FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - NOVEL POLYMORPHS OF
ERYTHROMYCIN COMPOUND

2. Applicant(s)
(a) NAME : . ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company.
(c) ADDRESS : Alembic Campus, Alembic Road,
Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of invention;
The present invention relates to novel polymorphs of Telithromycin of formula (I) and its process of preparation. The novel polymorphs are designated as Form I, Form II and Form III.

Background of the invention and prior art:
Telithromycin is chemically known as ll,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-a-L-ribohexopyranosyl)oxy]-6-0-methyl-3-oxo-12,11 -(oxycarbonyl[4-[4-(3-pyridinyl)-lH-imidazol-l-yl]butyl]imino)-erythromycin. It is marketed under brand name "Ketek" and is prescribed for the treatment of bacterial infections. Telithromycin of formula (I) is a ketolide which differs chemically from the macrolide group of antibacterials by the lack of a-L-cladinose at position 3 of the erythronolide A ring, resulting in a 3-keto function. It is further characterized by a C11-C12 carbamate substituted by an imidazolyl and pyridyl ring through a butyl chain. Telithromycin exhibits antibacterial activity and is used for treatment of community acquired pneumonia, acute exacerbation of chronic bronchitis, acute sinusitis, tonsillitis/pharyngitis.
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Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes in solid state. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures and/or x-ray diffraction pattern. Polymorphs of a compound can be characterized by x-ray diffraction pattern, Infrared Spectrum, DSC etc.
Telithromycin was first reported in US Patent No. 5,635,485, which disclose its process for preparation. The polymorphic forms of Telithromycin are not reported in literature. The inventors of present invention have observed that Telithromycin exhibits different polymorphic forms. These novel forms are characterized as Form I, Form II and Form III.
Object of the invention:
The primary object of the present invention is to provide the novel polymorphs of Telithromycin of formula (I).
Another object of the invention is to provide novel polymorphs of Telithromycin of formula (I) designated as Form I, Form II and Form III.
Yet another object of the invention is to provide process for preparation of novel polymorphs of Telithromycin of formula (I) designated as Form I, Form II and Form III.
Further object of the invention is to characterize the novel polymorphs of Telithromycin of formula (I) designated as Form I, Form II and Form HI.
Brief description of the drawings:
Figure-1 represents PXRD of Telithromycin Form I. Figure-2 represents PXRD of Telithromycin Form II. Figure-3 represents PXRD of Telithromycin Form III.
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Summary of the invention:
In accordance with the object of the present invention, one aspect provides novel polymorphs of Telithromycin designated as Form I, Form II and Form III.
According to another aspect of the present invention there is provided Telithromycin Form I, characterized by powder x-ray diffraction peaks at 6.0, 9.6, 11.1,11.4,13.3,19.6 ± 0.2° 2-0.
According to yet another aspect of the present invention there is provided Telithromycin Form II, characterized by powder x-ray diffraction peaks at 7.7, 10.0, 12.0, 12.9, 15.8, 18.8 ±0.2° 2-9.
Yet another aspect of the present invention provides Telithromycin Form III, characterized by powder x-ray diffraction peaks at 8.2, 10.4, 12.6, 15.7,16.9 ± 0.2° 2-9.
Another aspect of the present invention provides process of preparing novel polymorphs of Telithromycin designated as Form I, Form II and Form III.
Detailed description of the invention:
The term "Telithromycin" as used herein is intended to include Telithromycin and its pharmaceutically acceptable salts, and hydrates or solvates thereof or their mixtures in any state of purity, unless specifically mentioned. Telithromycin used for the present invention can be prepared by methods known perse or by any methods known to person skilled in art.
Telithromycin Form I is characterized by powder x-ray diffraction peaks at 6.0, 9.6, 11.1, 11.4, 13.3, 19.6 ± 0.2° 2-0. It is further characterized by powder x-ray diffraction peaks at 7.7, 10.0, 13.9, 14.1, 15.5, 16.3, 17.5, 18.0, 18.6, 18.9, 19.2, 20.6, 27.0 ± 0.2° 2-0.
The process for preparing Telithromycin Form I comprises,
(a) treating Telithromycin with halogenated solvent to obtain solution
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(b) treating the above solution with anti-solvent to obtain Telithromycin Form I.
Telithromycin is treated with halogenated solvent at temperature of about 20°C to about boiling temperature of the solvent, preferably at about room temperature, to obtain a solution. Further this solution is treated with an anti-solvent and stirred for about 1 hour to about 5 hours at temperature of about 20°C to about 35°C, preferably at about room temperature to obtain Telithromycin Form I. Telithromycin Form I can be further isolated by conventional methods such as filtration or centrifugation and dried.
The halogentated solvent is selected from group comprising of dichloro methane, ethylenedichloride, chloroform, carbontetrachloride or like, preferably dichloro methane. The anti-solvent is selected from group comprising of methyl t-butyl ether, diethyl ether, diisopropyl ether, cyclohexane, n-heptane, n-hexane or like, preferably methyl t-butyl ether.
Telithromycin Form II is characterized by powder x-ray diffraction peaks at 7.7, 10.0, 12.0, 12.9, 15.8, 18.8 ± 0.2° 2-9. It is further characterized by powder x-ray diffraction peaks at 11,6, 16.6, 17.5, 17.9, 18.8, 19.3,20.5,21.2,21.8 ± 0.2° 2-6.
Telithromycin Form I can also be prepared from Telithromycin Form II, Form III or mixtures thereof by the general process described above for the preparation of Form I.
The process for preparing of Telithromycin Form II comprises, treating Telithromycin with solvent selected from the group comprising of esters, cycloalkanes or ethers optionally in presence of saturated hydrocarbons or ketones to obtain Telithromycin Form II.
Telithromycin is treated with solvent selected from the group comprising of esters, cycloalkanes or ethers at temperature of about 20°C to about boiling temperature of the solvent, preferably at about room temperature. This reaction mass can be optionally treated further with solvent selected from the group comprising of saturated hydrocarbons or ketones at temperature of about 20°C to about boiling temperature of the solvent, preferably at about room temperature for about 1 hour to about 10 hours, preferably for
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about 6 hours to about 8 hours to obtain .Telithromycin Form II. If desired the reaction mass can be cooled to about 15°C to 25°C. Telithromycin Form II can be isolated by conventional methods such as filtration or centrifugation and dried.
The ester is selected from group comprising of ethyl acetate, butyl acetate, methyl acetate or like, preferably ethyl acetate. The cycloalkane is selected from group comprising of cyclohexane, cycloheptane, cyclopentane or like, preferably cyclohexane. The ether is selected from group comprising of diethyl ether, diisopropyl ether, tetrahydrofuran and like". Saturated hydrocarbon is selected from group comprising of n-heptane, n-hexane, n-pentane or like, preferably n-heptane. The ketone is selected from group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone or like, preferably acetone.
Telithromycin Form II can also be prepared from Telithromycin Form I, Form III or mixtures thereof by the general process described above for the preparation of Form II.
Telithromycin Form III is characterized by powder x-ray diffraction peaks at 8.2, 10.4, 12.6,15.7,16.9 ± 0.2° 2-0. It is further characterized by powder x-ray diffraction peaks at 12.0, 13.7,16.3, 18.3,20.6, 21.5,21.9 ± 0.2° 2-9.
The process for preparation of Telithromycin Form III comprises, treating Telithromycin with solvent selected from the group comprising of cycloalkanes in presence of aromatic hydrocarbon to obtain Telithromycin Form III
Telithromycin is treated with solvent selected from the group comprising of cycloalkanes at temperature of about 20°C to about boiling temperature of the solvent, preferably at about room temperature, in the presence of aromatic hydrocarbons for about 1 hour to about 10 hours, preferably for about 6 hours to about 8 hours to obtain Telithromycin Form III. If desired the reaction mass can be cooled to about 15°C to 25°C. Telithromycin Form III can be isolated by conventional methods such as filtration or centrifugation and dried.
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The cyloalkane is selected from group comprising of cyclohexane, cycloheptane, cyclopentane and like, preferably cyclohexane. The aromatic hydrocarbon is selected from group comprising of toluene, benzene and like, preferably toluene.
Telithromycin Form III can also be prepared from Telithromycin Form I, Form II or mixtures thereof by the general process described above for the preparation of Form III.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Examples:
Example 1: Process for preparing Telithromycin Form I
5 ml dichloromethane was added to 10 g of Telithromycin to obtain clear solution. 100 ml of methyl t-butyl ether is added and reaction mass was stirred for about 3 hours at 25°C to 30°C. The solid was filtered and washed with methyl t-butyl ether and dried at 25°C tp 30°C under vacuum to obtain Form-I.
Example 2: Process for preparing Telithromycin Form II
10 g Telithromycin Form I prepared in Example 1 is taken in 80 ml mixture of ethyl acetate and n-heptane. The reaction mixture is refluxed at 80°C for about 6 to 8 hours and then cooled to about 15°C. The product is filtered, washed and dried in vacuum at 40°C to obtain Telithromycin Form II.
Example 3: Process for preparing Telithromycin Form III
10 g Telithromycin Form I prepared in Example 1 is taken in 80 ml mixture of cyclohexane and toluene. The reaction mixture is stirred at about 25°C to about 30°C for about 6 to 8 hours. The product is filtered, washed and dried in vacuum at 40°C to obtain Telithromycin Form III. 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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We claim:
1. Telithromycin Form I.
2. Telithromycin Form I characterized by powder x-ray diffraction peaks at 6.0, 9.6,11.1, 11.4, 13.3,-19.6 ±0.2° 2-6.
3. Telithromycin Form I characterized by powder x-ray diffraction spectrum which is substantially the same as powder x-ray diffraction spectrum shown in Figure 1.
4. A process for preparation of Telithromycin Form I comprising of

(a) treating Telithromycin with halogenated solvent to obtain solution
(b) treating the above solution with anti-solvent to obtain Telithromycin Form I

5. A process as claimed in claim 4, wherein said halogenated solvent is selected from group comprising of dichloro methane, ethylenedichloride, chloroform, carbontetrachloride or like.
6. A process as claimed in claim 5, wherein said halogenated solvent is dichloro methane.
7. A process as claimed in claim 4, wherein said anti-solvent is selected from group comprising of methyl t-butyl ether, diethyl ether, diisopropyl ether, cyclohexane, n-heptane, n-hexane or like.
8. A process as claimed in claim 7, wherein said anti-solvent is methyl t-butyl ether.
9. Telithromycin Form II.
10. Telithromycin Form II characterized by powder x-ray diffraction peaks at 7.7, 10.0,
12.0, 12.9, 15.8, 18.8 ±0.2° 2-0.
11. Telithromycin Form II characterized by x-ray diffraction spectrum which is
substantially the same as powder x-ray diffraction spectrum shown in Figure 2.
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12. A process for preparation of Telithromycin Form II comprising, treating Telithromycin with solvent selected from the group comprising of esters, cycloalkanes or ethers, optionally in presence of solvent selected from the group comprising of saturated hydrocarbons or ketones to obtain Telithromycin Form II.
13. A process as claimed in claim 12, wherein said ester is selected from group comprising of ethyl acetate, butyl acetate, methyl acetate or like.

14. A process as claimed in claim 13, wherein said ester is ethyl acetate.
15. A process as claimed in claim 12, wherein said cycloalkane is selected from group comprising of cyclohexane, cycloheptane, cyclopentane or like.
16. A process as claimed in claim 15, wherein said cycloalkane is cyclohexane.

17. A process as claimed in claim 12, wherein said ether is selected from group comprising of diethyl ether, diisopropyl ether, tetrahydrofuran and like.
18. A process as claimed in claim 12, wherein said saturated hydrocarbon is selected from group comprising of n-heptane, n-hexane, n-pentane or like.
19. A process as claimed in claim 18, wherein said saturated hydrocarbon is n-heptane
20. A process as claimed in claim 12, wherein said ketone is selected from group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone or like.
21. A process as claimed in claim 20, wherein said ketone is acetone
22. Telithromycin Form III.
23. Telithromycin Form III characterized by powder x-ray diffraction peaks at 8.2, 10.4, 12.6, 15.7, 16.9 ±0.2° 2-9.
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24. Telithromycin Form III characterized by powder x-ray diffraction spectrum which is
substantially the same powder x-ray diffraction spectrum shown in Figure 3.
25. A process for preparation of Telithromycin Form III comprising, treating
Telithromycin with solvent selected from the group comprising of cycloalkane in
presence of aromatic hydrocarbon to obtain Telithromycin Form in
26. A process as claimed in claim 25, wherein said cyloalkane is selected from group comprising of cyclohexane, cycloheptane, cyclopentane and like.
27. A process as claimed in claim 26, wherein said cyloalkane is cyclohexane.
28. A process as claimed in claim 26, wherein said aromatic hydrocarbon is selected from group comprising of toluene, benzene and like.
29. A process as claimed in claim 28, wherein said aromatic hydrocarbon is toluene.
30. The novel polymorphs of Telithromycin and its process for preparation such as herein described by accompanying description, text, drawings and examples.
Dated this 6th day of October 2005

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A B S T R A C T
TITLE : NOVEL POLYMORPHS OF ERYTHROMYCIN COMPOUND
The present invention relates to novel polymorphs of Telithromycin designated as Form I, II and III and its process for preparation.
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