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-IV OF ANHYDROUS CRYSTALLINE
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-IV of anhydrous crystalline azithromycin.
The following specification particularly descrybes the invention and the manner in which it is to be performed.
1

4. DESCRIPTION
The present invention provides novel polymorphic form 'W-IV of anhydrous crystalline 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-1
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.
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
2

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 is a continuing need for preparing anhydrous crystalline 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 crystalline azithromycin in a novel polymorphic form referred as polymorphic form 'W-IV, which is stable, consistently reproducible and useful to make pharmaceutical compositions. It was surprisingly found that when anhydrous crystalline azithromycin was isolated from the reaction mass after removal of organic solvent, it is obtained in a novel polymorphic form.
In one of the aspect of the present invention there is provided a novel polymorphic form 'W-IV of anhydrous crystalline azithromycin having a characteristic XRD pattern as depicted in Figure I with the 2 theta values at 7.86, 8.72, 10.36, 11.12, 12.62, 13.20, 14.26, 15.68, 17.16, 19.36, 20.34, 23.00, 23.84 ± 0.2° 29.
3

In another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the anhydrous crystalline azithromycin polymorphic form 'W-IV and one or more pharmaceutically acceptable excipient.
In another aspect of present invention provides the process of preparation of anhydrous crystalline azithromycin polymorphic form 'W-IV. The process includes step of:
a) combining the anhydrous azithromycin with the organic solvent
b) removal of moisture from the solution of step a)
c) isolating anhydrous crystalline azithromycin polymorphic from the reaction mass thereof.
Anhydrous azithromycin used as starting material can be prepared by the method known in the art. Anhydrous azithromycin obtained thereof was dissolved in organic solvent such as methylene chloride, chloroform, isopropyl alcohol, ethyl acetate and acetonitrile. The organic: solvent was completely removed under reduced pressure at temperature below 40°C. The solid obtained was, treated with nitrile solvent, isolated and dried to produce anhydrous crystalline azithromycin polymorphic form 'W-IV having moisture content below 0.5% and purity more than 98% when measured by HPLC.
Powder XRD of the samples was determined by Rigaku X-Ray diffractometer model no. 2200-v Japan.
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.
4

EXAMPLE
Preparation of anhydrous crystalline azithromycin polymorphic form 'W-IV
Anhydrous azithromycin (20.0 gm) was dissolved in acetonitrile (100.0 ml). The
acetonitrile was removed completely under vacuum at temperature below 40°C.
The solid obtained was suspended in acetonitrile (30 ml) and reaction mass was
cooled to 0-5°C. The solid was isolated and dried under vacuum to get the titled
product.
Yield: 17.0 gm
Moisture 0.5%
purity: 99.1% (by HPLC)
5

WE CLAIM:
1. Novel polymorphic form "W-IV" of anhydrous crystalline azithromycin.
2. Anhydrous crystalline azithromycin of claim 1 having characteristics 2 theta values at 8.88, 11.20, 12.78, 13.40, 15.88, 17.80, 19.48, 23.22, 23.98 ± 0.2° 20.
3. A process of preparation of anhydrous crystalline azithromycin polymorphic form 'W-IV. The process comprising:

a) combining the anhydrous azithromycin with the organic solvent
b) removal of moisture from the solution of step a)
c) isolating anhydrous crystalline azithromycin polymorphic from the reaction mass thereof.

4. A process of claim 3 wherein organic solvent is methylene chloride, chloroform, isopropyl alcohol, ethyl acetate, acetonitrile and the like.
5. Anhydrous crystalline azithromycin having moisture content below 0.5%.
6. Anhydrous crystalline azithromycin having purity more than 99% when
measured by HPLC.
7. A pharmaceutical composition comprising a therapeutically effective amount
of anhydrous crystalline azithromycin polymorphic form 'W-IV and one or
more pharmaceutically acceptable carriers, excipient or diluents.

6