FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION AND PURIFICATION
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 and purification 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 and purification of 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.

Formula I
US Patent No. 4,572,909 discloses number of pharmaceutically 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 a industrial methylated spirit suspension.
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.
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US Patent No. 5,808,084 described the process of preparing benzylidene intermediate which are useful for preparing amiodipine.
US Patent No. 6, 046,337 describes a process for the preparation of amiodipine besyiate in which benzene sulphonic acid reacts with hexaminium iodide of amiodipine to form amiodipine besyiate.
Various other processes of preparation and purification of amiodipine, 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 an improved process for the preparation of amiodipine besyiate by reacting amiodipine base in an alcohol with benzene sulphonic acid. Further the inventors surprisingly found that when amiodipine besyiate was purified by using alcohol and antisolvent the yield losses are only 15-20% and purity of anhydrous amiodipine besyiate is 99% or more.
In one of the aspect of present invention there is provided a process for the preparation of amiodipine besyiate, wherein the said process includes the step of:
a) reacting amiodipine base with benzene sulphonic acid in an alcohol,
b) isolating the crude amiodipine besyiate from the reaction mass thereof.
The process involves treating alcoholic solution of amiodipine base with the alcoholic solution of benzene sulphonic acid under stirring. The alcohol includes straight chain or branched Ci to C4 alcohol such as methanol, ethanol, propanol,
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isopropanol and the like. The crude amiodipine besylate was isolated after cooling the reaction mass to 0-5°C.
In another aspect of present invention there is provided a process for the purification of amiodipine besylate, wherein the said process includes step of:
a) dissolving amiodipine besylate in an alcohol,
b) adding an antisolvent to the solution of step a),
c) isolating pure anhydrous amiodipine besylate from the reaction mass thereof.
The process of purification involves dissolving amiodipine besylate in an alcohol. The alcohol used' for dissolving the amiodipine besylate includes straight chain or branched C1 to C5 alcohol such as methanol, ethanol, propanol, isopropanol and the like. The solution of amiodipine besylate was concentrated and residue treated with the anti solvent or its mixture with alcohol. The anhydrous amiodipine besylate was then isolated from the reaction mass thereof, having purity of 99% or more when measured by HPLC.
The antisolvent includes such as hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichloromethane and the like.
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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Examples
Preparation of amiodipine besylate
The amiodipine base (58.3 g) was taken in Isopropyl alcohol (235 ml) followed by
the solution of Benzene sulphonic acid (22.8 g) in isopropyl alcohol (57 ml) was
added under stirring. The reaction mixture was stirred for 3 hr then cooled to 0°C
to 5°C and filtered to obtain crystals of amiodipine besylate:
Yield: 77.2 g
Purity: 99% (by HPLC)
Purification of anhydrous amiodipine besylate
Amiodipine besylate (77 g) was dissolved in methanol (310 ml) under reflux. The
solution was filtered and concentrated. To the residue obtained ethyl acetate
(1600 ml) was added and the reaction mixture was cooled to 0°C. The mixture
was further stirred for 1 hour. The precipitated solid was centrifuged and
anhydrous amiodipine besylate was isolated.
Yield : 63 g
Purity: 99.8% (by HPLC)
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WE CLAIM
1. A process for the preparation of amlodipine besylate, wherein the said process
comprising,
a) reacting amlodipine base with benzene sulphonic acid in an alcohol,
b) isolating the crude amlodipine besylate from the reaction mass thereof

2. A process of claim 1wherein the alcohol includes straight chain or branched Ci to C4 alcohol such as methanol, ethanol, propanol, isopropanol or the mixtures thereof.
3. A process for the purification of amlodipine besylate, wherein the said process comprising:
a) dissolving' amlodipine besylate in an alcohol,
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b) adding an antisolvent to the solution of step a),
c) isolating pure anhydrous amlodipine besylate from the reaction mass thereof.

4. A process of claim 3, wherein the alcohol includes straight chain or branched Ci to C4 alcohol such as methanol, ethanol, propanol, isopropanol or the mixtures thereof.
5. A process of claim 3, wherein the anti solvent includes such as hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichloromethane and the like and mixtures thereof.
6. Anhydrous Amlodipine besylate having the purity 99.8% or more.
Dated this 30th day of Mar, 2007

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