invention have directed their efforts towards developing a process for the preparation of Rabeprazole sodium which is operationally simple, easily scalable and economically viable.

[H]

Object of the invention

[12] It is a primary object of the present invention to provide a process for the preparation of amorphous form of Rabeprazole sodium.

[13]

[14] Another object of the present invention is to provide a process for the preparation of amorphous form of Rabeprazole sodium which is operationally simple, easily scalable and economically viable.

[15]

Summary of the invention

[16] An aspect of the present invention provides a process for the preparation of

amorphous form of Rabeprazole sodium of formula (I) comprising,

(I)

[18] (a) preparing mixture of methanol and sodium hydroxide;

[19] (b) adding Rabeprazole base to said solution;

[20] (c) optionally charcoalizing and filtering the reaction mixture,

[21] (d) distilling off methanol from the reaction mixture to obtain residue;

[22] (e) adding toluene to the residue and removing it by distillation to obtain concentrate;

[23] (f) further adding toluene and ethyl acetate to obtain a clear solution;

[24] (g) adding methyl-tert. butyl ether to the solution obtained in step (f) to obtain

amorphous form of Rabeprazole sodium; or

[25] (h) adding solution obtained in step (f) to methyl-tert. butyl ether to obtain

amorphous form of Rabeprazole sodium.

[26]

Brief description of the drawing

[27] Figure- 1 : PXRD of amorphous form of Rabeprazole obtained by process of Example

[28]

Detailed description of the invention

[29] The present invention provides a process for the preparation of amorphous form of

Rabeprazole sodium of formula (I) comprising,

[30]

(I)

[31] (a) preparing mixture of methanol and sodium hydroxide;

[32] (b) adding Rabeprazole base to said solution;

[33] (c) optionally charcoalizing and filtering the reaction mixture,

[34] (d) distilling off methanol from the reaction mixture to obtain residue;

[35] (e) adding toluene to the residue and removing it by distillation to obtain concentrate;

[36] (f) further adding toluene and ethyl acetate to obtain a clear solution;

[37] (g) adding methyl-tert. butyl ether to the solution obtained in step (f) to obtain

amorphous form of Rabeprazole sodium; or

[38] (h) adding solution obtained in step (f) to methyl-tert. butyl ether to obtain

amorphous form of Rabeprazole sodium.

[39]

[40] Rabeprazole base used in the process of present invention can be prepared by any method known in the art.

[41]

[42] In a preferred embodiment of present invention, a solution of sodium hydroxide

pellets in methanol is prepared. The volume of methanol is in range of two times to five times the weight of Rabeprazole sodium, preferably four times. Sodium hydroxide is in range of 0.9 molar equivalent to 1.5 molar equivalents, preferably 1 mole equivalent.

[43]

[44] Rabeprazole base is added to solution of sodium hydroxide in methanol at temperature of about 2O⁰C to 3O⁰C. The reaction mixture can be optionally charcoalized and filtered.

[45]

[46] Further methanol is removed from the reaction mixture preferably under vacuum at temperature of about 5O⁰C to 6O⁰C to obtain residue. Toluene is added to the residue in amount of 1 to 5 ml per gram of Rabeprazole base used, preferably 1 ml per gram. Further, toluene is removed from the reaction mixture by distillation under vacuum at temperature of about 5O⁰C to 6O⁰C to obtain a concentrate.

[47]

[48] To the concentrate is added toluene in amount of 1 to 5 ml per gram of Rabeprazole base used, preferably 1 ml per gram and ethyl acetate in amount of 0.5 to 1.5 ml per gram of Rabeprazole base used, preferably 0.5 ml per gram to obtain a clear solution.

[49]

[50] Further, to the solution of Rabeprazole sodium in toluene-ethylacetate is added

methyl tert. butyl ether in the range of 7 times to 12 times the weight of Rabeprazole sodium used preferably 10 times, to obtain precipitate of amorphous form of

Rabeprazole sodium.

[51]

[52] Alternatively, the solution of Rabeprazole sodium in toluene-ethylacetate is added to methyl tert. butyl ether in the range of 7 times to 12 times the weight of Rabeprazole sodium used preferably 10 times, to obtain precipitate of amorphous form of

Rabeprazole sodium.

[53]

[54] The amorphous form of Rabeprazole obtained by process of present invention can be isolated by conventional methods known to person skilled in the art like filtration, cen- trifugation and the like.

[55]

[56] D₉₀ of Rabeprazole sodium obtained by the process of present invention has particle size in range of lOOμm to 200μm.

[57]

[58] Advantages of present invention:

[59] i) Simple and scalable process

[60] ii) Avoids use of costly lyophilization technique

[61] iii) Product obtained is pure and free flowing

[62] iv) High yield process.

[63]

[64] The following example illustrates the invention further. It should be understood

however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.

[65]

[66] Example: Preparation of Amorphous form of Rabeprazole

[67]

[68] Charge 300 ml methanol and 11.12 g of sodium hydroxide in the reactor. Cool the reaction mixture to 20 to 3O⁰C. Charge 100 g Rabeprazole sulphoxide in the reaction and stir it at 20-30⁰C for about 1 hour. Add 10 g charcoal to the reaction mixture and stir it for one hour at 20-30⁰C. Filter the reaction mixture through hyflo bed. Distill out methanol under vacuum at 55⁰C to obtain residue. Charge 100 ml toluene and distill out under vacuum at 55⁰C. Charge 100 ml toluene and 50 ml ethyl acetate to obtain a clear solution. Add the solution to 1000 ml methyl tert. butyl ether. Stir the reaction mass for one hour to obtain amorphous form of Rabeprazole sodium. Filter the product and dry the product under vacuum at 55-6O⁰C (100 g).

[69]

[70]

Claims

[Claim 1] 1. A process for the preparation of amorphous form of Rabeprazole sodium of formula (I) comprising,

(I)

(a) preparing mixture of methanol and sodium hydroxide;

(b) adding Rabeprazole base to said solution;

(c) optionally charcoalizing and filtering the reaction mixture,

(d) distilling off methanol from the reaction mixture to obtain residue;

(e) adding toluene to the residue and removing it by distillation to obtain concentrate;

(f) further adding toluene and ethyl acetate to obtain a clear solution;

(g) adding methyl-tert. butyl ether to the solution obtained in step (f) to obtain amorphous form of Rabeprazole sodium; or

(h) adding solution obtained in step (f) to methyl-tert. butyl ether to obtain amorphous form of Rabeprazole sodium.

[Claim 2] 2. Amorphous form of Rabeprazole sodium obtained by process of claim 1 having particle size D₉₀ in the range of lOOμm to 200μm.