FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - NOVEL FORM OF TELITHROMYCIN.
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 describes the invention

Field of invention:
The present invention relates to a novel substantially amorphous form of Telithromycin of formula (I) and its process of preparation. Moreover the present invention provides process for preparing Telithromcyin having OVI less than about 5000 ppm. It also provides process for preparing Telithromycin substantially free from volatile impurities.

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,ll-(oxycarbonyl[4-[4-(3-pyridinyl)-lH-imidazol-l-yl]butyl]imino)-erythromycin. It is marketed under brand name "Ketek" and is indicated 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. The polymorphic and pseudopolymorphic solids display different physical properties, including those due to packing, and various thermodynamic, spectroscopic, interfacial and mechanical properties (See H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, N.Y., 1999, pp. 1-2). Polymorphic and pseudopolymorphic forms of the drug substance (also known as the "active pharmaceutical ingredient" (API)), as administered by itself or formulated as a drug product (also known as the final or finished dosage form, or as the pharmaceutical composition) are well known and may affect, for example, the solubility, stability, flowability, fractability, and compressibility of drug substances and the safety and efficacy of drug products, (see, e.g., Knapman, K Modem Drug Discoveries, March 2000: 53). 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. Presently no polymorphic forms of Telithromycin are reported in literature. Surprisingly inventors of present invention have found that Telithromycin exists in substantially amorphous form.
One important physical property that can vary between two polymorphic forms is solubility, which can affect the bioavailability of the drug. Therefore there is a need to develop new polymorphic forms of a drug since it provides new opportunity to improve the performance characteristics of a pharmaceutical product.
Object of the invention:
The primary object of the present invention is to provide the novel substantially amorphous form of Telithromycin of formula (I) and its process of preparation.
Another object of the present invention is to provide Telithromycin having OVI less than 5000 ppm and its process of preparation.
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Yet another object of the present invention is to provide Telithromycin substantially free from volatile impurities and its process of preparation.
Summary of the invention:
Accordingly present invention provides novel substantially amorphous form of Telithromycin and its process of preparation.
Another aspect of the present invention provides Telithromycin having OVI less than about 5000 ppm and its process of preparation.
Present invention also provides Telithromycin substantially free from volatile impurities and its process of preparation.
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.
The term "treating" as used herein in specification and claims refers to simple dictionary meaning: "To subject to a process, action, or change, especially to a chemical or physical process or application".
The process for preparing substantially amorphous Telithromycin comprises,
(a) treating Telithromycin with acid
(b) optionally degassing the reaction mass
(c) treating above reaction mass with base to obtain substantially amorphous form of Telithromycin
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Telithromycin is treated with aqueous solution of acid at temperature of about 5°C to about 40°C. The reaction mass can be degassed for about 1 hour to about 10 hours. Further it is treated with base at temperature of about 5°C to about 40°C and the stirring can be continued for about 10 hours to about 30 hours at temperature of about 5°C to about 30°C, preferably room temperature to obtain substantially amorphous Telithromycin. It can be further isolated by conventional methods such as filtration or centrifugation and dried.
The acid can be selected from group comprising of HCl, H2SO4, acetic acid, formic acid and like, preferably HCl. The base can be selected from group comprising of alkali or alkaline earth metal hydroxides, carbonates or bicarbonate like sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and like, preferably sodium carbonate.
Degassing can be conveniently performed by application of vacuum or by purging nitrogen in the reaction mass, or by any method known to person skilled in art.
In accordance with another aspect of the present invention, there is provided process for preparing Telithromycin having OVI less than about 5000 ppm, more preferably less than 2500 ppm.
The process comprises,
(a) treating Telithromycin with acid
(b) optionally degassing the reaction mass
(c) treating above reaction mass with base to obtain Telithromycin having OVI less than about 5000 ppm.
Yet another aspect of the present invention provides process for preparing Telithromycin substantially free from volatile impurities.
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The process comprises,
(a) treating Telithromycin with acid
(b) optionally degassing the reaction mass
(c) treating above reaction mass with base to obtain Telithromycin substantially free from volatile impurities.
Another aspect of the present invention provides Telithromycin of particle size comprising a plurality of Telithromycin particles wherein the mean particle size (do.i) is greater than about 30 urn and (do.9) is less than about 400 urn.
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:
40 ml HC1 solution (2 ml HC1 in 38 ml water) was added to 5 g of Telithromycin. Vacuum was applied to the solution for about 4 to 5 hours. After releasing the vacuum the pH of the solution was adjusted to about 7 by using saturated sodium bicarbonate solution. The reaction mixture was stirred overnight and filtered to obtain amorphous Telithromycin (yield: 4.4 g). PXRD: As characterized in Figure-1.
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.

Sonali Bhokarikar
Of S. Majumdar & Co.
Applicant's Agent
Dated this 28lh day for October 2005.
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