FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A FACILE PROCESS FOR PURIFICATION OF AZITHROMYCIN
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 a facile process for purification of azithromycin
The following specification particularly describes the invention and the manner in which it is to be performed.
1

4. DESCRIPTION
The present invention provides a facile process for purification of azithromycin. More particularly the present invention provides a facile process for the purification of azithromycin from 'impurity-O'.
A/-methyl-11-aza-10-deoxo-10-dihydroerythromycin A, known by its generic name Azithromycin of Formula I, is a broad-spectrum semi-synthetic macrolide antibiotic compound belonging to the erythromycin A family.

Formula-I
The processes for preparation of Azithromycin are disclosed in the U.S. patent 4,517,359 and U.S. patent 4,474,768. The ring expansion of erythromycin-A and subsequent conversion to azithromycin is described in the '768 patent.
U.S. patent 4,963,531 provides a process for preparing azithromycin dihydrate. The '531 patent further provides that on storage at low humidity the azithromycin dihydrate loses water.
European Patent EP 1313749 B1 provides a method for preparation of azithromycin which comprises removing an organic solvent from the solution comprising the hydrated compound in the organic solvent or a solution of the hydrated compound in a mixture of the organic solvent and water so as to provide anhydrous compound.
2

U.S. Patent No. 6,268,489 discloses azithromycin dihydrate as a crystalline form of azithromycin, which is stable and non-hygroscopic. The '489 patent also discloses azithromycin monohydrate as a crystalline form of azithromycin which is unstable and hygroscopic.
Several other processes for the preparation of azithromycin, intermediates useful in the preparation of azithromycin and different polymorphic forms of azithromycin are known in the art such as U.S. patent Nos. 4526889, 4963528, 4886792, 5686587, 5869629, 6013778, 6504017, 6420537, 6365574, 6703372, 6451990, 6586576, 6528492, 6936591, 6949519, 6268489, 5250518, 6977243, 7053192, 7081525, U.S. patent application Nos. 2003139583, 2004043944, 2004043945, 2004138149, 2004014951, 2005090459, 2005119468, 20050222052, 2006063725, 20050222052, 2006019908, 2006183890, PCT application Nos. WO 2002009640, WO 2005003144, WO 2007015265, WO 2007017898, WO2007029266.
The present inventors have developed a novel process for purification of azithromycin from 'impurity-O', which is consistently reproducible. The present inventors have surprisingly found that when azithromycin having 'Impurity-O' is dissolved in the solvent mixture and adjusted the pH 5.0 to 6.0, azithromycin free from 'impurity-O' can be isolated. The process is easily adoptable at industrial scale.
The term 'Impurity-O' means compound having the structure as per formula-ll.

H3CO CH3
N
Formula-ll
3

The term azithromycin includes any form of azithromycin such as dihydrate, monohydrate, solvate, anhydrous crystalline azithromycin, crude azithromycin or amorphous azithromycin.
In the aspect of present invention provides a process for purification of azithromycin. The process includes step of:
a) combining the azithromycin having 'Impurity-O' with the solvent mixture,
b) adjusting the pH 5.0 to 6.0,
c) isolating azithromycin free of 'impurity-O' from the reaction mass thereof.
The azithromycin starting material can be prepared by the method known in the art. Azithromycin having 'Impurity-O' was dissolved in solvent mixture. Solvent mixture includes the mixture of water and organic solvent such as chloroform, methylene chloride, ethyl acetate, toluene and the like. The pH of reaction mixture is adjusted to 5.0 to 6.0 by acid such as hydrochloric acid. The aqueous layer was separated and added with organic solvent such as acetonitrile, propionitrile and the like. The pH of reaction mixture is adjusted to 10 to 10.5 by addition of base such as sodium hydroxide in water and azithromycin free of 'impurity-O' isolated from the reaction mass thereof.
The purity of azithromycin is found to be 99% or more when measured by HPLC and 'impurity-O' below 0.1 %.
The present invention is further illustrated by the following examples 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.
4

EXAMPLE Process for purification of azithromycin
Azithromycin (100 gm) having impurity-0 (0.5 to 0.8 %) dissolved in mixture of water (435 ml) and chloroform (100 ml). The pH of reaction mixture was adjusted to 5.0 to 6.0 by dilute hydrochloric acid. The reaction mixture was stirred for 15 minutes. The aqueous and organic layer was separated. Aqueous layer was washed with chloroform (100 ml). The traces of chloroform were removed from aqueous layer under vacuum. To the aqueous layer acetonitrile (250 ml) was added and adjusted pH 10.0 to 10.5 by 20 % sodium hydroxide solution. The pure azithromycin was isolated from the reaction mass thereof.
Yield : 85.0 gm.
Purity: 99.5 %
lmpurity-0 : 0.05 % to 0.10 %
5

WE CLAIM:
1. A process for purification of azithromycin. The process comprising:
a) combining the azithromycin having 'Impurity-O' with the solvent mixture,
b) Adjusting the pH 5.0 to 6.0,
c) isolating azithromycin free of 'impurity-O' from the reaction mass thereof.

2. A process of claim 1 wherein solvent mixture is water and organic solvent.
3. A process of claim 1 wherein organic solvent includes such as chloroform, methylene chloride, ethyl acetate, toluene and the like.
4. A process of claim 1 wherein the pH 5.0 to 6.0 is adjusted by addition of acid such as hydrochloric acid.
5. A process of claim 1 wherein the azithromycin free from Impurity-O isolated at basic pH more than 7.5.
6. A process of claim 5 wherein the pH is adjusted by addition of base.
7. A process of claim 6 wherein the base includes such as sodium hydroxide in water.
8. A process of claim 1, wherein the purity of azithromycin is 99% or more when measured by HPLC and 'impurity-O' below 0.1 %.
Dated this 26 TH day of May, 2007

6

Abstract
The present invention provides a facile process for purification of azithromycin. Further the present invention provides a facile process for the purification of azithromycin from 'impurity-O'.
7