Field of the Invention:

The present invention relates to novel crystalline forms of 2-{4-[(5,6-diphenylpyrazin-2- yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide compound of formula-1, which is
represented by the following structural formula:

5
formula-1

The present invention also relates to process for the preparation novel crystalline forms of the compound of formula-1.

10 Background of the Invention:

2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)

acetamide is known as Selexipag. It is developed by Nippon Shinyaku under the brand name

Uptravi®, for the treatment of pulmonary arterial hypertension.

15 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)

acetamide was firstly described in US7205302B2 herein after referred as US’302. The said

patent also describes its process for the preparation.

US8791122 (herein after referred as US’122) patent describes crystalline Form-I, II and

20 III of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide.

PCT publication WO2017040872A1 discloses crystalline form-IV and V of selexipag and processes for preparation the same.
In general discovering new crystalline forms, salts, hydrates of a pharmaceutical product can provide materials having desirable processing properties. such as ease of handing, storage
25 stability, and ease of purification. New salts, polymeric forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of pharmaceutical product i.e. dissolution profile, bio availability etc. It enlarges the repertoire of materials the formulation scientist has available for formulation optimization for example by

providing a product with different properties e.g. a different crystal habit, higher crystallinity or polymeric stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. Hence, there is a need to develop novel crystalline forms, salts for existing drug molecules.
5 The novel crystalline forms of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl) acetamide described herein help meet this and other needs.

The present invention provides novel crystalline forms and its process for the preparation of compound of formula-1.
10

Brief Description:

The first aspect of the present invention is to provide novel crystalline Form of 2-{4- [(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1, herein after designated as crystalline Form-P.

15 The second aspect of the present invention is to provide a process for the preparation of crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1.

The third aspect of the present invention is to provide novel crystalline Form of 2-{4- [(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound
20 of formula-1, herein after designated as crystalline Form-L.

Brief description of the drawings:

Figure 1: Illustrates the PXRD pattern of crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Figure 2: Illustrates the IR spectrum of crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl)

25 (isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

Figure 3: Illustrates the DSC thermogram of crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-

2-yl) (isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

Figure 4: Illustrates the PXRD pattern of crystalline Form-L of 2-{4-[(5,6-diphenylpyrazin-2-

yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

Figure 5: Illustrates the DSC thermogram of crystalline Form-L of 2-{4-[(5,6-diphenylpyrazin-

2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

Detailed Description:

5 As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene
10 glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2- dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra
15 chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2- methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-
20 pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or

glycerol and the like; “polar solvents” such as water or mixtures thereof.

The first aspect of the present invention provides crystalline Form-P of 2-{4-[(5,6- diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of
25 formula-1. The crystalline Form-P of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 3.3, 6.6, 9.7, 12.6, 13.5, 16.2, 17.4, 18.1, 18.6, 19.1,
19.3, 19.7, 20.3, 21.3, 23.0 & 27.9 ± 0.2° 2θ. The said crystalline Form-P is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure-1, by its IR spectrum shown in figure-2 and its DSC thermogram shown in figure-3.
30

The second aspect of the present invention provides a process for the preparation of the crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl

sulfonyl) acetamide compound of formula-1; comprising of:

a) Melting the compound of formula-1 at a suitable temperature optionally under reduced pressure,
b) combining the compound obtained in step-a) to the solvent system,

5 c) stirring the reaction mixture at a suitable temperature,

d) filtering the solid obtained in step-c) provides the crystalline Form-P of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Wherein in step-a) the suitable temperature is 90 to 150°C, preferably 130-145°C;

10 in step b) the solvent system may be a single solvent or mixture of solvents and is selected from hydrocarbon solvents, ester solvents, chloro solvents, ketone solvents; preferably hydrocarbon solvents; most preferably n-heptane;
in step c) the suitable temperature is below 40°C.

15 Preferred embodiment of the present invention provides a process for the preparation of the crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1; comprising of:
a) Melting the compound of formula-1 at 140-145°C,

b) adding the compound obtained in step-a) to pre-cooled n-heptane,

20 c) stirring the reaction mixture at below 30°C,

d) filtering the solid obtained in step-c) provides the crystalline Form-P of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

Another embodiment of the present invention provides a process for the preparation of

25 the crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1; comprising of:
a) Melting the compound of formula-1 at 140-145°C,

b) adding the compound obtained in step-a) to n-heptane,

c) stirring the reaction mixture at 30-40°C,

30 d) filtering the solid obtained in step-c) provides the crystalline Form-P of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

The third aspect of the present invention provides crystalline Form-L of 2-{4-[(5,6- diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1. The crystalline Form-L of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 3.3, 4.2, 6.6, 11.8, 12.6, 13.5, 16.2, 17.4, 18.1, 18.6,
5 19.1, 19.3, 19.7, 20.3, 21.3, 23.0 & 27.9 ± 0.2° 2θ. The said crystalline Form-L is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure-4 and by its DSC thermogram in figure-5.

In another embodiment of the present invention provides process for the preparation of

10 crystalline Form-L of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1.
comprising of:

a) Heating the compound of formula-1 a suitable temperature,

b) combining the obtained compound in step-a) to a solvent system,

15 c) stirring the reaction mixture at a suitable temperature,

d) filtering the obtained solid in step-c) provides the crystalline Form-L of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1. Wherein in step-a) the suitable temperature is 100 to 180°C, preferably 130-170°C;
in step b) the solvent system may be a single solvent or mixture of solvents and is selected from

20 hydrocarbon solvents, ester solvents, chloro solvents, ketone solvents; preferably hydrocarbon solvents; most preferably n-heptane;
in step c) the suitable temperature is below 40°C, further stirring the reaction mixture for 2 to 20

hours.

Preferred embodiment of the present invention provides a process for the preparation of

25 the crystalline Form-L of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1; comprising of:
a) Heating the compound of formula-1 to 130-170°C,

b) adding the compound obtained in step-a) to n-heptane,

c) stirring the reaction mixture for 2 to 20 hours at below 35°C,

30 d) filtering the obtained solid in step-c) provides the crystalline Form-L of 2-{4-[(5,6-

diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of

formula-1.

2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition
5 requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

PXRD analysis of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-

10 (methylsulfonyl) acetamide was carried out using BRUKER D8 ADVANCED/AXS X-Ray

diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of

0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.

2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)

15 acetamide compound of formula-1 used in the present invention is synthesized by the prior known processes or according to US7205302B2.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as
20 limitation of the scope of the invention.

Examples:

Example-1: Preparation of crystalline Form-L of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C for 15 minutes. The obtained oily

25 residue was added to 100 mL of pre-cooled n-heptane at 0-5°C. Stirred the reaction mixture for 6 hr at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 9 gm; PXRD of the obtained compound is depicted in figure-4 and DSC thermogram is depicted in figure-5.
Example-2: Preparation of crystalline Form-P of compound of formula-1

30 Melting the compound of formula-1 (10 gm) at 140-145°C for 15 minutes. The obtained oily residue was added to 100 mL of pre-cooled n-heptane at 0-5°C. Stirred the reaction mixture for

36 hours at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.
Yield: 9 gm; PXRD of the obtained compound is depicted in figure-1, its IR is depicted in figure-

2 and its DSC is depicted in figure-3.

5 Example-4: Preparation of crystalline Form-P of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C for 15 minutes. The above obtained oily residue was added to 100 mL of n-heptane at 30-40°C. Stirred the reaction mixture for 36 hours at 25-35°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.
10 Yield: 9 gm; PXRD of the obtained compound is similar to the figure-1.

Example-5: Preparation of amorphous form of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C for 15 minutes and the above obtained oily residue was cooled to 0-5°C. Unload the obtained compound and dried to get the title compound. Yield: 9 gm; Purity by HPLC: 99.74%.
15 Example-6: Preparation of 2-chloroN-(methylsulfonyl)acetamide

The mixture of methane sulfonamide (50 gm) and chloroacetyl chloride (92 gm) was heated to

110-115°C and stirred the reaction mixture for 7 hours at the same temperature. The reaction mixture was cooled to 25-30°C and dichloromethane was added to the reaction mixture at the same temperature. Cooled the reaction mixture to 15-20°C and stirred for 1 hour at the same
20 temperature. Filtered the precipitated solid and washed with dichloromethane. The obtained solid was recrystallized using dichloromethane to get pure title compound.
Yield: 80 gm. M.R.: 110-115°C. Purity by HPLC: 98.85%.

Example-7: Preparation of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-1-ol

The mixture of 5-chloro-2,3-diphenylpyrazine (100 gm) and 4-(isopropylamino)butan-1-ol

25 (245.5 gm) was heated to 195-200°C and stirred the reaction mixture for 12 hours at the same temperature. The reaction was cooled to 25-30°C and n-heptane was added to the reaction mixture. The reaction mixture was further cooled to 10-15°C, water was slowly added to the reaction mixture and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. Dichloromethane (300 mL) was added to the obtained solid and stirred
30 for 5 minutes. Both the organic and aqueous layers were separated. The organic layer was dried with sodium sulphate, distilled off the solvent from the organic layer completely under reduced

pressure and co-distilled with n-heptane. 400 mL of n-heptane was added to the obtained compound at 25-30°C, heated the reaction mixture to 45-50°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 15-20°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound.
5 Yield: 82 gm. M.R.: 100-105°C. Purity by HPLC: 95.4%.

Example-8: Preparation of crystalline Form-P of compound of formula-1.

Sodium t-butoxide (40 gm) was added to pre-cooled solution of 4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butan-1-ol (25 gm) in n-methyl pyrrolidone (100 ml) at 0-5°C and stirred the reaction mixture for 45 min at same temperature. 2-chloro-N-(methylsulfonyl)acetamide
10 (35.5 gm) was slowly added to the reaction mixture at 0-5°C and stirred for 5 hours. The reaction mixture was poured into pre-cooled water at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was washed with methyl tertiary butyl ether. Acidified the reaction mixture using acetic acid at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and separated both the organic and aqueous layers. The aqueous
15 layer was extracted with ethyl acetate and combined the organic layers. The organic layer was washed with aqueous sodium chloride solution and dried the organic layer with sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure and co- distilled with methanol. Methanol (1000 ml) was added to the obtained residue at 25-30°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid and washed with
20 methanol. Dissolved the obtained compound in 1200 ml of methanol at 60-65°C and filtered the solution through hyflow bed and washed with methanol. Cooled the filtrate to 25-30°C and stirred for 3 hours at the same temperature filtered the precipitated solid. The obtained wet compound was purified using the same process in methanol for two times. The obtained wet solid was dissolved in a mixture of ethyl acetate (150 ml) and ethanol (150 ml) at 80-85°C.
25 Charcoal (10 gm) was added to the solution at 80-85°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with a mixture of ethanol and ethyl acetate. The filtrate was cooled to 25-35°C and stirred for 5 hours at same temperature. Filtered the precipitated solid and washed the mixture of ethyl acetate and ethanol. Heated the obtained compound to 160-165°C for 15 minutes. The above obtained oily residue
30 was added to 500 ml of pre-cooled n-heptane at 0-5°C. Stirred the reaction mixture for 45 hours

at below 30°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.
Yield: 12.5 gm. Purity by HPLC: 99.76%. PXRD of the obtained compound is illustrated in figure-1.
5 Example-9: Preparation of compound of formula-1.

Sodium t-butoxide (40 gm) was added to pre-cooled solution of 4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butan-1-ol (25 gm) in n-methyl pyrrolidone (100 ml) at 0-5°C and stirred the reaction mixture for 45 min at same temperature. 2-chloro-N-(methylsulfonyl)acetamide (35.5 gm) was slowly added to the reaction mixture at 0-5°C and stirred for 5 hours. The reaction
10 mixture was poured into pre-cooled water at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was washed with methyl tertiary butyl ether. Acidified the reaction mixture using acetic acid at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and separated both the organic and aqueous layers. The aqueous layer was extracted with ethyl acetate and combined the organic layers. The organic layer was
15 washed with aqueous sodium chloride solution and dried the organic layer with sodium sulphate.

Distilled off the solvent completely from the organic layer under reduced pressure and co- distilled with methanol. Methanol (1000 ml) was added to the obtained residue at 25-30°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid and washed with methanol. Dissolved the obtained compound in 1200 ml of methanol at 60-65°C and filtered the
20 solution through hyflow bed and washed with methanol. Cooled the filtrate to 25-30°C and stirred for 3 hours at the same temperature. The obtained wet compound was purified using the same process in methanol for two times. The obtained wet solid was dissolved in a mixture of ethyl acetate (150 ml) and ethanol (150 ml) at 80-85°C. Charcoal (10 gm) was added to the solution at 80-85°C and stirred for 10 minutes at the same temperature. Filtered the reaction
25 mixture through hy-flow bed and washed with a mixture of ethanol and ethyl acetate. The filtrate was cooled to 25-35°C and stirred for 5 hours at same temperature. Filtered the precipitated solid, washed the mixture of ethyl acetate and ethanol and dried to get the title compound.
Yield: 15 gm.

30

Example-10: Preparation of crystalline Form-P of compound of formula-1

The mixture of the compound of formula-1 (10 gm) and 100 ml of n-heptane was stirred for 45 hours at 25-35°C. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 9 gm.
5

10

15

20

25

30

We claim:

1. A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1 having characteristic absorption peaks at 3.3, 6.6, 9.7, 12.6,
5 13.5, 16.2, 17.4, 18.1, 18.6, 19.1, 19.3, 19.7, 20.3, 21.3, 23.0 and 27.9 ± 0.2° 2θ in an X-ray powder diffractogram and a pharmaceutically acceptable slats.

formula-1

10 2. A pharmaceutical composition according to claim-1, wherein the crystalline Form-P of 2-{4- [(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide has a melting point range 111-118°C as determined by differential scanning calorimetry at a scan rate
5°C / minute.

3. A process for the preparation of the crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl)

15 (isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1;

comprising of:

a) Melting the compound of formula-1 at a suitable temperature optionally under reduced pressure,
b) combining the compound obtained in step-a) to the solvent system,

20 c) stirring the reaction mixture at a suitable temperature,

d) filtering the solid obtained in step-c) provides the crystalline Form-P of 2-{4-[(5,6-di phenyl pyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
4. The process according to claim 3 wherein in step-a) the suitable temperature is 90 to 150°C, preferably 130-145°C; in step b) the solvent system may be a single solvent or mixture of
25 solvents and is selected from hydrocarbon solvents, ester solvents, chloro solvents, ketone solvents; preferably hydrocarbon solvents; most preferably n-heptane; in step c) the suitable temperature is below 40°C.
5. A process for the preparation of the crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1;

comprising of:

a) Melting the compound of formula-1 at 140-145°C,

b) adding the compound obtained in step-a) to pre-cooled n-heptane, c) stirring the reaction mixture at below 30°C,
5 d) filtering the obtained solid in step-c) provides the crystalline Form-P of 2-{4-[(5,6- diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
6. A process for the preparation of the crystalline Form-P of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1;
10 comprising of:

a) Melting the compound of formula-1 at 140-145°C,

b) adding the compound obtained in step-a) to n-heptane, c) stirring the reaction mixture at 30-40°C,
d) filtering the solid obtained in step-c) provides the crystalline Form-P of 2-{4-[(5,6-diphenyl

15 pyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

7. A process for the preparation of the crystalline Form-L of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1;
comprising of:

a) heating the compound of formula-1 to 140-170°C,

20 b) adding the compound obtained in step-a) to pre-cooled n-heptane at 0-10°C, c) stirring the reaction mixture for 2 to 20 hours at below 35°C,
d) filtering the solid obtained in step-c) provides the crystalline Form-L of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
8. A process for the preparation of the crystalline Form-L of 2-{4-[(5,6-diphenylpyrazin-2-yl)

25 (isopropyl) amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1 and characterized by any one of the following ;
i) X-Ray diffraction pattern having peaks at about 3.3, 4.2, 6.6, 11.8, 12.6, 13.5, 16.2, 17.4, 18.1,

18.6, 19.1, 19.3, 19.7, 20.3, 21.3, 23.0 & 27.9 ± 0.2° 2θ; or

ii) having PXRD pattern substantially in accordance with the figure- 4 ; or

30 iii) its differential scanning calorimetry (DSC) thermogram shown in figure-5. and the process comprising of :

a) heating the compound of formula-1 to 140-170°C,

b) adding the compound obtained in step-a) to pre-cooled n-heptane at 0-10°C, c) stirring the reaction mixture for 2 to 20 hours at below 35°C,
a) filtering the solid obtained in step-c) provides the crystalline Form-L of 2-{4-[(5,6-diphenyl

5 pyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.

9. Crystalline forms of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl) amino] butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1 obtained according to any preceding claims.
10. Crystalline forms of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl) amino] butoxy}-N- (methylsulfonyl) acetamide compound of formula-1 obtained according to any preceding claims
10 having particle size of D(0.9) < 200 μm, preferably D(0.9) < 150 μm.

15 Dated this day of March 2018.

Authorized Signatory
20 (Chakilam Nagaraju) Maithri Drugs Private Limited

*********

25