Field of the Invention:

The present invention relates to a novel amorphous form of selexipag sodium (lb) and selexipag potassium (Ic) and methods for preparing the same. The present invention also relates to a process for the preparation of amorphous form of selexipag (la). The present invention further relates to a solid dispersion of amorphous selexipag, amorphous selexipag sodium and amorphous selexipag potassium and method for its preparation. Background of the Invention:

The present invention comprises of selexipag (la) which has an PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect etc. The chemical name for selexipag is (2-{4-[(5,6-diphenylpyrazin-2-yl) (propan-2- yl)amino]butoxy}-N-(methanesulfonyl)acetamide, and is represented by the following structure.

Selexipag (la) is disclosed in the PCT application WO 2002/088084. The patent US 8,791 , 122 discloses crystalline form I, form II, form III and amorphous forms of selexipag, while PCT application WO 2011024874 discloses base addition salts like t- butylamine, potassium, sodium and dimethylaminoethanol of selexipag in crystalline form.

It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms. For some therapeutic indications one bioavailability pattern may be favored over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form. Therefore, there is a need to develop an amorphous form of selexipag or its salt which has improved characteristics. The patent as well as publication literature lack in providing information on an amorphous form of selexipag sodium and potassium. The inventors of the present invention provide here efficient and simple processes to obtain amorphous selexipag sodium and potassium.

The discovery of further solid dispersions of an active pharmaceutical ingredient (API) can provide further prospective opportunities to improve the performance profile of a pharmaceutical composition comprising the said API.

Summary of the invention: The present invention provides amorphous form of selexipag sodium (lb) and selexipag potassium (Ic) and methods for their preparation. The present invention also provides a process for the preparation of amorphous form of selexipag (la). The present invention further provides a solid dispersion of amorphous selexipag, amorphous selexipag sodium and amorphous selexipag potassium.

The present invention further describes process for the preparation of solid dispersion of amorphous selexipag, amorphous selexipag sodium and amorphous selexipag potassium.

Brief Description of the accompanying drawings:

Figure 1 : X-ray powder diffractogram (XRPD) for amorphous selexipag (la).

Figure 2: X-ray powder diffractogram (XRPD) for amorphous selexipag sodium (lb). Figure 3: X-ray powder diffractogram (XRPD) for amorphous selexipag potassium (Ic). Figure 4: X-ray powder diffractogram (XRPD) for amorphous selexipag solid dispersion with syloid. Figure 5: X-ray powder diffractogram (XRPD) for amorphous selexipag sodium solid dispersion with syloid.

Figure 6: X-ray powder diffractogram (XRPD) for amorphous selexipag potassium solid dispersion with syloid.

Detailed description of the invention:

An embodiment of the present invention provides a process for the preparation of amorphous selexipag (la) comprising: a) dissolving the selexipag free base in suitable solvent;

b) removing solvent and isolating amorphous form of selexipag.

The term "suitable solvent" in the above method includes water; alcohol such as methanol, ethanol, n-propanol, isopropanol; ketone such as acetone, 2-butanone, methyl isobutyl ketone; ester such as ethyl acetate, isopropyl acetate; ether such as ethyl ether, methyl t-butyl ether, di-isopropyl ether, tetrahydrofuran; nitrile such as acetonitrile, propionitrile, butyronitrile; chlorinated hydrocarbon such as dichloromethane, ethylene dichloride, chloroform; amide such as dimethylformamide & mixtures thereof. Preferred solvent being mixture of acetonitrile and water or mixture of acetonitrile and hexane.

Removing solvent and isolating amorphous form of selexipag can be achieved by various methods such as concentration on rotavapor, removal of solvent by evaporation, distillation, crash cooling, flash evaporation, rotational drying, spray drying, agitated thin film drying (ATFD), lyophilization (freeze drying); more preferably lyophilization and concentration on rotavapor.

The process of lyophilization is carried out at -70 to -80 °C with 10-15 mm Hg of vacuum.

Concentration on rotavapor is carried out at 30-110 °C, preferably at 40-60 °C under vacuum. The amorphous form of selexipag (la) obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) pattern as shown in figure 1.

Another embodiment of the present invention provides a novel amorphous form of selexipag sodium (lb). Another embodiment of the present invention is process for the preparation of amorphous selexipag sodium (lb) comprising following steps: a) dissolving selexipag free base in suitable solvent;

b) addition of sodium ion source;

c) removing solvent and isolating amorphous form of selexipag sodium.

The term "suitable solvent" in the above method includes water; alcohol such as methanol, ethanol, n-propanol, isopropanol; ketone such as acetone, 2-butanone, methyl isobutyl ketone; ester such as ethyl acetate, isopropyl acetate; ether such as ethyl ether, methyl t-butyl ether, di-isopropyl ether, tetrahydrofuran; nitrile such as acetonitrile, propionitrile, butyronitrile; chlorinated hydrocarbon such as dichloromethane, ethylene dichloride, chloroform; amide such as dimethylformamide & mixtures thereof. Preferred solvent being acetone. The sodium ion source used in step b includes bases like sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium methoxide or mixtures thereof; the most preferred source is sodium hydroxide.

The sodium ion source is added directly to the reaction mass or used in the form of solution of sodium ion source in solvent selected from water, methanol, ethanol, isopropyl alcohol, propanol, n-butanol, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone or mixtures thereof.

The amorphous form of selexipag sodium (lb) obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) pattern as shown in figure 2. Another embodiment of the present invention provides a novel amorphous form of selexipag potassium (Ic). Yet another embodiment of the present invention is process for the preparation of amorphous selexipag potassium (Ic) comprising following steps: a) dissolving selexipag free base in suitable solvent;

b) addition of potassium ion source;

c) removing solvent and isolating amorphous form of selexipag potassium.

The term "suitable solvent" in the above method includes water; alcohol such as methanol, ethanol, n-propanol, isopropanol; ketone such as acetone, 2-butanone, methyl isobutyl ketone; ester such as ethyl acetate, isopropyl acetate; ether such as ethyl ether, methyl t-butyl ether, di-isopropyl ether, tetrahydrofuran; nitrile such as acetonitrile, propionitrile, butyronitrile; chlorinated hydrocarbon such as dichloromethane, ethylene dichloride, chloroform; amide such as dimethylformamide & mixtures thereof. Preferred solvent being tetrahydrofuran.

The potassium ion source used in step b includes bases like potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium acetate, potassium methoxide or mixtures thereof; the most preferred source is potassium hydroxide.

The potassium ion source is added directly to the reaction mass or used in the form of solution of potassium ion source in solvent selected from water, methanol, ethanol, isopropyl alcohol, propanol, n-butanol, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone or mixtures thereof.

The amorphous form of selexipag potassium (Ic) obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) pattern as shown in figure 3. Removing solvent and isolating amorphous form of selexipag sodium or selexipag potassium can be achieved by various methods such as concentration on rotavapor, removal of solvent by evaporation, distillation, crash cooling, flash evaporation, rotational drying, spray drying, agitated thin film drying (ATFD) and lyophilization (freeze drying).

Another embodiment of the present invention provides a process for the preparation of an amorphous solid dispersion of selexipag or selexipag sodium or selexipag potassium and one or more pharmaceutically acceptable carrier comprising the steps of: a) dissolving selexipag or selexipag sodium or selexipag potassium in suitable solvent ;

b) addition of the pharmaceutically acceptable carrier; and

c) isolating amorphous solid dispersion of selexipag or selexipag sodium or selexipag potassium.

The term "solid dispersion" defines a system in a solid state wherein one component is dispersed more or less evenly throughout the other component or components.

Any physical form of selexipag, selexipag sodium or selexipag potassium such as crystalline, amorphous or their mixtures can be utilized in step a. The term "suitable solvent" in the step a described above includes water; alcohols such as methanol, ethanol, n-propanol, isopropanol; ketones such as acetone, 2-butanone, 2- Pentanone, methyl isobutyl ketone; esters such as ethyl acetate, isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether, tetrahydrofuran; nitriles such as acetonitrile, propionitrile, butyronitrile; chlorinated hydrocarbons such as chloroform, ethylene dichloride, chloroform; and mixtures thereof; the most preferred solvent is mixture of water and acetonitrile.

Preferably, the dissolving step comprises heating the mixture of selexipag or selexipag sodium or selexipag potassium in suitable solvent. Preferably, the heating is at a temperature of about 10 -100°C, until obtaining complete dissolution. 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. In the preferred embodiment the pharmaceutically acceptable carrier includes silica excipients like silicon dioxide, syloid, colloidal silica.

Isolation of amorphous solid dispersion of selexipag or selexipag sodium or selexipag potassium can be achieved by various methods such as concentration, removal of solvent by evaporation, distillation, crash cooling, flash evaporation, rotational drying, spray drying, agitated thin film drying (ATFD), and lyophilization (freeze drying).

The amorphous solid dispersion of selexipag with syloid obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) as shown in figure 4. The amorphous solid dispersion of selexipag sodium with syloid obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) as shown in figure 5. The amorphous solid dispersion of selexipag potassium with syloid obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) as shown in figure 6.

The selexipag used as starting material for the present invention can be prepared by any of the methods known in the art. For example as disclosed in the PCT application WO 2002/088084, which is herein incorporated as reference.

The amorphous solid dispersion of selexipag, selexipag sodium, selexipag potassium of the present invention may be formulated as solid oral dosage forms such as powders, granules, pellets, tablets and capsules, suppositories, sachets, troches or lozenges; liquid oral dosage forms such as syrups, suspensions, dispersions, emulsions; and injectables.

The present invention is illustrated by the following representative example and are not intended to limit the scope of the invention.

Examples

The powder X-ray diffraction spectrum is measured using Philips (PAN analytical X'pert pro) diffractogram (copper anti cathode) and expressed in terms of inter planar distance d, Bragg' s angle 2 theta, intensity (expressed as a percentage of the most intense peak). The scanning parameters include: measurement range 3-40 degrees two theta; measurement temperature 25 °C; continuous scan.

The lyophilizer used for lyopilization is VERTIS New York- 12525.

The rotavapor used for concentration is Buchi-R-215 with 100-150 revolutions per minute. Example 1: Preparation of amorphous selexipag (la):

2 Gm of selexipag was dissolved in acetonitrile (20 ml). The reaction mixture was stirred and acetonitrile (20 ml) was added. The reaction mass was concentrated. The resulting solid material was scratched and unloaded. The solid was dissolved in hexane (20 ml), warmed and cooled. The reaction mixture was filtered and the solid was suck dried.

Yield: 0.8 gm (w/w).

Example 2: Preparation of amorphous selexipag solid dispersion with syloid:

Selexipag (1.8 g) was dissolved in acetonitrile (40 ml). A solution of syloid (0.2 gm) in water (5 ml) was prepared and added to the above reaction mixture. The reaction mixture was concentrated under vacuum at 40 °C using rotavapor and dried.

Yield: 1.6 gm w/w.

Example 3: Preparation of amorphous selexipag solid dispersion with syloid:

Selexipag (2 g) was dissolved in acetonitrile (40 ml). The reaction mixture was stirred and water (30 ml) was added to the reaction mixture. The reaction mass was freezed in acetone dry ice mixture at -78°C. The freezed reaction mixture was lyophilized. The solid was unloaded.

Yield: 1.9 gm w/w.

Example 4: Preparation of amorphous selexipag sodium (lb):

2 Gm of selexipag was dissolved in acetone (30 ml). The reaction mixture was stirred and cooled. A solution of 0.177 gm of sodium hydroxide in water (1 ml) was added drop wise to the reaction mass. The reaction mixture was stirred and maintained. The reaction mass was concentrated on rotavapor. The reaction mass stripped out with ethyl acetate and dried on rotavapor.

Yield: 1.8 gm w/w

Example 5: Preparation of amorphous selexipag potassium (Ic):

2.5 Gm of selexipag was dissolved in tetrahydrofuran (65 ml). The reaction mixture was stirred. A solution of 0.31 gm of potassium hydroxide in water (8.5 ml) was added dropwise to the reaction mass. The reaction mixture was stirred and heated to 40°C. The reaction mass was cooled and concentrated on Rotavapor. The obtained residue was dissolved in ethyl acetate (13 ml). The solution was heated, stirred and maintained. The reaction mass was cooled. The layers were separated. To the aqueous layer methanol was added. The solution was concentrated under vacuum. The residue was stripped with ethyl acetate (15 ml x 2). The residue was degassed to get a solid and the solid was dried. Yield: 1.49 gm ( / )

Example 6: Preparation of amorphous selexipag sodium solid dispersion with syloid:

Selexipag (3 g) was dissolved in tetrahydrofuran (80 ml). The reaction mixture was stirred. A solution of sodium hydroxide (0.27 gm) in water (10.2 ml) was added to the reaction mixture. The reaction mixture was heated to 40°C, stirred and maintained. The reaction mixture was concentrated under vacuum to give a residue. The residue was dissolved in mixture of water and ethyl acetate (10 + 15 ml) and heated. The reaction mixture was cooled and the layers were separated. Syloid (0.3 gm) was added to the aqueous layer followed by addition of acetonitrile (20 ml). The reaction mixture was stirred and maintained. The contents of the reaction mixture were freezed in acetone dry ice freezing mixture. The mixture was lyophilized, the mixture was removed from lyophilizer and the solid was dried.

Yield: 2.2 g (w/w)

Example 7: Preparation of amorphous selexipag potassium solid dispersion with sylloid:

Selexipag (3 g) was dissolved in tetrahydrofuran (80 ml). The reaction mixture was stirred. A solution of potassium hydroxide (0.37 gm) in water (10.2 ml) was added to the reaction mixture. The reaction mixture was heated to 40°C, stirred and maintained. The reaction mixture was concentrated under vacuum to give a residue. The residue was dissolved in mixture of water and ethyl acetate (10 + 15 ml) and heated. The reaction mixture was cooled and the layers were separated. Syloid (0.3 gm) was added to the aqueous layer followed by addition of acetonitrile (20 ml). The reaction mixture was stirred and maintained. The contents of the reaction mixture were freezed in acetone dry ice freezing mixture. The mixture was lyophilized, the mixture was removed from lyophilizer and the solid was dried.

Yield: 2.9 g (w/w)