WO2018078383A1

WO2018078383A1 - Pharmaceutical composition comprising amorphous selexipag

Info

Publication number: WO2018078383A1
Application number: PCT/GB2017/053243
Authority: WO
Inventors: Dharmaraj Ramachandra Rao; Geena Malhotra; Srinivas Laxminarayan Pathi; Ravikumar Puppala; Anand Ramesh RANKIREDDI; Narayanaswami KOMMULA; Manish Gopaldas Gangrade
Original assignee: Cipla Limited; King, Lawrence
Priority date: 2016-10-27
Filing date: 2017-10-27
Publication date: 2018-05-03

Abstract

The present invention is directed to solid state forms of selexipag (Formula (I)), including an amorphous form of selexipag and a selexipag-containing premix, to methods for their preparation, to pharmaceutical compositions comprising them and to their use in medicine, particularly for the treatment of pulmonary arterial hypertension. (Formula (I))

Description

PHARMACEUTICAL COMPOSITION COMPRISING AMORPHOUS SELEXIPAG

Technical field of the Invention

The present invention is directed to novel solid state forms of selexipag, including an amorphous form of selexipag and a selexipag-containing premix, to methods for their preparation, to pharmaceutical compositions comprising them and to their use in medicine, particularly for the treatment of pulmonary arterial hypertension.

Background of the invention

UPTRAVI® (selexipag) is a selective non-prostanoid IP prostacyclin receptor agonist which leads to vasodilation of the pulmonary circulation.

The chemical name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N(methylsulfonyl) acetamide.

Selexipag has the following structural Formula I:

Formula I

UPTRAVI® is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

Selexipag is a pale yellow crystalline powder that is practically insoluble in water. U.S. Patent No. US7205302B2 (hereinafter referred to as the '302 patent) discloses compounds which are useful as a PGb receptor agonist, and a pharmaceutical composition. The '302 patent also discloses selexipag and processes for preparing the same.

US8791122B2 (hereinafter referred to as the ' 112 patent) discloses different crystalline forms of selexipag including Form - I, II, ΙΠ. The ' 112 patent also discloses methods for producing the crystals, and a pharmaceutical composition containing the crystal as an active ingredient.

WO 2016/193994 discloses an amorphous form of selexipag and a process for the preparation thereof.

A new polymorph of a compound possesses physical properties that differ from, and can be advantageous over, other crystalline or amorphous forms and exhibit different physical properties such as melting point, X-ray diffraction patterns, density, stability, and solubility.

There remains an unmet need for additional solid state forms of selexipag having good physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.

Therefore, it is desirable to have a stable amorphous form of selexipag which has high purity to meet the needs of regulatory agencies and also to provide a highly reproducible process for its preparation.

In view of the above, it is desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of amorphous form of selexipag. The amorphous form provided herein is stable under ordinary stability conditions with respect to purity and storage.

Objects of the invention

A primary object of the present invention is to provide an amorphous form of selexipag.

It is an object of the present invention to provide a process for the preparation of an amorphous form of selexipag.

It is an object of the present invention to provide a pharmaceutical composition comprising an amorphous form of selexipag.

It is an object of the present invention to provide a premix of selexipag.

It is an object of the present invention to provide a process for the preparation of a premix of selexipag.

It is an object of the present invention to provide an amorphous selexipag premix. It is an object of the present invention to provide a pharmaceutical composition comprising a selexipag premix.

Summary of the invention The present invention provides a solid state form of selexipag selected from the group consisting of: (i) amorphous selexipag; and (ii) a premix comprising selexipag and one or more pharmaceutically acceptable excipients.

According to one aspect, the present invention provides an amorphous form of selexipag.

According to yet another aspect of the present invention there is provided a process for the preparation of an amorphous form of selexipag comprising:

(i) mixing selexipag in a suitable solvent;

(ii) basifying the mixture with suitable base;

(iii) acidifying the solution with an acid;

(iv) filtering the solid; and (v) drying the amorphous selexipag so formed.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising an amorphous form of selexipag together with one or more pharmaceutically acceptable carriers, excipients or diluents.

According to another aspect of the present invention there is provided the use of an amorphous form of selexipag for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. According to another aspect of the invention, there is provided a process for preparing a premix of selexipag comprising:

(a) dissolving selexipag and premixing agent in a suitable solvent;

(b) distilling out the solvent from the solution obtained in step (a); and

(c) drying the selexipag premix so formed.

According to another aspect of the present invention there is provided a premix of selexipag and a pharmaceutical composition comprising the same. The present invention also provides a premix of selexipag in amorphous form and a pharmaceutical composition comprising the same. According to another aspect of the present invention there is provided a complex of selexipag and cyclodextrin and a pharmaceutical composition comprising the same. Suitable cyclodextrins include, but are not limited to, the natural cyclodextrins, a- cyclodextrin, β- cyclodextrin, and γ-cyclodextrin, and derivatives thereof.

Brief description of drawings

Figure 1 is an X-ray powder diffraction pattern of amorphous selexipag premix with Copovidone. Figure 2 is an X-ray powder diffraction pattern of amorphous form of selexipag with EUDRAGIT®.

Figure 3 is an X-ray powder diffraction pattern of amorphous selexipag. Figure 4 is a differential scanning calorimetry (DSC) curve of amorphous Selexipag.

Figure 5 is a differential scanning calorimetry (DSC) curve of a Selexipag premix with Copovidone (1 :2). Figure 6 is a differential scanning calorimetry (DSC) curve of a Selexipag premix with Copovidone (1 : 1).

Figure 7 is a differential scanning calorimetry (DSC) curve of Selexipag spray dried in Acetone (WO2016193994A).

Figure 8 is a differential scanning calorimetry (DSC) curve of Selexipag spray dried in dichloromethane (DCM) (WO2016193994A)

Figure 9 is a differential scanning calorimetry (DSC) curve of a Selexipag premix with EUDRAGIT®.

Figure 10 is an infrared (IR) pattern of amorphous Selexipag.

Figure 11 is an infrared (IR) pattern of a Selexipag premix comprising Copovidone. Figure 12 is an infrared (IR) pattern of a Selexipag premix comprising EUDRAGIT®. Detailed description of the invention

Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist in two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystalline lattice.

Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray powder diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

X-Ray Powder diffraction data were collected using a Rigaku D-Max 2200 X-Ray diffractometer. The D-Max 2200 system was equipped with a 1.2kW Cu anode X-ray tube and a scintillation detector. Cu K-alpha radiation (λ=1.5405Α) was used to obtain all patterns. Nickel filter was placed in the receiving path of the X-ray to remove Cu K-beta radiation. Samples were ground using mortar and pestle to reduce the crystal size and orientation effects. Material was then tightly packed in a glass holder using glass slides to match the surface level of the sample holder and analysed using the following parameters.

I. Source : Cu Ka

II. Wavelength : -1.5405 A°

in. Voltage : 40 KV

IV. Current : 30 mA

V. Scan axis : theta/2 theta

VI. Measurement method : Continuous

VII. Scanning range : 3°-40° 2Θ

vni. Goniometer speed : 2° 20/min

IX. Sampling width : 0.02° 2Θ

X. Divergence slit : 1°

XI. Receiving slit : 0.3 mm

XII. Counting unit : cps ΧΠΙ. Detector type : Scintillation counter

The IR experiments were performed on a Bruker Alpha IR. The sample was prepared using KBr dispersion (sample concentration 1%).

The Differential Scanning Calorimetry (DSC) experiments were performed on a TA Waters Discovery DSC. The following experimental conditions were used:

A summary of DSC data obtained is provided in the table below:

In one aspect, the present invention provides a process for the preparation of amorphous selexipag comprising the steps of:

(i) mixing of selexipag in a suitable solvent;

(ii) basifying the mixture with suitable base;

(iii) acidifying the solution with an acid;

(iv) filtering the solid; and

(v) drying the amorphous form of selexipag so formed.

According to the process of the present invention, the solvent used for mixing of selexipag in step (i) is selected from the group consisting of alcohols, chlorinated organic solvents, ketones, esters, water, or any combination thereof. Preferably, the solvent is water.

The base used in step (ii) may be selected from one or more of alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; alkoxides such as sodium methoxide, potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate; an organic base such as ammonia, triethylamine, diisopropylamine, dimethyl amine, Dimethylaminopyridine diisopropylethylamine, diisopropylmethylamine, pyridine, piperidine, morpholine and N-methyl piperidine or any combination thereof. Preferably, the base is ammonia.

The acid used in step (iii) may be selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, trifluoroacetic acid, trifluoromethane sulfonic acid, methane sulfonic acid, acetic acid, ortho phosphoric acid or any combination thereof. Preferably, the acid is acetic acid, phosphoric acid or hydrochloric acid.

The pH of the solution in step (iii) may be acidified with an acid to a pH between about 2 to about 6. The mixing temperature of step (i) may range from about 10°C to about 35°C.

The selexipag used in step (i) may be prepared in accordance with conventional methods known in the art, for example as disclosed in US7205302 and US8791122 which incorporated by reference herein.

An amorphous selexipag according to the present invention shows an X-ray powder diffraction pattern as depicted in Figure 3.

An amorphous selexipag according to the present invention demonstrates a differential scanning calorimetry (DSC) curve as depicted in Figure 4. The glass transition temperature of amorphous selexipag of the type presently disclosed may be in the range of 36°C to 56°C. Preferably, the glass transition temperature amorphous selexipag is 45.9°C.

The IR experiments were performed on a Bruker Alpha IR. The sample was prepared using KBr dispersion (sample concentration 1%). The amorphous selexipag has an a IR spectrum with characteristic absorption bands at about 3342, 3028, 2935, 1725, 1557, 1513, 1471, 1438, 1398, 1343, 1234, 1154, 1123, 1028, 1007, 972, 864, 803, 771, 755, 699 ± 2 cm^"1. Amorphous selexipag may be characterised by IR pattern as shown in Figure 10.

The amorphous form of selexipag can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets and pellets using conventional methods.

The present invention includes administration of an effective amount of stable amorphous form of selexipag (either alone or as the active component of a pharmaceutical composition) for treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

Premixes are characterised by a variety of associated properties such as stability, flow and solubility. Although there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit improved properties. The term "premix" is used herein to describe combinations of selexipag and at least one premixing agent. As used herein, the term "premixing agent" means a component, which is a pharmaceutically acceptable excipient, which is used to form a premix with selexipag. It will be appreciated that more than one premixing agent may be used to form a premix with selexipag in accordance with the present invention. The premixing agents, which are pharmaceutically acceptable excipients, used in the present invention include, but are not limited to, polyvinylpyrrolidone (also called povidone), copolymers of PVP and vinyl acetate such as copovidone (e.g. Kollidon VA 64 polyvinyl alcohol, polyethylene glycol, polyol (Mannitol), sodium starch glycolate, colloidal silicon dioxide(aerosil), hydroxypropyl methylcellulose, low substituted hydroxypropylcellulose, hydroxypropylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, sugars, EUDRAGIT®, such as EUDRAGIT® E PO, and combinations comprising one or more of the foregoing agents. Preferred premixing agents are copovidone and EUDRAGIT®, particularly EUDRAGIT® E PO. The present invention also provides a selexipag premix having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical composition. Furthermore, selexipag may be present in stable amorphous form in the selexipag premix.

The premix of the present invention is prepared by combining selexipag with suitable premixing agents in pharmaceutically acceptable proportions. In one aspect, the present invention provides a process for the preparation of a selexipag premix comprising the steps of:

(a) dissolving selexipag and a pharmaceutically acceptable excipient in one or more suitable solvent(s);

(b) distilling out the solvent(s) from the solution obtained in step (a); and

(c) drying the selexipag premix so formed. The premixing agent (pharmaceutically acceptable excipient) used in step (a) comprises one or more pharmaceutically acceptable excipients including, but not limited to, polyvinylpyrrolidone (povidone), co-polymers of PVP and vinyl acetate such as copovidone (e.g. Kollidon VA 64 polyvinyl alcohol, polyethylene glycol, polyol (Mannitol), sodium starch glycolate, colloidal silicon dioxide(aerosil), hydroxypropyl methylcellulose, low substituted hydroxypropylcellulose, hydroxypropylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, sugars, EUDRAGIT® and combinations comprising one or more of the foregoing agents. Preferred pharmaceutically acceptable excipients for use as premixing agents are copovidone and EUDRAGIT®, particularly EUDRAGIT® E PO. The weight ratio of selexipag to premixing agent (pharmaceutically acceptable excipient) may range from about 1 :10 to about 10:1. Preferably, the weight ratio is about 1 :1 or about 1 :2.

The process for preparing a selexipag premix in accordance with the present invention comprises dissolving selexipag in one or more suitable solvents. Suitable solvents include organic solvents such as, but not limited to, polar solvents such as C1-C4 alcohols (for example methanol, ethanol, propanol, butanol and rectified spirit); chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride alone or in combination. Rectified spirit is a mixture of ethanol (95.6%) and water produced as an azeotrope by distillation. Preferably, the solvent is ethanol or rectified spirit.

The dissolution temperature in step (a) may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution. Preferably, the dissolution temperature ranges from about 10°C to about 100°C.

The process for preparing the selexipag premix, wherein step (b) may be carried out by filtration and step (c) may be carried out by drying under vacuum.

A selexipag premix with copovidone according to the present invention shows an X-ray powder diffraction pattern as depicted in Figure 1. A selexipag premix with copovidone (1 :2) according to the present invention may demonstrate a differential scanning calorimetry (DSC) curve as depicted in Figure 5. The glass transition temperature of selexipag premix with copovidone (1 :2) of the type presently disclosed may be in the range of 35°C to 49°C. Preferably, the glass transition temperature amorphous selexipag is 42.4°C.

A selexipag premix with copovidone (1 :1) according to the present invention may demonstrate a differential scanning calorimetry (DSC) curve as depicted in Figure 6. The glass transition temperature of selexipag premix with copovidone (1 : 1) of the type presently disclosed may be in the range of 40°C to 49°C. Preferably, the glass transition temperature amorphous selexipag is 44.4°C.

The IR experiments were performed on a Bruker Alpha IR. The sample was prepared using KBr dispersion (sample concentration 1%). The selexipag premix comprising copovidone may have a IR spectrum with characteristic absorption bands at about 3446, 2963, 1737, 1666, 1556, 1464, 1438, 1373, 1241, 1157, 1121, 1023, 971, 848, 774, 736, 702, 650 ± 2 cm^"1. Amorphous selexipag may be characterised by IR pattern as shown in Figure 11.

A selexipag premix with EUDRAGIT® according to the present invention may show an X-ray powder diffraction pattern as depicted in Figure 2.

A selexipag premix with EUDRAGIT® according to the present invention may demonstrate a differential scanning calorimetry (DSC) curve as depicted in Figure 9. The glass transition temperature of selexipag premix with EUDRAGIT® of the type presently disclosed may be in the range of from 32°C to 50°C. Preferably, the glass transition temperature amorphous selexipag is 40.8°C.

The IR experiments were performed on a Bruker Alpha IR. The sample was prepared using KBr dispersion (sample concentration 1%). The selexipag premix comprising EUDRAGIT® may have a IR spectrum with characteristic absorption bands at about 3435, 2957, 2823, 2772, 1731, 1557, 1468, 1389, 1272, 1148, 1062, 1017, 965, 848, 772, 749, 670 ± 2 cm^"1. Amorphous selexipag may be characterised by IR pattern as shown in Figure 12.

Selexipag spray dried in Acetone demonstrates a differential scanning calorimetry (DSC) curve as depicted in Figure 7. The glass transition temperature of selexipag spray dried in Acetone is in the range of 6°C to 16°C, specifically the glass transition temperature is 11.1 °C. This example was carried out as disclosed in WO2016193994A.

Selexipag spray dried in dichloromethane (DCM) demonstrates a differential scanning calorimetry (DSC) curve as depicted in Figure 8. The glass transition temperature of selexipag spray dried in MDC is in the range of 19°C to 28°C, specifically the glass transition temperature is 23.6°C. This example was carried out as disclosed in WO2016193994A.

In another aspect, the present invention provides a premix of selexipag. In yet another aspect, the present invention provides a premix of selexipag in amorphous form.

In yet another aspect, the present invention provides a complex of selexipag and cyclodextrin.

In yet another aspect, the present invention provides a composition comprising the said complex of selexipag and cyclodextrin which can be easily processed into pharmaceutical formulations.

The invention will now be illustrated further in relation to the following examples without restricting the scope of the invention in any way.

Examples

Example 1 - Amorphous selexipag

Charged 10 gm of selexipag to 200 ml water. The mixture was stirred at 25°C to 30°C for 15 minutes. Charged 10 ml of liquid ammonia solution to the mixture to get clear solution. The mixture was cooled to 10°C to 15°C and adjusted the pH with dilute hydrochloride solution and stirred at 10°C to 15°C for 15 minutes. The solid was isolated by filtration, washed with water and dried under vacuum at 25 °C to 30°C to obtain amorphous form of selexipag.

Example 2 - Amorphous selexipag Charged 10 gm of selexipag to 200 ml water. The mixture was stirred at 25°C to 30°C for 15 minutes. Charged 10 ml of liquid ammonia solution to the mixture to get clear solution. The mixture was cooled to 10°C to 15°C and adjusted the pH with dilute acetic acid solution and stirred at 10°C to 15°C for 15 minutes. The solid was isolated by filtration, washed with water and dried under vacuum at 25 °C to 30°C to obtain amorphous form of selexipag.

Example 3 - Amorphous selexipag

Charged 10 gm of selexipag to 200 ml water. The mixture was stirred at 25°C to 30°C for 15 minutes. Charged 10 ml of liquid ammonia solution to the mixture to get clear solution. The mixture was cooled to 10°C to 15°C and adjusted the pH with dilute ortho phosphoric acid solution and stirred at 10°C to 15°C for 15 minutes. The solid was isolated by filtration, washed with water and dried under vacuum at 25°C to 30°C to obtain amorphous form of selexipag.

Example 4 - Selexipag premix

Charged 10 gm of selexipag to 200 ml ethanol and 20 gm copovidone. The mixture was stirred at 30-35°C for 15 minutes and the temperature was raised to 75±3°C and maintained at the same temperature to get clear solution. The solvent was distilled under vacuum at 45-50°C (outer temperature) to get solid premix. The premix was dried at 50°C under vacuum.

Example 5 - Selexipag premix

Charged 10 gm of selexipag to 100 ml rectified spirit (a mixture of 95.6% ethanol and water) and 20 gm copovidone. The mixture was stirred at 30-35°C for 15 minutes and the temperature was raised to 75±3°C and maintained at the same temperature to get clear solution. The solvent was distilled under vacuum at 45-50°C (outer temperature) to get solid premix. The premix was dried at 50°C under vacuum.

Example 6 - Selexipag premix

Charged 200ml of Acetone and lOg of Selexipag were stirred at 25 to 30°C. To the mixture was added charged 50g of Eudragit® and heated to 40±3°C. Distilled out acetone under vacuum below 45°C. The obtained solid was dried under vacuum at 45±5°C for 12hrs.

Example 7 - Selexipag spray dried with Acetone (as described in WO2016193994A)

Selexipag (5g) was dissolved in acetone (100ml). The solution was spray-dried at a temperature of about 70°C and an outlet temperature of about 65° C, and flow rate of 5 ml/minute. The resulting Selexipag was characterised by DSC as shown in Figure 7, with a glass transition temperature of 11.1 °C.

Example 8 - Selexipag dried in dichloromethane (PCM) (as described in WO2016193994A)

Selexipag (5g) was dissolved in Dichloromethane (50ml). The solution was then spray-dried at temperature of about 50° C and an outlet temperature of about 42° C, and flow rate of 5ml/minute. The resulting Selexipag was characterised by DSC as shown in Figure 8, with a glass transition temperature of 23.6°C.

Claims

1. A solid state form of selexipag selected from the group consisting of: (i) amorphous selexipag; and (ii) a premix comprising selexipag and one or more pharmaceutically acceptable excipients.

2. Amorphous selexipag having a Differential Scanning Calorimetry (DSC) curve substantially as depicted in Figure 4.

3. Amorphous selexipag according to claim 2, having a glass transition temperature of about 45.9°C.

4. Amorphous selexipag according to any one of claims 2 to 3 having an XRD pattern substantially as depicted in Figure 3.

5. Amorphous selexipag according to any one of claims 2 to 4 having an IR pattern substantially as depicted in Figure 10.

6. A process for preparing amorphous selexipag comprising the steps of: i. mixing selexipag in a solvent;

ii. basifying the mixture with a base;

iii. acidifying the solution with an acid;

iv. filtering the solid; and

v. drying the amorphous form of selexipag so formed.

7. A process according to claim 6, wherein the solvent is selected from the group consisting of alcohols, chlorinated organic solvents, ketones, esters and water, or any combination thereof.

8. A process according to claim 7, wherein the solvent is water.

9. A process according to any one of claims 6 to 8, wherein the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, alkoxides, bicarbonates, an organic base, or any combination thereof.

10. A process according to claim 9, wherein the organic base is ammonia, triethylamine, diisopropylamine, dimethyl amine, dimethylaminopyridine diisopropylethylamine, diisopropylmethylamine, pyridine, piperidine, morpholine and N-methyl piperidine, or any combination thereof.

11. A process according to any one of claims 6 to 10, wherein the base is ammonia.

12. A process according to any one of claims 6 to 11, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, trifluoroacetic acid, trifluoromethane sulfonic acid, methane sulfonic acid, acetic acid and ortho phosphoric acid, or any combination thereof.

13. A process according to claim 12, wherein the acid is hydrochloric acid, phosphoric acid or acetic acid.

14. A pharmaceutical composition comprising amorphous selexipag and a pharmaceutically acceptable excipient.

15. Amorphous selexipag for use in the treatment of pulmonary arterial hypertension.

16. Use of amorphous selexipag in the manufacture of a medicament for the treatment of pulmonary arterial hypertension.

17. A method of treating pulmonary arterial hypertension comprising administering to a patient in need thereof, a therapeutically effective amount of amorphous selexipag.

18. A premix comprising selexipag and one or more pharmaceutically acceptable excipients.

19. A premix according to claim 18 wherein the weight ratio of selexipag to pharmaceutically acceptable excipient ranges from about 1 :10 to about 10:1.

20. A premix according to claim 18 or claim 19, wherein selexipag is present in an amorphous form.

21. A premix according to any one of claims 18 or 20, wherein the pharmaceutically acceptable excipient is copovidone.

22. A premix according to claim 21 having an XRD pattern as depicted in Figure 1.

23. A premix according to claim 21 or 22 having an IR pattern substantially as depicted in Figure 11.

24. A premix according to any one of claims 18 to 23, wherein the weight ratio of selexipag to copovidone is about 1 :1.

25. A premix according to claim 24, having a Differential Scanning Calorimetry (DSC) curve substantially as depicted in Figure 6.

26. A premix according to claim 25, having a glass transition temperature of about 44.4°C.

27. A premix according to any of claims 18 to 23, wherein the weight ratio of selexipag to copovidone is about 1 :2.

28. A premix according to claim 27, having a having a Differential Scanning Calorimetry (DSC) curve substantially as depicted in Figure 5.

29. A premix according to claim 28, having a glass transition temperature of about 42.4°C.

30. A premix according to any one of claims 18 to 20, wherein the pharmaceutically acceptable excipient is EUDRAGIT®.

31. A premix according to claim 30 having an XRD pattern as depicted in Figure 2.

32. A premix according to claim 30 or 31 having an IR pattern substantially as depicted in Figure 12.

33. A premix according to any one of claims 30 to 32, having a Differential Scanning Calorimetry (DSC) curve substantially as depicted in Figure 9.

34. A premix according to claim 33, having a glass transition temperature of about 40.8°C.

35. A process for preparing a premix of selexipag comprising the steps of: i. dissolving selexipag and at least one pharmaceutically acceptable excipient in a solvent to form a solution;

ii. distilling out the solvent from the solution; and

iii. drying the selexipag premix so formed.

36. A process according to claim 35, wherein the pharmaceutically acceptable excipient is EUDRAGIT® or copovidone.

37. A process according to claim 35 or claim 36, wherein the solvent is selected from the group consisting of polar solvents, chlorinated organic solvents, and any combination thereof.

38. A process according to claim 37, wherein the solvent is ethanol or rectified spirit.

39. A process according to any of one claims 35 to 38, wherein the weight ratio of selexipag to pharmaceutically acceptable excipient ranges from about 1 :10 to about 10:1.

40. A process according to any one of claims 35 to 39, wherein selexipag is present in amorphous form.

41. A pharmaceutical composition comprising a premix according to any one of claims 18 to 34.

42. A pharmaceutical composition according to claim 41, for use in the treatment of pulmonary arterial hypertension.

43. A method for treating pulmonary arterial hypertension comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 41.