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:
A PROCESS FOR CONVERTING CRYSTALLINE AZITHROMYCIN TO
ANHYDROUS AMORPHOUS 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 process for converting crystalline azithromycin to anhydrous amorphous azithromycin
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 a process for converting crystalline azithromycin to anhydrous amorphous azithromycin.
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.
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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.
There are several methods are known in the. art to make product amorphous such as spray drying, drying via agitated thin film technique and lyophilization.
The present inventors have developed a novel process to convert crystalline azithromycin to amorphous azithromycin, which is stable, consistently reproducible and useful for making pharmaceutical composition. The present inventors have surprisingly found that when crystalline azithromycin is dissolved in the organic solvent capable to remove moisture by azeotropic distillation and the subsequent drying of the resultant product at 60-70°C, produces anhydrous amorphous azithromycin, which is easily adoptable at industrial scale.
In the aspect of present invention provides the process for converting crystalline azithromycin to anhydrous amorphous azithromycin. The process includes step of:
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a) combining the crystalline azithromycin with the organic solvent
b) isolating anhydrous amorphous azithromycin from the reaction mass thereof.
The term azithromycin includes any crystalline form of azithromycin such as dihydrate, monohydrate, solvate, anhydrous crystalline Azithromycin. The Azithromycin starting material can be prepared by the method known in the art. Anhydrous crystalline azithromycin obtained thereof was dissolved in organic solvent such as chloroform, methylene chloride, isopropanol, acetonitrile and the like. The moisture of the reaction mass was completely removed by means such as by adding solid drying agents such as sodium sulphate, potassium carbonate and the like, or by use of molecular sieve or partially removed by azeotropic distillation. The product was isolated from the reaction mass thereof and dried at 60-70°C to obtain anhydrous amorphous azithromycin.
In another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the anhydrous amorphous azithromycin and one or more pharmaceutically acceptable excipient.
The purity of azithromycin is 99% or more when measured by HPLC and moisture content is below 1.0% when measured by Karl fisher reagent.
While the present invention has been described in terms of its specific embodiments, 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 amorphous azithromycin
Crystalline azithromycin (20.0 gm) was dissolved in methylene chloride (200.0 ml). The methylene chloride was removed to get syrupy mass. To the syrupy mass, acetonitrile (200.0 ml) was added. The acetonitrile (150 ml) was partially removed to precipitate the product. Further the reaction mixture was allowed to cool at 0-5°C and the slurry was stirred for one hour. The solid obtained was filtered, washed with acetonitrile and dried under vaccum at 60-70°C to get the titled compound. Yield: 17.0 gm Moisture: 0.87% HPLC: 99.3%
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WE CLAIM:
1. A process for converting crystalline azithromycin to anhydrous amorphous
azithromycin. The process comprising:
a) combining the azithromycin with the organic solvent
b) isolating anhydrous amorphous azithromycin from the reaction mass thereof.

2. A process of claim 1 wherein organic solvent chloroform, methylene chloride, isopropanol, acetonitrile and the like.
3. A process of claim 1 wherein the anhydrous amorphous azithromycin is isolated by drying the product at 60-70°C.
4. Anhydrous amorphous azithromycin having purity 99% or more when
measured by HPLC.
5. Anhydrous amorphous azithromycin having moisture below 1%.
6. A pharmaceutical composition comprising a therapeutically effective amount of anhydrous amorphous azithromycin and one or more pharmaceutically acceptable carriers, excipient or diluents.
Dated this 27TH day of April, 2007 For Wockhardt Limited

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