WO2013072923A1

WO2013072923A1 - Process for the preparation of crystalline linezolid

Info

Publication number: WO2013072923A1
Application number: PCT/IN2012/000621
Authority: WO
Inventors: Shriprakash Dhar DWIVEDI; Ashok Prasad; Kuldeep Natwarlal Jain
Original assignee: Cadila Healthcare Limited
Priority date: 2011-09-19
Filing date: 2012-09-18
Publication date: 2013-05-23

Abstract

The present invention discloses a stable crystalline Form-I of linesolid process for preparation thereof.

Description

PROCESS FOR THE PREPARATION OF CRYSTALLINE LINEZOLID FIELD OF THE INVENTION

The invention relates to an improved process for the preparation of crystalline linezolid. In particular, the invention relates to an improved process for the preparation of crystalline Form-I of linezolid substantially free from crystalline Form-Il of linezolid. More particularly, the present invention relates to a stable crystalline Form-I of linezolid. The invention also relates to pharmaceutical compositions that include the stable crystalline Form-I of linezolid.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Linezolid [(S)-N-[[3-(3-flouro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl] acetamide is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical Formula CJ6H20FN3O4 and the following structure (I):

(I)

Linezolid is described in the Merck Index (13 edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.5°C. Linezolid and related compounds, processes for their preparation and their therapeutic uses were also disclosed in U.S. Patent No. 5,837,870 and International (PCT) Publications WO 95/07271 arid WO 99/24393 as well as in reference articles like J. Med. Chem. 39(3), 673-679, and Tetrahedron Lett. 40(26), 4855, 1999.

U.S. Patent Nos. 6,444,813 and 6,559,305 (the US '305) disclose crystal Form II of linezolid. The US '305 patent further discloses that the crystal Form II is characterized by powder X-ray diffraction pattern andian infrared (IR) spectrum. Several processes for the preparation of crystalline Form of linezolid have been disclosed, for example in U.S. Patent Nos. 7,649,096 B2, 7,718,799 B2, 7,718,800 B2, 7,732,597 B2, 7,714,128 B2.

International (PCT) publication Nos. WO 2007/116284 Al, WO 2009/063505 A2, WO 2010/031769 Al, WO 2010/081404 Al, WO 2010/084514 A2, WO2011/029460 Al, WO 2011/77310 Al, disclose various processes for the synthesis of linezolid and its crystalline form.

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing. For example, an amorphous form may form hydrates more readily or may be more difficult to filter and wash free of impurities than a crystalline form (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms). Thus, a present crystalline form can overcome the problems like thermodynamic stability, solubility, storage, compressibility etc important for Formulation and product manufacturing and doesn't degrade to crystalline Form-II of linezolid.

There is a need to provide an improved process for the preparation of linezolid over the prior art reference, which can atleast provide the storage stable crystalline Form-I of linezolid which is substantially free from Form-II.

SUMMARY OF THE INVENTION

In one general aspect, there is provided stable linezolid crystalline Form-I.

In another general aspect, there is provided stable micronized linezolid crystalline Form-I. In another general aspect, there is provided an improved process for the preparation of crystalline Form-I of linezolid, the process comprising heating linezolid in one or more of suitable solvent in a hydrogenator and obtaining crystalline Form-I of linezolid.

The crystalline Form-I of linezolid of the present invention is characterized by its powder X-ray diffraction pattern as shown in FIG1, IR spectrum as shown in FIG.2, and differential scanning calorimetry endothermic peak as shown in FIG3.

The crystalline Form-I of linezolid of the present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.3, 13.4, 14.6, 17.9, 18.3, 19.8, 20.9, 22.1, 25.3, 27.6, 28.3 and 29.6 degrees.

FIG.2 shows DSC analysis of crystalline Form-I of linezolid of the present invention characterized by having an endothermic peak in the range of about 181°C- 184°C. The crystalline Form-I of linezolid of present invention is also characterized by IR analysis. FIG.3 shows Infrared spectrum of Linezolid with characteristics peaks at about 3336, 2968, 2816, 1743, 1662, 1516, 1471, 1452, 1423, 1228, 1117, 937, 754 and -1

661 cm .

In another general aspect, there is provided an improved process for preparation of crystalline form of linezolid of Formula (I),

(I)

the process comprising:

a) acetylating linezolid amine of Formula (II) at below 5°C in one or more suitable

solvents

(II) b) to obtain a solution of linezolid

cj removing the solvents to obtain a residue;

d) triturating the residue In one or more suitable solvents comprising one or more of aromatic hydrocarbons, halogenated hydrocarbons, esters, nitriles, aprotic solvents, or mixtures thereof below 80°C to obtain linezolid; and

e) crystallizing the linezolid in one or more suitable solvents in a hydrogenator to obtain the linezolid of Formula (I).

In another general aspect, there is provided an improved process for preparation of crystalline Form-I of linezolid of Formula (I),

(I)

the process comprising:

a) providing a linezolid solution in one or more halogenated hydrocarbon solvents; b) extracting in one or more aromatic hydrocarbon solvents and heating to obtain a reaction mixture;

c) obtaining a wet-cake from the reaction mixture and heating the wet-cake in one or more suitable C -C . alkyl ester solvents to obtain a solution;

1 4 ^J

d) cooling the solution at about 50°C to obtain linezolid; and

e) crystallizing the linezolid in one or more suitable solvents in a hydrogenator to obtain the crystalline Form-I of linezolid of Formula (I).

In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of linezolid together with one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of linezolid having particle size d0.9 from 30 m to 200 μηι.

In another general aspect, there is provided stable pharmaceutical composition of linezolid crystalline Form-I comprising a therapeutically effective amount of stable micronized crystalline Form-I of linezolid having particle size d0.9 less than about 25 μηι.

BRIEF DESCRIPTION OF THE DRAWINGS FIG 1 - represents the PXRD of crystalline Form of linezolid as per Example-6.

FIG 2 - represents the DSC of crystalline Form of linezolid as per Example-6.

FIG 3 - represents the IR spectrum of crystalline Form of linezolid as per Example-6. FIG 4 - represents the PXRD of crystalline Form-II of linezolid as per Example-7. FIG 5 - represents the PXRD comparison of crystalline Form of linezolid during stability up to 6 Months.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "stable" refers to crystalline linezolid Form-I that includes either of the following:

a) crystalline Form-I does not convert to Form-II or any other solid form when stored at a temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months.

b) crystalline Form-I does not convert to Form-II or any other solid form when stored up to about six months or more.

The stable crystalline Form-I does not show an X-ray powder diffraction peak at a diffraction angle (2Θ) of about 23.5° when stored at a temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months and containing less than about 0.15% (wt/wt) any single individual impurities like linezolid amine or linezolid alcohol or linezolid acetyl or desflouro and (R)-isomer by area percentage of HPLC temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months.

As used here in the term "obtain" or "obtaining" may include decantation or unloading from hydrogenator or pressure reactor. The product obtained may be further or additionally dried to achieve the desired moisture values and remove traces of solvents atleast under ICH limits. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

As used here in the term "micronized" may include reduction in particle size of linezolid crystalline Form-I obtained as such by the process of present invention. In particular, the term "micronized" includes particle size d0.9 of linezolid crystalline Form-I less than about 25 μπι.

The micronized linezolid crystalline Form-I may be prepared by unit operation that involves reduction of particle size like jet-milling, ball-milling, multi-milling, shifting, sieving and the like. As used here in the term "about" may include the values from ±0.2° in case of 2-

-1

theta for X-ray diffractogram values and from ±5 cm in case of Infrared spectrum. Preferably the term "about" may include the values from ±3°C in case of differential scanning calorimetry.

The present invention can comprise (open ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein. As used herein, "comprises" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggest otherwise.

All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "general", "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials. In the case of substantially pure crystalline linezolid, "pure" also means about 99% of one crystalline form free from crystalline Form-II, as appropriate or in the case of crystalline solids.

Embodiments of the process may include one or more of the following features. For example, the solution or suspension may be obtained by dissolving or suspending linezolid in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction mixture in a process in which linezolid is formed. The solvent containing linezolid may be heated to obtain a solution in hydrogenator or pressure reactor. It can be heated from about 35°C to about reflux temperature of the solvent used, for example from about 35°C to about 120°C.

Impurity "linezolid amine" is (S)-[N-[3-(3-flouro-4-mo holinylphenyl)-2-oxo-5- oxazolidinyl] methyl]amine. Impurity "desflouro" is (S)-N-[3-(4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]acetamide.

Impurity "linezolid alcohol" is (R)-[N-[3-(3-flouro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methanol.

Impurity "linezolid acetyl" is (R)-[N-[3-(3-flouro-4-mo holinylphenyl)-2-oxo-5- oxazolidinyl-5-yl] methyl acetate

The chemical structures of impurities linezolid amine, desflouro, linezolid alcohol, linezolid acetyl and linezolid (R)-isomer are:

Linezolid Amine

Linezolid Alcohol

Des-flouro Linezolid

Linezolid Acetyl

(R)-Isomer of Linezolid

In one general aspect, there is provided stable linezolid crystalline Form-I.

In general, the stable linezolid crystalline Form-I is having particle size d0.9 in the range of 30 μιη to 200 μηι. In another general aspect, there is provided stable micronized linezolid crystalline Form-I.

In general, the micronized linezolid crystalline Form-I is having particle size d0.9 less than about 25 μιη, particularly less than 15 μηι.

The embodiments of the invention includes micronization of linezolid crystalline Form-I having particle size d0.9 in the range of 30 μηι to 200 μπι.

In another general aspect, there is provided crystalline Form-I of linezolid substantially free from Form-II of linezolid. The term "substantially free" herein means crystalline form of linezolid prepared by the process of the present invention contains 1% or less of crystalline Form-II of linezolid, particularly contains 0.5% or less of. crystalline Form-II of linezolid, more particularly less contains no detectable quantity of crystalline Form-II of linezolid, measured by X-ray powder diffraction pattern.

The crystalline Form-I of linezolid of the present invention is characterized by its powder X-ray diffraction pattern as shown in FIG.1, IR spectrum as shown in FIG.2, and differential scanning calorimetry endothermic peak as shown in FIG3.

Form-II of linezolid is characterized by having peaks at about 23.5°C which is not present in crystalline form of linezolid prepared by the process of present invention.

The crystalline Form-I of linezolid of present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.3, 13.4, 14.6, 17.9, 18.3, 19.8, 20.9, 22.1, 25.3, 27.6, 28.3 and 29.6 degrees.

FIG.2 shows DSC analysis of crystalline Form-I of linezolid of present invention characterized by having an endothermic peak in the range of about 181°C-184°C.

The crystalline Form-I of linezolid of present invention is also characterized by IR analysis. FIG.3 shows Infrared spectrum of Linezolid with characteristics peaks at about 3336, 2968, 2816, 1743, 1662, 1516, 1471, 1452, 1423, 1228, 1 117, 937, 754 and -1

661 cm .

In another general aspect, there is provided an improved process for the preparation of crystalline Form-I of linezolid, the process comprising heating linezolid in one or more of suitable solvent in a hydrogenator and obtaining crystalline Form-I of linezolid.

In general, the crystalline Form-I of linezolid may be prepared by heating linezolid in one or more of suitable solvent selected from diisopropyl ether, methyl tert- butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane and the like in a hydrogenator. In particular, the reaction involves heating linezolid in heptane at about 105°C to 110°C under 3 Kg pressure in presence of nitrogen. The reaction mixture may be further cooled before filtration and washing the wet-cake with heptane. The crystalline Form-I of linezolid is obtain by drying wet-cake at 70°C to 75°C in a vacuum oven.

In one general aspect, there is provided an improved process for preparation of linezolid of Formula (I),

(I)

the process comprising:

a) acetylating linezolid amine of Formula (II) at below 5°C in one or more suitable solvents to obtain a-so ution of linezolid;

Formula (II)

b) removing the solvents to obtain a residue;

c) triturating the residue in one or more suitable solvents comprising one or more of aromatic hydrocarbons, halogenated hydrocarbons, esters, nitriles, aprotic solvents, or mixtures thereof below 80°C to obtain linezolid; and

d) crystallizing the linezolid in one or more suitable solvents in a hydrogenator to obtain the linezolid of Formula (I).

In general, the suitable solvent in step (a) comprises one or more of acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, toluene, xylene, methylene dichloride, chlorobenzene or mixtures thereof. In particular, methylene dichloride.

Embodiments of the process includes acetylating linezolid amine of Formula (II) in methylene dichloride with acetic anhydride below 5°C. Particularly, at 0°C to 5°C and reaction mixture may be maintained for 30 minutes in step (a). The linezolid product obtain in the reaction mixture may be isolated as residue by complete removal of methylene dichloride. In general, the methylene dichloride layer may be washed with 10% sodium bicarbonate solution at room temperature before subjecting to complete removal of the solvent. Embodiments of the process further include removing traces of methylene dichloride by co-distillation with toluene to provide linezolid residue.

In general, the suitable solvent in step (c) comprises one or more of aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like, halogenated hydrocarbons like methylene dichloride, chlorobenzene, ethylene dichloride and the like, esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, nitriles like acetonitrile, propionitrile and the like, aprotic polar solvents like N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrroIidone, dimethylsulfoxide and the like. In particular, toluene or xylene.

Embodiments of the process include heating linezolid residue in suitable solvent, particularly aromatic hydrocarbons like toluene or xylene below 80°C. In particular, the linezolid residue may be heated at about 35°C to about 80°C, More particular, at about 50°C to 55°C.

In general, the reaction mixture may be cooled after heating at about 50°C to 55°C in toluene or xylene to obtain linezolid wet-cake by filtration. The wet-cake may be again heated in suitable solvent comprises of esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate below 80°C, Particularly at about 70°C to 80°C.

The inventors of the invention have found that the precipitated linezolid when filtered at above 15°C provides better yield and purity. Thus, the precipitated linezolid may be filtered at about 18°C to 22°C and dried at 65°C to 70°C to obtain pure linezolid substantially free from linezolid amine, linezolid alcohol, desflouro and linezolid acetyl impurities. Further, linezolid is substantially free from its (R)-isomer.

In general, the pure linezolid may be converted to crystalline Form-I of linezolid by crystallizing linezolid in one or more of suitable solvent selected from diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane and the like in a hydrogenator. In particular, the reaction involves heating linezolid in heptane at about 105°C to 110°C under 3 Kg pressure in presence of nitrogen. The reaction mixture may be further cooled before filtration and washing the wet-cake with heptane. The crystalline Form-I of linezolid is obtain by drying wet-cake at 70°C to 75°C in a vacuum oven.

An improved process for preparation of crystalline Form-I of linezolid of Formula (I),

the process comprising:

c) obtaining a wet-cake from the reaction mixture and heating the wet-cake in one or more suitable C1-C4 alkyl ester solvents to obtain a solution;

d) cooling the solution at about 50°C to obtain linezolid; and

In general, the halogenated hydrocarbon solvent comprises one or more of methylene dichloride, ethylene dichloride, chloroform, chlorobenzene and the like. In particular, methylene dichloride.

In general, the aromatic hydrocarbon solvent comprises one or more of toluene, o-xylene, m-xylene, p-xylene, ethylbenzene and the like. Further, the alkyl ester

solvent comprises one or more of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like.

In general, the suitable solvent in step (e) comprises one or more of diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane and the like.

In particular, the reaction of step (f involves heating linezolid in heptane at about 105°C to 110°C under 3 Kg pressure in presence of nitrogen. The reaction mixture may be further cooled before filtration and washing the wet-cake with heptane. Crystalline form of linezolid is obtain by drying wet-cake at 70°C to 75°C in a vacuum oven.

In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of linezolid having particle size d0.9 from 30 μπι to 200 um. In another general aspect, there is provided stable pharmaceutical composition comprising a therapeutically effective amount of stable micronized crystalline Form-I of linezolid having particle size d0.9 less than about 25 μηι.

In another general aspect, there is provided stable linezolid crystalline Form-I having bulk density of about 0.40 g/mL and tapped density of about 0.60 g/mL.

In another general aspect, there is provided stable micronized linezolid crystalline Form-I having bulk density of about 0.28 g/mL and tapped density of about 0.40 g/mL.

Ih another general aspect, the stability of crystalline Form-I of linezolid prepared by the process of the present invention with PSD d0.9 in the range of 30 to 200 um and micronized linezolid crystalline Form-I is outlined in Table-I as below:

TABLE-I

F-I = Form-I free from Form-II

ND = Not Detected. As set forth in the following schemes, the process of the invention for the preparation of Linezolid involves the following chemical reactions.

(I)

5 Scheme- 1 ^

The crystalline Form of linezolid can be characterized by PXRD, DSC, IR as follows:

(i) Characterization by PXRD

Analytical method: Powder X-ray Diffraction was measured by using a Rigaku D/MAX 2200 VPC diffraction meter, the powder x-ray diffraction pattern was measured at room 10 temperature using a CuKa filled tube (40kV, 40 mA) as the x-ray source with a wide- angle goniometer, a scattering slit, an diverging slit, a graphite secondary monochromator and a scintillation counter. Data collection was done in 20 continuous scan mode at a scan speed of 37minute in scan steps of 0.02° in the range of 2° to 40°.

The crystalline Form of linezolid of present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.3, 13.4, 14.6, 17.9, 18.3, 19.8, 20.9, 22.1, 25.3, 27.6, 28.3 and 29.6 degrees. The crystalline form of linezolid is further characterized by X-ray powder diffraction pattern substantially as depicted in FIG.1

The XRPD peaks of crystalline Form-I of linezolid is as shown in below table:

TABLE-II

24 29.45 · 3.03 weak

25 29.60 3.01 weak

26 30.64 2.91 weak

27 33.16 2.69 weak

28 33.45 2.67 weak weak intensity: I/Io is less than 20

medium intensity: I/Io is in between 21 to 35

strong intensity: I/Io is in between 36 to 50

v. strong intensity: I/Io is greater than 50

(ii) Characterization by Differential Scanning Calorimetry (DSC)

Analytical method: Differential scanning calorimetric analysis was performed using a Perkin Elmer Diamond DSC control unit and a DSC 300°C differential scanning calorimeter. 2-5 mg samples were placed in crimped aluminum pans and heated from 50°C to 300°C in a liquid nitrogen atmosphere at a heating rate of 10°C/minute. Zinc- Indium were used as the standard substance.

(iii) Characterization by IR

The IR spectrum was measured by the KJBr method. FIG.3 represents the IR spectra of crystalline Form-I of linezolid.

The process of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the claims in any manner.

EXAMPLES

Example-1 : 3-fluoro-4-morpholinyl-nitrobenzene

To a solution of 100 g of 3,4-difluoronitrobenzene and 69.9 g of triethylamine in 100- mL methylene dichloride, was added 60.2 g morpholine at 10°C to 15°C within 1 hour. The reaction mixture was stirred for 3 hours at room temperature. After the completion of the reaction, methylene dichloride was distilled under vacuum below 50°C. The residue so obtained was diluted with 300 mL water and stirred for 30 minutes. The product thus obtained was filtered and washed with water. The product was dried at 65°C to 70°C to get 140 g (98%) 3-fluoro-4-morpholinyl-nitrobenzene.

Example-2: N-carbobenzoxy-3-fluoro-4-morpholinyI aniline To a suspension of 100 g of 3-fluoro-4-morpholinyl-nitrobenzene in 1 L of methanol under nitrogen, was added 28 g of Raney Nickel in an autoclave. The reaction mixture was bubbled with H gas at room temperature initially and further under 5

2

Kg/cm pressure. The reaction mixture was maintained under the same conditions for about 10 hours till completion of the reaction. The pressure was released followed by nitrogen flushing. The reaction mixture was filtered and washed with 100 mL methanol. The filtrate was concentrated and then 380 mL of water was added. The reaction mixture was cooled to 0°C and treated with 49 g of sodium bicarbonate and 205 mL benzyl chloroformate solution (50% in toluene). The reaction was stirred at room temperature for 1 hour and 620 mL water was added. The product obtained upon stirring was filtered and washed with a mixture of water-methanol. The product was dried at 60°C to 65°C to get 140 g (95%) of N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline.

ExampIe-3: (R)-fN-f3-(3-fluoro-4-morphoIinylphenylV-2-oxo-5- oxazolidinyll methyl] methane sulfonate

To a solution of 100 g of N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline in 500 mL of freshly distilled tetrahydrofuran at -80°C under nitrogen, was added 105 mL of n-butyl lithium/hexane via syringe within 90 minutes, and the mixture stirred for 60 minutes. Further, a solution of 45.9 g of (R)-glycidylbutyrate in 80 mL of tetrahydrofuran was added within 90 minutes, and stirred for 60 minutes. The reaction mixture was removed from the dry ice bath, and allowed to come to ambient temperature. After stirring for 4-6 hours, the reaction mixture was quenched in 134 g of saturated aqueous ammonium chloride solution, followed by 500 mL of toluene, and the aqueous layer extracted with toluene. The combined organic layers were washed with 360 mL of brine. The organic layer was treated with 4 g activated charcoal and stirred for 30 minute and filtered. The filtrate was concentrated under vacuum at 60°C to remove toluene completely. In the mixture of residue of (R)-N-[[3-[3-fluoro-4- moφholinyl]-phenyl]-2-oxo-5-oxazolidinyl]methanol, 300 mL methylene dichloride and 46 g triethylamine mixture was added within 90 minutes. The reaction mixture was warmed to 45°C and stirred for 3 hours. Methylene dichloride was removed under vacuum below 50°C and the residue was cooled to room temperature. The residue were triturated with 500 mL of toluene and stirred for 1 hour and filtered. The wet-cake was washed with toluene and slurried in water for 1 hour. The solid was filtered and washed with water. The product dried at 60°C to 65°C to get 95 g (84%) of (R)-[N-[3-(3- fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]methane sulfonate.

Example-4: (R)-[N-f3-(3-fluoro-4-morpholinylphenyl>-2-oxo-5- oxazolidinyll methyil- Phthalimide

To the solution of 100 g (R)-| H3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]- methyl]methane sulfonate in 1L Ν,Ν-dimethylformamide, was added 74.3 g of potassium phthalimide and the reaction mixture was heated to 80°C for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was quenched in 2L water in another RBF and stirred for 1 hour. The precipitated product was filtered and washed with 200 mL water. The product was dried at 60°C to 65°C to get 100 g (87.7%) of (R) - [N- [3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]Phthalimide.

ExampIe-5: ; (SMN-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyllmethyll- acetamide (Linezolid)

Methanol (500 mL) and aqueous methylamine (500 mL of 40%) were added to a flask containing the 100 g phthalimido oxazolidinone of Example-4. The suspension was heated at 65°C for 3 hours and cooled to room temperature. 500 mL methylene dichloride and 500 mL water were added to the reaction mixture and stirred for 30 minutes. The separated aqueous layer was extracted with 1 L of methylene dichloride and allowed to settle. The combined organic layer was washed with brine solution and distilled to remove 2 times of methylene dichloride under vacuum below 50°C. The reaction mixture was cooled to 0°C and 72 g acetic anhydride was added to it. The reaction mixture was stirred at 25°C and treated with 10% sodium bicarbonate solution (280 mL, 28g). The separated organic layer was washed with water and allowed to settle for 30 minutes. The organic layer was treated with 5 g activated carbon and stirred for 30 minutes. The reaction mixture was filtered and methylene dichloride was completely removed under vacuum below 50°C. The residue (linezolid oil) was co- distilled with 100 mL toluene to obtain 83 g Linezolid as a residue. The residue was cooled to room temperature and 300 mL toluene was added to it. The reaction mixture was heated at 50°C to 55°C for 3 hours and cooled to room temperature. The solid was filtered and washed with 100 mL toluene to obtain 64.8 g wet-cake. The wet-cake was taken in another RBF and 1.5 L ethyl acetate was added. The reaction mixture was heated below 78°C and 5 g activated carbon was added to the clear solution. The reaction mixture was fine filtered and washed with 100 mL ethyl acetate. Approx. 700 mL ethyl acetate was distilled below 78°C and reaction mixture was cooled to room temperature. Finally, the reaction mixture was cooled to 18°C to 20°C and stirred for 1 hour. The product was filtered and washed with 100 mL ethyl acetate. The wet-cake was dried at 65°C to 70°C to obtain 60 g (69%) Linezolid.

ExampIe-6; Linezolid (crystalline Form-D

Linezolid (50 g) obtained in Example-5 and n-heptane (1 L) was heated at 105°C to 110°C for 4 hours in an autoclave. The pressure of autoclave was set to 3 Kg with nitrogen pressure and reaction mixture was continuously stirred. The reaction mixture was cooled to 25°C and nitrogen pressure was released. The product thus obtained was filtered and washed with 100 mL n-heptane. The wet-cake was dried in hot air oven at 65°C to 70°C to obtain 98 g (98%) linezolid crystalline form having purity by HPLC 99.9%. Linezolid crystalline form was characterized by X-ray powder diffraction as shown in FIG.1, IR spectrum as shown in FIG2 and DSC analysis as shown in FIG3. PSD: d0.9 = 41 μπι. The sample was charged for stability at 40°C/75% RH.

Impurity profile: Linezolid Amine (Not detected), Desflouro (0.04%), Linezolid Alcohol (Not detected), Linezolid Acetyl (Not detected). R-Isomer (Not detected) Form-II content: Not detected.

Example-7: Micronized linezolid (crystalline Form-I)

Linezolid (50 g) obtained in Example-6 with a particle size d0.9 = 41 μηι was jet- milled till the particle size reduced to d0.9 < 25 urn. The sample was charged for stability at 40°C/75%RH. The initial sample of crystalline Form-I of linezolid was having particle size d0.9 = 6 μιη. The purity of micronized crystalline Form-I of linezolid was 99.9% by HPLC. Linezolid crystalline Form-I was characterized by X- ray powder diffraction as shown in FIG 1, IR spectrum as shown in FIG.2 and DSC analysis as shown in FIG.3.

Reference Example-8: Linezolid (crystalline Form-ID as per U.S. Patent No. 6,559,305 Bl

Linezolid (Example-6) with more than 99.95% enantiomeric purity, less than 0.05% of the R enantiomer, (10 grams) was mixed with ethyl acetate (100 mL) and heated to 60°C to 65°C with constant stirring. The linezolid was completely dissolved and the mixture was stirred for an additional 30 minutes. The temperature was maintained at 55°C in the flask and one neck of the flask is un-stoppered to allow slow evaporation of the solvent. A gentle stream of nitrogen is blown across the open neck to aid in evaporation. Solids spontaneously precipitated from solution and the volume is reduced by about 25% of the initial volume. The flask is sealed and mixed for 90 minutes while maintaining the mixture at 55°C. The mixture was then cooled to about 23°C while being stirred. The solids were isolated by vacuum filtration using to give linezolid in crystal form. Analysis by powder X-ray diffraction indicates that the solids are linezolid crystal Form II. X-ray powder diffraction is as shown in FIG.4.

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.

Claims

We claim:

1. A stable crystalline Form-I of linezolid.

2. The stable crystalline Form-I of linezolid as claimed in claim 1, wherein the crystalline Form-I does not convert to Form-II or any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of up to about 75%.

3. The stable crystalline Form-I of linezolid as claimed in claim 1, wherein the crystalline Form-I does not convert to Form-II or any other solid form when stored up to about six months or more.

4. A stable crystalline Form-I of linezolid having a particle size d0.9 in the range of

30 πι Ιο 200 μηι.

5. A stable micronized crystalline Form-I of linezolid.

6. A stable micronized crystalline Form-I of linezolid having a particle size d0.9 less than 25 μπι.

7. The stable micronized linezolid crystalline Form-I as claimed in claim 6, wherein the particle size d0.9 is less than 15 μιη.

8. Crystalline Form-I of linezolid substantially free of crystalline Form-II of linezolid.

9. The crystalline Form-I of linezolid as claimed in claim 9, wherein the linezolid contains 1% or less of crystalline Form-II of linezolid.

10. The crystalline Form-I of linezolid as claimed in claim 9, wherein the linezolid contains 0.5% or less of crystalline Form-II of linezolid.

1 1. The crystalline Form-I of linezolid as claimed in claim 9, wherein the linezolid contains no detectable quantity of crystalline Form-II of linezolid.

12. The crystalline Form-I of linezolid according to any preceding claims characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.3, 13.4, 14.6, 17.9, 18.3, 19.8, 20.9, 22.1, 25.3, 27.6, 28.3 and 29.6 degrees.

13. An improved process for the preparation of crystalline Form-I of linezolid, the process comprising heating linezolid in one or more suitable solvents in a hydrogenator and obtaining the crystalline Form-I of linezolid.

14. The process as claimed in claim 13, wherein the suitable solvent comprises one or more of diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane, or mixtures thereof.

15. The process as claimed in claim 13, wherein the linezolid is heated at 105°C to about 110°C under 3 Kg pressure under nitrogen.

16. An improved process for the preparation of linezolid of Formula (I),

(I)

the process comprising:

a) acetylating linezolid amine of Formula (II) at below 5°C in one or more suitable solvents to obtain a solution of linezolid;

Formula (II)

b) removing the solvents to obtain a residue;

17. The process as claimed in claim 16, wherein the suitable solvent at step (a) comprises one or more of acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, toluene, xylene, methylene dichloride, chlorobenzene, or mixtures thereof.

18. The process as claimed in claim 16, wherein the acetylation is carried out with acetic anhydride.

19. The process as claimed in claim 16, wherein the suitable solvent at step :(c) comprises one or more of aromatic hydrocarbons like toluene, xylene, and ethylbenzene, halogenated hydrocarbons like methylene dichloride, chlorobenzene, and ethylene dichloride, esters like ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate, nitriles like acetonitrile, and propionitrile, and aprotic solvents like Ν,Ν-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.

20. The process as claimed in claim 16, wherein the suitable solvent at step (d) comprises one or more of diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane, or mixtures thereof.

21. An improved process for the preparation of crystalline Form-I of linezolid of Formula (I),

(I)

the process comprising:

c) obtaining a wet-cake from the reaction mixture and heating the wet-cake in one or more suitable C^-C^ alkyl ester solvents to obtain a solution; d) cooling the solution at about 50°C to obtain linezolid; and

22. The process as claimed in claim 21, wherein the halogenated hydrocarbon solvent comprises one or more of methylene dichloride, ethylene dichloride, chloroform, and chlorobenzene.

23. The process as claimed in claim 21, wherein the aromatic hydrocarbon solvent comprises one or more of toluene, o-xylene, m-xylene, p-xylene, . and ethylbenzene.

24. The process as claimed in claim 21, wherein the C -C alkyl ester solvent

1 4

comprises one or more of ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate.

25. The process as claimed in claim 21, wherein the suitable solvent at step (e) comprises one or more of diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, and cyclohexane.

26. The process as claimed in claim 21, wherein heating at step (b) and (c) is at a temperature from about 50°C to about 120°C.

27. A pharmaceutical composition comprising a therapeutically effective amount of a stable crystalline Form-I of linezolid together with one or more pharmaceutically acceptable carriers, excipients or diluents.

28. A pharmaceutical composition comprising a therapeutically effective amount of a stable crystalline Form-I of linezolid having a particle size d0.9 from 30 μηι to 200 μηι.

29. A stable pharmaceutical composition comprising a therapeutically effective amount of a stable micronized crystalline Form-I of linezolid having a particle size d0.9 less than about 25 μηι.

30. A stable crystalline Form-I of linezolid having a bulk density of about 0.40 g/mL and tapped density of about 0.60 g/mL.

31. A stable micronized crystalline Form-I of linezolid having a bulk density of about 0.28 g/mL and tapped density of about 0.40 g/mL.