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:
AN EFFICIENT PROCESS FOR PREPARATION OF ANHYDROUS AZITHROMYCIN HAVING HIGH PURITY
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 relates to a new and efficient process for the preparation of anhydrous Azithromycin. The anhydrous Azithromycin obtained has purity in excess of 99% when measured by HPLC.
The following specification particularly describes the invention and the manner
in which it is to be performed.
The present invention relates to a new and efficient process for the preparation of anhydrous Azithromycin form I. The anhydrous Azithromycin obtained has purity in excess of 99% when measured by HPLC.
Azithromycin is chemically, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-/7ibo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy- 3,5,6,8,10,12,14-heptamethyl-11 -[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1 -oxa-6-azacyclopentadecan-15-one having structure depicted in Formula I. Azithromycin is indicated for the treatment of patients with

mild to moderate infections caused by susceptible strains of the microorganisms. It is also indicated for the treatment of acute bacterial sinusitis and community-acquired pneumonia.

US patents US 4,474,768 and US 4,517,359 provide a process for making Azithromycin. US Patent No. 6,268,489 provides a stable dihydrate form of azithromycin similarly US 6,855,813 provides stable form of azithromycin monohydrate.
European Patent EP 1313749 B1 provdes 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.
The present inventors have surprisingly found an efficient process for the preparation of anhydrous Azithromycin, which involves removal of moisture from Azithromycin hydrates and crystallizing the anhydrous Azithromycin from a suitable organic solvent. The process of present invention is cost-effective and easily scalable at commercial scale when compared with that reported in the 749 Patent.
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In one of the aspect of the present invention there is provided a process for preparation of anhydrous azithromycin wherein the said process comprises of
a) removing the moisture from a solution/suspension of azithromycin,
b) stirring the resultant mass in a water miscible solvent,
c) optionally recovering the solvent by distillation,
d) isolating anhydrous azithromycin from reaction mass thereof.
Azithromycin used as starting material can be prepared by any method known in the art. A solution of Azithromycin obtained from the last stages of synthetic process can also be employed as starting material. The so obtained Azithromycin is subjected to removal of moisture present as hydrate. The moisture can be removed by drying under vacuum, dissolving or suspending azithromycin in a solvent capable of removing moisture by azeotropic distillation or by passing the solution of azithromycin through a bed of activated molecular sieves or variant thereof wherein the activated bed removes moisture. For removing moisture by aziotropic distillation methylene chloride can be employed.
The so obtained azithromycin, which has lowered moisture content, is then taken up in a suitable organic solvent. The organic solvent can be selected from a group comprising of acetonitrile, ethanol, methanol or the like. If desired, excess of such organic solvent can be used to make a clear solution of azithromycin in such solvent. After forming the solution, the solvent can be recovered to get a desired solubility profile of azithromycin. Cooling of this mixture leads to separation of anhydrous azithromycin from the resultant mass which can be isolated by filtration or centrifugation. The so obtained anhydrous azithromycin Form-1 has moisture content less than 1.0% w/w when measured by Karl-Fischer analysis. The purity of anhydrous azithromycin obtained as part of present invention is 99% or more.
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In another aspect of the present invention there is provided anhydrous azithromycin having purity 99% or more when measured by HPLC.
In yet another aspect of the present invention there is provided anhydrous azithromycin having moisture content of about 1.0%w/w or less.
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 1
Azithromycin (500 gm, moisture content = 2.64%) was dissolved in
dichloromethane (8.0 Lit). The solution was heated and the solvent was
completely removed under vacuum. To the residue obtained was added
acetonitrile (2.5 Lit) and the reaction mass was gradually cooled to 15 to 20° C.
The resulting slurry was stirred at the same temperature for three hours and
filtered, the solid obtained was dried under vacuum to get anhydrous
azithromycin.
Yield: 325 gm
Purity: 99.62% (by HPLC)
Moisture Content: 0.6% w/w.
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WE CLAIM
1. A process for preparation of anhydrous azithromycin wherein the said process
comprises of
a) removing the moisture from a solution/suspension of azithromycin,
b) stirring the resultant mass in a water miscible solvent,
c) optionally recovering the solvent by distillation,
d) isolating anhydrous azithromycin from reaction mass thereof.

2. A process as claimed in claim 1 wherein the moisture from the solution / suspension is removed by aziotropic distillation.
3. A process of claim 2 wherein solvent is methylene chloride.
4. A process of claim 1 wherein water miscible organic solvent is acetonitrile, ethanol, methanol or mixtures thereof.
5. A process of claim 1 wherein the solvent is recovered under vacuum.
6. A process of claim 1 wherein the resulting mass is cooled prior to isolation of anhydrous azithromycin.
7. Anhydrous azithromycin having purity 99% or more when measured by HPLC.
8. Anhydrous azithromycin of claim 7 having purity greater than 99.5%.
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9. Anhydrous azithromycin having moisture content of about 1.0%w/w or less.
10. Anhydrous azithromycin of claim 9 having moisture content of about 0.7%w/w
or less.

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