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-V 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-V of anhydrous crystalline 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-V of anhydrous crystalline azithromycin. More particularly the present invention provides acetonitrile solvate of anhydrous crystalline azithromycin referred as polymorphic form 'W-V.
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 am 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.
The present inventors have now developed a process of preparation of acetonitrile solvate of anhydrous crystalline azithromycin referred as polymorphic form 'W-V, which is stable on storage and consistently reproducible. It was surprisingly found that when anhydrous azithromycin was crystallized from acetonitrile and dried under vacuum at temperature below 50°C, the acetonitrile solvate of anhydrous crystalline azithromycin could be isolated. It was further noted that when acetonitrile solvate of anhydrous crystalline azithromycin was heated at temperature of 45°C or above, anhydrous amorphous azithromycin was obtained.
Acetonitrile solvate of anhydrous crystalline azithromycin hereafter referred as polymorphic form 'W-V and it is further characterised by the presence of 1 to 10 % of acetonitrile content.
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In one of the aspect of the present invention there is provided a azithromycin polymorphic form 'W-V having a characteristic XRD pattern as depicted in Figure I. The azithromycin polymorphic form 'W-V has characteristic 2 theta values at 8.08, 8.90, 10.58, 11.28, 12.78, 13.36, 14.44, 15.86, 17.86, 18.58, 19.46, 20.48, 23.14, 23.98 ±0.2° 20.
In another aspect of present invention provides the process of preparation of azithromycin polymorphic form 'W-V. The process includes step of:
a) combining the azithromycin with the acetonitrile solvent
b) optionally removing the moisture
c) crystallising and isolating anhydrous crystalline azithromycin acetonitrile solvate from the reaction mass thereof.
In yet another aspect of present invention provides the process of preparation of anhydrous amorphous azithromycin by heating the acetonitrile solvate of anhydrous crystalline azithromycin at temperature of 45°C or above for sufficient time.
Azithromycin obtained by methods known in the art was dissolved in acetonitrile solvent. The reaction mixture was heated for complete dissolution and cooling of reaction mass precipitates the product, which was dried under vaccum at 40 ± 5 °C to yield acetonitrile solvate of anhydrous crystalline azithromycin. Further heating of acetonitrile solvate of anhydrous crystalline azithromycin at temperature of 45°C or above for sufficient time, resulted in the formation of anhydrous amorphous azithromycin.
The polymorphic form W-V is having purity 98% or more when measured by HPLC, and moisture content less than 0.5% when measured by Karl fisher reagent.
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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.
EXAMPLE
Preparation of acetonitrile solvate of anhydrous crystalline azithromycin (polymorphic form 'W-V')
Azithromycin (20.0 gm) was dissolved in acetonitrile (100.0 ml). The reaction mixture was heated at about 62°C to get clear solution. The reaction mixture was allowed to cool at 45-47°C to precipitate the product. The slurry obtained was further cooled to 0-5°C and stirred for one hour. Solid obtained was filtered and washed with acetonitrile and dried under vaccum at 40 ± 5 °C to get the titled compound.
Yield: 17.0 gm
Moisture: 0.41%
HPLC purity: 98.0%
Preparation of anhydrous amorphous azithromycin
Acetonitrile solvate of anhydrous crystalline azithromycin (10.0 gm) was heated to a temperature of 55 ± 5 °C for 8 hours and the titled compound was obtained. Yield: 9.0 gm
HPLC purity: 98.5%
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WE CLAIM:
1. Azithromycin polymorphic form 'W-V.
2. Azithromycin polymorphic form 'W-V according to claim 1 is acetonitrile solvate of anhydrous crystalline azithromycin.
3. Acetonitrile solvate of anhydrous crystalline azithromycin of claim 2 having characteristics 2 theta values at 8.08, 8.90, 10.58, 11.28, 12.78, 13.36, 14.44, 15.86, 17.86, 18.58, 19.46, 20.48, 23.14, 23.98 ± 0.2° 29.
4. Acetonitrile solvate of anhydrous crystalline azithromycin of claim 2 wherein the acetonitrile content is 1 to 10 %.
5. A process of preparation of azithromycin polymorphic form 'W-V. The process
comprising:
a) combining the azithromycin with the acetonitrile solvent
b) optionally removing the moisture from the mixture of step a)
c) crystallising and isolating acetonitrile solvate of anhydrous crystalline azithromycin from the reaction mass thereof.

6. A process of claim 5 wherein the product is isolated by drying the product at a temperature below 50°C.
7. Anhydrous crystalline azithromycin of claim 5 having moisture below 0.5%.
8. Anhydrous crystalline azithromycin of claim 5 having purity 98.5% or more when measured by HPLC.
9. A process of preparation of anhydrous amorphous azithromycin by heating the acetonitrile solvate of anhydrous crystalline azithromycin at temperature of 45°C or above for sufficient time.
10. A process of claim 9, wherein the sufficient time is 1 hour to 8 days.
Dated this 27TH day of April, 2007

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