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:
NOVEL POLYMORPHIC FORM 'W-lll' OF ANHYDROUS 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 novel polymorphic form 'W-lll' of anhydrous 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 novel polymorphic form 'W-lll' of azithromycin. More particularly the present invention provides novel anhydrous polymorphic form 'W-lll
A/-methyl-11-aza-10-deoxo-10-dihydroerythroimycin 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 form of azithromycin, which is stable and non-hygroscopic. The '489 patent also discloses azithromycin monohydrate as a 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 is a continuing need for preparing anhydrous azithromycin in novel polymorphic form that is useful for commercial purposes, substantially free of organic solvents and is stable.
The present inventors have developed anhydrous azithromycin in a novel polymorphic form referred as polymorphic form 'W-lll', which is stable, consistently reproducible and useful to make pharmaceutical compositions. It was surprisingly found that when azithromycin is dissolved in the organic solvent capable to remove moisture by azeotropic distillation and the subsequent drying of the resultant product at 80-90°C, the anhydrous azithromycin was obtained in a novel polymorphic form having moisture content below 0.5%.
In one of the aspect of the present invention there is provided a novel anhydrous polymorphic form 'W-lll' of anhydrous azithromycin having a characteristic XRD
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pattern as depicted in Figure I with the 2 theta values at 6.40, 8.40, 10.36, 12.32, 12.86, 13.68, 15.00, 15.96, 16.90, 17.58, 18.64, 19.22, 20.06, 22.06 ± 0.2° 20.
In another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the anhydrous azithromycin polymorphic form 'W-lll' and one or more pharmaceutical^ acceptable excipient.
In another aspect of present invention provides the process of preparation of anhydrous azithromycin polymorphic form 'W-lll'. The process includes step of:
a) combining the azithromycin with the organic solvent
b) removal of moisture from the reaction mixture thereof
c) isolating anhydrous azithromycin polymorphic form 'W-lll' from the reaction mass thereof.
The term azithromycin incorporates azithromycin dihydrate, monohydrate or their solvates. Azithromycin used as starting material can be prepared by the method known in the art. 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 by azeotropic distillation. The product was isolated from the reaction mass thereof and dried under vaccum at 80-90°C to obtain anhydrous azithromycin polymorphic form 'W-lll'.
The novel polymorphic form is having purity 98% or more when measured by HPLC, and moisture content less than 0.5% when measured by Karl fisher reagent.
Powder XRD of the samples was determined by Rigaku X-Ray diffractometer model no. 2200-v Japan.
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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.
EXAMPLE
Preparation of anhydrous azithromycin polymorphic form 'W-lll'
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 was partially distilled out to get the precipitate. 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 80-90°C to get the titled compound.
Yield: 17.0 gm
Purity: 98.56%
Moisture: 0.37%
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WE CLAIM:
1. Novel polymorphic form "W-IH" of anhydrous azithromycin.
2. Anhydrous azithromycin of claim 1 having characteristics 2 theta values at 6.40, 8.40, 10.36, 12.32, 12.86, 13.68, 15.00, 15.96, 16.90, 17.58, 18.64, 19.22, 20.06, 22.06 ±0.2° 29.
3. A process of preparation of anhydrous azithromycin polymorphic form 'W-lll'. The process comprising:

a) combining the azithromycin with the organic solvent,
b) removal of moisture from the reaction mixture thereof,
c) isolating anhydrous azithromycin polymorphic form 'W-lll' from the reaction mass thereof.

4. A process of claim 3 wherein organic solvent chloroform, methylene chloride, isopropanol, acetonitrile and the like.
5. A process of claim 3 wherein the isolated anhydrous azithromycin was dried at 80-90°C.
6. Anhydrous azithromycin having purity 98.5% or more when measured by HPLC.
7. Anhydrous azithromycin having moisture content below 0.5%
8. A pharmaceutical composition comprising a therapeutically effective amount of anhydrous azithromycin polymorphic form 'W-lll' and one or more pharmaceutically acceptable carriers, excipient or diluents.

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