DESC:FIELD OF INVENTION:
The present invention relates to a novel crystalline form of Selexipag. More particularly, it relates to a hydrated form of selexipag, herein after referred to as form L1 and a process for preparation thereof.

BACKGROUND OF THE INVENTION:
Selexipag (Uptravi®) has the chemical name “2-{4-[N-(5,6-diphenylpyrazin-2-yl)-n-isopropylamino]butyloxy}-n-(methylsulfonyl)acetamide” and is chemically represented by the compound of formula (I) as follows.

Selexipag, discovered and synthesized by Nippon Shinyaku, is indicated for the treatment of pulmonary arterial hypertension (PAH). It has an excellent PGI2 receptor agonistic activity, platelet aggregation inhibitory action, vasodilating action, bronchial muscle dilating action, lipid deposition inhibitory effect, leukocyte activation inhibitory action and the like.
U.S. Patent No. 7,205,302 B2 discloses selexipag and its pharmaceutically acceptable salts thereof along with the processes to make selexipag and pharmaceutically acceptable salts.
U.S. Patent No. 8,791,122 B2 discloses an amorphous form and three crystalline forms of selexipag designated as Form I, II and III.
The PCT publication WO 20110/24874 A1 discloses base addition salts like t-butylamine, potassium, sodium and dimethylaminoethanol of selexipag.
The PCT publication WO 2016/1193994 A1 discloses amorphous form and amorphous co-precipitates of selexipag with pharmaceutically acceptable excipients.
The PCT publication WO 2017/040872 A1 discloses Form IV and Form V of selexipag.
The PCT publication WO 2017/1109772 A1 discloses stable amorphous form of selexipag.
The discovery of new salts, crystal forms and solvates of a pharmaceutically useful compound offers an opportunity to improve the performance profile of a pharmaceutical product (dissolution profile, bioavailability, etc.), ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. Crystalline forms often show desired different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, to the purity levels and uniformity required for regulatory approval.
It has now been found that selexipag can exist, in addition to the above mentioned crystalline forms, also in crystalline hydrate form which is stable at room temperature and having improved physical and/or chemical properties.

SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a novel crystalline form of selexipag. More particularly the invention provides a hydrated form of selexipag, herein after referred to as 'form L1'.
In another aspect, the present invention provides a process for the preparation of selexipag form L1.
In yet another aspect, the invention provides a pharmaceutical composition comprising selexipag form L1 and at least one pharmaceutically acceptable excipient, carrier or diluent.

BRIEF DESCRIPTION OF THE DRAWINGS:
Fig. 1 : Powder X-ray diffraction pattern/diffractogram (PXRD) pattern of selexipag form L1 of the present invention.
Fig. 2 : Differential Scanning Calorimetry (DSC) pattern of selexipag form L1 of the present invention.
Fig. 3 : Thermal Gravimetric Analysis (TGA) pattern of selexipag form L1 of the present invention.
Fig. 4 : Infra-red spectroscopy (IR) spectrum of selexipag form L1 of the present invention.

DETAILED DESCRIPTION OF THE INVENTION:
The selexipag form L1 of the present invention is a hydrate form which is crystalline, stable, non-hygroscopic in nature and does not contain any solvent molecule.
The term "hydrate" as used herein designates a crystalline molecular compound in which water molecules are incorporated into the crystal lattice.
The term "stable" as used herein means selexipag form L1 that substantially does not convert to any related substances or other solid form.
The term "substantially as depicted in" as used herein means a pattern that is not necessarily identical to those depicted herein, but falls within the limits of experimental or statistical error or deviations when considered by the person skilled in the art.
The term "room temperature" as used herein refers to a temperature of about 20°C to about 25 °C.
The term "contacting," as used herein, refers to the act of bringing together two or more components by dissolving, mixing, suspending, blending, slurrying, or stirring.
In one embodiment, the present invention provides a selexipag form L1 which is essentially a hydrate as defined above. It is a stable polymorphic form that does not undergo any polymorphic transition under various humid conditions and having enhanced flow property, dissolution properties that can be easily formulated into pharmaceutical compositions.
Crystalline selexipag hydrate form L1 of the present invention comprises 0.2 to 1.0 equivalents of water molecule, which corresponds to a water content ranging from about 0.5% to about 4.0%.
In another embodiment, the present invention provides selexipag form L1 characterized by PXRD pattern substantially as depicted in Figure 1, wherein the more intense diffraction peaks are observed at 4.6, 14.9, 15.5, 19.7, 20.9 and 21.4 ± 0.2°2-theta.
In another embodiment, the present invention provides selexipag form L1 characterized by DSC pattern substantially as depicted in Figure 2.
In another embodiment, the present invention provides selexipag form L1 characterized by TGA pattern substantially as depicted in Figure 3.
In another embodiment, the present invention provides selexipag form L1 characterized by IR spectrum substantially as depicted in Figure 4, having peaks at 3601, 3059, 2927, 1721, 1557, 1472, 1154 and 697 ± 1 cm-1.
In another embodiment, the present invention provides a process for the preparation of selexipag form L1, comprising
i) contacting selexipag in water with a base,
ii) adding an acid, and
iii) isolating selexipag form L1 from reaction mixture thereof.
Selexipag used as the starting material can be obtained by any of the methods known in the art, for example, U.S. Patent Nos. 7,205,302 and 8,791,122 which are incorporated herein by reference.
The base used herein is selected from alkali hydroxide selected from sodium hydroxide, potassium hydroxide; alkali carbonates selected from sodium carbonate, potassium carbonate; alkali bicarbonates selected from sodium bicarbonate, potassium bicarbonate; alkyl amines selected from methylamine, ethylamine, and trimethylamine; ammonia or ammonium hydroxide.
The acid used herein is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, methanesulfonic acid, citric acid, fumaric acid, maleic acid, malic acid, D-tartaric acid, L-tartaric acid, benzoic acid, gentisic acid, benzenesulfonic acid, salicylic acid, p-acetamidobenzoic acid, or p-toluenesulfonic acid.
The selexipag form L1 of the present invention may be isolated or recovered by conventional means, such as filtration, concentration, evaporation, extraction, etc. and may be purified if required, by standard procedures, such as distillation, recrystallization or chromatography.
The selexipag form L1 of the present invention may be further dried, preferably spin dried, in, for example, a vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or a pilot plant rota vapor.
The selexipag form L1 of the present invention may be micronized to achieve the better particle size distribution in order to make suitable Formulation. Micronization may be performed prior to drying or after the drying, by using one or a combination of ball milling, jet milling, jet blending, high-pressure homogenation, or any other conventional milling method.
The selexipag form L1 of the present invention has purity more than 99% when measured by high performance liquid chromatography (HPLC).
The selexipag form L1 as described herein can be formulated into pharmaceutical compositions comprising therapeutically effective amount of selexipag form L1 and one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be solid oral dosage forms such as powders, granules, pellets, tablets and capsules, pills, suppositories, sachets, troches or lozenges; liquid oral dosage forms such as syrups, suspensions, dispersions, emulsions; and injectables.
The pharmaceutically acceptable carriers include, but not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, , maltose, raffinose, .alpha.-, .beta.- and .gamma.-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl beta.-cyclodextrin chitosan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxylpropyl methylcellulose acetate succinate (HPMC-AS), carboxymethylethylcellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co- (lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacryl copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxylvinyl polymer, polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), polyethyleneglycols of various molecular weights, polyethylene-/polypropylene-/polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and co-polymers thereof with PVP or with other polymers, polyacrylates, hypromellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn starch and potato starch pregelatinized starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, silica excipients like silicon dioxide, syloid, light anhydrous silicic acid or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low- substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes or the like. Other pharmaceutically acceptable carriers that can be used include, but are not limited to, film formers, plasticizers, colorants, viscosity enhancers, preservatives, antioxidants, or the like.
The selexipag form L1 as described herein is suitable for method of treating pulmonary arterial hypertension comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising selexipag form L1 as described herein.
EXPERIMENTAL:
Powder X-ray diffraction pattern (PXRD), differential scanning calorimetry (DSC), thermal Gravimetric Analysis (TGA), and infra-red (IR) spectroscopy were used to characterize the selexipag form L1.
Powder X-ray diffraction pattern (PXRD): The PXRD of the samples were determined by using a PANalytical X'Pert powder diffraction meter, the X-ray powder diffraction pattern was measured at room temperature using a Cu Ka filled tube (45 kV and 40 mA) as the X-ray source. Data collection was done in 2? continuous scan mode in the range of 3.5 to 40.
Differential Scanning Calorimetry (DSC): The DSC was performed using a Diamond DSC PERKIN ELMER differential instrument. 2-3 mg samples were placed in crimped aluminium pans and heated from 30 ° to 250° in a dry nitrogen atmosphere at a heating rate of 10°C/min.
Thermal Gravimetric Analysis (TGA): The TGA was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open aluminium pans and heated from 50 ° to 300° in a dry nitrogen atmosphere at a heating rate of 10°C/min.
Infra-red spectroscopy (IR): The IR was performed using a spectrum 400 using a neat liquid sample or dispersion of solid sample material in KBr.
Water content: Water content was measured by Karl-Fischer auto titrator Metrohm Titrando as per the methods known in the art.
To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLES:
Example 1:
In a round bottom flask containing 450 ml of water cooled at 5°C, 15gm of selexipag was added. To this mixture, 125 ml of liq. ammonia was added dropwise with stirring at 5°C - 10°C to obtain the clear solution. The solution was cooled to 0°C - 5°C and then 132 ml of hydrochloric acid was added to this solution with stirring at 0°C - 5°C and maintained for 2-3 hrs. The solid obtained was filtered and washed with 1000 ml water and dried in oven under vacuum to give selexipag form L1 characterized by X-ray diffraction pattern (PXRD) as depicted in Fig. 1, differential scanning calorimetry (DSC) as depicted in Fig. 2, thermal Gravimetric Analysis (TGA) as depicted in Fig. 3, and infra-red (IR) spectroscopy as depicted in Fig. 4.
Yield: 13.4 gm (89.33%)
Purity: 99.54% (HPLC).
,CLAIMS:1) Selexipag Form L1.
2) The selexipag Form L1 of claim 1, characterized by PXRD pattern having peaks at 4.6, 14.9, 15.5, 19.7, 20.9 and 21.4 ± 0.2° 2-theta.
3) A process for preparation of selexipag Form L1 comprising the steps of
i) contacting Selexipag in water with a base,
ii) adding an acid, and
iii) isolating Selexipag Form L1.
4) The process of claim 3, wherein the base is ammonia.
5) The process of claim 3, wherein the acid is hydrochloric acid.
6) The selexipag Form L1 of claim 1, characterized in that the water content is 0.5% to about 4.0%.
7) The selexipag Form L1 of claim 1, having high performance liquid chromatography (HPLC) purity greater than 99%.
8) The selexipag Form L1 of claim 1, characterized by at least one of:
PXRD pattern substantially as depicted in Figure 1,
DSC pattern substantially as depicted in Figure 2,
TGA pattern substantially as depicted in Figure 3,
IR spectrum substantially as depicted in Figure 4.
9) The selexipag Form L1 of claim 1 for use in pharmaceutical composition comprising selexipag Form L1 and one or more pharmaceutically acceptable carriers, excipients or diluents.

10) The selexipag Form L1 of claim 1 for use in the treatment of pulmonary arterial hypertension.