Claims:We Claim:
1) A process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm

(I)
wherein the process comprising the steps of:
a. providing a solution of Pirfenidone having particle size ? 250 µm in an organic solvent at temperature 25-70°C;
b. addition of solution formed in step a. to water at temperature ranging between 0°C to 25°C;
c. filtered and washed with water followed by drying to get the highly pure pirfenidone having particle size (d0.9) < 200 µm.

2) The process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, according to claim 1, wherein the ratio of organic solvent and water in the range of 1: 2 to 1:10.

3) The process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, according to claim 1, wherein the organic solvent used in step a. is water miscible organic solvent.

4) The process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, according to claim 1, wherein the organic solvent selected from alcohol solvents as methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate or dimethyl formamide or acetone or dichloromethane and mixtures thereof.

5) A process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, wherein to manufacture selectively the particle size in the range 100 - 200 µm, the process comprises the addition of pirfenidone solution prepared in organic solvent to water at temperature ranging between 15°C to 25°C.

6) A process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, wherein to manufacture selectively the particle size in the range 20 - 100 µm, the process comprises the addition of pirfenidone solution prepared in organic solvent to water at temperature ranging between 0°C to 15°C.

7) A highly pure Pirfenidone according to claim 1, having HPLC purity of atleast 99.8 % and particle size (d0.9) < 200 µm and XRPD pattern characterised by 2? peaks at 8.7, 14.3, 14.9, 18.4, 18.7, 19.8, 21.0, 22.1, 22.9, 24.3, 26.8, 27.2, 30.3 and 32.4 ± 0.5.

8) The process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, according to claim 5, wherein to manufacture selectively the particle size in the range 100 - 200 µm and having the HPLC purity of atleast 99.8 %, the process comprises the addition of pirfenidone solution prepared in methanol to water at temperature ranging between 15°C to 25°C.

9) The process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, according to claim 6, wherein to manufacture selectively the particle size in the range 20 - 100 µm and having the HPLC purity of atleast 99.8 %, the process comprises the addition of pirfenidone solution prepared in methanol to water at temperature ranging between 0°C to 15°C.

Dated this: 06th day of June 2017
, Description:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Pirfenidone having particle size (d0.9) < 200 µm.

BACKGROUND OF THE INVENTION
Pirfenidone is an oral dosage form for the treatment of idiopathic pulmonary fibrosis, approved by the FDA on October 15, 2014, which is sold under the brand name ESBRIET® and the molecular formula is C12H11NO with a molecular weight of 185.23. The structural formula of Pirfenidone is :

Formula I
Pirfenidone was first disclosed in US 2,947,755, however there is no process for Pirfenidone disclosed in this patent for the preparation of pirfenidone.

S.Gadekar et.al. in the patent US 3,839,346 discloses a process for the preparation of Pirfenidone, which involves the condensation of 5-methylpyridin-2(1H)-one with 1-iodo benzene using zinc precipitated copper powder, followed by crystallizing the crude Pirfenidone using hot water. The process is shown in the scheme given below:

Scheme I

Ramachandran et.al. in the patent US 8,519,140 B2 discloses a process for the preparation of Pirfenidone by condensing bromobenzene with 5-methyl-2-pyridone using cuprous oxide, in an organic solvent. The product obtained according to this process is milled to get particle size less than 150 µm. However, milling is a conventional process and not a process method.

Scheme II

It is very difficult to obtain Pirfenidone with particle size (d0.9) < 200 µm as this compound is having less minimum ignition energy (about 1.4 mJ) and hence it is hazardous to handle during physical operations involving dust generation. To manage physical operations of such compounds, necessary safety precautions have to be taken and static ignition sources have to be avoided. Hence, it is difficult task to perform physical operations such as milling, grinding, micronizing etc. In addition, physical operations to reduce particle size also result in material loss. As the melting point of Pirfenidone is also less (about 109°C), physical operations also lead to change in description of the product during continuous unit operations. Pirfenidone particles tend to fly easily when the particle size reaches to less than 200 microns and thus it is more difficult to bring the particle size to less than 100 microns through physical operations. Hence, there is a need to develop a process to obtain particle size of pirfenidone (d 0.9) < 200 µm. Inventors of the present invention have found that variation in the precipitating process will achieve the pirfenidone with particle size (d0.9) < 200 µm.

SUMMARY OF THE INVENTION
Particular aspects of the present invention relates to a process for the preparation of pirfenidone (I) having particle size < 200µm comprising the steps of:

Formula I
a. providing a solution of Pirfenidone in an organic solvent at temperature 25-70°C;
b. slow addition of solution formed in step a. to water at temperature ranging between 0°C to 25°C;
c. filtered and washed with water followed by drying to get the highly pure pirfenidone having particle size (d0.9) < 200 µm.

In another particular aspect of the present invention relates to a process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, wherein to manufacture selectively the particle size in the range 100 - 200 µm, the process comprises the addition of pirfenidone solution prepared in organic solvent to water at temperature ranging between 15°C to 25°C.

In another particular aspect of the present invention relates to process for preparing Pirfenidone (I) having particle size (d0.9) < 200 µm, wherein to manufacture selectively the particle size in the range 20 - 100 µm, the process comprises the addition of pirfenidone solution prepared in organic solvent to water at temperature ranging between 0°C to 15°C.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline
Pirfenidone (I).
Fig. 2 is an example of histogram of particle size distribution of Pirfenidone (I).

DETAILED DESCRIPTION OF THE INVENTION
As set forth herein, embodiments of the present invention provide an efficient process for the preparation of Pirfenidone (I) having particle size d(0.9) < 200 µm comprising the steps of:
a. providing a solution of Pirfenidone having particle size ? 250 µm in an organic solvent at temperature 25-70°C;
b. addition of solution formed in step a. to water at temperature ranging between 0°C to 25°C;
c. filtered and washed with water followed by drying to get the highly pure pirfenidone having particle size (d0.9) < 200 µm.

Individual steps of the embodiments are detailed herein below.

In the process step a. of providing a solution of according to the present invention, it comprises the source Pirfenidone that may be obtained according any of prior disclosure. In this step, Pirfenidone obtained is dissolved in an organic solvent at temperature 25-70°C wherein organic solvent selected from group consisting of alcohol solvents methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate or dimethyl formamide or acetone or dichloromethane and mixtures thereof.

According to one of the particular embodiment of the present invention, solution of pirfenidone as in step a. prepared at temperature 25-60°C.

In one of the embodiment according to present invention, organic solvent used in step a. is water miscible organic solvent.

In a particular embodiment of the present invention, methanol is used in step a. to obtain solution of pirfenidone at temperature 55-60°C.

In process step b. of the present invention relates to addition of solution formed in step a. to water at temperature 0°C to 25°C.

In one of the particular embodiment of the present invention, solution formed in step a. is added to water at a rate so as to form the pirfenidone as the precipitate at temperature 0°C to 25°C and the solution is added to pre-cooled water in time duration for not more than one hour.
In one of the particular embodiment of the present invention, pirfenidone solution prepared in an organic solvent is added to pre-cooled water at temperature 0°C to 15°C to get selectively the particle size in the range 20 - 100 µm.

In another particular embodiment of the present invention, pirfenidone solution prepared in an organic solvent is added to pre-cooled water at temperature 15°C to 20°C to get selectively the particle size in the range 100-200 µm.

In one of the particular embodiment, in process step b. volume of water plays a critical role as the volume of the solution formed in step a. to water is in the range of 1:2 to
1: 10.

In a one of the particular embodiment of the present invention, ratio of the solution to water is 1:5.

In one of the particular embodiment of the present invention, the solution formed in step a. to the pre-cooled water at temperature ranging 0°C to 25°C and the contents are stirred at agitator speed in a specified RPM (Revolutions per minute) of the stirrer / agitator to get the desired particle size. The specified RPM (Revolutions per minute) is in the range of 30 – 600 and such range variation is owing to plant reactors which often preferably utilize RPM up to 70 – 150 and in laboratory similar results are obtainable if RPM in the range 400 – 600.

In the process step c. of the present invention is filtering the precipitated compound formed in step b. and washed with water followed by drying the obtained compound at temperature 55-60°C.

In yet another embodiment according to present invention, according to step c. pirfenidone is separated by suitable techniques such as filtration, centrifugation and the like.

Accordingly, Pirfenidone having particle size (d0.9) ? 250 µm is dissolved in methanol at temperature 25-70°C. In another process water cooled to 0-25°C. Increase the rpm of agitator to about 600 rpm and add above prepared Pirfenidone solution within 15-30 minutes. Precipitated solid was filtered and washed with water and dried at 50-60°C to get pirfenidone with particle size distribution (d0.9) < 200 µm.

Accordingly, Pirfenidone having particle size (d0.9) ? 250 µm is dissolved in methanol at temperature 25-70°C. In another process water cooled to 0-15°C. Increase the rpm of agitator to about 600 rpm and add above prepared Pirfenidone solution within 15-30 minutes. Precipitated solid was filtered and washed with water and dried at 50-60°C to get pirfenidone with particle size distribution (d0.9) in the range of 20 - 100 µm.

Accordingly, Pirfenidone having particle size (d0.9) ? 250 µm is dissolved in methanol at temperature 25-70°C. In another process water cooled to 15-25°C. Increase the rpm of agitator to about 600 rpm and add above prepared Pirfenidone solution within 15-30 minutes. Precipitated solid was filtered and washed with water and dried at 50-60°C to get pirfenidone with particle size distribution (d0.9) in the range of 100 - 200 µm.

In one of the particular embodiment of the present invention provides a highly pure Pirfenidone having HPLC purity of atleast 99.8 % and particle size (d0.9) < 200 µm and XRPD pattern as Fig. 1.

In another embodiment of the present invention provides Crystalline Pirfenidone (I) characterized by X-ray powder diffraction pattern comprising diffraction angle peaks selected form 8.7, 14.3, 14.9, 18.4, 18.7, 19.8, 21.0, 22.1, 22.9, 24.3, 26.8, 27.2, 30.3 and 32.4 ± 0.5 2?°.

The present invention thus provides pirfenidone (I) with improved particle size control, and improved particle size distribution control, and in particular, a smaller particle size distribution span.

The term particle size d(0.9) as discussed herein are known to those skilled in the art. particle size d(0.9) refers to the maximum particle diameter below which 90% of the sample volume exists.
The invention was further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES
Example-1:
In clean and dry 250.0 mL RBF, Pirfenidone (having particle size d(0.9) = 459 µm) 25.0 g was dissolved in Methanol 37.5 mL at 25-35°C. In another 250.0 mL RBF charged water 112.5 mL and cooled to 0-5°C. Increase the rpm of agitator to 600 rpm and add above prepared Pirfenidone solution within 15-30 minutes. Precipitated solid was filtered and washed with 25.0 mL water and dried at 50-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 34.013 µm , >99.95% HPLC purity and 82.0% yield.

Example-2:
In clean and dry 100.0 mL RBF, Crude Pirfenidone (having particle size d(0.9) ? 250 µm) 10.0 g was dissolved in methanol 15.0 mL at 25-35°C and charcolized and washed with 5.0 mL methanol. In another 100.0 mL RBF charged water 45.0 mL and cooled to 0-5°C. Increase the rpm of agitator to 600 rpm and add above prepared Pirfenidone solution within 5-10 minutes. Precipitated solid was filtered and washed with 20.0 mL water and dried at 50-60°C to get pirfenidone (I) with particle size distribution (PSD) d0.9 = 44.382 µm with >99.95% HPLC purity and 68.8% yield.

Example-3:
5-Methylpyridin-2(1H)-one (100 g), potassium carbonate 127g and N,N-Dimethyl formamide(200 mL) was charged in clean and dry RBF. Heat the reaction mass to 70-80°C and maintain for 1 hour. Add Copper powder (4.7 g) at 70-80°C and maintain for another 1 hour for copper activation. Add Bromobenzene (173 g) at 70-80°C and heat the reaction mass to reflux (130-145°C) and maintain for 12 hours for reaction completion. After completion of reaction, mass was cooled to room temperature (25-35°C) and charge Dichloromethane (800 mL). The mixture was filtered and washed with dichloromethane (200 mL). The filtrate was washed with water (1000 mL) and the washed aq.layer was extracted with dichloromethane (200 mL). The combined organic layer was washed with 20% sodium hydro sulfite solution (200 mL) followed by water (200 mL). The organic layer was treated with activated carbon (10 g) and wash with dichloromethane (100 mL). The combined organic layer was distilled to get residual product to which water (500 mL) was charged and acidified with aq. HCl (100 mL) to get clear solution. The mass was treated with activated carbon (10 g) and passed through hyflo. The obtained filtrate was basified with 20% Sodium hydroxide solution to basic pH (10.5-11.5) at 10-15 °C to crystallize the product. Cyclohexane was charged to the mass and stirred for 2-3 hours at 10-15 °C. Finally, the product was separated by filtration and dried to get crude Pirfenidone (5-methyl-1-phenylpyridin-2(1H)-one) (PFD-1A) with 78% yield and >99.5% HPLC purity.
In clean and dry 100.0 mL RBF, above prepared crude Pirfenidone (having particle size d(0.9) = 446 µm) 10.0 g was dissolved in dichloromethane 40.0 mL, filtered the salts at 25-35°C and distill off the solvent. Add methanol 15.0 mL at 25-35°C and make a clear pirfenidone solution. In another 100.0 mL RBF charged water 45.0 mL and cooled to 0-5°C. Increase the rpm of agitator to 600 rpm and add above prepared Pirfenidone solution within 5-10 minutes. Precipitated solid was filtered and washed with 20.0 mL water and dried at 50-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 93.573 µm with 100% HPLC purity and 69.0% yield.

Example-4:
In clean and dry 100.0 mL RBF, Pirfenidone (having particle size d(0.9) = 450 µm) 10.0 g was dissolved in Methanol 20.0 mL at 50-55°C. In another 100.0 mL RBF charged water 55.0 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 15-30 minutes by keeping agitator speed as 600 rpm. Precipitated solid was filtered and washed with 10.0 mL water and dried at 50-60°C to get pirfenidone with particle size distribution (PSD) d(0.9) = 28.0 µm, > 99.95% HPLC purity and 75.0% yield.

Example-5:
In clean and dry 100.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 10.0 g was dissolved in Methanol 30.0 mL at 50-55°C. In another 250.0 mL RBF charged water 90.0 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 15-30 minutes. Precipitated solid was filtered and washed with 10.0 mL water and dried at 50-60°C to get pirfenidone with particle size distribution (PSD) d(0.9) = 40.673 µm, > 99.95% HPLC purity and 62.0% yield.

Example-6:
In clean and dry 100.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 10.0 g was dissolved in Methanol 25.0 mL at 55-60°C. In another 250.0 mL RBF charged water 75.0 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 15-30 minutes. Precipitated solid was filtered and washed with 20.0 mL water and dried at 50-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 21.17 µm with 100% HPLC purity and 65.0% yield.

Example-7:
In clean and dry 100.0 mL RBF, Pirfenidone(having particle size d(0.9) ? 250 µm) 10.0 g was dissolved in Methanol 10.0 mL at 55-60°C. In another 100.0 mL RBF charged water 40.0 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 15-45 minutes. Precipitated solid was filtered and washed with 20.0 mL water and dried at 50-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 28.079 µm with 100% HPLC purity and 72.0% yield.
Example-8:
In clean and dry 100.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 10.0 g was dissolved in Methanol 20.0 mL at 25-30°C. In another 100.0 mL RBF charged water 45.0 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 15-30 minutes to pre-cooled water at by keeping agitator speed as 400 rpm. Precipitated solid was filtered and washed with 20.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 94.606 µm, 100% HPLC purity and 75.0% yield.

Example-9:
In clean and dry 50.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 5.0 g was dissolved in Isopropanol 7.5 mL at 25-30°C. In another 50.0 mL RBF charged water 22.5 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 5-15 minutes to pre-cooled water at by keeping agitator speed as 600 rpm. Precipitated solid was filtered and washed with 10.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 42.796 µm, 100% HPLC purity and 72.0% yield.

Example-10:
In clean and dry 50.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 5.0 g was dissolved in Ethanol 7.5 mL at 50-60°C. In another 50.0 mL RBF charged water 22.5 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 5-15 minutes to pre-cooled water at by keeping agitator speed as 600 rpm. Precipitated solid was filtered and washed with 10.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 41.157 µm, 100% HPLC purity and 75.6% yield.

Example-11:
In clean and dry 50.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 5.0 g was dissolved in Acetone 7.5 mL at 50-55°C. In another 50.0 mL RBF charged water 22.5 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 5-15 minutes to pre-cooled water at by keeping agitator speed as 600 rpm. Precipitated solid was filtered and washed with 10.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 30.027 µm, 100% HPLC purity and 70.0% yield.

Example-12:
In clean and dry 50.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 5.0 g was dissolved in Ethyl acetate 7.5 mL at 25-30°C. In another 50.0 mL RBF charged water 22.5 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 5-15 minutes to pre-cooled water at by keeping agitator speed as 600 rpm. Precipitated solid was filtered and washed with 10.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 71.899 µm, 100% HPLC purity and 66.0% yield.

Example-13:
In clean and dry 50.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 5.0 g was dissolved in DMF 7.5 mL at 50-55°C. In another 50.0 mL RBF charged water 22.5 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 5-15 minutes to pre-cooled water at by keeping agitator speed as 600 rpm. Precipitated solid was filtered and washed with 10.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 25.269 µm, 100% HPLC purity and 46.0% yield.

Example-14:
In clean and dry 100.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 25.0 g was dissolved in Methanol 37.5 mL at 25-30°C. In another 250.0 mL RBF charged water 112.5.0 mL and cooled to 0-5°C. Add above prepared Pirfenidone solution within 15-30 minutes to pre-cooled water at by keeping agitator speed as 220 rpm. Precipitated solid was filtered and washed with 25.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 232.58 µm, and 80.0% yield.

Example-15:
In clean and dry 100.0 mL RBF, Pirfenidone (having particle size d(0.9) ? 250 µm) 25.0 g was dissolved in Methanol 37.5 mL at 25-30°C. In another 250.0 mL RBF charged water 112.5.0 mL and cooled to 15-20°C. Add above prepared Pirfenidone solution within 15-30 minutes to pre-cooled water at by keeping agitator speed as 600 rpm. Precipitated solid was filtered and washed with 25.0 mL water and dried at 55-60°C to get pirfenidone (I) with particle size distribution (PSD) d(0.9) = 128.99 µm, and 79.4% yield.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.