DESC:FIELD OF THE INVENTION
The present invention relates to process for the preparation of crystalline form I and form III of Selexipag of compound of formula I. The present invention further relates to pharmaceutical compositions containing them, and method of treatment using the same.

Formula-I
BACKGROUND OF THE INVENTION
Selexipag, previously also known as NS-304 or ACT-293987, is a potent orally available and highly selective long acting non-prostanoid prostaglandin 12 (PGI-2) receptor agonist, and has been filed for approval in the E.U. and in the U.S. by Actelion for the treatment of pulmonary arterial hypertension. As a prodrug it is in vivo transformed by the liver to its active metabolite.

Selexipag and its synthesis are described in WO 2002/088084. In example 84 Selexipag is isolated after chromatographic purification.

WO 2010/150865 (IN2011CN09790A) discloses three crystalline Forms of Selexipag, designated Form I, Form II and form III. It is described that these forms were obtained either in pure form or as binary mixtures from a polymorph screening using 32 different solvents and 16 different solvent mixtures (see test example 4). The crystalline forms of WO 2010/150865 are described as useful for the preparation of pharmaceutical formulations and oral dosage forms, such as tablets comprising crystalline Selexipag, are described. It should be noted that amorphous Selexipag was only described in one single experiment using 1,3,5-trimethylbenzene as solvent (table 4, experiment 30) in WO 2010/150865.

WO 2016193994 (IN 2086/MUM/2015), WO 2017029594 (IN 4305/CHE/2015) and WO 2017109772 all of these applications disclose amorphous form of Selexipag and its preparation.

Another WO 2017040872 discloses two crystalline forms of Selexipag, designated as form IV and form V.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Selexipag, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g. measured by thermo gravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state ( C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Prior art processes for preparation of Form I and Form III of Selexipag do not possess desired repeatability and reproducibility of desired polymorphic purity. Hence there is a need to develop new robust process for preparation of Form I and Form III of Selexipag which produces desired polymorphic purity and can be used for commercial purposes.

Present inventors have identified novel process for the preparation of form I and form III of Selexipag. The process as disclosed herein is highly reproducible and is suitable for scale up production.
SUMMARY OF THE INVENTION
In one aspect, the present application provides a process for the preparation of crystalline Selexipag Form I, comprising:

(a) contacting Selexipag with suitable solvent(s);
(b) optionally heating the reaction mixture obtained in step (a);and
(c) isolating crystalline form I of Selexipag.

In another aspect, the present application provides a process for the preparation of crystalline Selexipag Form III, comprising:
(a) contacting Selexipag with suitable solvent(s);
(b) optionally heating the reaction mixture obtain in step (a); and
(c) isolating crystalline form III of Selexipag.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of crystalline form I of Selexipag
Figure 2 is an illustration of a PXRD pattern of crystalline form III of Selexipag
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

In one embodiment, the present application provides a process for the preparation of crystalline Selexipag Form I, comprising:
(a) contacting Selexipag with suitable solvent(s);
(b) optionally heating the reaction mixture obtained in step (a);and
(c) isolating crystalline form I of Selexipag.

The solvent used in step (a) is disclosed herein with the example.

In another aspect, the present application provides a process for the preparation of crystalline Selexipag Form III, comprising:
(a) contacting Selexipag with suitable solvent(s);
(b) optionally heating the reaction mixture obtain in step (a); and
(c) isolating crystalline form III of Selexipag.

The solvent used in step (a) is disclosed herein with the example.

The crystalline form I and form III of Selexipag obtained by the process disclosed in the present invention is substantially pure and stable.

As used herein, the term “substantially pure” with reference to a particular polymorphic form means that the polymorphic form includes less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% by weight of any other physical forms of the compound.

In yet another embodiment, the present invention provides tryptamine salt of Selexipag and process for preparing thereof.

In further embodiment, the present invention provides process for the preparation of tryptamine salt of Selexipag comprising steps of:
(a) providing reaction mixture of Selexipag in solvent(s);
(b) adding base tryptamine to reaction mixture; and
(c) isolating tryptamine salt of Selexipag.

The solvent(s) used in step (a) is disclosed herein with the example.

The reaction mixture may optionally involve heating or cooling or both within the temperature range of about 0oC to 200oC. Heating of reaction mixture is carried out between 50oC to 200oC. Cooling of reaction mixture is carried out between 0oC to 30oC.

Wherever applicable in the example of the present invention, the reaction mixture may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The present invention adopts following general method for the isolation such as methods including cooling, crash cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization or evaporation or the like or combinations thereof. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

Optionally, isolation may be effected by combining a suitable anti-solvent with the solution. Anti-solvent as used herein refers to a liquid in which Selexipag is less soluble or poorly soluble. An anti-solvent has no adverse effect on the quality of Selexipag and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: water, saturated or unsaturated, linear or branched, cyclic or acyclic, C1-C10 hydrocarbons, such as hexanes, heptane, cyclo hexane, or methyl cyclo hexane, ethers, such as diethyl ether, diisopropyl ether, or mixtures thereof.

The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

In one aspect, the present invention provides form I and form III of Selexipag having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.
In another embodiment, the present invention provides pharmaceutical compositions comprising crystalline form I and from III of Selexipag.

The starting material “Selexipag” used for is prepared by techniques conventional method reported in the prior art, the isolated product or the product /residue from the reaction mixture is used to prepare the crystalline form(s) of the present invention.

To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter, thermogram, thermal gravimetric analyzers thermogram, melting point information, polarized light microscopy, hot stage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few are used.
EXAMPLES
The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.
X-Ray powder diffractograms were measured on a PANalytical X'Pert PRO X-Ray Diffractometer using CuKa1 radiation. The samples were measured in reflection mode in the 2?-range 2.5-40° using an X' celerator detector.

Example-1: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 2 volume of n-butanol. The reaction mixture was heated at about 1100C-1200C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.30 g).
Example-2: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 5 volume of toluene and 1 volume of water. Water was removed by azeotropic distillation with toluene at 1100C-1200C. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.20 g).
Example-3: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 5 volume acetone. Propylene glycol (1 eq.) was charged. The reaction mixture was heated at about 500C-600C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form I of Selexipag (0.85 g). (The same reaction can also be repeated without addition of propylene glycol).
Example-4: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 5 volume acetone. Urea (1 eq.) was added and the reaction mixture was cooled to ambient temperature. The solid was filtered and dried to obtain crystalline form I of Selexipag (0.91 g). (The same reaction can also be repeated without addition of urea)
Example-5: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 1 volume methyl isobutyl ketone. The reaction mixture was heated at about 1100C-1200C to obtain clear solution and maintained for 5 hours. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.80 g).
Example-6: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 4 volume acetic acid. The reaction mixture was heated at about 800C-900C to obtain clear solution. Water (10 volume) was added and the reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.00 g).
Example-7: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 2 volume of isopropyl acetate and 4.5 volume of methanol. The reaction mixture was heated at about 600C-700C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.40 g).
Example-8: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 5 volume of chlorobenzene. The reaction mixture was stirred for 5 hrs at ambient temperature. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.10 g).
Example-9: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 7 volume of dimethoxyethane. The reaction mixture was stirred for 24 hrs at ambient temperature. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.40 g).
Example-10: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 5 volume of cyclo pentyl methyl ether. The reaction mixture was heated at about 900C-1000C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 12 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.60 g).
Example-11: Preparation of crystalline Form I of Selexipag
Selexipag (1.0 g) was charged in 5 volume of methanol. Phosphoric acid (1 eq.) was added and the reaction mixture was stirred for 24 hrs at ambient temperature. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.60 g).
Example-12: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 3 volume of acetonitrile and water (9:1). The reaction mixture was heated at about 1000C-1100C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.20 g).
Example-13: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 4 volume of dimethyl formamide and water (1:1). The reaction mixture was heated at about 900C-1000C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.50 g).
Example-14: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 2 volume of propylene glycol. The reaction mixture was heated at about 900C-1000C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 20 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (0.80 g).
Example-15: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 4 volume of acetonitrile. The reaction mixture was heated at about 75-850C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred overnight. Cyclohexane (2 volume) was added. The solid was filtered and dried to obtain crystalline form III of Selexipag (0.8 g).

Example-16: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of toluene. The reaction mixture was heated at about 95-1050C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for two days. The solid was filtered and washed with cyclohexane and dried to obtain crystalline form III of Selexipag (1.45 g).Filter the solid.
Example-17: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of acetonitrile. The reaction mixture was heated at about 75-850C to obtain clear solution. Propylene glycol (1 eq.) was added and the reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (0.9 g).
Example-18: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of acetonitrile. The reaction mixture was heated at about 75-850C to obtain clear solution. Anisole (1 eq.) was added and the reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (0.6 g).
Example-19: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of methyl ethyl ketone. The reaction mixture was heated at about 75-850C to obtain clear solution. Benzyl alcohol (1 eq.) was added and the reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (0.9 g).
Example-20: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of methyl ethyl ketone. The reaction mixture was heated at about 75-850C to obtain clear solution. Anisole (1 eq.) was added and the reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (0.4 g).
Example-21: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 14 volume of isopropyl alcohol. The reaction mixture was heated at about 75-850C to obtain clear solution. Cyclohexane (14 volume) was added and the reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.80 g).
Example-22: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 3 volume of methyl isobutyl ketone. The reaction mixture was heated at about 110-1200C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.10 g).
Example-23: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 3 volume of cyclo pentyl methyl ketone. The reaction mixture was heated at about 110-1200C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.10 g).
Example-24: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of acetone. The reaction mixture was heated at about 50-600C to obtain clear solution. Benzyl alcohol (1 eq.) was added and the reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (0.98 g).
Example-25: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 3 volume of acetone. Urea (1 eq.) was added and the reaction mixture was stirred for two days at ambient temperature. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.85 g). (The same reaction can also be repeated without addition of Urea)

Example-26: Preparation of crystalline Form III of Selexipag
Selexipag (3.0 g) was charged in 3 volume of toluene. The reaction mixture was heated at about 75-850C to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (2.0 g).
Example-27: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 2 volume of o-dichloro benzene. The reaction mixture was heated at about 130-1400C to obtain clear solution and maintain the reaction mixture for 5 hours. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.60 g).
Example-28: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of isopropyl acetate. Pyridine (1 eq.) was added and the reaction mixture was heated at to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.80 g). (The same reaction can also be repeated without addition of Pyridine).
Example-29: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 4 volume of ethyl acetate. Tetra methyl urea (1 eq.) was added and the reaction mixture was heated at about 75-850C to obtain clear solution. Glycine (1 eq.) was added and the reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.60 g). (The same reaction can also be repeated without addition of Tetra methyl urea).
Example-30: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 2 volume of anisole. The reaction mixture was heated to reflux at 1500-1600C for 5 hrs. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.80 g).
Example-31: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 3 volume of anisole. Succinic acid (0.7 eq.) was added and the reaction mixture was heated to reflux at 1500-160 0C for 7 hrs. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.30 g). (The same reaction can also be repeated without addition of Succinic acid).
Example-32: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 3 volume of t-butyl benzene. Succinic acid (0.7 eq.) was added and the reaction mixture was heated to reflux for 7 hrs. The reaction mixture was cooled to ambient temperature and stirred overnight. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.0 g). (The same reaction can also be repeated without addition of Succinic acid).
Example-33: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of acetone. DM water (10 volume) was added and the reaction mixture and stirred for two hours. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.80 g).
Example-34: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of acetone. N-heptane (15 volume) was added and the reaction mixture and stirred for two hours. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.75 g).
Example-35: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of diethyl carbonate and the reaction mixture was heated to obtain clear solution. The reaction mixture was cooled to ambient temperature and stirred for 2 hrs. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.70 g).

Example-36: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 5 volume of 2-butanone at heated at 50 to 55 C. reaction mixture was cooled to 10-15 0C and stirred for 15 minutes. Tert-butyl methyl ether (15 volume) was added at 10-15 0C and the reaction mixture was stirred for two hours. The obtained solid was filtered and dried to obtain crystalline form III of Selexipag (1.65 g).
Example-37: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 3 volume of chloroform at 25-30 0C and h. Xylene (10 volume) was added and the reaction mixture and stirred for two hours. The obtained solid was filtered and dried to obtain crystalline form III of Selexipag (1.71 g).
Example-38: Preparation of crystalline Form III of Selexipag
Selexipag (2.0 g) was charged in 3 volume of 1,2-dimethoxy ethane. The reaction mixture was heated at about 75-850C to obtain clear solution. The reaction mixture was cooled to ambient temperature. Cyclo hexane (10 volume) was added and the reaction mixture and stirred for two hours. The solid was filtered and dried to obtain crystalline form III of Selexipag (1.54 g).
Example-38: Preparation of tryptamine salt of Selexipag:
Selexipag (2.0 g) dissolved in isopropyl acetate (12 ml), tryptamine (0.645 g) was added and solution was cooled to -60oC. Maintain the temperature till solid observed. Filter the solid at ambient temperature and dried at 60 oC under vacuum to give the title salt. Dry weight: 1.20 g DSC: 150.40 oC

Date this 7th December 2018.

,CLAIMS:We Claim:

1. A process for preparation of Form I of Selexipag comprising the steps of:
(a) contacting Selexipag with suitable solvent(s);
(b) optionally heating the reaction mixture obtained in step (a);and
(c) isolating crystalline form I of Selexipag.

2. The process as claimed in claim 1 wherein suitable solvent(s) is selected from n-butanol, toluene, water, acetone, propylene glycol, methyl isobutyl ketone, acetic acid, isopropyl acetate, chloro benzene, methanol, di methoxy ethane, cyclo pentyl methyl ether, phosphoric acid, acetonitrile, dimethyl formamide and mixtures thereof.

3. The process as claimed in claim 1 optionally comprises further adding suitable antisolvent(s) selected from water, saturated or unsaturated, linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as hexanes, heptane, cyclo hexane, or methyl cyclo hexane, ethers such as diethyl ether, diisopropyl ether, or mixtures thereof.

4. A process for preparation of Form III of Selexipag comprising the steps of:
(a) contacting Selexipag with suitable solvent(s);
(b) optionally heating the reaction mixture obtain in step (a); and
(c) isolating crystalline form III of Selexipag.

5. The process as claimed in claim 4 wherein suitable solvent(s) is selected from acetonitrile, cyclo hexane, toluene, propylene glycol, anisole, methyl ethyl ketone, benzyl alcohol, isopropyl alcohol, isopropyl acetate, methyl isobutyl ketone, cyclo pentyl methyl ketone, acetone, urea, o-dichloro benzene, pyridine, ethyl acetate, tetra methyl urea, n-heptane, water, glycine, succinic acid, t-butyl benzene and mixtures thereof.

6. The process as claimed in claim 4 optionally comprises further adding suitable antisolvent(s) selected from water, saturated or unsaturated, linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as hexanes, heptane, cyclo hexane, or methyl cyclo hexane, ethers such as diethyl ether, diisopropyl ether, or mixtures thereof.

7. The process as claimed in step (b) of claim 1 or step (b) of claim 4 wherein heating the reaction mixture is carried out within temperature range of about 50 oC to 200 oC.

Date this 7th December 2018.