DESC:FIELD OF THE INVENTION
The present invention relates to a novel process for crystallization of metaxalone.
BACKGROUND OF THE INVENTION
Metaxalone (I) is chemically known as 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone, it is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. It is marketed under the brand name Skelaxin® in the USA.

US patent 3,062,827 specifically claims metaxalone and also describes crystallization of metaxalone from ethylacetate.
US patent 3,446,814 discloses recrystallization of metaxalone from chlorobenzene.
The PCT application WO 2003/061552 describes purification of metaxalone using mixture of solvents selected from polar and non-polar solvent, the preferred solvent system being mixture of acetone and toluene.
US patent 6,562,980 describes preparation of pure metaxalone by crystallization from ethyl acetate.
The Indian patent application IN 71/MUM/2005 describes preparation of polymorphic Form I of metaxalone by using solvent-anti solvent procedure wherein the solvent is selected from methanol, ethanol, isopropanol and the anti-solvent is selected from hydrocarbon, petroleum ether and ethyl acetate.
US patent 7,750,165 describes process for preparation of polymorphic forms of metaxalone A and B which are prepared by crystallising metaxalone from organic solvents preferably ethyl acetate, acetonitrile or methyl ethyl ketone.
The Indian patent application IN 1748/CHE/2007 describes pharmaceutical compositions comprising metaxalone having particle size distribution D90 is in the range of 100 µm to 250 µm. It also describes pharmaceutical compositions comprising metaxalone having bulk density in the range of about 0.3-0.8 gm/ml and tapped density in the range of about 0.5-1.0 gm/ml.
The PCT application WO 2004/019937 describes micronised metaxalone having particle size distribution: D99 preferably <40 µm, D90 preferably <30 µm, D50 preferably <100 µm.
Another PCT application WO 2005/016310 describes metaxalone having average particle size of less than about 2 microns.
The PCT application WO 2010/121324 describes dry milling of metaxalone to provide particle size distribution of less than 2000 nm.
The PCT application WO 2009/019662 describes the particle size of micronized or nanonized metaxalone in the range of 1 nm to 50 µm.
OBJECTIVE OF THE INVENTION
An objective of the present invention is to provide a novel and industrially viable process for crystallization of metaxalone.
SUMMARY OF THE INVENTION
The present invention is directed to a novel process for crystallization of metaxalone from mixture of acetonitrile-water which involves two stages of cooling; first at 40-45 °C and second at 0-5°C.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment of the present invention provides a process for crystallization of metaxalone comprising the steps of:
a) heating metaxalone in mixture of acetonitrile-water,
b) cooling the mixture of step (a) to 40-45°C,
c) further cooling the mixture of step (b) to 0-5°C,
d) stirring the slurry of step (c) at 0-5°C and
e) isolation.
Crude metaxalone is dissolved in acetonitrile-water mixture by heating to 70-75°C for 10-20 minutes. The resulting mixture is slowly cooled to 40-45 °C in about half an hour to obtain slurry.
The slurry containing metaxalone in mixture of acetonitrile-water is cooled to temperature of 40-45 °C over a period of 30-40 minutes then stirred for 30-120 minutes, preferably 50-60 minutes. The slurry is further cooled to 0-5°C over a period of 50-70 minutes then stirred for 30-120 minutes, preferably 50-60 minutes.
To the slurry of metaxalone in acetonitrile-water mixture at 40-45 °C optionally seed crystals are added for effective crystallization. Activated carbon may be added to the solution of crude metaxalone which is then filtered and further subjected to two stage cooling as described above.
The quantity of acetonitrile to metaxalone is 1 to 10 times (volume/weight); preferably 2-6 times (weight/volume).
The quantity of water to metaxalone is 2 to 15 times (volume/weight); preferably 4-9 times (weight/volume).
The crude metaxalone may be prepared according to any of the processes known from the literature such as US 3,446,814, US 6,562,980 and WO 2003/061552.
The pure metaxalone may be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
The isolated metaxalone may be dried using different techniques of drying like tray drying and rotatory drying techniques with or without application of vacuum and/or under inert condition.
Metaxalone, obtained by the process of the present invention has bulk density in the range of 0.3 to 0.7 gm/ml and the tapped density in the range of 0.4 to 0.8 gm/ml.
Metaxalone obtained by the process of present invention has particle size distribution in the range of d10 is < 20 µm, d50 is <200 µm, and d90 is <500 µm.

Metaxalone bulk drug according to the present invention can advantageously be used for the preparation of pharmaceutical composition. The process for the preparation of pharmaceutical composition comprises mixing the metaxalone according to the present invention with pharmaceutically acceptable excipient. The excipients are selected from disintegrants, fillers, binders, surfactants and lubricants.
The pharmaceutical compositions are particularly suitable for oral administration especially in the form of a tablet or a capsule useful as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions.
The present invention is described in the following example, however it should be noted that the scope of the present invention is not limited by the examples.
EXPERIMENTAL DETAILS:
Bulk density and tapped density are measured according to the method given in United States Pharmacopeia 37, 2014, 616 "Bulk Density and Tapped Density of Powders"
Prarticle size is determined by Malvern mastersizer 2000, version 5.22.
Example-1:
Crude metaxalone (25 gm) was dissolved in acetonitrile (87.5 ml) at a temperature of 70 °C then activated carbon (1.25 gm) was added, stirred and filtered through celite then washed the bed with acetonitrile (12.5 ml). DM water (150 ml) was added to the filtrate while maintaining the temperature at about 55-60 °C followed by further heating to temperature of 70-75 °C and stirred. The reaction mixture was cooled to temperature of 45 °C in 30 minutes and stirred for 60 minutes at temperature of 40-45 °C. The reaction mass further cooled to temperature of 5 °C and stirred for 60 minutes. Solid was filtered, washed with acetonitrile-water mixture (8.3: 16.6 ml) and dried.
Bulk Density: 0.491 gm/ml
Tapped Density: 0.614 gm/ml
Example-2:
Crude metaxalone (25 gm) was dissolved in acetonitrile (87.5 ml) at a temperature of 70 °C then activated carbon (1.25 gm) was added, stirred and filtered through celite then washed the bed with acetonitrile (12.5 ml). DM water (125 ml) was added to the filtrate while maintaining the temperature at about 55-60 °C followed by further heating to temperature of 70-75 °C and stirred. The reaction mixture was cooled to temperature of 45 °C in 45 minutes then seed crystal (125 mg) was added and stirred for 60 minutes at temperature of 40-45 °C. The reaction mass further cooled to temperature of 5 °C and stirred for 60 minutes. Solid was filtered, washed with acetonitrile-water mixture (8.3: 16.6 ml) then the wet solid was leached with ethyl acetate (100 ml). Solid was filtered and dried.
Bulk Density: 0.494 gm/ml;
Tapped Density: 0.593 gm/ml.
,CLAIMS:1. A process for crystallization of metaxalone comprising;
a) heating metaxalone in mixture of acetonitrile-water,
b) cooling the mixture of step (a) to 40-45°C,
c) further cooling the mixture of step (b) to 0-5°C,
d) stirring the slurry of step (c) at 0-5°C and
e) isolation.
2. The process according to claim 1, wherein the quantity of acetonitrile to metaxalone is 2 to 10 times (weight/volume).
3. The process according to claim 2, wherein the quantity of acetonitrile to metaxalone is 3-5 times (weight/volume).
4. The process according to claim 1, wherein quantity of water to metaxalone is 2 to 15 times (weight/volume).
5. The process according to claim 4, wherein quantity of water to metaxalone is 3-8 times (weight/volume).
6. The process according to claim 1, further comprising optionally adding seed crystals in step (b).
7. The process according to claim 1, wherein the crystallized metaxalone has bulk density in the range of 0.3 to 0.7 gm/ml.
8. The process according to claim 1, wherein the crystallized metaxalone has tapped density in the range of 0.4 to 0.8 gm/ml.
9. The process according to claim 1, wherein the crystallized metaxalone has particle size distribution in the range of d10 is < 20 µm, d50 is <200 µm, and d90 is <500 µm.
10. A pharmaceutical composition comprising metaxalone according to preceding claims.