FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention- LINEZOLID PREMIX
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS 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
is to be performed:

FIELD OF THE INVENTION
The present invention relates to Linezolid premix and process for the preparation of the said premix. The present invention also relates to pharmaceutical compositions comprising said Linezolid premix.
BACKGROUND OF THE INVENTION
Linezolid of formula I, has very valuable pharmacological and therapeutic properties, and is useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as N-[[(5S)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide.

Linezolid is chemically known as N-[[(5S)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide and marketed by Pfizer in US under brand name Zyvox. Linezolid is a synthetic antibacterial agent of the oxazolidinone class. It is used for the treatment of infections caused by multi-resistant bacteria including streptococci and methicillin-resistant Staphylococcus aureus. Linezolid was first disclosed in U.S. Pat. No. 5,688,792.
The compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life. The

compound transformations can occur also in the different solid state, because of changes in humidity or temperature or oxidative degradation conditions.
The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. Consequently, a stable Linezolid would be a significant contribution to the art.
Therefore Linezolid in premix is an approach by the present inventors towards attaining a significantly more stable polymorph product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.
Premix or co-precipitation is a recognized technique for increasing the stability of drugs. Techniques such as solvent deposition, lyophilization, solvate formation and solid premix have therefore been developed to try to overcome the problem of poor stability of drug and increase the self life of the drug.
The solvent-based process uses organic solvents to dissolve and intimately disperse the drug and carrier molecules. Identification of a common solvent for both drug and carrier can be problematic, and complete solvent removal from the product can be a lengthy process. In addition, large volumes of solvents are generally required which can give rise to toxicological problems. The drug and carrier are typically dissolved in a solvent such as methylene chloride, acetone, ethanol and mixtures thereof and the solvent is later removed by precipitation techniques, evaporation or the like, while the drug/carrier solid dispersion is collected as a powdered mass.
In the case where there is difficulty with thermal instability and immiscibility between the drug and the carrier, the hybrid fusion-solvent method can be employed. The drug is first dissolved in a small quantity of organic solvent and added to the molten carrier. The solvent is then evaporated to generate a product that is subsequently milled to produce a powder. The pharmacokinetics, dissolution rates and processes for formulation of much

different solid pharmaceutical dispersion is discussed at length in an article by Ford J., in Pharm. Acta. Helv. 61, 3; 69-88 (1986).
Premix or co-precipitation techniques employ the use of an organic solvent or solvents to dissolve drug and carrier molecules. Separation of the drug and carrier from the solvent on precipitation can rely on the solubility properties of either the drug or carrier. For example, Simonelli et al, Journal of Pharmaceutical Sciences, Vol. 58, No. 5, May 1969, describes a co-precipitation process wherein sulfathiazole is dissolved in sodium hydroxide, followed by addition of polyvinylpyrrolidone; hydrochloric acid is then added to effect co-precipitation. This process is based on co-precipitation employing the solubility of the drug at different pH values. Such reliance on the solubility of the drug may be problematic in that it is not generally applicable to Linezolid, as many such drugs do not exhibit a pH dependent solubility. Florence et al, Communications, J. Pharm. Pharmac, 1976, 28 601, describes co-precipitation of trifluoperazine embonate and the polymers poly DL-aspartic acid and polymethylmethacrylate. The co-precipitates were prepared by dissolving the drug and polymer in Toluene and adding the solution to a rapidly stirred volume of water. Both polymers and drug are insoluble in water.
Premixes are characterized by a variety of associated properties such as stability, flow, and solubility. Typical premixes represent a compromise of the above properties, as for example, an increase in stability and dissolution properties of the premix. Although there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit an improved mix of properties. Thus, the instant invention provides a premix in which Linezolid exists in stable form and process of manufacture of the premix and pharmaceutical compositions comprising said Linezolid.
OBJECT OF THE INVENTION:
Therefore, it is an object of the invention to provide a premix of Linezolid and process for preparation of the said premix.

Another object of the invention is to provide pharmaceutical compositions comprising the aforementioned Linezolid premix.
SUMMARY OF THE INVENTION:
In one of the aspect, of the present invention provides Linezolid premix having enhanced stability and dissolution properties and process for preparation thereof.
In another aspect, of the present invention a process of preparing a Linezolid premix comprising Linezolid, and a pharmaceutically acceptable carrier or excipient, which process comprises:
(i) providing an intimate mixture comprising the solvent system, Linezolid, and
optionally, water;
(ii) removing any water present from the mixture;
(iii) precipitating the premix of Linezolid and the carrier or excipient.
In another aspect, of the present invention provides for pharmaceutical compositions comprising said Linezolid premix.
Other features and advantages will be apparent from the specification which describes an embodiment of this invention.
BRIEF DESCRIPTION OF DRAWINGS
The crystalline nature of Linezolid in the premix has been characterized by XRD. Fig. 1 is an XRD of Linezolid premix

DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in details in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated.
In an embodiment, the present invention provides a premix of Linezolid having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical compositions. Linezolid premix having enhanced stability and dissolution properties, according to the invention, wherein Linezolid is stabilized by combining with suitable carrier or excipients. Further, Linezolid is present in stable form in the premix of Linezolid.
According to present invention, the ratio of Linezolid to pharmaceutical acceptable carrier or excipients is in a range of 1:1 to 50: 1.
The premix of the present invention is prepared by combining Linezolid with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties.
Suitable carrier or excipients include pharmaceutically acceptable polymers/agents used
in the process for manufacturing of the premix may be selected from group of cellulose
derivatives but not limited to croscarmellose Sodium, micro crystalline cellulose,
hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),
hydroxypropylmethylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), Hypromellose, vinylpyrrolidone monomers but not limited to Polyvinylpyrrolidone and polyol but not limited to Mannitol. The said polymers/agents are used to facilitate the presence of a Linezolid.

The solvent system used in the process for manufacturing of the premix may be selected from a group of organic, aqueous, hydroalcoholic solvents either alone or in combinations thereof. The said solvents are selected from toluene, acetone, Isopropyl alcohol, ethanol, methanol, methylene chloride, dimethylacetamide, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and combinations thereof, and optionally, water. Generally 9:1 toluene/water, 9:1 tetrahydrofuran/water, or 1:1 acetone/methanol mixtures are employed in a process according to the present invention.
In another embodiment, the present invention provides process for preparing the said Linezolid premix by co-precipitation technique which alleviates the above described disadvantages associated with known techniques, and have also found that co-precipitation offers an advantageous preparation route for premix of Linezolid.
In another embodiment of present invention a process of preparing a Linezolid premix comprising Linezolid, and a pharmaceutically acceptable carrier or excipient, which process comprises:
(i) providing an intimate mixture comprising the solvent system, Linezolid, and
optionally, water;
(ii) removing any water present from the mixture;
(iii) precipitating the premix of Linezolid.
As used herein, the term "premix" can denote a solution, suspension, emulsion, colloid, dispersion or the like. Generally, the term "premix" as used herein denotes a solution.
It is generally advantageous to first pre-mix the carrier or excipient together with the solvent or solvents and optional water, and Linezolid. Optionally, the carrier or excipient, Linezolid and solvent can be subjected to heating sufficient to facilitate dissolving. Remove any water present from the mixture azeotropically. Cool the reaction mixture co-precipitating the Linezolid and the carrier or excipient.

The resultant premix of Linezolid can be separated from the remaining components, suitably by filtering or the like, and the co-precipitate washed to remove residual solvent, and dried. The premix can then be formulated in a suitable pharmaceutical form employing known formulatory techniques, substantially as hereinafter described.
There is further provided by the present invention a process of preparing a pharmaceutical composition comprising a solid dispersion substantially as hereinbefore described, which process comprises mixing a solid dispersion substantially as hereinbefore described together with a pharmaceutically acceptable carrier.
Conveniently the following combinations of carrier or excipient and co-precipitation medium can be employed in a process according to the present invention:
Example: 1.
Preparation of Linezolid premix with Ac-di-sol (Croscarmellose Sodium)
Charge toluene (500ml), Linezolid (lOOg) and Ac-di-sol (13.3g) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove any water present from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture for 1-2 hours at 25-30°C. Filter the product and wash the product with toluene (50ml). Suck it dry and unload the product. Dry the product in vacuum tray dryer at 55-60°C. Yield: 105g.
Example: 2.
Preparation of Linezolid premix with MCC (Micro crystalline cellulose)
Charge toluene (150ml), Linezolid (30g) and MCC (3.75g) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove any water present from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture

for 1-2 hours at 25-30°C. Filter the product and wash the product with toluene (5ml). Suck it dry and unload the product. Dry the product in vacuum tray dryer at 55-60°C. Yield: 32 g.
Example: 3.
Preparation of Linezolid premix with Hydroxypropyl cellulose LH 11
Charge toluene (50ml), Linezolid (lOg) and Hydroxypropyl cellulose LH 11 (1.33g) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove any water present from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture for 1-2 hours at 25-30°C. Filter the product and wash the product with toluene (5ml). Suck it dry and unload the product. Dry the product in vacuum tray dryer at55-60°C. Yield: 10.5 g.
Example: 4.
Preparation of Linezolid premix with Hydroxypropyl cellulose EXF
Charge toluene (50ml), Linezolid (lOg) and Hydroxypropyl cellulose EXF (1.33g) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove any water present from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture for 1-2 hours at 25-30°C. Filter the product and wash the product with Toluene. Suck it dry and unload the product. Dry the product in vacuum tray dryer at 55-60°C. Yield: 10 g.

Example: 5.
Preparation of Linezolid premix with Ac-di-sol (Croscarmellose Sodium)
Process: Charge toluene (500ml), Linezolid (lOOg), Ac-di-sol (13.3g) and water (25ml) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove water from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture for 1-2 hours at 25-30°C. Filter the product and wash the product with toluene (50ml). Suck it dry and unload the product. Dry the product in vacuum tray dryer at 55-60°C. Yield: 105g.
Example: 6.
Preparation of Linezolid premix with MCC (Micro crystalline cellulose)
Charge toluene (150ml), Linezolid (30g), and water (7.5ml) and MCC (3.75g) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove water from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture for 1-2 hours at 25-30°C. Filter the product and wash the product with toluene (5ml). Suck it dry and unload the product. Dry the product in vacuum tray dryer at 55-60°C. Yield: 32 g.
Example: 7.
Preparation of Linezolid premix with Hydroxypropyl cellulose LH 11
Charge toluene (50ml), Linezolid (lOg), Hydroxypropyl cellulose LH 11 (1.33g) and water (2.5ml) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove water from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture for 1-2 hours at 25-30°C. Filter the product and wash the product

with toluene (5ml). Suck it dry and unload the product. Dry the product in vacuum tray dryer at 55-60°C. Yield: 10.5 g.
Example: 8.
Preparation of Linezolid premix with Hydroxypropyl cellulose EXF
Charge toluene (50-ml), Linezolid (lOg), Hydroxypropyl cellulose EXF (1.33g) and water (2.5ml) at 25-30°C to the flask and raise the temperature of the reaction mixture to 110-115°C under stirring. Maintain the reaction mixture at 110-115°C for 4-5 hours and remove water from the mixture azeotropically. Cool the reaction mixture to 25-30°C. Stir the reaction mixture for 1-2 hours at 25-30°C. Filter the product and wash the product with Toluene. Suck it dry and unload the product. Dry the product in vacuum tray dryer at 55-60°C. Yield: 10 g.

We Claim,
1. Linezolid premix comprising Linezolid, and premixing agents which process
comprises:
(i) providing an intimate mixture comprising the solvent system, Linezolid
and premixing agents and optionally, water;
(ii) removing any water present from the mixture;
(iii) precipitating the premix of Linezolid.
2. Linezolid premix comprises of Linezolid in combination with suitable premixing agents as claimed in claim 1, wherein the premixing agents is selected from group of cellulose derivatives but not limited to croscarmellose Sodium, Micro crystalline cellulose (MCC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmefhylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymefhylacrylate (HPMCP), Hypromellose, vinylpyrrolidone, Polyvinylpyrrolidone or Mannitol.
3. The premix of Linezolid according to claim 1, wherein ratio of Linezolid to premixing agents is in a range of 1 ; 1 to 30: 1.
4. A process of manufacturing a Linezolid premix according to claims 1, wherein Linezolid is dissolved in a solvent system selected from a group of organic solvents, aqueous solvents, alcoholic solvents either alone or in combination.
5. The premix of Linezolid according to claim 4, wherein solvents selected are water, toluene, acetone, Isopropyl alcohol, ethanol, methanol, methylene chloride, dimethylacetamide, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and combinations thereof, and optionally, water.

6. A pharmaceutical compositions comprising Linezolid premix according to claim 1, along with pharmaceutically acceptable excipients.
7. A pharmaceutical compositions according to claims 7, wherein pharmaceutically acceptable excipients are selected from the group of diluents, chelating agents, disintegrant, glidant, lubricants and optionally anti adherents and coating material.