FIELD OF THE INVENTION
The present invention generally relates to processes for particle size reduction of pirfenidone by wet milling techniques.
BACKGROUND OF THE INVENTION
Pirfenidone is an anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis (1PF), It works by reducing lung fibrosis through down regulation of the production of growth factors and procollagens I and II. Pirfenidone was approved by USFDA as Oral/Capsule and Oral/Tablet for the treatment of idiopathic pulmonary fibrosis. Pirfenidone is chemically known as 5-methyl-l-phenyl-2-l(H)-pyridone and represented by the following structural formula (I):
Idiopathic pulmonary fibrosis (IPF) is a rare disease of unknown etiology that is characterized by progressive fibrosis of the interstitium of the lung, leading to decreasing iung volume and progressive pulmonary insufficiency.
The process for the preparation of pirfenidone was first disclosed in US3 839346 ("the '346 patent"). The disclosed process involves reaction of 5-methyl-2-(lH)-pyridone with iodo benzene in presence of anhydrous potassium carbonate and zinc precipitated copper powder to get pirfenidone. Further, this patent remains silent about particle size of obtained pirfenidone.
US patent No. 8519140 ("the '140 patent") disclosed an improved process for the preparation of pirfenidone and the obtained pirfenidone was milled through a loop mill in order to reduce the particle size to less than I50um.
PCT. Application WO2017/122139 ("the '139 application") disclosed preparation of pirfenidone with particle size of D90 50-100u.m by solvent and anti-solvent technique.


In pharmaceutical industry, particle characterization of powder materials has become one of the crucial aspects in drug product development and quality control of solid oral dosage forms. The particle size distribution (PSD) of the drug substance may have significant effects on final drug product performance (e.g., dissolution, bioavailability, content uniformity, stability, etc.). Furthermore, the PSDs of both drug substance and excipients can affect drug product manufacturability (e.g., flowability, blend uniformity, compactibility, etc.), which, ultimately, can impact safety, efficacy, and quality of the drug product. The PSDs of pharmaceutical powders have profound influence on almost every step of manufacturing processes for solid oral dosage forms, including pre-mixing/mixing, granulation, drying, milling, blending, coating, encapsulation, and compression. Therefore, the impact of particle sizes of pharmaceutical powders on drug product manufacturability and performance should be evaluated at different pharmaceutical development phases for each specific drug application.
The present inventors have found that by performing safety studies pirfenidone is a dust explosive, shock sensitive and having a very low minimum Ignition energy. Based on the studies, it was observed that pirfenidone is a St2H class (violent explosion nature) with sparks and fumes and having very low minimum ignition energy of 1.7mJ, which indicates the material can ignite even at low ignition energy.
Particle size reduction process disclosed under the '140 Patent involves loop mill technique. A loop mill grinds materials by using a high speed jet of compressed air or inert gas in dry state to impact particles into each other. Dry milling process used in the loop mill particle size reduction always generates energetic particles that generate thermal energy which generally leads to explosion or burnings.
Based on these studies, inventors have realized that known dry mill technique is not appropriate selection for a material that has aforementioned drawbacks, for instance pirfenidone to avoid explosion due to static charge dissipation (Hammer Milling and Jet Milling Fundamentals Gary Liu, P.E. June, 2017).
Hence there is a need in the art to develop an alternative particle size reduction technique, which is suitable for sensitive materials that having a nature of dust explosive, shock sensitive and low ignition energy. Therefore the present invention provides alternative milling techniques in order to overcome the afore mentioned drawbacks. More specifically, the present invention provides wet mill techniques like colloid mill, ultra-sonication and high speed homogenizer techniques to reduce the particle size distribution of pirfenidone to below about 500 urn.

The present invention provides wet milling techniques for particle size reduction, which [
are suitable for sensitive materials that are having properties like dust explosive, shock I
sensitive and low ignition energy. Specifically, the present invention provides a process for reduction of particle size of pirfenidone by wet mill techniques. More specifically the present invention provides a process for particle size reduction of pirfenidone to below about 500 urn by wet mill techniques, which process avoids the aforementioned drawbacks associated with the known dry milling techniques.
In accordance with one embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling in water.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling using a suitable apparatus selected from colloid mill, ultrasonicator or high speed homogenizer.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling using a suitable apparatus selected from colloid mill, ultrasonicator or high speed homogenizer in water.
In accordance .with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 jim, by wet milling.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 p.m, by wet milling using a suitable apparatus selected from colloid mill, ultrasonicator or high speed homogenizer.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 u,m, by wet milling using a suitable apparatus selected from colloid mill, ultrasonicator or high speed homogenizer in water.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500
um, by wet milling; comprising: mixing ,pirfejiidone-haying?a particle size distribution of
, ~ r = T r F rHFNNAI U'i^'^1' A"

above about 500 um in water for a sufficient period of time, and recovering the pirfenidone having a particle size distribution of below 500 urn.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling using a suitable apparatus; comprising: mixing pirfenidone having a particle size distribution of above about 500 um in water for a sufficient period of time, and recovering the pirfenidone having a particle size distribution of below 500 um; wherein the suitable apparatus is selected from colloid mill, ultrasonicator or high speed homogenizer.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling using colloid mill.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling using colloid mill in water.
In accordance with another embodiment, the present invention provides a process for. particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling using colloid mill.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling using colloid mill in water.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about-500 jim, by wet milling; comprising:
a) mixing pirfenidone having a particle size distribution of above about 500 urn with water,
b) circulating the step a) mixture in to colloidal mill, and
c) recovering the pirfenidone:
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling using ultrasonicator.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling using ultrasonicator in water.

In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 jim, by wet milling; comprising:
a) mixing pirfenidone having a particle size distribution of above about 500 urn with water,
b) sonicating the step a) mixture in a ultrasonicator, and
c) recovering the pirfenidone.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling using high speed homogenizer.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 jxm, by wet milling using high speed homogenizer in water.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling; comprising:
a) mixing pirfenidone having a particle size distribution of above about 500 um with water in a high speed homogenizer,
b) stirring the step a) mixture, and
c) recovering the pirfenidone.
In accordance with another embodiment, the-present invention provides a process for
particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling using a suitable apparatus; comprising: mixing pirfenidone having a particle size distribution of above about 500 um in water for a sufficient period of time, and recovering the pirfenidone having a particle size distribution of above about 10 um and below about 500 um; wherein the suitable apparatus is selected from colloid mill, ultrasonicator or high speed homogenizer.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling; comprising:
a) mixing pirfenidone having a particle size distribution of above 500 um with water,
b) circulating the step a) mixture in to colloidal mill, and
c) recovering the pirfenidone having a particle size distribution of above about 10 um and below about 500 um.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising pirfenidone prepared by the process of the invention and at least one pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides wet milling techniques for particle size reduction, which are suitable for sensitive materials that are having properties like dust explosive, shock sensitive and low ignition energy. Specifically, the present invention provides a process for particle size reduction of pirfenidone by wet mill techniques. More specifically the present invention provides a process for particle size reduction of pirfenidone to below about 500 um by wet mill techniques, which process avoids the aforementioned drawbacks associated with the known dry milling techniques.
The known milling processes involve dry milling of pirfenidone by loop mill method. The loop mill grinds materials by using a high speed jet of compressed air or inert gas in dry state to impact particles into each other. Dry milling process used in the loop mill particle size reduction always generates an energetic particle that generates thermal energy which generally leads to explosion or burnings. The present milling process involves milling, of pirfenidone in wet medium preferably in aqueous medium, wherein the thermal energy generated by the energetic particles is absorbed by the moisture on the particle surfaces and thereby preventing explosion or burning caused by localized hot spots. Thus, the process is safer than the dry milling processes, particularly in the commercial scale operations.
As used herein, the term "particle size distribution" is expressed in terms of D90, D50 and Dio, which corresponds to the diameter of 90 percent by volume of the particles, 50 percent by volume of the particles and 10 percent by volume of the particles are present, respectively.
As used herein, the term "recovering" refers to a process of obtaining pirfenidone by means of filtration, decantation, extraction, distillation, evaporation, centrifugation or a combination thereof.
As used herein, the term "mixing" refers to suspending pirfenidone in a medium.
As used herein, the term "about" refers to a variation of 10% from the indicated values, or in case of a range of values, means a 10% variation from both the lower and upper limits of such ranges.

As used herein, the starting material pirfenidone having a particle size distribution of above about 500 urn may be obtained from any processes known in the art; preferably the starting material used herein is obtained from reference examples 4 & 5.
In accordance with one embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling.
In another embodiment, the present invention provides a process for particle size reduction j
of pirfenidone by wet milling using a suitable apparatus selected from colloid mill, ultrasonicator or high speed homogenizer.
In another embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling in water using a suitable apparatus selected from colloid mill, ultrasonicator or high speed homogenizer.
In another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling using a suitable apparatus selected from colloid mill, ultrasonicator or high speed homogenizer.
Colloid mill:
In a specific embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling using colloid mill.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone by wet milling using colloid mill in water.
In accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling using colloid mill.
in accordance with another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling; comprising:
a) mixing pirfenidone having a particle size distribution of above about 500 urn witfi water,
b) circulating the step a) mixture in to colloidal mill, and
c) recovering the pirfenidone.

Colloid mill is a machine used in the process of milling of solid particles to reduce size of the particles or making homonization of the solid particles present in suspension or emulsion. Colloid mill instrument and method of milling for the use of pharmaceutical products is known from the art; for example Colloid mill instrument used in the present invention is having following identification: Colloid mill/TKA MK 2000/05 or any equivalent colloid mill instrument can be used as long as pirfenidone with required particle size is produced during the process of the invention.
The input pirfenidone may be any crystalline or other form of pirfenidone with any particle size preferably above about 500 u.m, including various solvates, hydrates, salts and co-crystals as long as pirfenidone with required particle size is produced during the process of the invention or pirfenidone obtaining as existing slurry from a previous processing step.
The aforementioned step a) process involves mixing pirfenidone having a particle size distribution of above about 500 (xm with water. Then the resultant step a) mixture is circulated in to colloid mill. The circulation temperature should be sufficient to form the required particle size. Typically the circulation temperature can be from about 5°C to about 65°C; preferably at about 25°C to about 50°C.
Reduction of particle size of the invention is dependent on the number of revolutions per minute (rpm) of the colloid mill and duration of circulation of the reaction suspension. The rpm and the circulation time are not particularly limited to specific values but an exemplary the same may be employed in the range of about 500 to about 10000 rpm for a period of about 5 minutes to about 30 hours; preferably about 1000 to about 8000 rpm for a period of about 30 minutes to about 24 hours.
After attaining the required particle size, preferably to below 500 um, the resultant product may be recovered by known methods, for example decantation, filtration and the like; preferably by filtration. Optionally before recovery of the product, the reaction mixture may be allowed to cool to about 0°C to about 15°C and stirred for about 30 min to 10 hours at same temperature. The resultant product may be dried using conventional methods known in the art at a temperature ranging from about 40°C to about 75°C for a period of 2 hours to 10 hours. Preferably drying is carried out at about 50°C to about 65°C for a period of 4 hours to 6 hours.
Pirfenidone particles obtained by the reduction process using colloid mill is having a particle distribution of about Dio less than 50 urn, preferably less 20 urn; D50 less than 100 um, preferably 50 um; D90 less than 200 um, preferably 100 urn.

In another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling
using ultrasonicator.
i
In another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 p, by wet milling using ultrasonicator in water.
In a preferred embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 urn, by wet milling; comprising:
a) mixing pirfenidone having a particle size distribution of above about 500 jim with water,
b) sonicating the step a) mixture in a ultrasonicator, and
c) recovering the pirfenidone.
Ultrasonication is an efficient means for the wet-milling and micro-grinding of particles. In particular for the manufacturing of superfine-size slurries, ultrasonication has many advantages, when compared with common size reduction equipment, such as: ball mills, bead mills, disc mills or jet mills.. Ultrasonication allows for the processing of high-concentration and high-viscosity slurries - therefore reducing the volume to be processed. . Ultra sonic waves do not allow agglomerates to form as observed during conventional
■ ■ crystallization process. Accordingly, sonication is a safe process that allows easy scale up--
based on constant power per unit volume.
The input pirfenidone may be any crystalline or other form of pirfenidone with any particle size preferably above about 500 um, including various solvates, hydrates, salts and cocrystals as long as pirfenidone with required particle size is produced during the process of the invention or pirfenidone obtaining as existing slurry from a previous processing step.
The step of mixing pirfenidone having a particle size distribution of above about 500 um with water is placed in an ultrasonicator and sonicating for a sufficient period of time. The ultrasonicator temperature should be sufficient to form the required particle size. Typically the sonication temperature can be from about 5°C to about 65°C for a period of about 30 min to about 10 hours. Preferably the sonication temperature is about 25°C to about 50°C for a period of about 1 hour to about 5 hours.

After attaining the required particle size, preferably to below 500 urn, the resultant product may be recovered by known methods, for example decantation, filtration and the like; preferably by filtration. Optionally before recovery of the product, the reaction mixture may be allowed to cool to about 0°C to about 15°C and stirred for about 30 min to 10 hours at same temperature. The resultant product may be dried using conventional methods known in the art at a temperature ranging from about 40°C to about 75°C for a period of 2 hours to 10 hours. Preferably drying is carried out at about 50°C to about 65°C for a period of 4 hours to 6 hours.
Pirfenidone particles obtained by the reduction process after ultrasonication is having a particle distribution of about Dio less than 50 urn, preferably less 30 um; D50 less than 150 urn, preferably 100 um; D90 less than 300um, preferably 250 um.
High speed homogenizer:
In another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling using high speed homogenizer.
In another embodiment, the present invention provides a process for particle size reduction of pirfenidone having a particle size distribution of above about 500 um, by wet milling using high speed homogenizer in water.
In a preferred embodiment, the present invention provides a process for particle size
. reduction of pirfenidone having a particle'size distribution of above about 500 um, bywet
milling; comprising:
a) mixing pirfenidone having a particle size distribution of above about 500 um with water in a high speed homogenizer,
b) stirring the step a) mixture, and
c) recovering the pirfenidone.
The input pirfenidone may be any crystalline or other form of pirfenidone with any particle size preferably above about 500 urn, including various solvates, hydrates, salts and cocrystals as long as pirfenidone with required particle size is produced during the process of the invention or pirfenidone obtaining as existing slurry from a previous processing step.
The step of mixing pirfenidone having a particle size distribution of above about 500 u.m with water is placed in high speed homogenizer and stir for a sufficient period of time. The high speed homogenizer temperature should be sufficient to form the required particle size.

Typically the stirring temperature can be from about 5°C to about 65°C for a period of about 30 min to about 10 hours. Preferably the stirring temperature is about 25°C to about 50°C for a period of about 1 hour to about 5 hours.
The stirring speed of the reaction mixture is not particularly limited but may be employed in the range of 500-10000 rounds per minute, preferably 1000-7000 rounds per minute.
After attaining the required particle size, preferably to below 500 um, the resultant product may be recovered by known methods, for example decantation, filtration and the like; preferably by filtration. Optionally before recovery of the product, the reaction mixture may be allowed to cool to about 0°C to about 15°C and stirred for about 30 min to 10 hours at same temperature. The resultant product may be dried using conventional methods known in the art at a temperature ranging from about 40°C to about 75°C for a period of 2 hours to 10 hours. Preferably drying is carried out at about 50°C to about 65°C for a period of 4 hours to 6 hours.
The resultant product may be further dried using conventional methods known in the art at a temperature ranging from about 40°C to about 75°C for a period of 2 hours to 10 hours. Preferably drying is carried out at about 50°C to about 65°C for a period of 4 hours to 6 hours.
Pirfenidone particles obtained by the reduction process after high speed homogenizer is having a particle distribution of about Dio less than 50 am, preferably less 30 urn; Dso less than 150 urn, preferably 100 urn; D90 less than 300um, preferably 250 urn.
In another embodiment, the present invention provides a pharmaceutical composition, comprising pirfenidone prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., solid, liquid, powder, injectable solution, etc.
The particle size distribution of pirfenidone is measured utilizing: Instrument model: Malvem; Mastersizer 3000; particle refraction index of sample: 1.700; Absorption: 0.01 and Analysis model: general purpose, normal sensitivity, non-spherical particles.
EXAMPLES
The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any wav.

Particle size reduction of pirfenidone using colloid mill (IKA MK 2000/05)
Pirfenidone (Particle size distribution: Dio: 1330 uxn; D50: 1950 urn and D90: 2840 y.m) and Water (3 vol) were charged into IKA colloid mill at 25°C to 35°C and circulated the reaction mass at 25°C to 35°C till required particle size was obtained. Particle size distribution of the sample with different time interval was monitored by collecting the sample from reaction mass. After achieving the required particle size, stirred the reaction mixture for 30-60 min at 25°C to 35°C. Further, the reaction mixture temperature was allowed to cool to 0°C to 5°C and stirred for 2-3 hrs at same temperature. Filter the solid and washed with the wet cake with chilled water (0.5 vol), dried the solid in an oven under vacuum at 60°C for 4-6 hours.
The following examples were performed using the above described process with different circulation time and different rpm and obtained results are tabulated as below:


I
i
EXAMPLE-2:
Particle size reduction of pirfenidone using high speed homogenizer (Silverson L5M-A Lab Mixer)
Water (300 mL) and Pirfenidone (lOOgr; Particle size distribution: Dio: 1330 urn; D50: 1950 urn and D90: 2840 urn) were charged into reaction vessel at 25°C to 35°C and was placed High speed homogenizer into the reaction mass till required particle size was obtained at 25°C to 35°C. Particle size distribution of the sample with different time interval was monitored by collecting the sample from reaction mass. After achieving the required particle size, stirred the reaction mixture for 30-60 min at 25°C to 35°C. Further, the reaction mixture temperature was allowed to cool to 0°C to 5°C and stirred for 2-3 hrs at same temperature. Filter the solid and washed with the wet cake with chilled water (100 mL), dried the solid in an oven under vacuum at 60°C for 4-6 hours.
The following examples were performed using the above described process with different
rpm and time; the obtained results are tabulated below:

Particle size reduction of pirfenidone using ultra sonication by sonoprocessor (RTUL 10SP-20-3000-SD)

Water (300 mL) and Pirfenidone (200gr; Particle size distribution: Dio: 1330 um; D50: 1950 urn and D90: 2840 um) were charged into reaction vessel at 25°C to 35°C and was placed Sonoprocessor into the reaction mass till required particle size was obtained at 25°C to 35°C. Particle size distribution of the sample with different time interval was monitored by collecting the sample from reaction mass. After achieving the required particle size, stirred the reaction mixture for 30-60 min at 25°C to 35°C. Further, the reaction mixture temperature was allowed to cool to 0°C to 5°C and stirred for 2-3 hrs at same temperature. Filter the solid and washed the wet cake with chilled water (100 mL), dried the solid in an oven under vacuum at 60°C for 4-6 hours.
The following examples were performed using the above described process with different sonication time; the obtained results are tabulated below:
1
Dust explosion test by Modified Hartmann Apparatus:
This test was performed based on procedures from VDI 2263, Part 1 (Section 2.1.1), "Dust fires and dust explosions; hazards, assessment, protective measures", using a Modified Hartmann Apparatus. Pirfenidone was dried at 50°C under vacuum, sieved through 63^ sieve. Weighed amount of product was charged into a modified hartmann tube of 1.2 liter volume. The product was converted into a dust cloud in glass cylindrical tube with compressed air and electrodes with continuous spark was used as ignition source to ignite the dust cloud. Based on dust fire or extent of opening of the hinged cover rating 0, 1 or 2 are assigned.



Shock sensitive test by Fall hammer test:
This test was performed by Lutoif/ESCIS method using swissi process safety GmbH falling hammer MP03. The hammer (weight 5 kg) was raised and fixed at a height of 80 cm. A Pirfenidone capsule was placed on the lower part of the stamp. The upper stamp was placed on the sample. The hammer was released by using release lever. Result: Detonation was observed (spart and/or smoke/fumes).
Reference Example 3:
Minimum Ignition Energy test by M1KE3:
This test was performed based on international test method VDI 2263 part 1.2.5 using MIKE3. Pirfenidone was dried at 50°C under vacuum, sieved through 63|i sieve. The product was converted into a dust cloud in glass cylindrical tube with compressed air. The spark for ignition was provided with moving electrodes assembly at different energy levels from 1 mJ to'1000 mJ. The energy just sufficient to ignite the dust under ignition^ was determined. This ignition energy was then successively halved with, variation of the dust concentration and the ignition delay time in a series of tests until no ignition takes place in at least 10 successive experiments. The minimum ignition energy MIE lies between the lowest energy value at which ignition occurred and at the energy value at which no ignition observed for 10 successive experiments. The recommendations for interpreting MIE results are based on energy levels available on MIKE 3 apparatus. According to usual practice, MIE can be ranked as follow:


Preparation of pirfenidone:
A mixture of 5-methyl-lH-pyridin-2-one (100 g), bromo benzene (259 g) and dimethylformamide (200 mL) were added in to a round bottom flask and stirred up to complete dissolution. Potassium carbonate (254 g) and copper (I).chloride (18.2 g) was added to the above reaction mass and then heated to 130-140°C. The reaction mass was stirred at 130-140°C for 10 hrs. After the reaction completion, the reaction mass was cooled to 25-35°C. Toluene (500 ml), aqueous sodium chloride (75 g of sodium chloride in 500 ml of water) was added to the reaction mass and stirred for 15-30 mins at 25-35°C. The reaction mass was filtered and the filtrate was allowed to settle. Organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Organic layers combined and was washed with aqueous sodium chloride, treated with carbon and filtered through hyflo. The solvent from the filtrate was distilled off completely under vacuum at below 60°C. Toluene (300 ml) was added to the obtained residue and stirred for 30 mins. The reaction mass was heated to 77-83°C and stirred for 45 mins. The reaction mass was , allow to cool to 25-35°C and stirred for 60 mins. The reaction mass was further allowed to ; cool to 0-6°C. The solid obtained was filtered, washed with toluene and dried under vacuum. DM water (500 ml) was added to the above obtained wet compound followed by ...
■•, 50% aqueous sodium hydroxide solution (10 g of sodium hydroxide in 20 ml of water) at
25-35°C. The reaction mass was heated to 75-85°C and stirred for 30-60 mins. The reaction mass was then gradually allowed to cool to 25-35°C and stirred for 60 mins. The reaction mass was further allowed to cool to 0-5°C and stirred for 3 hrs. The obtained solid was filtered, washed with water and dried to provide the title compound. Yield: 120 g.
Reference Example 5:
Purification of Pirfenidone
Dissolving crude Pirfenidone (50g) in ethyl acetate (100 mL) at 65-75°C and the reaction mass was treated with activated carbon (5g) and filtered through a short bed of Hyflo. The filtrate was partially concentrated, under reduced pressure while maintain temperature below 60°C. The mixture was gradually allowed to cool to 30±5°C and then stirred for another 30-60 min. The suspension was again allowed to cool to 0-5°C and maintained for another 2-3h, at the same temperature. The precipitated material was filtered and then dried
_ _ . _ J n . ft Q

at 60±5°C, for 6-8h, to afford Pirfenidone as white colored powder (HPLC purity 99.9%;
dimer content 0.03%). Yield: 45 g.
Particle size distribution: D10: 1330 um, D50: 1950 urn, D90: 2840 um
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.