WO2018022704A1 - Crystalline form vi of selexipag - Google Patents

Crystalline form vi of selexipag Download PDF

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WO2018022704A1
WO2018022704A1 PCT/US2017/043867 US2017043867W WO2018022704A1 WO 2018022704 A1 WO2018022704 A1 WO 2018022704A1 US 2017043867 W US2017043867 W US 2017043867W WO 2018022704 A1 WO2018022704 A1 WO 2018022704A1
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selexipag
theta
degrees
solid state
according
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PCT/US2017/043867
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French (fr)
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Nidia VILLALVA
Ivon CANTE
Yaneth CONTRERAS
Ruth OROPEZA
Ales Gavenda
Hana KANTOR
Alexandr Jegorov
Alejandra MILLAN
Jiri Faustmann
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Teva Pharmaceuticals International Gmbh
Teva Pharmaceuticals Usa, Inc.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20Nitrogen atoms

Abstract

The present disclosure relates to solid state forms of Selexipag, processes for preparation thereof and pharmaceutical compositions thereof.

Description

CRYSTALLINE FORM VI OF SELEXIPAG

Cross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application Nos.

62/367,009, filed July 26, 2016; 62/436,797, filed December 20, 2016; 62/469,215, filed March 9, 2017; and 62/525,464, filed June 27, 2017, which applications are incorporated herein by reference in their entireties.

Field of the Invention

[0002] The present disclosure relates to solid state forms of Selexipag, processes for preparation thereof and pharmaceutical compositions thereof.

Background of the Invention

[0003] Selexipag has the chemical name 2-{4-[(5,6-diphenylpyrazin-2- yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide. Selexipag has the following chemical structure:

Figure imgf000002_0001

[0004] Selexipag is being developed by Actelion and Nippon Shinyaku for the treatment of arteriosclerosis obliterans, pulmonary hypertension and Raynaud's disease secondary to systemic sclerosis.

[0005] Selexipag is disclosed in US 7,205,302. US 8,791,122, US 9,284,280 and US 2014- 0155414 disclose polymorphs of Selexipag, denominated forms I, II and III. WO

2017/040872 discloses form IV and V of Selexipag.

[0006] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Selexipag, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (1 C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0007] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0008] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as 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. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a 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 polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

[0009] For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Selexipag.

Summary of the Invention

[0010] The present disclosure relates to solid state forms of Selexipag, processes for preparation thereof, and pharmaceutical compositions comprising these solid state forms. [0011] The present disclosure also provides uses of the solid state forms of Selexipag for preparing other solid state forms of Selexipag, Selexipag salts and solid state forms thereof.

[0012] The present disclosure also provides solid state forms of Selexipag of the present disclosure for uses in the preparation of other solid state forms of Selexipag, Selexipag salts and solid state forms thereof.

[0013] The present disclosure further provides processes for preparing other solid state forms of Selexipag, Selexipag salts and solid state forms thereof.

[0014] The present disclosure also encompasses the described solid state forms of Selexipag for uses in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.

[0015] The present disclosure further encompasses uses of any one or combination of the described solid state forms of Selexipag for the preparation of pharmaceutical compositions and/or formulations.

[0016] The present disclosure further provides pharmaceutical compositions comprising any one or combination of the solid state forms of Selexipag according to the present disclosure.

[0017] The present disclosure also encompasses pharmaceutical formulations comprising any one or combination of the described solid state forms of Selexipag and at least one pharmaceutically acceptable excipient.

[0018] The present disclosure encompasses processes to prepare said pharmaceutical formulations of Selexipag comprising combining any one or combination of the described solid state forms and at least one pharmaceutically acceptable excipient.

[0019] The present disclosure further provides solid state forms defined herein as well as the pharmaceutical compositions or formulations of the solid state forms of Selexipag as medicaments, particularly for the treatment of arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.

[0020] The present disclosure also provides methods of treating arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis; comprising administering a therapeutically effective amount of any one or combination of the solid state forms of Selexipag of the present disclosure, or at least one of the herein described pharmaceutical compositions or formulations, to a subject suffering from arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis, or otherwise in need of the treatment. [0021] The present disclosure also provides uses of the solid state forms of Selexipag of the present disclosure, or at least one of the above pharmaceutical compositions or formulations for the manufacture of medicaments for treating arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.

Brief Description of the Figures

[0022] Figure 1 shows an X-ray powder diffractogram (XRPD) of Form VI of Selexipag.

[0023] Figure 2 shows an XRPD of Form VII of Selexipag.

[0024] Figure 3 shows an TGA thermogram of Form VII of Selexipag.

[0025] Figure 4 shows an XRPD of Form IV of Selexipag.

[0026] Figure 5a shows solid state 1 C-NMR spectrum of Form VI of Selexipag at the range of 200-0 ppm.

[0027] Figure 5b shows solid state 1 C-NMR spectrum of Form VI of Selexipag at the range of 200-100 ppm.

[0028] Figure 5c shows solid state 1 C-NMR spectrum of Form VI of Selexipag at the range of 100-0 ppm.

[0029] Figure 6a shows full range FT-IR spectrum of Form VI of Selexipag.

[0030] Figure 6b shows FT-IR spectrum of Form VI of Selexipag at the range of 1800-400 cm"1.

[0031] Figure 7 shows an XRPD of Form VI of Selexipag (prepared according to example 9).

[0032] Figure 8 shows an XRPD of Form II of Selexipag.

Detailed Description of the Invention

[0033] The present disclosure relates to solid state forms of Selexipag, processes for preparation thereof and pharmaceutical compositions comprising the solid state form(s). The disclosure also relates to the conversion of the described solid state forms of Selexipag to other solid state forms of Selexipag, Selexipag salts and their solid state forms thereof.

[0034] The solid state forms of Selexipag according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowabihty, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density.

[0035] A crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure. Such data include, for example, powder X-ray diffractograms (XRPD) and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called "fingerprint") which can not necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Selexipag referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of the Selexipag, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0036] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, the solid state form of Selexipag described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject solid state form of Selexipag. Accordingly, in some embodiments of the disclosure, the described solid state forms of Selexipag may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other solid state forms of Selexipag.

[0037] As used herein, unless stated otherwise, XRPD peaks reported herein are optionally measured using CuKa radiation, λ = 1.5419A. Preferably, PXRD peaks reported herein are measured using CuK a radiation, λ = 1.5419 A, at a temperature of 25 ± 3°C. Alternatively, if an instrument with a different wavelength is used, for example, when using high resolution XRD method, such as synchrotron, the data may be corrected to wavelength of 1.5419 respectively.

[0038] As used herein, unless stated otherwise, 1 C solid state NMR was measured at 125 MHz at 0°C at a spin rate of 11 kHz.

[0039] As used herein, unless stated otherwise, FT-IR was measured using a KBr pellet.

[0040] As used herein, unless stated otherwise, TGA was carried out at a heating rate of 10°C/min, preferably under a nitrogen flow, preferably wherein the nitrogen flow is at the rate of 50 mL/min.

[0041] The modifier "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses the range "from 2 to 4." When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1 " means from 0.9-1.1.

[0042] As used herein, the term "isolated" in reference to solid state forms of Selexipag of the present disclosure corresponds to a solid state form of Selexipag that is physically separated from the reaction mixture in which it is formed.

[0043] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "room temperature", often abbreviated "RT." This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, about 22°C to about 27°C, or about 25°C.

[0044] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, about 10 to about 18 hours, or about 16 hours.

[0045] As used herein, and unless stated otherwise, the term "anhydrous" in relation to crystalline Selexipag relates to crystalline Selexipag which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an "anhydrous" form does not contain more than about 1% (w/w) of either water or organic solvents as measured for example by TGA. [0046] The term "solvate", as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate. " The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0047] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding MTBE (1.5 v/v) to a 100 mL reaction mixture would indicate that 150 mL of MTBE was added.

[0048] As used herein the term "non-hygroscopic" in relation to crystalline Selexipag refers to less than about 0.2% (w/w) absorption of water at about 25°C and about 80% relative humidity (RH) by the crystalline Selexipag as determined for example by TGA. Water can be, for example, atmospheric water.

[0049] As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 50 mbar.

[0050] As used herein the term "crystalline Form IV " in relation to crystalline Selexipag refers to crystalline Selexipag Form IV as described in PCT/US 16/050021. For example, crystalline Form IV is characterized by any one of the following: an XRPD partem having peaks at 4.3, 6.5, 11.9, 16.2, 18.0, 19.1 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta, an XRPD pattern having peaks at 4.3, 6.5, 1 1.9, 16.2, 18.0, 19.1 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta and also having any one or more additional peak selected from: 12.4, 12.8, 13.3, 14.5, and 21.9 degrees two theta ± 0.2 degrees two theta; an XRPD pattern having peaks at 4.4, 6.6, 12.0, 16.3, and 21.1 degrees 2-theta ± 0.2 degrees 2-theta, an XRPD pattern having peaks at 4.4, 6.6, 12.0, 16.3, and 21.1 degrees 2-theta ± 0.2 degrees 2-theta and also having any one or more additional peak selected from: 12.6, 13.0, 13.5, 14.6, and 22.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4 of the present disclosure or by the following unit cell data: Cell length a 41.231 A

Cell length b 14.486 A

Cell length c 8.863 A

Cell angle alpha 90.00°

Cell angle beta 90.00°

Cell angle gamma 90.00°

Cell volume 5393.47 A3

Cell measurement temperature ambient

Symmetry cell setting orthorhombic

Symmetry space group name Pccn

[0051] Crystalline Form IV can be characterized by any data or combinations of data described in PCT/US 16/050021 (published as WO 2017/040872).

[0052] As used herein the term "crystalline Form II " in relation to crystalline Selexipag refers to crystalline Selexipag Form II as described in US 9,340,516. For example, crystalline Form II is characterized by an XRPD pattern having peaks at 9.0, 12.9, 20.7 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta or by an XRPD pattern as depicted in Figure 8

[0053] The present disclosure comprises a crystalline form of Selexipag designated as Form VI. The crystalline Form VI of Selexipag can be characterized by data selected from one or more of the following:

a) an XRPD pattern having peaks at 8.2, 10.1, 12.5, 14.3 and 16.4 degrees 2- theta i 0.2 degrees 2-theta;

b) an XRPD pattern having peaks at 10.1, 12.6, 13.1 , 14.0, and 14.3 degrees 2- theta i 0.2 degrees 2-theta;

c) an XRPD pattern as depicted in Figure 1 ;

d) an XRPD pattern as depicted in Figure 7;

e) a solid state 1 C-NMR spectrum having characteristic peaks at 171.8, 148.6, 137.0, 130.7 and 129.1 ppm ± 0.2 ppm;

f) a solid state 1 C-NMR spectrum having the following chemical shift absolute differences from a reference peak at 126.0 ppm ± 1 ppm: 45.8, 22.5, 1 1.0, 4.7, and 3.1 ppm ± 0.2 ppm;

g) a solid state 1 C-NMR spectrum as depicted in Figures 5a or 5b or 5c; and/or characterized by data selected from:

h) a combination of any one or more of (a), (c), (e), (f) and (g), or i) a combination of any one or more of (b), (d), (e), (f) and (g).

[0054] Crystalline Form VI of Selexipag may be further characterized by data selected from one or more of the following:

a) an XRPD partem having peaks at 8.2, 10.1 , 12.5, 14.3 and 16.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 9.0, 10.6, 13.5, 14.0 or 18.8 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD partem having peaks at 10.1 , 12.6, 13.1, 14.0, and 14.3 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 10.6, 13.5, 16.4, 20.9 or 21.1 degrees 2-theta ± 0.2 degrees 2-theta;

c) a solid state 1 C-NMR spectrum having peaks at: 171.8, 152.3, 148.6, 140.1 , 138.0, 137.0, 130.7, 129.8, 129.1, 127.4, 126.0, 71.1 , 66.2, 44.6, 41.4, 26.6, 22.9, 19.6 and 18.9 ppm ± 0.2 ppm;

d) a FT-IR spectrum having peaks at 744, 845, 1373, 1438, and 1505 cm"1 ± 4 cm"1;

e) a FT-IR spectrum as depicted in Figures 6a or 6b; and/or

characterized by data selected from:

f) a combination of any one or more of (a), (c), (d) and (e), or

g) a combination of any one or more of (b), (c), (d) and (e).

[0055] Crystalline Form VI of Selexipag may be further characterized by a FT-IR spectrum having peaks at 492, 51 1 , 541 , 567, 586, 701 , 705, 744, 760, 775, 800, 828, 845, 872, 922, 968, 996, 1009, 1029, 1057, 1072, 1082, 1094, 1 109, 1 131, 1147, 1 159, 1171 , 1 184, 1242, 1284, 1292, 1306, 1321 , 1341, 1373, 1403, 1438, 1471 , 1483, 1505, 1566, 1582, 1722, 2562, 2874, 2922 and 2977 cm"1 ± 4 cm"1.

[0056] Crystalline Form VI of Selexipag may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 8.2, 10.1, 12.5, 14.3 and 16.4 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD partem as depicted in Figure 1 or by solid state 1 C-NMR spectrum having characteristic peaks at 171.8, 148.6, 137.0, 130.7 and 129.1 ppm ± 0.2 ppm and a FT-IR spectrum as depicted in Figures 6a or 6b.

[0057] In certain embodiments, the present disclosure comprises polymorphically pure Form VI, i.e. Form VI (as described in any of the embodiments disclosed herein) which is substantially free of any other solid state (or polymorphic) forms. The term polymorphically is defined herein above. Particularly, polymorphically pure form VI of the present disclosure contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or 0% of crystalline Form II of Selexipag, which is defined herein above. Thus, crystalline Form VI of Selexipag described herein contains greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of Crystalline Form VI of Selexipag.

Accordingly, in some embodiments of the disclosure, Crystalline Form VI of Selexipag may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of Crystalline Form II of Selexipag.

[0058] Typically, the amount of crystalline Selexipag form II in the crystalline Selexipag form VI of the present disclosure can be measured by PXRD using the peaks at 12.9 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta to quantify the amount of form II.

[0059] The polymorphically pure crystalline Form VI of Selexipag can be characterized by data selected from one or more of the following:

a) an XRPD pattern having peaks at 10.1, 12.6, 13.1 , 14.0, and 14.3 degrees 2- theta ± 0.2 degrees 2-theta;

b) an XRPD pattern as depicted in Figure 7;

c) a solid state 1 C-NMR spectrum having characteristic peaks at 171.8, 148.6, 137.0, 130.7 and 129.1 ppm ± 0.2 ppm;

d) a solid state 1 C-NMR spectrum having the following chemical shift absolute differences from a reference peak at 126.0 ppm ± 1 ppm: 45.8, 22.5, 1 1.0, 4.7, and 3.1 ppm ± 0.2 ppm;

e) a solid state 1 C-NMR spectrum as depicted in Figures 5a or 5b or 5c; and f) combinations of these data.

[0060] Polymorphically pure Crystalline Form VI of Selexipag may be further

characterized by data selected from one or more of the following:

a) an XRPD partem having peaks at 10.1 , 12.6, 13.1, 14.0, and 14.3 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 10.6, 13.5, 16.4, 20.9 or 21.1 degrees 2-theta ± 0.2 degrees 2-theta;

b) a solid state 1 C-NMR spectrum having peaks at: 171.8, 152.3, 148.6, 140.1 , 138.0, 137.0, 130.7, 129.8, 129.1, 127.4, 126.0, 71.1 , 66.2, 44.6, 41.4, 26.6, 22.9, 19.6 and 18.9 ppm ± 0.2 ppm;

c) a FT-IR spectrum having peaks at 744, 845, 1373, 1438, and 1505 cm"1 ± 4 cm1; d) a FT-IR spectrum as depicted in Figures 6a or 6b; and

e) combinations of these data.

[0061] Crystalline Form VI of Selexipag may be further characterized by a FT-IR spectrum having peaks at492, 511, 541, 567, 586, 701, 705, 744, 760, 775, 800, 828, 845, 872, 922, 968, 996, 1009, 1029, 1057, 1072, 1082, 1094, 1109, 1131, 1147, 1159, 1171, 1184, 1242, 1284, 1292, 1306, 1321, 1341, 1373, 1403, 1438, 1471, 1483, 1505, 1566, 1582, 1722, 2562, 2874, 2922 and 2977 cm"1 ± 4 cm"1.

[0062] As discussed above, depending on which other solid state form it is compared with, Form VI of Selexipag may according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density. Particularly, crystalline Form VI of Selexipag of the present disclosure exhibits for example enhanced solubility in aqueous medium at pH=l.1 (HCl buffer) and at pH 6.8 (phosphate buffer) in comparison with Form I of US 8,791,122. The increased solubility of Form VI of Selexipag is particularly advantageous, as Selexipag is practically insoluble in such a medium. The increased solubility of Form VI of Selexipag may enhance bioavailability of the API.

[0063] The present disclosure further comprises a process for preparing Crystalline Form VI of Selexipag. The process comprises:

a) preparing a concentrated solution of Selexipag in ethyl acetate;

b) preparing a suspension comprising Selexipag Form IV in ^-heptane; and c) quickly adding the suspension of step b) into the concentrated solution of step a) to obtain a mixture, from which Form VI precipitates.

[0064] Typically, the concentrated solution in step a) comprises Selexipag at a

concentration of from about 0.05 to about 2.5, or from about 0.08 to about 1, or from about 0.1 to about 0.5 g/mL.

[0065] The quick addition in step c) is usually an addition over a period of less than 5 minutes. The addition is typically done while stirring, typically at a speed of about 220 rpm. The obtained mixture can be further stirred, preferably at the same speed, preferably for a period of at least about 120 minutes. [0066] The precipitated solid is then filtered; preferably it is washed with cold ^-heptane. The washed solid is then drained (i.e. dried), preferably overnight, for example, a period of aboutl2 hours. Optionally, the solid can be further stored at ambient temperature for example at a temperature of from about 15°C to about 25°C.

[0067] The present disclosure further comprises a second process for preparing

Crystalline Form VI of Selexipag. The process comprises crystallizing Form VI from a mixture comprising methyl ethyl ketone ("MEK") as a solvent and n-heptane as an anti- solvent.

[0068] Typically, the crystallization comprises providing a solution of Selexipag in MEK and combining the obtained solution with n-heptane to obtain a suspension.

Preferably, the n-heptane is cooled prior to combining it with the solution. Typically it is cooled to temperature of from about +5°C to about -20°C, from about -5°C to about -15°C, or preferably about -10°C.

[0069] Preferably, combining the solution with n-heptane is done by reverse addition, i.e., the solution of Selexipag in MEK is added to n-heptane. Preferably, the addition is done under stirring.

[0070] The obtained suspension can be further stirred. Preferably, stirring is performed at a temperature of from about -5°C to about -10°C. Preferably, stirring is performed for a period of from about 0.5 hour to about 1.5 hours, preferably 1 hour.

[0071] The suspension can be further maintained, typically at a temperature of from about - 15°C to about -30°C, preferably about -20°C.

[0072] The process for preparing Crystalline Form VI may further comprise recovering the crystalline form. The recovery may be done, for example, by filtering the suspension, and drying. Typically, drying is done by maintaining the filtered mass on the filter or in a cabinet dryer under nitrogen stream, preferably, at room temperature.

[0073] The present disclosure further comprises a third process for preparing Crystalline Form VI of Selexipag. The process comprises crystallizing Form VI from a mixture comprising a solvent selected from methyl ethyl ketone ("MEK"), ethanol, and n-octanol; and an anti-solvent selected from n-heptane, n-octane and n-hexane; or from a mixture comprising n-butanol and n-heptane.

[0074] Preferably, the process comprises crystallizing Form VI from a mixture comprising MEK n-heptane; MEK and n-octane; MEK and n-hexane; ethanol and n-heptane; n-butanol and n-heptane; or n-octanol and n-heptane. [0075] Typically, the crystallization comprises providing a solution of Selexipag in a solvent as described above and combining the obtained solution with an antisolvent to obtain a suspension.

[0076] Preferably, the antisolvent is cooled prior to combining it with the solution.

Typically it is cooled to temperature of from about +5°C to about -20°C, from about -5°C to about -15°C, or preferably about -10°C.

[0077] The obtained suspension can be further stirred. Preferably, stirring is performed at a temperature of from about -5°C to about -10°C. Preferably, stirring is performed for a period of from about 0.5 hour to about 1.5 hours, preferably 1 hour.

[0078] The process for preparing Crystalline Form VI may further comprise recovering the crystalline form. The recovery may be done, for example, by filtering the suspension, and drying. Typically, drying is done by maintaining the filtered mass on the filter or in a cabinet dryer under nitrogen stream, preferably, at room temperature.

[0079] The present disclosure comprises a crystalline form of Selexipag designated as Form VII. The crystalline Form VII of Selexipag can be characterized by data selected from one or more of the following: an XRPD pattem having peaks at 6.3, 8.6, 16.6, 17.2 and 18.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattem as depicted in Figure 2; and combinations of these data. Crystalline Form VII of Selexipag may be further characterized by the XRPD pattern having peaks at 6.3, 8.6, 16.6, 17.2 and 18.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 20.1, 21.7, 22.3, 24.1 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0080] Crystalline Form VII of Selexipag may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 6.3, 8.6, 16.6, 17.2 and 18.6 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattem as depicted in Figure 2.

[0081] The above crystalline Form VII of Selexipag may be an ethyl acetate solvate. Form VII can be characterized by the TGA thermogram depicted in Figure 3.

[0082] The present disclosure further comprises a process for preparing Crystalline Form VII of Selexipag. The process comprises:

a) preparing a concentrated solution of Selexipag in ethyl acetate;

b) preparing a suspension comprising Selexipag Form IV in ^-heptane; and c) adding the concentrated solution of step a) into the suspension of step b) into to obtain a mixture, from which Form VII precipitates. [0083] Typically, the concentrated solution in step a) comprises Selexipag at a

concentration of from about 0.05 to about 2.5, or from about 0.08 to about 1, or from about 0.1 to about 0.5 g/mL.

[0084] Typically, the ratio of the n-heptane in the suspension and the ethyl acetate in the concentrated solution is of about less than 5 [i.e. less than about 1 :5 of n-heptane :

ethylacetate], preferably from about 4 to about 5 [i.e. 1 :4 to about 1 :5], or from about 4.3 to about 5 [i.e. about 1 :4.3 to about 1 :5].

[0085] The addition in step c) is done while stirring, typically at a speed of about 236 rpm. The obtained mixture can be further stirred, preferably at the same speed, preferably for a period of from about 10 minutes to about 120 minutes, preferably for at least about 90 minutes, or more preferably about 120 minutes.

[0086] The precipitated solid is then filtered; preferably it is washed with cold ^-heptane. The washed solid is then drained (i.e. dried) for about 15 minutes. Optionally, the drained (i.e. dried) solid can be further stored at ambient temperature, for example at a temperature of from about 15°C to about 25°C.

[0087] The present disclosure also provides uses of the solid state forms of Selexipag for preparing other solid state forms of Selexipag, Selexipag salts and their solid state forms thereof.

[0088] The present disclosure also provides the solid state forms of Selexipag of the present disclosure for use in the preparation of other solid state forms of Selexipag, Selexipag salts and their solid state forms thereof, particularly crystalline Selexipag Form IV. In a specific embodiment, the present disclosure provides crystalline Selexipag Form VII for use in the preparation of crystalline Selexipag Form IV.

[0089] The present disclosure provides a process for preparing crystalline Selexipag Form

IV comprising drying crystalline Selexipag Form VII. Typically, the drying is done under vacuum, at about 50°C for a sufficient time, for example about 24 hours.

[0090] The present disclosure further encompasses processes for preparing Selexipag salts or solid state forms thereof. The processes comprise preparing any one or combination of the solid state forms of the present disclosure, and converting it to Selexipag salt. The conversion can be done, for example, by processes comprising reacting the obtained Selexipag solid state form with an appropriate base to obtain the corresponding base-addition salt.

[0091] In another embodiment, the present disclosure encompasses the above described solid state forms of Selexipag for uses in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.

[0092] In another embodiment, the present disclosure encompasses uses of the above described solid state forms of Selexipag for the preparation of pharmaceutical compositions and/or formulations. The present disclosure also provides the solid state forms of Selexipag of the present disclosure for uses in the preparation of pharmaceutical compositions and/or formulations.

[0093] The present disclosure further provides pharmaceutical compositions comprising any one or combination of the solid state forms of Selexipag according to the present disclosure.

[0094] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising any one or combination of the above described solid state forms of Selexipag and at least one pharmaceutically acceptable excipient.

[0095] The present disclosure encompasses processes to prepare said formulations of Selexipag comprising combining any one or combination of the above solid state forms of Selexipag and at least one pharmaceutically acceptable excipient.

[0096] The solid state forms of Selexipag as defined herein, as well as the pharmaceutical compositions or formulations thereof, can be used as medicaments, particularly for the treatment of arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.

[0097] The present disclosure also provides methods of treating arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis; comprising administering a therapeutically effective amount of any one or combination of the solid state forms of Selexipag in the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis, or otherwise in need of the treatment.

[0098] The present disclosure also provides uses of the solid state forms of Selexipag the present disclosure, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.

[0099] The solid state forms of Selexipag the present disclosure can be used to prepare Crystalline Form IV of Selexipag. [00100] In additional embodiment, the present disclosure further comprises processes for preparing Crystalline Form IV of Selexipag. The process comprises:

a) preparing a concentrated solution of Selexipag in ethyl acetate;

b) preparing a suspension comprising Selexipag Form IV in ^-heptane; and c) quickly adding the concentrated solution of step a) into the suspension of step b) into to obtain a mixture, from which Form IV precipitates.

[00101] Typically, the concentrated solution in step a) comprises Selexipag at a concentration as defined above.

[00102] Typically, the ratio of the ^-heptane in the suspension and the ethyl acetate in the concentrated solution is of about more than about 5, preferably more than about 5.5, more preferably from about 5.6 to about 8.3, or from about 5.6 to about 8.5, or from about 5.6 to about 9.0.

[00103] The quick addition in step c) is usually an addition over a period of less than 5 minutes

[00104] The addition in step c) can be done while stirring, typically at a speed of about 155 rpm. The obtained mixture can be further stirred, preferably at the same speed, preferably for a period of from about 10 minutes to about 120 minutes, preferably for at least about 90 minutes, or about 120 minutes.

[00105] The precipitated solid is then filtered, preferably it is washed with cold (-10°C) n- heptane. The washed solid is then drained (i.e. dried) within the range from about 15 minutes until overnight. The drained (i.e. dried) solid can be further dried, typically under vacuum. Preferably the product is dried at a temperature of about 45°C, or about 50°C, preferably for a period of about 14 hours.

[00106] Typically, step b) of the above described processes comprises preparing a suspension of Selexipag in n-heptane, preferably by suspending Selexipag form IV in n- heptane, and stirring, preferably wherein the stirring is for 15-180 minutes (more preferably at 30-90 minutes) at a temperature of about -10 to about 25°C (preferably about -5 to about 10°C), preferably the stirring is conducted at a rate of about 50-190 rpm, more preferably 100-180 rpm.

[00107] The present disclosure further comprises a second process for preparing Crystalline Form IV of Selexipag. The process comprises crystallizing Form IV from a mixture comprising a solvent selected from methyl iso-butyl ketone ("MIBK"), isopropyl acetate, isobutyl acetate, n-butyl acetate, toluene, m-xylene, diisopropyl ketone ("DIPK"), diisobutyl ketone ("DIBK"); and an anti-solvent selected from n-heptane, n-octane and n-hexane; or from a mixture comprising n-butanol and n-hexane.

[00108] Preferably, the process comprises crystallizing Form IV from a mixture comprising n-butyl acetate and n-heptane; toluene and n-heptane; toluene and n-hexane; m-xylene and n- heptane; diisopropyl ketone and n-heptane; diisobutyl ketone and n-heptane or n-butanol and n-hexane.

[00109] Typically, the crystallization comprises providing a solution of Selexipag in a solvent as described above and combining the obtained solution with an antisolvent to obtain a suspension.

[00110] Preferably, the antisolvent is cooled prior to combining it with the solution.

Typically it is cooled to temperature of from about +5°C to about -20°C, from about -5°C to about -15°C, or preferably about -10°C.

[00111] The obtained suspension can be further stirred. Preferably, stirring is performed at a temperature of from about -5°C to about -10°C. Preferably, stirring is performed for a period of from about 0.5 hour to about 1.5 hours, preferably 1 hour.

[00112] The process for preparing Crystalline Form VI may further comprise recovering the crystalline form. The recovery may be done, for example, by filtering the suspension, and drying. Typically, drying is done by maintaining the filtered mass on the filter or in a cabinet dryer under nitrogen stream, preferably, at room temperature.

[00113] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.

Analytical Methods

[00114] X-ray powder diffraction method:

[00115] Powder X-ray Diffraction was performed on PANalytical or X'Pert Pro X-Ray powder diffractometers; CuKa radiation (λ = 1.541874 A); X'Celerator detector with active length 2.1221 degrees 2-theta; laboratory temperature 25 ± 2°C; zero background sample holders. Prior to analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder. Optionally, silicon powder can be added in a suitable amount as internal standard in order to calibrate the positions of the diffractions. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed using a cover glass.

Measurement parameters:

Scan range 3 - 40 degrees 2-theta

Scan mode continuous

Step size 0.0167 degrees

Step size 42 s

Sample spin 60 rpm

Sample holder zero background silicon plate

[00116] Differential scanning calorimetry (DSC) method

[00117] DSC measurements were performed on a differential scanning calorimeter DSC Discovery (TA Instruments). Aluminum crucibles 40 μΐ were used for sample preparation. Typical sample weight was between 1 and 5 mg.

Measurement parameters:

Temperature range at least 25 - 200°C;

Heating rate l°C/min;

Nitrogen flow 50 mL/min.

[00118] Thermogravimetric analysis (TGA) method

[00119] TGA measurements were performed on a Thermogravimetric analyzer TGA Discovery (TA Instruments). Alumina crucibles 100 μΐ were used for sample preparation. Usual sample weight was between 5 and 15 mg.

Measurement parameters:

Temperature range at least 25 - 200°C;

Heating rate 10° CI min;

Nitrogen flow 50 mL/min.

[00120] Solid state 1 C-NMR method

[00121] 1 C CP/MAS NMR spectra were measured at 125 MHz using Bruker Avance III HD 500 WB/US NMR spectrometer (Karlsruhe, Germany, 2013) at magic angle spinning (MAS) frequency ωτ/2π = 11 kHz. In all cases finely powdered samples were placed into 4- mm ZrC>2 rotors and the standard "cpmas" pulse program was used. During acquisition of the data the high-power dipolar decoupling SPINAL 64 was applied. The flip-pulse length was 4.8 μβ. Applied nutation frequency of B^H) field was ω /2π = 89.3 kHz. Nutation frequency of Bi(1 C) and Bi^H) fields during cross-polarization was α>ι/2π = 62.5 kHz. The cross- polarization contact time was 2 ms. The 1 C scale was calibrated with glycine as external standard (176.03 ppm - low-field carbonyl signal). The number of scans was 55, repetition delay was 4 s.

[00122] The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation of samples. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Avy2 was less than 3.5 Hz at 250 ms of acquisition time). Taking into account frictional heating of the samples during fast rotation all NMR experiments were performed at 305 K (precise temperature calibration was performed)

[00123] FT-IR method

[00124] KBr pellet was prepared and FTIR transmission spectrum was recorded on Nicolet 380 spectrometer, equipped with KBr beam splitter and DTGS KBr detector.

Instrument parameters:

Spectral range: 4000-400 cm"1

Resolution: 4.0 cm"1

Number of scans: 64

Sample gain: 1

Optical velocity: 0.6329

Aperture: 100

Examples

[00125] The following examples may include steps in which a mixture, a solution or a suspension are stirred. Typically, the stirring is performed by a PTFE stirrer blade.

Example 1: Preparation of Selexipag

[00126] A. Route 1

[00127] Crude Selexipag can be obtained by any method known in the art, for example by the method described in US 7,205,302 or according to the following.

[00128] B. Route 2

[00129] Step a: Preparation of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino)butan-l-ol

[00130] To 50 g (0.161 mol) of 5-bromo-2,3-diphenylpyrazine, 116 g (0.884 mol, 5.5 eq/mol) of 4-(isopropylamino)-butan-l-ol and 13.33 g of KI (0.080 mol, 0.5 Eq/mol) were added. The reaction mixture was stirred, warmed and then heated up to 140°C for about 18- 20 hrs. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to room temperature. After the reaction was completed, the following work up step was performed:

[00131] Option 1 : Ethyl acetate was added (500 mL, 10 vol) and the organic phase was washed with water (150 mL, 3 vol). The organic phase was separated and aqueous phase was extracted with ethyl acetate (150 mL, 3 vol). The organic phases were joined and washed with water (200 mL, 2 vol) three times.

[00132] The solvent was distilled off under vacuum at not more than ("NMT") 40°C until 1 vol (oil appearance).

[00133] Option 2: The material (mixture) was dissolved in acetone (250 mL, 5 vol), the solution obtained was cooled down to 0°C to 5°C and anti-solvent / water was added (1000 mL, 20 vol) for 40 minutes, then the suspension was stirred for about 30 minutes at about 0°C-5°C. The solid material was filtered and washed with water (200 mL, 4 vol). Crude wet product was obtained as yellow solid yielding 101.8 % WY (87 % MY), HPLC purity 90.8% on area at this stage.

[00134] The crude material, obtained in either of the above described options, was purified through crystallization from acetone :«-heptane as follows: to a solution of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol crude in acetone (175 mL, 3.5 vol) at 0°C - 5°C, hexane (600 mL, 12 vol) dropwise in about 120 min was added, then the precipitated mixture was cooled down to about -10°C and stirred for about 60 min. The product was filtered off and washed with hexane (250 mL, 5 vol) and dried under vacuum at 25°C. Pure product was obtained as yellowish solid yielding overall 77.2%, (66.5% MY), HPLC purity 98.2% on area.

[00135] Step b: Preparation (2-bromo-N-(methylsulfonyl)-acetamide)

[00136] To a suspension of 50 g (0.526 mol) of methanesulfonamide in toluene (625 mL, 12.5 vol) and isopropyl acetate (625 mL, 12.5 vol), 159.1 g (0.789 mol) of bromo-acetyl- bromide ("BAB") was added under nitrogen atmosphere. The reaction mixture was heated up to about 90°C for about 8 hours under a nitrogen stream. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to about 40°C and concentrated under vacuum until 10 volumes. Subsequently, toluene was added (250 mL, 5 vol) and distilling off solvents is carried out at NMT 30°C until 10 volumes. Then was added dichloromethane (100 mL, 2 vol) and the mixture was cooled down at 0°C and is stirred for 90 min. The solid was filtered and washed with

dichloromethane (100 mL, 2 vol). Crude product was obtained as beige solid material yielding 187% WY (83% MY), HPLC purity 99.2% at this stage. [00137] The crude material (83 g) was purified through re-slurring with dichloromethane (166 mL, 2 vol; preferably 332 mL, 4 vol) by stirring at about 32°C for about 60 min. The crystallization mixture was cooled down to about 0°C-5°C and stirring for 30 min, filtered off and washed with dichloromethane (100 mL, 2 vol). Subsequently, the material was dried at 35°C for 24 hours. Pure and dried material was obtained as white off solid yielding overall 173%, (77% MY), HPLC purity 99.6 % on area.

[00138] Step c: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino]butoxy]-N-(methylsulfonyl)-acetamide) - Selexipag

[00139] To 10 g (0.028 mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino) butan-l-ol was added a strong base (6.0 eq/mol), previously suspended in an appropriate solvent, within a range of from -10°C to 40°C under a nitrogen atmosphere and stirred for 60 min. Then, a solution of 17.9 g (3.0 eq/mol) of 2-bromo-N-(methylsulfonyl)-acetamide, previously dissolved in the same solvent, is added dropwise within a range of from 120 tol 80 min, controlling the exothermic temperature. The reaction was monitored by TLC up to completion. Subsequently, the mixture reaction was cooled down around 5°C and water is added by controlling the exotherm (NMT 15°C). Finally, an acetic acid solution was added and the suspension was stirred for about 60 min at 0°C -5°C. The product (crude) was filtered off and washed with water. An amorphous solid was obtained. The crude product was purified by crystallization from ethanol:THF.

[00140] Step d: Purification of Selexipag

[00141] Crude Selexipag can be purified by crystallization in an organic solvent for example alcohols such as ethanol, iso-amyl alcohol, iso-propyl alcohol, butanol; ethers such as tetrahydrofuran, hydrocarbons such as heptane and mixed solvents thereof.

[00142] C. Route 3

[00143] 33.3 g (0.297 mol, 6.0 eq/mol) of potassium tert-butoxide were dissolved in DMF (2.8 vol) in a flask (500 mL) under nitrogen atmosphere and stirred for 15 min. Then, a solution of 17.9 g (0.049 mol, 1.0 eq/mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl) amino) butan-l-ol (SLX-4) dissolved in DMF (1.2 vol) was added in one portion. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C at 150 rpm Then, a solution of 32.1 g (0.15 mol, 3.0 Eq/mol) of 2-bromo-N-(methylsulfonyl)- acetamide (SLX-9), previously dissolved in DMF (1.3 vol), was added dropwise for 120 minutes by controlling the temperature (exothermic process).

[00144] The reaction mixture was quenched with cool water (0.33 vol), transferred into a flask of more capacity (1000 mL) and placed in an ice bath. Cool water (38.32 vol) was added to the reaction mixture and the pH was adjusted to 5.0 with AcOH (0.33 vol). The mixture was stirred at 300 rpm for 40 min. Then, the flask with the reaction mixture was stored in the refrigerator at 8°C. After 8h, the solid was filtered and washed with cool water (5 vol, 2 times). The crude product (yellow solid) was drained (i.e. dried) for 30 min and was stored at 8°C.

Example 2: Preparation of crystalline Selexipag Form IV

[00145] A. Route 1

[00146] 3.0 g of Selexipag was dissolved in dimethylformamide ("DMF") (12 mL, 4 vol). The obtained solution was added dropwise to a pre-cooled acetic acid solution (0.06 M, 120 mL, from 2°C to 8°C) to obtain a suspension. The suspension was stirred within a range of from 2°C to 8°C for 30 min; then the material was filtered, washed with water (10 mL, 3.3 vol) and drained (i.e. dried) for 10 minutes. The solid material (amorphous) was suspended in heptane (25 mL, 7.5 vol) and the obtained suspension was stirred for 30 minutes at room temperature. The material was filtered, washed with heptane (20 mL, 6.6 vol) and drained (i.e. dried) under vacuum for at least 30 minutes at room temperature to obtain the Form IV Crystal.

[00147] B. Route 2

[00148] Crude Selexipag (1.0 g, amorphous solid, obtained from the synthesis) was dissolved in ethyl acetate (5 vol, 5 mL), then water was added (10 vol, 10 mL) into the solution, the mixture was stirred for about 10 minutes and the pH was adjusted to a range of from 8.0 to 9.0 by titration with K2CO3 solution. The phases were separated; the pH of the aqueous phase was adjusted to a range of from 3.5 to 5.0 by titration with acetic acid. Then, ethyl acetate (10 vol, 10 mL) was added into the aqueous phase, the obtained mixture was stirred and the phases were separated. The organic phase was distilled off under reduced pressure (from 2 to 3 volumes), and a solution was obtained. The obtained concentrated solution was quickly added to a mixture (suspension) of Form IV in ^-heptane (17 mL, 17 vol), over a period of less than 5 minutes, (the suspension temperature was of from 15°C to 25°C), and a suspension was obtained. The obtained suspension was stirred (155rpm) for 90 minutes at a temperature of from 0°C to 5°C. The suspension was filtered, washed with heptane, squeezed for 15 minutes and dried at 25°C, under vacuum, for about 14 hours. The product was analyzed by PXRD - Form IV was obtained.

[00149] The above procedure can be performed by dissolving the crude amorphous starting material in any suitable organic solvent, for example ester solvent. Example 3: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino] butoxy] -N-(methylsulfonyl)-acetamide) - Selexipag

Figure imgf000024_0001

SLX-4 SLX-9 SLX-6

[00150] 9.2 grams (0.082 mol, 5.9 eq/mol) of potassium tert-butoxide were combined with DMF (2.7 vol, 13.5 mL) in a flask (50 mL) under nitrogen atmosphere and a suspension was formed and was stirred for 20 min. Then, 5.0 g (0.014 mol, 1.0 eq/mol) of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol (SLX-4) as solid powder was added under nitrogen atmosphere. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C and at 170 rpm. Then, a solution of 8.9 g (0.041 mol, 3.0 eq/mol) of 2-bromo- N-(methylsulfonyl)-acetamide (SLX-9), previously dissolved in DMF (1.3 vol, 6.5 mL), was added dropwise for 120 minutes by controlling the temperature (exothermic process). After the end of addition, the reaction was completed, and the reaction mixture was quenched with cold water (0.5 vol, 2.5 mL), subsequently transferred into a flask of more capacity (500 mL) and placed into an ice bath. Cold water (40 vol, 200 mL) was added into the suspension and the pH was adjusted within the range from 4.0 to 5.0 with acetic acid. The obtained mixture was stirred for 120 min. The crude amorphous product was collected by filtration and washed twice with cold water (5 vol, 25 mL). The product was drained (i.e. dried) for 30 min and isolated as a yellow-brown solid which was stored within the range from 2°C to 8°C for approximately 17 hours. Then, the crude amorphous material was dissolved in ethyl acetate (15 vol, 75 mL) and water was added into the solution (30 vol, 150 mL). The pH was adjusted from 8.0 to 9.0 by addition of potassium carbonate solution, the phases were separated and the aqueous phase was washed twice with ethyl acetate (7.5 vol, 37.5 mL). The pH of the final aqueous phase was adjusted to a range from 4.0 to 5.0 with acetic acid. Then, ethyl acetate was added (30 vol, 150 mL) and the phases were separated. The organic phase was washed twice with water (7.5 vol, 37.5 mL). The organic phase was distilled off under reduced pressure (from 6 to 7 volumes, or from 6 to 15 volumes) and a solution was obtained.

[00151] In a different flask (capacity of 250 mL with a PTFE stirrer blade), a suspension of 0.05 g of Selexipag Form IV in ^-heptane (30 volumes, 150 mL) was stirred for 60 minutes within the range 0°C to 5°C and this suspension was added into the above ethyl acetate concentrated solution at room temperature over a period of less than 5 minutes. The final suspension was cooled down to 0°C to 5°C and stirred (220 rpm) for 120 minutes. The solid product was filtered off and washed twice with cold heptane (5 vol, 25 mL). The product was drained (i.e. dried) overnight. The product was analyzed by PXRD - Form VI was obtained, PXRD pattern is depicted in Figure 1.

Example 4: Preparation of Selexipag Form VII

[00152] To 37.4 g (6.0 Eq/mol) of potassium fert-butoxide were added into the reactor vessel followed by the addition of dimethylformamide (54 mL, 2.7 vol) under nitrogen atmosphere, into glove box equipment. The suspension obtained was stirred for 20 min at 20°C and 160 rpm. After that, 20.0 g (0.06 mol) of 4-((5,6-diphenyl-pyrazin-2- yl)(isopropyl)amino)-l-butanol (SLX-4) as solid powder were added. The whole reaction was performed under nitrogen atmosphere. The mixture obtained was stirred for 60 min within the range from 20°C to 25°C. Then a solution of 2-bromo-N-(methylsulfonyl)-acetamide (SLX- 9) (35.9 g, 3.0 Eq/mol) previously dissolved in dimethylformamide (26 mL, 1.3 vol), was added dropwise for 180 minutes by controlling the temperature. After the end of the addition the reaction was accomplished and the reaction mixture was quenched with cold water (10 mL, 0.5 vol). The mixture was transferred into a reactor vessel of more capacity (2 L with PTFE stirrer blade 10.1x12cm), cold water (750 mL, 37.5 vol) was added into the suspension and the pH was adjusted within the range from 4.0 to 5.0 with acetic acid (18 mL, 0.9 vol). The mixture was stirred for 60 min at 0°C - 5°C. The crude amorphous product was filtered, washed twice with cold water (100 mL, 5 vol, 2 times), the product was drained (i.e. dried) for 7 min and isolated as a yellowish amorphous solid.

[00153] Crude product was purified by dissolution with ethyl acetate (200 mL, 10 vol) and water was added into the solution (400 mL, 20 vol). The pH was adjusted from 8.0 to 9.0 by addition of potassium carbonate solution (30%, around 18 mL, 0.9 vol), the mixture was stirred (240 rpm, 20.5°C) and the phases were separated. The aqueous phase was washed twice with ethyl acetate (100 mL, 5 vol). Then, ethyl acetate (400 mL, 20 vol) was added into the aqueous phase the obtained mixture was stirred at 240 rpm. Then, the pH was adjusted within the range from 4.0 to 5.0 with acetic acid (around 20 mL, 1.0 vol) after that the phases were separated. The organic phase was washed twice with water (200 mL, 5 vol). The obtained solution was transferred into a flask of 1 L and sodium sulphate was added to remove the water residuals. The mixture was stirred for 15 minutes at 240 rpm. Afterwards, the solution was filtered to remove the solids and the obtained solution was filter though cartridge of activated charcoal (three times) at temperature of not more than 40°C. The final solution was distilled under atmospheric pressure until 6-7 final volumes (internal temperature around 69°C).

[00154] In parallel, a suspension of 0.5 g of Selexipag Form IV in ^-heptane (600 mL, 30 volumes) was prepared into another reactor [flask (1 L, PTFE stirrer blade 6.8x1.7cm)]. The suspension was stirred for 60 minutes within the range 0°C to 5°C at 236 rpm.

[00155] The solution obtained after distillation of ethyl acetate was cooled down within the range from 30°C to 35°C and added into the suspension during 30 minutes by dropwise. The mixture was stirred (236 rpm) for 120 minutes within the range from 0°C to 5°C. The product was filtered and washed twice with cold « -heptane (100 mL, 5 vol). The product was drained (i.e. dried) for 15 minutes. After that the product was analyzed by PXRD Form VII was obtained, PXRD pattern is depicted in Figure 2.

Example 5: Preparation of Selexipag Form IV

[00156] Selexipag Form VII (100 mg) was dried under vacuum at 50°C for 24 hours. The product was analyzed by PXRD - Form IV was obtained.

Example 6: Preparation of Selexipag Form IV

[00157] Step a): preparation of concentrated solution:

[00158] Selexipag (Form VII, 40 g) was dried at temperature of NMT 50°C over a period of 54 hours under vacuum. Then, the solid was suspended in ethyl acetate (1200 mL, 30 vol) at 30°C. Afterwards, water was added (600 mL, 15 vol). The mixture was stirred until dissolution. The stirring was stopped to allow the phases to separate. The organic phase was kept and the aqueous phase was extracted twice with ethyl acetate (300 mL, 7.5 vol). The obtained organic phase was combined with the first organic phase. The obtained solution was filtrated and distilled at reduced pressure until 240 mL as the final volume. 30 mL of concentrated solution were crystallized as is described herein below.

[00159] Step b): preparation of seed suspension:

[00160] In parallel, a suspension of Selexipag Form IV (0.125 g) in n-heptane (250 mL) was added to a glass reactor vessel (0.5 L reactor, PTFE stirrer blade 7.4 x 1.8 cm). The suspension was stirred (150 rpm) for 60 minutes at a temperature of from about 0°C to about 5°C.

[00161] Step c): crystallization of Form IV:

[00162] The 30 mL concentrated solution obtained in step a) was quickly added to the suspension of Form IV in n-heptane obtained in step b); over a period of around 1 minute. The temperature of the concentrated solution was within the range of from 20°C to 25°C and the temperature of the suspension of Form IV in n-heptane was within the range of from 0°C to 5°C. The obtained combined suspension was stirred (150 rpm) for 120 minutes at a temperature of from 0°C to 5°C. The combined suspension was filtered, the obtained solid was washed twice with cold n-heptane (25 mL) and drained (i.e. dried). The product was analyzed by PXRD - Form IV was obtained.

Example 7: Preparation of Selexipag Form VII

[00163] Step a): preparation of concentrated solution:

[00164] 240 mL of concentrated solution was prepared as described in Example 6 step a). 26 mL of concentrated solution was crystallized as is described herein below.

[00165] Step b): preparation of seed suspension:

[00166] In parallel, a suspension of Selexipag Form IV (0.11 g) in n-heptane (132 mL) was added to a glass reactor vessel (0.25 L reactor diameter 8.1 cm, reactor length 19 cm, PTFE stirrer blade 6.8 x 1.7 cm). The suspension was stirred (220 rpm) for 60 minutes at a temperature of from about 0°C to about 5°C.

[00167] Step c): crystallization of Form VII:

[00168] The 26 mL of concentrated solution obtained in step a) was quickly added to the suspension of Form IV in n-heptane obtained in step b), over a period of around 1 minute. The temperature of the concentrated solution was within the range of from 20°C to 25°C and the temperature of the suspension of Form IV in n-heptane was within the range of from 0°C to 5°C. The obtained combined suspension was stirred (150 rpm) for 120 minutes at a temperature of from 0°C to 5°C. The suspension was filtered, the obtained solid was washed twice with cold n-heptane (22 mL) and drained (i.e. dried). The product was analyzed by PXRD - Form VII was obtained.

Example 8: Preparation of Selexipag Form IV

[00169] Step a): Preparation of crude Selexipag:

[00170] Dimethylformamide (364.3 mL) and potassium tert-butoxide (251.5 g, 6.0 Eq/mol) were added into the reactor vessel under nitrogen atmosphere, in glove box equipment. The obtained suspension was stirred for about 29 minutes at room temperature. Then, 4-((5,6- diphenyl-pyrazin-2-yl)(isopropyl)amino)-l-butanol (SLX-4) (135.0 g, 0.06 mol) as solid powder was added. The reactor walls were washed with dimethylformamide (135 mL, 1 vol). The whole reaction was performed under nitrogen atmosphere. The obtained mixture was stirred (220 rpm) for around 60 minutes at a temperature of from 20°C to 25°C. Then, a solution of 2-bromo-N-(methylsulfonyl)-acetamide (SLX-9) (242.6 g, 3.0 Eq/mol) in dimethylformamide (175.5 mL, 1.3 vol) was added dropwise over a period of about 5 hours (4 hours and 39 minutes) while controlling the temperature. After the end of the addition, the reaction was accomplished and the reaction mixture was quenched with cold water (67.5 mL, 0.5 vol). The mixture was transferred into a reactor vessel of more capacity (10 L with agitator 4-blades, PTFE, high viscosity diameter 7.5 in, fits shaft size 19 mm), then cold water (5.4 L, 40 vol) was added into the mixture and the pH was adjusted within the range from 4.0 to 5.0 (pH = 4.64) with acetic acid (121.5 mL, 0.9 vol). The mixture was stirred for 2 hours at a temperature of about 0°C - 5°C (temperature = 0.6°C). The crude amorphous product was filtered, and washed twice with cold water (675 mL, 5 vol). The product was drained (i.e. dried) for 15 minutes and was isolated as a yellowish amorphous solid.

[00171] Step b): Preparation of concentrated solution:

[00172] The crude product was purified by dissolution in ethyl acetate (2.025 L, 15 vol). Afterwards, water (4.05 L, 30 vol) was added into the solution. The pH was adjusted from 8.0 to 9.0 (pH = 8.74) by addition of potassium carbonate 30% solution (140 mL). Then, the stirring was stopped to allow the phases to separate. The organic phase was discharged. The aqueous phase was washed twice with ethyl acetate (1.012 L, 7.5 vol). The pH of the aqueous phase was adjusted within the range from 4.0 to 5.0 (pH = 4.72) with acetic acid (135 mL, 1 vol), then immediately ethyl acetate (4.05 L, 30 vol) was added into the aqueous phase and the obtained mixture was stirred for about 10 minutes. Afterwards, the stirring was stopped to allow the phases to separate. The organic phase was washed twice with water (1.012 L, 7.5 vol). Afterwards, the solution was filtered to remove particles. The final solution was transferred into the reactor to distill the ethyl acetate at atmospheric pressure until a final volume of 800 mL (5.9 vol).

[00173] Step c): Preparation of seed suspension:

[00174] In parallel, a suspension of Selexipag Form IV (3.38 g) in n-heptane (6.75 L, 50 volumes) was added to the reactor (10 L with agitator 4-blades, PTFE, high viscosity diameter 7.5 in, fits shaft size 19 mm). The suspension was stirred at 95 rpm within the temperature range from 0°C to 5°C, for 1.8 hours.

[00175] Step d): Crystallization of Form IV:

[00176] The 800 mL of concentrated solution obtained in step b) was quickly added (time period 7 minutes and 43 seconds) to the suspension of Form IV in n-heptane obtained in step c). The temperature of the concentrated solution was around 27°C and the temperature of the suspension of Form IV in n-heptane was around -1°C. The obtained suspension was stirred at 95 rpm for 60 minutes at low temperature from 0°C to 5°C (temperature = 0.6°C). The suspension was filtered, the obtained solid was washed twice with cold n-heptane (675 mL, 5 vol) and drained (i.e. dried) for 1 hour. The product was analyzed by PXRD - Form IV was obtained. The solid product was sieved by using a mesh of 1000 microns. The sieved Form IV product was dried for total period of 8 hours at 50°C under vacuum (during this step the product was removed from vacuum drying and homogenized every 2 hours). The dried product was analyzed by PXRD - Form IV was obtained.

Example 9: Preparation of Selexipag Form VI

[00177] Selexipag (2 g) was dissolved in methyl ethyl ketone (20 mL) at 42°C and the obtained solution was cooled down to 15°C. In a different vessel, n-heptane was cooled to a temperature of about -10°C. The solution of Selexipag in MEK was then added to 40 mL of pre-cooled (-10°C) n-heptane (reverse addition) and a mixture was formed. The addition was done through a fine filter under stirring and the temperature was kept at -10°C. In parallel, Form VI seeds (5 mg) were added to the mixture (at the beginning of the reverse addition). Selexipag was crystallized from the mixture about 10 minutes after the addition was completed. Afterwards, the obtained suspension was stirred for about one hour at a temperature of from about -5°C to about -10°C, and then it was kept in a freezer at -20°C overnight. The crystalline product was separated by filtration and dried on the filter under nitrogen at room temperature. The obtained product was analyzed by PXRD - Form VI was obtained, PXRD pattern is depicted in Figure 7.

Example 10: Preparation of Selexipag Form VII

[00178] Selexipag (50 mg) and ethyl acetate (0.5 mL) were heated in a HPLC vial (with magnetic stirring) until dissolution occurred at 60°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 60°C to -5°C over a period of 20 minutes. At a temperature about 20-25°C, 1 mL of chilled n-heptane (pre-cooled to -10°C) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase formed. The crystalline phase was separated on a small filter (glass sinter) and dried by nitrogen purging.

[00179] The above described procedure can also be applied using n-dibutyl ether or methyl tert-butyl ether ("MTBE") instead of n-heptane, using similar parameters.

Example 11: Preparation of Selexipag Form VI

[00180] Selexipag (50 mg) and methylethylketone (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 42°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 42°C to -5°C over a period of 20 minutes. At temperature about 20-25°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form VI was obtained.

[00181] The above described procedure can also be applied using n-octane or n-hexane as antisolvent instead of n-heptane.

Example 12: Preparation of Selexipag Form VI

[00182] Selexipag (50 mg) and Ethanol (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 70°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 70°C to -5°C over a period of 20 minutes. At temperature about 20-25°C pre-chilled (-10°C) n-Heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form VI was obtained.

Example 13: Preparation of Selexipag Form VI

[00183] Selexipag (50 mg) and n-butanol (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 70°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 70°C to -5°C over a period of 20 minutes. At temperature about 20-25°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form VI was obtained.

Example 14: Preparation of Selexipag Form VI

[00184] Selexipag (25 mg) and n-octanol (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 78°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 78°C to -5°C over a period of 20 minutes. At temperature about 45-50°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form VI was obtained.

Example 15: Preparation of Selexipag Form IV [00185] Selexipag (50 mg) and n-Butyl acetate (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 80°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 80°C to -5°C over a period of 20 minutes. At temperature about 45-50°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form IV was obtained.

Example 16: Preparation of Selexipag Form IV

[00186] Selexipag (50 mg) and toluene (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 75°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 75°C to -5°C over a period of 20 minutes. At temperature about 45-50°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form IV was obtained.

[00187] The above described procedure can also be applied using n-hexane as antisolvent instead of n-heptane.

Example 17: Preparation of Selexipag Form IV

[00188] Selexipag (50 mg) and m-xylene (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 80°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 80°C to -5°C over a period of 20 minutes. At temperature about 45-50°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form IV was obtained.

Example 18: Preparation of Selexipag Form IV

[00189] Selexipag (50 mg) and DIPK (diisopropyl ketone - 0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 87°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 87°C to -5°C over a period of 20 minutes. At temperature about 30-35°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form IV was obtained.

Example 19: Preparation of Selexipag Form IV

[00190] Selexipag (50 mg) and DIBK (diisobutyl ketone - 0.5 mL) were heated in a HPLC- vial (with magnetic stirring) until the dissolution occurred at 99°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 99°C to -5°C over a period of 20 minutes. At temperature about 30-35°C pre-chilled (-10°C) n-heptane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form IV was obtained.

Example 20: Preparation of Selexipag Form IV

[00191] Selexipag (50 mg) and n-butanol (0.5 mL) were heated in a HPLC-vial (with magnetic stirring) until the dissolution occurred at 80°C. Thereafter, the vial was cooled down by a rapid linear temperature ramp from 80°C to -5°C over a period of 20 minutes. At temperature about 45-50°C pre-chilled (-10°C) n-hexane (1 mL) was added. After cooling to -5°C, the content of the vial was stirred for about one hour, during which time a crystalline phase was formed. The crystalline phase was separated on a small filter equipped with glass sinter and dried by nitrogen purging. The obtained product was analyzed by PXRD - Form IV was obtained.

Claims

What is Claimed Is:
1. A crystalline form of Selexipag designated as Form VI, characterized by data selected from one or more of the following:
a) an XRPD pattern having peaks at 8.2, 10.1, 12.5, 14.3, and 16.4 degrees 2-theta ± 0.2 degrees 2-theta;
b) an XRPD pattern having peaks at 10.1 , 12.6, 13.1, 14.0, and 14.3 degrees 2-theta ± 0.2 degrees 2-theta;
c) an XRPD pattern as depicted in Figure 1
d) an XRPD partem as depicted in Figure 7;
e) a solid state 1 C-NMR spectrum having characteristic peaks at 171.8, 148.6, 137.0, 130.7 and 129.1 ppm ± 0.2 ppm;
f) a solid state 1 C-NMR spectrum having the following chemical shift absolute
differences from a reference peak at 126.0 ppm ± 1 ppm: 45.8, 22.5, 11.0, 4.7, and 3.1 ppm ± 0.2 ppm; and
g) a solid state 1 C-NMR spectrum as depicted in Figures 5a or 5b or 5c;
or characterized by data selected from:
h) a combination of any one or more of (a), (c), (e), (f) and (g), or
i) a combination of any one or more of (b), (d), (e), (f) and (g).
2. The crystalline Form VI of Selexipag according to claim 1, characterized by data selected from one or more of the following:
a) an XRPD pattern having peaks at 8.2, 10.1, 12.5, 14.3 and 16.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 9.0, 10.6, 13.5, 14.0 or 18.8 degrees 2-theta ± 0.2 degrees 2-theta;
b) an XRPD pattern having peaks at 10.1 , 12.6, 13.1, 14.0, and 14.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 10.6, 13.5, 16.4, 20.9 or 21.1 degrees 2-theta ± 0.2 degrees 2-theta;
c) a solid state 1 C-NMR spectrum having peaks at: 171.8, 152.3, 148.6, 140.1 , 138.0, 137.0, 130.7, 129.8, 129.1, 127.4, 126.0, 71.1 , 66.2, 44.6, 41.4, 26.6, 22.9, 19.6 and 18.9 ppm ± 0.2 ppm; and/or
d) a FT-IR spectrum having peaks at 744, 845, 1373, 1438, and 1505 cm"1 ± 4 cm"1; e) a FT-IR spectrum as depicted in Figures 6a or 6b; and/or
or characterized by data selected from: f) a combination of any one or more of (a), (c), (d) and (e), or g) a combination of any one or more of (b), (c), (d) and (e).
3. The crystalline Form VI of Selexipag according to claim 1 or claim 2, characterized by a FT-IR spectrum having peaks at 492, 51 1 , 541 , 567, 586, 701 , 705, 744, 760, 775, 800, 828, 845, 872, 922, 968, 996, 1009, 1029, 1057, 1072, 1082, 1094, 1109, 1131 , 1147, 1159, 1171 , 1184, 1242, 1284, 1292, 1306, 1321 , 1341 , 1373, 1403, 1438, 1471 , 1483, 1505, 1566, 1582, 1722, 2562, 2874, 2922 and 2977 cm"1 ± 4 cm"1.
4. The crystalline Form VI of Selexipag according to claim 1 , which is polymorphically pure, characterized by data selected from one or more of the following:
g) an XRPD pattern having peaks at 10.1 , 12.6, 13.1, 14.0, and 14.3 degrees 2-theta ± 0.2 degrees 2-theta;
h) an XRPD pattern as depicted in Figure 7;
i) a solid state 1 C-NMR spectrum having characteristic peaks at 171.8, 148.6, 137.0, 130.7 and 129.1 ppm ± 0.2 ppm;
j) a solid state 1 C-NMR spectrum having the following chemical shift absolute
differences from a reference peak at 126.0 ppm ± 1 ppm: 45.8, 22.5, 11.0, 4.7, and 3.1 ppm ± 0.2 ppm;
k) a solid state 1 C-NMR spectrum as depicted in Figures 5a or 5b or 5c; and
1) any combinations of these data.
5. The crystalline Form VI of Selexipag according to claim 4, characterized by data
selected from one or more of the following:
a) an XRPD pattern having peaks at 10.1 , 12.6, 13.1, 14.0, and 14.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 10.6, 13.5, 16.4, 20.9 or 21.1 degrees 2-theta ± 0.2 degrees 2-theta;
b) a solid state 1 C-NMR spectrum having peaks at: 171.8, 152.3, 148.6, 140.1 , 138.0, 137.0, 130.7, 129.8, 129.1, 127.4, 126.0, 71.1 , 66.2, 44.6, 41.4, 26.6, 22.9, 19.6 and 18.9 ppm ± 0.2 ppm
c) a FT-IR spectrum having peaks at 744, 845, 1373, 1438, and 1505 cm"1 ± 4 cm"1; d) a FT-IR spectrum as depicted in Figures 6a or 6b; and
e) any combinations of these data.
6. The crystalline Form VI of Selexipag according to claim 4 or claim 5, characterized by a FT-IR spectrum having peaks at 492, 51 1 , 541 , 567, 586, 701 , 705, 744, 760, 775, 800, 828, 845, 872, 922, 968, 996, 1009, 1029, 1057, 1072, 1082, 1094, 1109, 1131 , 1147, 1159, 1171 , 1184, 1242, 1284, 1292, 1306, 1321 , 1341 , 1373, 1403, 1438, 1471 , 1483, 1505, 1566, 1582, 1722, 2562, 2874, 2922 and 2977 cm"1 ± 4 cm"1.
7. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 6.
8. Use of the crystalline form according to any one of claims 1 to 6 in the manufacture of a pharmaceutical composition and/or formulation.
9. A pharmaceutical formulation comprising a crystalline form according to any one of claims 1 to 6 or the pharmaceutical composition of claim 7, and at least one pharmaceutically acceptable excipient.
10. A process for preparing the pharmaceutical formulation according to claim 9,
comprising combining a crystalline form according to any one of claims 1 to 6 or the pharmaceutical composition of claim 7, with at least one pharmaceutically acceptable excipient.
1 1. The crystalline form, according to any one of claims 1 to 6, the pharmaceutical
composition according to claim 7, or the pharmaceutical formulation according to claim 9, for use as a medicament.
12. The crystalline form, according to any one of claims 1 to 6, the pharmaceutical
composition according to claim 7, or the pharmaceutical formulation according to claim 9, for use in the treatment of arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.
13. A method of treating arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis, comprising administering a therapeutically effective amount of a crystalline form according to any one of claims 1 to 6, the pharmaceutical composition according to claim 7, or the pharmaceutical formulation according to claim 9, to a subject suffering from arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis, or otherwise in need of the treatment.
14. The crystalline form, according to any one of claims 1 to 6, the pharmaceutical composition according to claim 7, or the pharmaceutical formulation according to claim 9, for the manufacture of a medicament for treating arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.
15. Use of crystalline Form VI of Selexipag according to any one of claims 1 to 6 in the preparation of another solid state form of Selexipag, or a Selexipag salt or solid state form thereof.
16. A process for preparing Selexipag salt or a solid state form thereof comprising
preparing crystalline form VI of Selexipag according to any one of claims 1 to 6, and converting it to Selexipag salt or a solid state form thereof.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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EP2447254A1 (en) * 2009-06-26 2012-05-02 Nippon Shinyaku Co., Ltd. Crystals
WO2017040872A1 (en) 2015-09-03 2017-03-09 Teva Pharmaceuticals International Gmbh Solid state forms of selexipag

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US7205302B2 (en) 2001-04-26 2007-04-17 Nippon Shinyaku Co., Ltd. Heterocyclic compound derivatives and medicines
EP2447254A1 (en) * 2009-06-26 2012-05-02 Nippon Shinyaku Co., Ltd. Crystals
US20140155414A1 (en) 2009-06-26 2014-06-05 Nippon Shinyaku Co., Ltd. Crystals of 2- {4- [n- (5,6-diphenylpyrazin-2-yl) -n-isopropylamino]butyloxy}-n- (methylsulfonyl) acetamide
US8791122B2 (en) 2009-06-26 2014-07-29 Nippon Shinyaku Co., Ltd. Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same
US9284280B2 (en) 2009-06-26 2016-03-15 Nippon Shinyaku Co., Ltd. Use of form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide
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