WO2015068121A1 - Process for preparation of crystalline form i of linezolid and its compositions - Google Patents
Process for preparation of crystalline form i of linezolid and its compositions Download PDFInfo
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- WO2015068121A1 WO2015068121A1 PCT/IB2014/065837 IB2014065837W WO2015068121A1 WO 2015068121 A1 WO2015068121 A1 WO 2015068121A1 IB 2014065837 W IB2014065837 W IB 2014065837W WO 2015068121 A1 WO2015068121 A1 WO 2015068121A1
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- linezolid
- crystalline form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
Definitions
- the present invention provides a process for preparing crystalline form I of Linezolid, which comprises:
- a process for the preparation of Linezolid in the crystalline form I comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at an elevated temperature.
- step b) crystallizing from the solution of step a) at an elevated temperature; and c) recovering the solid of step b) at a temperature of above 40 °C to provide crystalline form I of Linezolid.
- step b) crystallizing from the solution of step a) at an elevated temperature; and c) recovering the solid of step b) at a temperature of about 40 °C to provide crystalline form I of Linezolid.
- step b) crystallizing from the solution of step a) at a temperature of above 80 °C; and c) recovering the solid of step b) at a temperature of about 80 to 100°C to provide crystalline form I of Linezolid.
- Linezolid used for providing a solution may be synthesized by a process described in the prior art, for example, US 5,688,792 or the process as described in the following scheme:
- the crystallization may be initiated by the cooling, stirring, partial distillation of the solvent, adding anti-solvent, seeding or combination thereof.
- the crystallization in the present invention is carried out at an elevated temperature, for example, above 40 ° and below 100 °C.
- the solution of the present invention is cooled to 85 °C to about 95 °C and maintained for a period of about 1 to 2 hours or more to enhance the crystallization of Linezolid solid at the same temperature.
- the solid of crystalline form I is recovered from the solution.
- the step of recovering the solid involves filtration by gravity or by suction, centrifugation, decantation, and the like at an elevated temperature of about 40 °C or about 75 °C.
- the solid may optionally be washed with suitable solvent such as water and then subjected for drying at elevated temperature, for example, 75 to 80 °C.
- the drying may be carried out in a vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like for any time period necessary to achieve desired quality of the product, for example, 5 hours or more.
- the resultant crystalline form I of Linezolid of the present invention is characterized by their X-ray powder diffraction ("XRPD") pattern by using Cu Ka radiation, having the wavelength 1.541 A using a Bruker X-ray Diffractometer D8.
- XRPD X-ray powder diffraction
- the crystalline form I of Linezolid is characterized by having X-ray diffraction pattern as shown in Fig. 1 comprising at least 4 characteristic peaks at diffraction angles 2-theta of 7.3, 9.3, 13.5, 14.7, 18.0, 18.4, 18.7, 19.8, 21.0, 22.1, 25.4, 27.6 and 29.6 ⁇ 0.2 degrees.
- the crystalline form I of Linezolid obtained from the present invention is substantially free of residual solvent that is the content of residual solvent is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines, for example, the content of DMF is less than about 500 ppm or less than about 100 ppm or less than 50 ppm.
- a tablet pharmaceutical composition comprising a filler or a diluent, which can be selected from several alternatives well known in the art.
- Suitable diluents or fillers include but are not restricted to lactose, sucrose, glucose, sorbitol, dextrates, dextrins, dextrose, fructose, mannitol, sorbitol, starch, carboxymethylcellulose calcium, microcrystalline cellulose (MCC), powdered cellulose, sodium chloride and mixtures thereof.
- MMC microcrystalline cellulose
- microcrystalline cellulose is the most preferred filler.
- a tablet pharmaceutical composition comprising a binder which can be selected from but not restricted to methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, polyvinylpyrrolidone (povidone), and polyvinylalcohol. Hydroxypropyl cellulose and polyvinylpyrrolidone is the most preferred binder.
- Example 1 Preparations of linezolid form-I.
- Example 3 Preparations of linezolid form-I from linezolid form-II.
- the layers were separated and the aqueous layer was stirred with dichloromethane (2x500ml).
- the total organic layer was collected and combined with water (500 ml) and subjected for pH adjustment of 1.5-2.0 with 15% aqueous HC1 solution (180-200.0ml) at 25-30°C.
- the resultant two layers were separated and then the aqueous layer was stirred with dichloromethane (2x300 ml).
- the aqueous layer was separated, treated with ceca carbon (10 gm) at 25-30 °C, filtered through hyflow bed and then washed the bed with water (200 ml).
- the filtrate was cooled to 20-25 C and then adjusted pH 6.5-6.8 by 25% aqueous NaOH solution (5-7 ml).
Abstract
The present invention relates to a process for the preparation of crystalline form I of linezolid, comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at elevated temperature. The present invention also relates to the use of crystalline form I of linezolid prepared by the method of the present invention for preparing pharmaceutical compositions.
Description
PROCESS FOR PREPARATION OF CRYSTALLINE FORM I OF LINEZOLID
AND ITS COMPOSITIONS
FIELD OF THE INVENTION The present invention relates to a process for the preparation of stable crystalline form I of Linezolid or hydrate, or solvate thereof. Further, the present invention relates to a pharmaceutical composition of linezolid comprising stable crystalline form I of Linezolid.
BACKGROUND OF THE INVENTION Linezolid, [(S)-N-[[3-(3-fluoro-4-mo holinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide] is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C16H20FN3O4 and the following structural formula (I).
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 marketed by Pfizer in US under brand name of Zyvox® Linezolid and its processes were disclosed in U.S. Patent No. 5,688,792, WO 95/07271, WO 99/24393, US 2011/0275805A1, WO 2012/019862A1, WO 2007/064818A1, J. Med. Chem. 1996, 39(3), 673-679, and Tetrahedron Lett. 40(26), 4855, 1999. The US 5,688,792 patent also discloses a process for isolation of Linezolid solid from ethyl acetate and the melting point of Linezolid as 181.5-182.5°C.
J. Med. Chem. 39(3), 673 (1996)) article discloses recrystallization process for Linezolid from ethyl acetate and hexane to provide white crystals, having mp 181.5-182.5 °C and IR (mineral oil mull, cm-1): "3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435".
US 6,559,305 discloses crystalline form II and its process. Further, the US '305 also stated that the originally produced crystal form was Form I and it differs from Form II in its IR spectrum, X-ray powder diffraction spectrum and melting point.
Various prior art references disclose solid state forms of Linezolid and process thereof, for example, US 7,714, 128 discloses form III; US 7,649,096 discloses process for crystalline Linezolid; EP 2593440 Al discloses anhydrous crystalline form II; US 2006/0111350 discloses crystalline Linezolid hydrate and amorphous; WO 2012/119653A1 discloses crystalline form A; WO 2013/120496 discloses process for stable form I; WO 2013/093751A1 discloses microcrystalline form of Linezolid; WO 2013/072923A1 discloses stable Form I; WO 2007/026369 discloses amorphous Linezolid; WO 2011/050826, WO 2011/050865 & WO 2011/051384 discloses a process for crystalline Linezolid.
WO 2011/077310 discloses a process for the preparation of crystalline form I of Linezolid which involves dissolution of Linezolid in n-propanol at reflux (95-100 °C), addition of charcoal, filtration of the solution thro hiflo bed, concentration of the filtrate partially and then cooled to 0-5 °C to afford Form I.
CN 102850290 discloses a process for the preparation of crystalline form I of Linezolid which involves dissolution of Linezolid in ester solvent or Toluene at 70-130 °C and cooled to room temperature to afford Form I. IN 5 /MUM/2011 discloses a process for the preparation of crystalline form I of Linezolid which involves dissolution of Linezolid in a solvent, and then cooled to room temperature to afford crystalline form I.
Still, there is a need to develop an alternative process for crystalline form I of Linezolid which improves stability of form I and suitable for the preparation of stable pharmaceutical composition of Linezolid.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing crystalline form I of linezolid and its composition. The present invention is providing simple, industrial scalable and cost- effective process, which affords good quality and yield.
In an aspect of the present invention, there is provided a process for the preparation of crystalline form I of Linezolid comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at an elevated temperature. The linezolid obtained by the process of the present invention is stable.
In preferred aspect of the present invention, there is provided a process for the preparation of crystalline form I of linezolid, which comprises:
a) providing a solution of Linezolid in a mixture of high boiling organic solvent and water at an elevated temperature;
b) crystallizing from the solution of step a) at an elevated temperature; and c) recovering the solid of step b) at a temperature of above 40 °C to provide crystalline form I of Linezolid.
In another preferred aspect of the present invention, there is provided a process for preparing crystalline form I of linezolid, which comprises:
a) providing a solution of Linezolid in a mixture of high boiling organic solvent and water at 95 to 200 °C;
b) crystallizing from the solution of step a) at an elevated temperature; and c) recovering the solid of step b) at a temperature of about 40 °C to provide crystalline form I of Linezolid.
In most preferred aspect, the present invention provides a process for preparing crystalline form I of Linezolid, which comprises:
a) providing a solution of Linezolid in a mixture of high boiling organic solvent and water at 95 to 200 °C;
b) crystallizing from the solution of step a) to a temperature of above 80 °C; and
c) recovering the solid of step b) at a temperature of above 80 °C to provide crystalline form I of Linezolid.
In another particular aspect, the present invention provides a process for preparing crystalline form I of Linezolid, which comprises:
a) providing a solution of Linezolid in a mixture of dimethyl formamide and water at 95 to 200 °C;
b) crystallizing from the solution of step a) at a temperature of above 80 °C; and c) recovering the solid of step b) at a temperature of about 80 to 100°C to provide crystalline form I of Linezolid.
The crystalline form I of Linezolid obtained from the process of the present invention is stable and suitable for the preparation of pharmaceutical composition. In another aspect of the present invention, there is provided a pharmaceutical composition comprising stable crystalline form I of linezolid and at least one or more pharmaceutical excipients, wherein the crystalline form I of linezolid is prepared by providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at an elevated temperature.
In another particular aspect of the present invention, there is provided a pharmaceutical tablet composition comprising stable crystalline form I of linezolid and at least one or more pharmaceutical excipients, wherein the crystalline form I of linezolid is prepared by providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at an elevated temperature.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an illustration of a XRPD spectrum of crystalline form I of Linezolid prepared according to the present invention.
Fig. 2 is an illustration of a XRPD spectrum of crystalline form I of Linezolid after 6 months of stability.
Fig. 3 is an illustration of DSC thermogram of crystalline form I of Linezolid prepared according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "stable" refers to and includes "crystalline Linezolid Form-I that 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 at least 6 months".
As used herein, unless stated otherwise, the term "Linezolid" refers to Linezolid or its pharmaceutically acceptable salts, or hydrates, or solvates thereof.
As used herein, unless stated otherwise, the term "elevated temperature" refers to a temperature of above 40 °C and below 200 °C.
As used herein, unless stated otherwise, the term "high boiling" refers to a solvent which has a boiling point greater than 40 °C or greater than 70 °C.
In an aspect of the present invention, there is provided a process for the preparation of Linezolid in the crystalline form I comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at an elevated temperature.
Providing solution of linezolid comprises dissolution of linezolid in a solvent or obtaining the solution of linezolid from the previous reaction step at an elevated temperature. Crystallizing refers to and includes crystallization using cooling, stirring, partially distilling the solvent, adding anti-solvent, seeding or a combination thereof at an elevated temperature.
Recovering refers to and includes recovering the solid from the suspension using conventional separation techniques, including filtration, at an elevated temperature of above 40 °C.
In a preferred aspect of the present invention, there is provided a process for the preparation of Linezolid in the crystalline form I, which comprises:
a) providing a solution of Linezolid in a mixture of high boiling organic solvent and water at an elevated temperature;
b) crystallizing from the solution of step a) at an elevated temperature; and c) recovering the solid of step b) at a temperature of above 40 °C to provide crystalline form I of Linezolid.
In another preferred aspect of the present invention, there is provided a process for preparing crystalline form I of Linezolid, which comprises:
a) providing a solution of Linezolid in a mixture of high boiling organic solvent and water at 95 to 200 °C;
b) crystallizing from the solution of step a) at an elevated temperature; and c) recovering the solid of step b) at a temperature of about 40 °C to provide crystalline form I of Linezolid.
In a most preferred aspect, the present invention provides a process for preparing crystalline form I of Linezolid, which comprises:
a) providing a solution of Linezolid in a mixture of high boiling organic solvent and water at 95 to 200 °C;
b) crystallizing from the solution of step a) to a temperature of above 80 °C; and c) recovering the solid of step b) at a temperature of above 80 °C to provide crystalline form I of Linezolid. In a particular aspect, the present invention provides a process for preparing crystalline form I of Linezolid, which comprises:
a) providing a solution of Linezolid in a mixture of dimethyl formamide and water at 95 to 200 °C;
b) crystallizing from the solution of step a) at a temperature of above 80 °C; and c) recovering the solid of step b) at a temperature of about 80 to 100°C to provide crystalline form I of Linezolid.
The step of the providing solution:
The solution of Linezolid may be obtained by the dissolution of Linezolid in a solvent or it may be taken from the previous reaction step. The solution of Linezolid is prepared at an elevated temperature. The elevated temperature is about 40 to about 200 °C or about 80 to about 130 °C. Any form of Linezolid, such as crystalline, amorphous, or mixtures of amorphous and crystalline forms of Linezolid in any proportions is acceptable for forming the solution.
The Linezolid used for providing a solution may be synthesized by a process described in the prior art, for example, US 5,688,792 or the process as described in the following scheme:
After completion of the acetylation reaction, the reaction mixture may be extracted into chlorinated solvent, for example, dichloromethane, to provide organic layer, which is then treated with carbon to obtain clear filtrate, which is finally concentrated to provide crude. The crude may be subjected further to isolate solid as per the prior art or it may be used for providing solution as per the present invention.
The solution of Linezolid of the present invention is provided in a solvent of water and/or an organic solvent. The organic solvent is selected from high boiling organic solvent such as N,N-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), Sulfolane, Cumene, Anisole, toluene, methylcyclohexane, ester, for example, isopropyl acetate and the like or
mixture thereof. In a preferred embodiment, the solution of the present invention is prepared in a mixture of water and high boiling organic solvent.
In most preferred embodiment, the solution of Linezolid comprises combining water to the Linezolid, heating the mixture to an elevated temperature, adding dimethylformamide to the mixture at an elevated temperature and stirring for a period of 10 minutes to 30 minutes or more.
The quantity of solvent used for the dissolution may range from 2 times to about 5 times or more of linezolid based on the solvent used. The concentration of Linezolid in the solution is not critical, but the quantity of solvent is kept to a minimum so as to avoid excessive product loss during the crystallization. The quantity of water in a mixture may be about 90%.
The step "crystallization" and "recovery" from the solution of Linezolid:
The crystallization may be initiated by the cooling, stirring, partial distillation of the solvent, adding anti-solvent, seeding or combination thereof. The crystallization in the present invention is carried out at an elevated temperature, for example, above 40 ° and below 100 °C.
The technique of cooling for crystallization may involve gradual cooling from the dissolution temperature to below 100 °C, for example, about 80 to 100 °C and stirred for a period of at least 1 hour. The technique of partial distillation may involve distillation under vacuum of about 100 mm Hg to about 700 mm Hg at an elevated temperature of above 40 °C. The distillation may be carried out to the extent where the precipitation of solid begins from the solution and stirred for a while, for example, at least 1 hour.
In a preferred embodiment, the solution of the present invention is cooled to 85 °C to about 95 °C and maintained for a period of about 1 to 2 hours or more to enhance the crystallization of Linezolid solid at the same temperature. The solid of crystalline form I is recovered from the solution.
The step of recovering the solid involves filtration by gravity or by suction, centrifugation, decantation, and the like at an elevated temperature of about 40 °C or about 75 °C. After separation, the solid may optionally be washed with suitable solvent such as water and then subjected for drying at elevated temperature, for example, 75 to 80 °C. The drying may be carried out in a vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like for any time period necessary to achieve desired quality of the product, for example, 5 hours or more.
The resultant crystalline form I of Linezolid of the present invention, unless stated otherwise, is characterized by their X-ray powder diffraction ("XRPD") pattern by using Cu Ka radiation, having the wavelength 1.541 A using a Bruker X-ray Diffractometer D8.
The crystalline form I of Linezolid is characterized by having X-ray diffraction pattern as shown in Fig. 1 comprising at least 4 characteristic peaks at diffraction angles 2-theta of 7.3, 9.3, 13.5, 14.7, 18.0, 18.4, 18.7, 19.8, 21.0, 22.1, 25.4, 27.6 and 29.6 ±0.2 degrees.
The crystalline form I of Linezolid obtained from the present invention has purity of greater than 99.5% or about 99.9%.
The crystalline form I of Linezolid obtained from the present invention is substantially free of residual solvent that is the content of residual solvent is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines, for example, the content of DMF is less than about 500 ppm or less than about 100 ppm or less than 50 ppm.
The Linezolid in crystalline form I of the present invention may be milled to get the desired particle size. The milling or micronization may be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.
The resultant Linezolid in crystalline form I obtained from the process of the present invention is stable and is well suited for pharmaceutical composition.
In an aspect of the present invention, there is provided a pharmaceutical composition comprising stable crystalline form I of linezolid and at least one or more pharmaceutical excipients, wherein the crystalline form I of linezolid is prepared by providing a solution in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at an elevated temperature.
The solution of linezolid in a solvent is provided at an elevated temperature of about 90 to about 200 °C, which is then subjected to crystallization using cooling, stirring, partially distilling the solvent or a combination thereof at an elevated temperature of about 80 °C to obtain suspension, which is then subjected for recovery of the solid from the suspension using separation techniques, for example, filtration, at an elevated temperature of above 40 °C, preferably at 80 to 90 °C to afford crystalline form I of Linezolid.
In another aspect of the present invention, there is provided a tablet pharmaceutical composition comprising stable crystalline form I of linezolid prepared by above process with at least one or more pharmaceutical excipients.
In an aspect of the present invention, there is provided a tablet pharmaceutical composition comprising a filler or a diluent, which can be selected from several alternatives well known in the art. Suitable diluents or fillers include but are not restricted to lactose, sucrose, glucose, sorbitol, dextrates, dextrins, dextrose, fructose, mannitol, sorbitol, starch, carboxymethylcellulose calcium, microcrystalline cellulose (MCC), powdered cellulose, sodium chloride and mixtures thereof. According to preferred embodiments microcrystalline cellulose is the most preferred filler.
In an aspect of the present invention, there is provided a tablet pharmaceutical composition comprising a binder which can be selected from but not restricted to methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, polyvinylpyrrolidone (povidone), and polyvinylalcohol. Hydroxypropyl cellulose and polyvinylpyrrolidone is the most preferred binder.
In an aspect, the present invention provides a tablet pharmaceutical composition comprising a disintegrant which can be selected from but not restricted to cross-linked
carboxymethylcellulose and its sodium salt, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium alginate Croscarmellose Sodium, Carboxymethyl cellulose, sodium starch glycolate or a combination of both. Croscarmellose Sodium is selected as the most preferred disintegrant.
In an aspect, the present invention provides a tablet pharmaceutical composition comprising a suitable glidant such as colloidal silicon dioxide (Aerosil-200). In an aspect, the present invention provides a tablet pharmaceutical composition comprising a lubricant which is selected from one or more of but not restricted to magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, and stearic acid. Magnesium stearate is selected as the most preferred lubricant. The present invention is further described by the following Example. These examples are for illustrative purpose and not to be construed to limit the scope of the invention.
Examples: Example 1: Preparations of linezolid form-I.
Linezolid (200 g) was dissolved in water (1 L) at 95-100°C and maintained for 30 minutes. Dimethyl formamide (24 ml) was added to the resulting solution at 95-100°C and stirred for 30 minutes. Slowly the reaction mass was cooled to 90°C and stirred for 5 hours. The solid material was filtered at 90°C and dried the material at 75-80°C under vacuum for 10-12 hours to obtain pure linezolid crystalline form-I.
Yield: 145 g
The sample was kept for stability at different conditions for a period of about 6 months as stated in the following Table:
2 25°C Matches with Matches with Matches with Matches
Form-I Form-I Form-I with Form-I
3 40°C Matches with Matches with Matches with Matches
Form-I Form-I Form-I with Form-I
Example 2: Preparations of linezolid form-I from mixture of linezolid form-I & II.
The mixture of linezolid form-I & II (10 g) was dissolved in methylcyclohexane (50 ml) heated to 100 °C and maintained for 4 hours at 100 °C. Drop wise diemthylformamide (2.5 ml) was added to the resulting solution and maintained at 100 °C for 1 hour. The solid material was filtered at 100 °C and dried at 75-80 °C under vacuum for 10-12 hours to obtain pure linezolid crystalline form-I.
Example 3: Preparations of linezolid form-I from linezolid form-II.
Linezolid form-II (10 g) was dissolved in the mixture of dimethylformamide (5 ml) and water (500 ml) at 120 °C, maintained for 15-30 minutes at 100-105°C. At atmospheric pressure, distilled out the solvents and removed the traces under vacuum for 15-30 minutes and further added water (50 ml) and maintained for 1 hour at 100 °C. The solid material was filtered at 100 °C and dried the compound at 75-80 °C under vacuum for 10- 12 hours to obtain pure linezolid crystalline form-I.
Example 4: Preparations of linezolid form-I from the reaction
To a solution of azide of formula II (100 gm), ethanol (800 ml) and water (200 ml), NH4CI (55.8gm) was added at 25-30 °C under stirring. Zinc powder (39.0 gm) was charged in one-lot to the reaction mixture, raised the temperature to reflux and stirred for 2 hours. The reaction mixture was cooled to 25-30 °C and 23% of aqueous ammonia (200ml) was charged. The reaction mixture was filtered through hyflow bed and washed the bed with water (100 ml) and dichloromethane (100 ml). Dichloromethane (900 ml) and water (300 ml) were charged to the filtrate and stirred for 10-15 minutes. The layers were separated and the aqueous layer was stirred with dichloromethane (2x500ml). The total organic layer was collected and combined with water (500 ml) and subjected for pH adjustment of 1.5-2.0 with 15% aqueous HC1 solution (180-200.0ml) at 25-30°C. The resultant two layers were separated and then the aqueous layer was stirred with dichloromethane (2x300 ml). The aqueous layer was separated, treated with ceca carbon (10 gm) at 25-30 °C, filtered through hyflow bed and then washed the bed with water (200 ml). The filtrate was
cooled to 20-25 C and then adjusted pH 6.5-6.8 by 25% aqueous NaOH solution (5-7 ml). Acetic anhydride (68.4gm) was added in single lot (pH drops to 2.0-3.0) at 20-25 °C followed by 25% aqueous NaOH solution (-180.0-190.0 ml) was added to adjust pH 6.2- 6.4 at 20-25 °C to the reaction solution and stirred for 1 hour. After the completion of the reaction, the reaction mixture was subjected for pH adjustment to 7.5-8.0 with 25% aqueous solution of sodium hydroxide at 25-30°C to extract the reaction mixture into dichloromethane. The organic layer was charcoalized, filtered through hyflow bed and washed with dichloromethane (200 ml). The filtrate was distilled out completely to obtain crude Linezolid at 30 °C under vacuum.
Water (350 ml) was added to the crude and raised the temperature to 95-100 °C. Dimethyl formamide (8.4 ml) was added drop wise to the reaction mixture at 98-100°C and maintained for 30 minutes at 100°C. The reaction mixture was cooled slowly up to 90°C and maintained for 5 hours at the same temperature. The resultant obtained solid was filtered and dried in oven at 75-80 °C for 10 hours to afford titled compound.
Dried weight: 50 gm.
XRPD pattern: Matches with the Fig. 1.
Purity by HPLC: 99.9%; Chiral purity: greater than 99.9% and R-isomer: not detected. Residual content: DMF (Below detection limit); ethanol (below detection limit); dichloromethane (below detection limit).
Loss on Drying (%w/w):0.36.
Example 5: Preparation of azide of formula II:
I. N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline
Ethyl acetate (400.0ml), 3,4-difluoronitrobenzene (lOO.Ogm) and morpholine (115.0gm) at 25-30 °C were charged into RBF, raised temperature to reflux (82-85 °C), stirred for 2 hours under reflux and then cooled to 25-30 °C. Ethyl acetate (600.0 ml) and aqueous HC1 solution 400ml (-6%) at 25-30 °C were charged to the reaction mixture and then layers were separated. To the organic layer, methanol (200.0 ml) and ammonium formate (156.24 gm) were charged at 25-30°C (N2 blanketing). 10% Pd/C (11.0 gm) was charged to the reaction mixture at 25-30°C (Temperature raise to 40-50°C due to exothermic
reaction) and Stirred at 45-50°C for 2hrs. The reaction mixture was cooled to 25-30°C, charged water (200.0 ml) and filtered over highflow bed to remove Pd/C and washed the highflow bed with water (200.0 ml). The separated organic layer was concentrated under vacuum at 35-40 °C to get thick slurry (NLT 650 mmHg). Acetone (200.0 ml) was charged to the reaction mass and concentrated at 35-40°C to get thick slurry (NLT 650 mmHg). Acetone (1700.0ml) water (900.0 ml) and sodium bicarbonate (103. Ogm) were charged at 25-30°C to the reaction mixture and then cooled to 0-5 °C. Benzyl chloroformate (115. Ogm) was added at 0-8°C within 5 mins and stirred at 0-5°C for lhour. Water (3000.0ml) was charged into reaction mass under agitation at 0-5°C, agitate for 30 mins at 20-25°C, filtered the solid and washed with water (2x600.0ml) followed by hexane (2x300.0ml). The solid was dried in air oven at 25-30°C for 30mins followed by at 45-50°C to obtain titled compound.
Dry Wight: 180-190 gm. //. preparation of (R)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl] methanol
N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline (100 g) and tetrahydrofuran (1100.0 ml) at 25-30 °C in RBF and cooled to -20°C to -30°C. n-BuLi (250.0ml) was added slowly for a period of 30-40 minutes to the reaction mixture at -20 °C to -30 °C and stirred for 35- 40 minutes. A solution of R-glycidyl butyrate (46. Ogm) in THF (50.0ml) was added to reaction mass at -20 °C to -30 °C within 20 to 30 minutes and maintained for 1 hour at -20 °C to -30 °C. The temperature of the reaction mass was slowly raised to 45-50°C within 40-60 minutes, maintained for 2 hours at 45-50 °C and then cooled to 25-30°C. The reaction mass was quenched with aqueous NH4C1 solution (5%) (400.0ml) at 25-30°C and then toluene (400.0 ml) was charged at 25-30°C. Two layers were separated and the obtained organic layer was concentrated under vacuum at 40-45°C to get thick slurry. Toluene (300ml) was added to the residue at 25-30°C, stirred for 30 minutes at 25-30°C, cooled to 5-10°C and stirred for lhour. The suspension was filtered, washed the solid with toluene (2x100.0 ml) and dried in air oven for 30 mins at 25-30°C followed by at 40-45°C to obtain titled compound.
Dry weight: 78gm
III. Preparation of (R)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyljmethansulfonate:
Dichloromethane (1800.0ml), f )-N-[[3-(3-fluoro-4-moφholinyl)phenyl]-2-oxo-5- oxazolidinyljmethanol (100. Ogm), triethyl amine (68.45gm) were charged into RBF at 25- 30°C and cooled to 0-5°C. A solution of methane sulphonyl chloride (53.78gm) and in MDC (200.0ml) was added slowly for a period of 25-30 minutes to the reaction mass at 0- 5°C and stirred for 2 hours. After reaction completion, the reaction mass was concentrated to thick slurry under vacuum at 35-40°C and then chased with water (200.0 ml) at 35-40°C to remove traces of dichloromethane. Water (800.0ml) was charged to the reaction mass at 35-40°C, cooled to 25-30°C and stirred for 30 minutes. The suspension was filtered, washed the solid with water (2x250.0ml) followed by with methanol (100.0ml) and suck dried. The wet solid was stirred in methanol (200.0 ml) for 30 minutes at 25-30°C, filtered the solid and washed with methanol (2x100.0ml) and then suck dried. The obtained solid was dried in an air oven at 25-30°C for 30 minutes followed by at 45-50°C to afford titled compound.
Dry weight : 112-122gm IV. Preparation of (R)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl] methyl] azide (Azide of Formula II):
Dimethyl formamide (1000.0ml), (R)-N-[[3-(3-fluoro-4-moφholinyl)phenyl]-2-oxo-5- oxazolidinyl]methansulfonate (100. Ogm) and sodium azide (69.5 lgm) were charged at 25- 30 °C in RBF and raised temperature to 80-85°C. The reaction mass was maintained at 80- 85°C for 2 hours. After completion of the reaction, water (1000.0ml) was added at 80- 85°C to reaction mass for a period of 10 mins and then seeded the reaction mass with the azide of Formula II (0.1 gm) at 70-75°C. Water (700.0 ml) was added to the reaction mass slowly at 70-75°C for a period of 10-15 mins and stirred for 15 minutes. Water (1500.0 ml) was added slowly at 60-65°C for a period of 25-30 minutes, cooled slowly to 5-10°C within 60-90 minutes and stirred for 1 hour. The suspension was filtered, washed the solid with water (2x250.0 ml), dried the solid at 45-50°C under vacuum (NLT 650 mmHg) to afford titled compound.
Dry weight : 76.0-82.0 gm
Example 6: Preparation ofLinezolid Tablet using crystalline form I of linezolid
The composition of above was prepared by dry granulation followed by compression.
Claims
A process for the preparation of stable crystalline form I of Linezolid comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at elevated temperature.
The process of claim 1, wherein the providing solution comprises dissolution of linezolid in a solvent at an elevated temperature.
The process of claim 1, wherein the solvent is selected from water, high boiling organic solvent or a mixture thereof.
The process of claim 3, wherein the organic solvent is selected from a group comprising Ν,Ν-dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), Sulfolane, Cumene, Anisole, toluene, methylcyclohexane, esters, and a mixture thereof.
The process of claim 1, wherein the crystallization comprises cooling, stirring, partial distillation or a combination thereof at an elevated temperature.
The process of claim 1, wherein the recovery comprises isolation of solid from the suspension using separation techniques at an elevated temperature.
The process of claim 1, wherein the elevated temperature is selected from the temperature of above 40 °C or above 70 °C.
A process for preparing crystalline form I of Linezolid, which comprises: a) providing a solution of Linezolid in a mixture of dimethyl formamide and water at 95 to 200 °C;
b) crystallizing from the solution of step a) at a temperature of above 80 °C; and
c) recovering the solid of step b) at a temperature of about 80 to 100 °C to provide crystalline form I of Linezolid.
9. The process of claim 8, wherein the solution is prepared by the dissolution of linezolid crude or solid in a mixture of dimethyl formamide and water.
10. The process of claim 8, wherein the ratio of water in a mixture is about 90%.
11. The process of claim 8, wherein the crystallization comprises cooling to about 80 to 100 °C from the dissolution temperature and stirring at the same temperature.
12. The process of claim 8, wherein the recovery of solid comprises filtration at about 80 to 100 °C.
13. A stable pharmaceutical composition comprising crystalline form I of linezolid as an active ingredient and at least one pharmaceutical excipient, wherein the crystalline form I is prepared by providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at elevated temperature.
14. A stable pharmaceutical tablet composition prepared by slugging comprising linezolid crystalline form I as an active ingredient prepared as process of claim 1.
15. The pharmaceutical composition of claim 13 is in the form of tablet, capsule or dry syrup for suspension or as liquid suspensions.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566242A (en) * | 2016-01-12 | 2016-05-11 | 江苏豪森药业集团有限公司 | Preparing method for linezolid and intermediate thereof |
| CN110483431A (en) * | 2019-09-04 | 2019-11-22 | 桂林南药股份有限公司 | Linezolid impurity compound, preparation method and its application |
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| CN110483431A (en) * | 2019-09-04 | 2019-11-22 | 桂林南药股份有限公司 | Linezolid impurity compound, preparation method and its application |
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