FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE
BESYLATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved process for the preparation of amlodipine besylate.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides an improved process for the preparation of amlodipine besylate. More particularly the present invention provides an improved process for the preparation of anhydrous amlodipine besylate.
Amlodipine besylate of formula I is chemically known as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate, monobenzenesulphonate. It is a long-acting calcium channel blocker, which is very useful in the treatment of ischaemic heart disease.


CH3

:„H„0,S L
Formula I
US Patent No. 4,572,909 discloses number of pharmaceutical^ acceptable salt forms of amlodipine such as hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts.
US Patent No. 4,879,303 discloses besylate salt of amlodipine and pharmaceutical compositions containing the same. The '303 patent disclosed the method for preparing amlodipine besylate by reacting the amlodipine base with benzene sulphonic acid in an industrial methylated spirit suspension.
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US Patent No. 5,438,145 describes process of preparing amlodipine besylate by reacting trityl protected amlodipine base with benzene sulphonic acid in a methanolic or aqueous methanolic medium.
US Patent No. 5,808,084 described the process of preparing benzylidene intermediate which are useful for preparing amlodipine.
US Patent No. 6, 046,337 describes a process for the preparation of amlodipine besylate in which benzene sulphonic acid reacts with hexaminium iodide of amlodipine to form amlodipine besylate.
Various other processes of preparation and purification of amlodipine, its isomers or polymorphs and salts thereof have been reported in US patent No. 6,828,339, US patent No. 6,846,932, US patent No. 6,784,297, US patent No. 6,596,874, US patent No. 7,153,790, European patent No. 0993447, European patent application Nos. EP 1458681, EP 1687273, EP 1407773, PCT publication Nos. WO 2003101965, WO 2004058711, WO 2005042485, WO 2005023769, WO 2006003672.
The present inventors have developed a process for the preparation of anhydrous amlodipine besylate. It was surprisingly found that when amlodipine base in water reacted with benzene sulphonic acid at temperature 30-35°C and the resultant amlodipine besylate hydrate crystallized with mixed organic solvent, the anhydrous amlodipine besylate is produced. The process is easily adoptable at industrial scale and economically viable.
In one of the aspect of present invention there is provided a process for the preparation of anhydrous amlodipine besylate, wherein the said process includes the step of:
a) reacting amlodipine base in water with benzene sulphonic acid at 30-35
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b) isolating the hydrated amlodipine besylate from the reaction mass thereof
c) converting hydrated amlodipine besylate to anhydrous amlodipine besylated in mixture of organic solvent.
The amlodipine base starting material can be prepared by the method known in the art. Amlodipine base obtained thereof is dissolved in water and treated with the benzene sulphonic acid under stirring at temperature 30-35 °C for 2 hours the hydrated amlodipine besylate is isolated after cooling the reaction mass to 5 °C or less. The hydrated amlodipine besylate is dried and covert to anhydrous amlodipine besylate in mixture of organic solvent such as methanol and ethyl acetate. The reaction mixture is cooled to 0-5°C. The precipitated product is isolated and dried at a temperature of 40°C-60°C to get the anhydrous amlodipine besylate having purity of 99% or more when measured by HPLC.
It is an important feature of the present invention that the entire process is carried out in water at temperature 30-35°C to yield hydrated amlodipine besylate, which was purified and converted to anhydrous amlodipine besylate.
The process of the present invention avoids use of organic solvent in making salt of amlodipine further reaction is carried out at room temperature which avoid the formation of impurities. Being the slightly solubility of amlodipine besylate in water thus improve the yield.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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Example
Preparation of anhydrous amlodipine besylate
To the suspension of Amlodipine base (674 gm) and Water (5.4 Itr) added a solution of Benzene Sulphonic acid (260 gm) in water (1.3 Itr) at 30-35°C under stirring. It is then cooled to 0 - 5°C for 1 hour and filtered, washed with cold water (1 Itr). Crude Amlodipine besylate is dried in oven at 40-45°C for 12 hours. Yield : 923 gm moisture content 2.77% .
Crude Amlodipine Besylate (920 gm) and Methanol (4.6 Itr) was heated at 50°C
to get a clear solution. The reaction mixture was concentrated to half of its
original volume at atmospheric pressure and to the concentrated mass Ethyl
Acetate (18 Itr) is added. Reaction mass was then cooled to 0-5°C filtered to
isolate the material. The product was dried in oven at 70°C and under reduced
pressure for 12 hours to get anhydrous Amlodipine Besylate.
Yield : 840 gm
Moisture content : 0.1%
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WE CLAIM
1. A process for the preparation of anhydrous amlodipine besylate, wherein the
said process comprising,
a) reacting amlodipine base in water with benzene sulphonic acid at 30-35 °C,
b) isolating the hydrated amlodipine besylate from the reaction mass thereof
c) converting hydrated amlodipine besylate to anhydrous amlodipine besylated in mixture of organic solvent.

2. A process of claim 1, wherein the organic solvent is methanol and ethyl acetate mixture.
3. A process of claim 2, wherein methanol and ethyl acetate ratio is 1:4.
4. A process of claim 1, wherein the anhydrous amlodipine besylate is isolated from the reaction mass by drying the solid between 40°C -60°C.
5. A process of claim 1, wherein the anhydrous amlodipine besylate having the purity 99.8% or more.
Dated this 26TH day of May, 2007 For Wockhardt Limited

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Abstract
The present invention provides an improved process for the preparation of amlodipine besylate. The present invention relates to an improved process for the preparation of anhydrous amlodipine besylate.
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