WO2017109772A1 - Amorphous form of selexipag - Google Patents

Amorphous form of selexipag Download PDF

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Publication number
WO2017109772A1
WO2017109772A1 PCT/IL2016/051351 IL2016051351W WO2017109772A1 WO 2017109772 A1 WO2017109772 A1 WO 2017109772A1 IL 2016051351 W IL2016051351 W IL 2016051351W WO 2017109772 A1 WO2017109772 A1 WO 2017109772A1
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WIPO (PCT)
Prior art keywords
selexipag
amorphous
stable amorphous
stable
solid
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PCT/IL2016/051351
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French (fr)
Inventor
Shai Rubnov
Ehud Marom
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Mapi Pharma Ltd.
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Application filed by Mapi Pharma Ltd. filed Critical Mapi Pharma Ltd.
Publication of WO2017109772A1 publication Critical patent/WO2017109772A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic 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
    • C07D241/14—Heterocyclic 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
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a stable amorphous form of selexipag, methods for its preparation, pharmaceutical compositions comprising same, and use thereof in treating pulmonary arterial hypertension.
  • Selexipag (ACT-293987, NS-304) is a prostacyclin receptor (IP receptor) antagonist indicated for the treatment of pulmonary arterial hypertension.
  • a new crystalline or amorphous form of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.
  • WO 2010/150865 and US 8,791 ,122 disclose an amorphous form and three crystalline forms of selexipag: 1) Form I is characterized by diffraction peaks in the X-ray powder diffraction pattern at 9.4°, 9.8°, 17.2° and 19.4° degrees two-theta; 2) Form II is characterized by diffraction peaks in the X-ray powder diffraction pattern at 9°, 12.9°, 20.7° and 22.6° degrees two-theta; and 3) Form III is characterized by diffraction peaks in the X-ray powder diffraction pattern at 9.3°, 9.7°, 16.8° , 20.6° and 23.5° degrees two-theta. No spectral or physical data are denoted for the alleged amorphous form.
  • the present invention provides a stable amorphous form of selexipag, pharmaceutical compositions comprising same, methods for its preparation and use thereof for the treatment of pulmonary arterial hypertension.
  • the present invention is based in part on the unexpected finding that the new stable amorphous form of selexipag disclosed herein possesses advantageous physicochemical properties which render its processing as a medicament beneficial.
  • the new form of the present invention has advantageous solubility properties as compared to the crystalline forms of WO 2010/150865. Consequently, the stable amorphous form of the present invention may possess improved bioavailability which would enable its easy formulation into a variety of solid dosage forms.
  • the present invention provides a stable amorphous form of selexipag with a high glass transition temperature (Tg).
  • the amorphous form of selexipag is characterized by an X-ray powder diffraction (XRPD) profile substantially as shown in any one or more of Figure 1 , Figure 8 or Figure 11.
  • XRPD X-ray powder diffraction
  • the present invention provides an amorphous form of selexipag characterized by a modulated Differential Scanning Calorimetry (mDSC) profile substantially as shown in Figure 9 or Figure 12.
  • mDSC modulated Differential Scanning Calorimetry
  • the present invention provides an amorphous form of selexipag characterized by a Differential Scanning Calorimetry (DSC) profile substantially as shown in Figure 13 or Figure 14.
  • the amorphous form of selexipag has a glass transition temperature between about 25 °C and about 45 °C.
  • the amorphous selexipag of the present invention is further characterized by a glass transition temperature (Tg) of about 35.9 °C or about 38.7°C or about 38.4°C or about 43.4°C as depicted in Figures 9, 12, 13 and 14, respectively.
  • Tg glass transition temperature
  • the amorphous form of selexipag is characterized by a Thermal Gravimetric Analysis (TGA) profile substantially as shown in Figure 2 or Figure 10.
  • TGA Thermal Gravimetric Analysis
  • the amorphous form of selexipag is characterized by a Dynamic Vapor Sorption (DVS) spectra substantially as depicted in Figure 6.
  • the amorphous form of selexipag is characterized by a Polarized Light Microscopy (PLM) spectra substantially as depicted in Figure 4A.
  • the stable amorphous selexipag is an anhydrous selexipag.
  • the present invention provides a pharmaceutical composition comprising the stable amorphous selexipag of the present invention as an active ingredient, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is in the form of a tablet.
  • the present invention provides a process for preparing a stable amorphous selexipag, the process comprising the steps of:
  • step (b) optionally, maintaining the selexipag obtained after step (a) at said temperature;
  • step (c) cooling down the resultant selexipag of step (a) or step (b) to obtain amorphous selexipag.
  • the heating temperature in step (a) or optional step (b) is about 160 °C.
  • the heating in step (a) occurs at a rate of about 10 "Crnin 1 .
  • step (c) occurs at a rate of 50 °Cmin _1 .
  • the cooling down is carried out under a nitrogen purge.
  • the solid selexipag in step (a) is a crystalline form I selexipag.
  • the heating in step (a) is carried out by TGA plate or an oil-bath.
  • the cooling in step (c) is carried out utilizing an ice bath.
  • the present invention provides a method of treating pulmonary arterial hypertension, by administering to a subject in need thereof an effective amount of the amorphous selexipag of the present invention, or a pharmaceutical composition comprising the amorphous selexipag of the present invention.
  • the subject is a human.
  • the present invention is directed to the amorphous selexipag of the present invention or the pharmaceutical composition comprising amorphous selexipag, for use in treating pulmonary arterial hypertension.
  • an effective amount of the amorphous selexipag of the present invention may be co- administered with at least one other drug useful for treating pulmonary arterial hypertension.
  • Figure 1 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus.
  • FIG. 2 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus.
  • TGA Thermogravimetric analysis
  • Figure 3 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag (panel A), obtained by heating selexipag Form I of US 8,791 ,122. X-ray diffraction pattern of Form I selexipag is shown in panel B. The heating of Form I selexipag was done utilizing TGA apparatus.
  • FIG 4 illustrates a characteristic Polarized Light Microscopy (PLM) image of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus (panel A). Also shown for comparison is the PLM image of crystalline selexipag Form I of US 8,791 ,122 (panel B).
  • PLM Polarized Light Microscopy
  • Panel A depicts the Differential Scanning Calorimetry (DSC) profile and Panel B depicts the Thermogravimetric Analysis (TGA) profile of selexipag Form I of US 8,791,122. .
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • Figure 6 illustrates a dynamic vapor sorption (DVS) isotherm plot of the amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus.
  • Panel A Sorption is represented by diamonds and desorption is represented by squares.
  • Panel B illustrates the corresponding kinetics of change in mass during sorption and desorption.
  • Figure 7 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag, obtained by heating selexipag Form I of US 8,791,122 using TGA method before (panel A) and after (panel B) exposure to 90% RH during DVS analysis.
  • Figure 8 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath.
  • Figure 9 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath.
  • Panel A depicts a heat flow curve
  • Panel B depicts a reversing heat flow curve.
  • Panel A demonstrates one exothermic and one endothermic peak at the onsets of 97.6°C and 131.6°C, respectively.
  • Panel B demonstrates a glass transition temperature of 35.9 °C characterizing the amorphous material.
  • FIG 10 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath.
  • TGA Thermogravimetric analysis
  • Figure 11 illustrates a characteristic X-ray diffraction pattern of the amorphous form of selexipag, obtained by the oil bath method after grinding in a ball grinder for 30 minutes.
  • Figure 12 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath after grinding in a ball grinder for 30 minutes.
  • Panel A depicts a heat flow curve
  • Panel B depicts a reversing heat flow curve.
  • Panel A demonstrates one exothermic and one endothermic peak at the onsets of 82.29°C and 121.14°C, respectively.
  • Panel B demonstrates a glass transition temperature of 38.7 °C characterizing the ground amorphous material.
  • Figure 13 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous form of selexipag obtained in situ by solid thermal heating- cooling method by DSC.
  • DSC Differential Scanning Calorimetry
  • Panel B represents heating selexipag above its melting point and quickly cooling down to form amorphous selexipag.
  • the sample was then heated under mDSC conditions to obtain the glass transition temperature based on the reverse heat flow curve (panel A).
  • Figure 14 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous form of selexipag obtained in situ by solid thermal heating- cooling method by DSC.
  • DSC Differential Scanning Calorimetry
  • Panel B represents heating selexipag above its melting point and quickly cooling down to form amorphous selexipag.
  • the sample was then heated under mDSC conditions to obtain the glass transition temperature based on the reverse heat flow curve (panel A).
  • Figure 15 illustrates the X-ray diffraction pattern of selexipag, after solvent- thermal heating/cooling in trimethylbenzene according to the method of US 8,791 ,122.
  • Panel A depicts a wet mixture and Panel B depicts a dry mixture of Form I and Form II selexipag.
  • the present invention is directed to a stable amorphous form of 2- ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ -N-(methanesulfonyl)acetamide (selexipag).
  • the present invention is further directed to pharmaceutical compositions comprising the stable amorphous form of selexipag and a pharmaceutically acceptable carrier and their use in treating pulmonary arterial hypertension.
  • the present invention is further directed to a method of preparing the stable amorphous form of selexipag of the present invention.
  • the present invention is further directed to the use of the stable amorphous form of selexipag, alone or in combination with other drugs, for the manufacture of a medicament for the treatment of pulmonary arterial hypertension.
  • Polymorphs are two or more solid state phases of the same chemical compound that possess different arrangement and/or conformation of the molecules.
  • Polyamorphism is the ability of a substance to exist in several different amorphous forms. Different forms of amorphous pharmaceuticals with readily discernible physical and chemical characteristics and some marked differences in their pharmaceutical performance have been reported. Even though amorphous materials do not exhibit long-range periodic atomic ordering, different amorphous phases of the same chemical substance can exhibit significant structural differences in their short- range atomic arrangement. These differences may lead to different physical and chemical properties such as density, stability, processability, dissolution and even bioavailability. Polyamorphism in pharmaceuticals is reviewed in Hancock et al.
  • amorphous form of Selexipag disclosed herein possesses improved physicochemical properties including hygroscopicity, bulk density and advantageous solubility properties. Furthermore, the amorphous Selexipag of the present invention has improved chemical and solid state stability. Hence the amorphous form of the invention may be more stable when stored over prolonged period of time.
  • stable refers to a state of a solid phase of a material, which allows isolation of said phase, substantially without any phase transformations or degradation taking place during the isolation of the material or upon storage.
  • the amorphous material of the invention does not undergo any substantial polymorphic transition upon storage and does not convert to a crystalline form upon exposure up to about 80% RH.
  • stable amorphous form of selexipag encompasses a solid form of amorphous selexipag that has less than about 10%, preferably less than about 5%, more preferably less than about 1 %, and most preferably does not contain any detectable crystalline form of selexipag.
  • WO 2010/150865 and US 8,791 ,122 disclose three crystalline forms of selexipag (Forms I, II, and III), and indicate that an amorphous form can be obtained by a slow cooling of a solution of selexipag dissolved in trimethylbenzene (US 8,791 ,122, Test Example 4, columns 14-15, Table 4, entry 30). No spectral or physical characterization was provided for the allegedly obtained amorphous solid. As described hereinbelow in Comparative Example 1, the Applicants have repeated the process of US 8,791 ,122 and have repeatedly failed to observe an amorphous form of selexipag. Instead, as depicted in Figure 15, repetition of the process of US 8,791,122 consistently yielded a mixture of selexipag Form I and Form II as described US 8,791 ,122.
  • the present invention provides a stable amorphous form of selexipag which is characterized by an X-ray powder diffraction (XRPD) pattern having a single broad peak expressed between about 10 and about 30 degrees two theta [2 ⁇ °], substantially as is shown in Figure 1.
  • XRPD X-ray powder diffraction
  • the stable amorphous form of selexipag of the invention is characterized by an XRPD pattern substantially as is shown in Figure 8.
  • the stable amorphous form of selexipag of the invention is characterized by an XRPD pattern substantially as is shown in Figure 11.
  • the amorphous form is further characterized by its glass transition temperature and by using various techniques including, but not limited to, polarized light microscopy (PLM), thermal analysis (e.g. thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), including modulated DSC (mDSC)).
  • PLM polarized light microscopy
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • mDSC modulated DSC
  • the stable amorphous form of selexipag of the present invention is characterized by a mDSC profile substantially as shown in Figure 9.
  • the mDSC profile demonstrates that the glass transition temperature (Tg) was 35.9°C on the reverse heat flow curve. Further, one exothermic peak at the onset of 97.6°C, and one endothermic peak at the onset of 131.6°C were observed on the heat flow curve.
  • the stable amorphous form of selexipag of the present invention is characterized by a mDSC profile substantially as shown in Figure 12. The mDSC profile demonstrates the glass transition temperature (Tg) was 38.7 °C on the reverse heat flow curve.
  • exothermic and one endothermic peak at the onsets of 82.29°C and 121.14°C were observed on the heat flow curve.
  • exothermic peak corresponds to the transition of amorphous selexipag to crystalline form I selexipag which occurs upon heating, and that the endothermic peak correlates with the melting point of crystalline form I selexipag ( Figure 5).
  • DSC shows one endothermic peak with the onset temperature of 124.1 °C, which is related to the melting point of Form I selexipag.
  • the stable amorphous form of selexipag of the present invention is characterized by a DSC profile substantially as shown in Figure 13.
  • the glass transition temperature (Tg) was 38.4°C in this experiment.
  • the stable amorphous form of selexipag of the present invention is characterized by a DSC profile substantially as shown in Figure 14.
  • the glass transition temperature (Tg) was 43.4°C in this experiment.
  • the stable amorphous form of selexipag of the present invention is further characterized by a Thermal Gravimetric Analysis (TGA) profile substantially as shown in Figure 2 or Figure 10.
  • TGA Thermal Gravimetric Analysis
  • the amorphous form has a glass transition temperature between about 25°C and about 45°C. In other embodiments, the amorphous form has a glass transition temperature between about 30°C and about 45°C. In other embodiments, the amorphous form has a glass transition temperature between about 35°C and about 45°C. In a specific embodiment, the glass transition temperature of amorphous selexipag is about 35.9% (i.e., about 36°C) as demonstrated in panel B of Figure 9. In another specific embodiment, the glass transition temperature of amorphous selexipag is about 38.7% (i.e., about 39°C) as demonstrated in panel B of Figure 12.
  • the glass transition temperature of amorphous selexipag is about 38.4% (i.e., about 38°C) as demonstrated in panel A of Figure 13. In another specific embodiment, the glass transition temperature of amorphous selexipag is about 43.4% (i.e., about 43°C) as demonstrated in panel A of Figure 14.
  • the amorphous form of selexipag is characterized by a
  • the amorphous form of selexipag is characterized by a Polarized Light Microscopy (PLM) image as depicted in Figure 4A.
  • PLM Polarized Light Microscopy
  • the PLM image of crystalline Form I of selexipag is provided for comparison in Figure 4B.
  • the amorphous selexipag is an anhydrous form of selexipag.
  • the present invention further provides a process for the preparation of a stable amorphous selexipag.
  • these processes involve the use of solid selexipag, such as crystalline selexipag as the starting material or any other selexipag prepared by any methods known in the art.
  • the solid selexipag starting material is heated to a temperature between 130 °C and about 200 °C, the heated solid selexipag is optionally maintained at the target temperature, followed by cooling to afford the formation of amorphous selexipag.
  • the solid selexipag is being heated to about 160 °C. In yet another embodiment, the heating of the solid selexipag occurs at a rate of about 10 °Cmin _1 . In another embodiment, the heating of the solid selexipag is carried out by TGA plate or an oil-bath. In another embodiment, the cooling of the solid selexipag occurs at a rate of about 50 "Crnin "1 . In another embodiment, the cooling down is carried out under a nitrogen purge. In yet another embodiment, the cooling of the solid selexipag is carried out utilizing an ice bath. In a specific embodiment, the starting material is crystalline form I selexipag (US 8,791,122).
  • the stable amorphous form of the present invention is useful for the treatment of pulmonary arterial hypertension.
  • the present invention thus provides pharmaceutical compositions comprising amorphous selexipag and a pharmaceutically acceptable carrier.
  • the pharmaceuticals can be safely administered orally or non- orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual.
  • the amorphous selexipag of the present invention is administered orally.
  • the pharmaceutical compositions can be formulated as tablets (including e.g. film-coated tablets and orally disintegrating tablets), powders, granules, capsules (including soft capsules), and sustained-release preparations as is well known in the art.
  • Pharmacologically acceptable carriers that may be used in the context of the present invention include various organic or inorganic carriers including, but not limited to, excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts.
  • the pharmaceutical compositions of the present invention may further include additives such as, but not limited to, preservatives, antioxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings.
  • Suitable excipients include e.g. lactose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride and titanium oxide.
  • Suitable lubricants include e.g. magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc and stearic acid.
  • Suitable binders include e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, a-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substitutional hydroxypropyl cellulose.
  • Suitable disintegrants include e.g.
  • crosslinked povidone any crosslinked l-ethenyl-2- pyrrolidinone homopolymer including polyvinylpyrrolidone (PVP) and l-vinyl-2- pyrrolidinone homopolymer
  • PVP polyvinylpyrrolidone
  • Suitable water-soluble polymers include e.g. cellulose derivatives such as hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like.
  • Suitable preservatives include e.g. sodium benzoate, benzoic acid, and sorbic acid.
  • Suitable antioxidants include e.g. sulfites, ascorbic acid and ot-tocopherol.
  • Suitable coloring agents include e.g. food colors such as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2 and the like.
  • Suitable sweetening agents include e.g. dipotassium glycyrrhetinate, aspartame, stevia and thaumatin.
  • Suitable souring agents include e.g. citric acid (citric anhydride), tartaric acid and malic acid.
  • Suitable bubbling agents include e.g. sodium bicarbonate.
  • Suitable flavorings include synthetic substances or naturally occurring substances, including e.g. lemon, lime, orange, menthol and strawberry.
  • the stable amorphous Selexipag of the present invention is particularly suitable for oral administration in the form of tablets including sublingual tablets and orally disintegrating tablets, capsules, pills, dragees, powders, granules, orally disintegrating wafers, and the like.
  • a tablet may be made by compression or molding, optionally with one or more excipients as is known in the art.
  • molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.
  • the active ingredient may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices and the like.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above- described excipients.
  • the present invention provides a method of treating pulmonary arterial hypertension comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising amorphous selexipag as described herein.
  • the subject in a human.
  • a “therapeutically effective amount” as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject.
  • the present invention further provides the administration of the amorphous selexipag of the present invention in combination therapy with one or more other active ingredients, for example other drugs for treating pulmonary hypertension selected from the group consisting of angiotensin-converting-enzyme inhibitor (ACE inhibitor), anticoagulant, diuretic agent, calcium channel blocker, endothelin receptor antagonist, blood vessel dilator and beta-adrenergic blocking agent.
  • ACE inhibitor angiotensin-converting-enzyme inhibitor
  • anticoagulant diuretic agent
  • calcium channel blocker calcium channel blocker
  • endothelin receptor antagonist endothelin receptor antagonist
  • blood vessel dilator and beta-adrenergic blocking agent.
  • the amorphous selexipag of the present invention can be given in combination therapy with an oxygen treatment.
  • the combination therapy may include the two or more active ingredients within a single pharmaceutical composition as well as the two or more active ingredients in two separate pharmaceutical compositions administered to the same subject simultaneously or at a time interval determined by
  • Tube Voltage 40 kV
  • Tube Current 40 mA.
  • Amorphous selexipag was prepared using a solid-thermal heating-cooling technique. 30 mg of form I selexipag were placed in a TGA pan, followed by heating of the solid sample from room temperature to 160 °C at a rate of 10 °C min "1 . The sample was kept in 160 °C for 5 minutes, then rapidly cooled back to room temperature under nitrogen purge at a rate of 50 °C min "1 . The resulted amorphous solid material was obtained in a quantitative yield and was analyzed by XRPD, PLM, TGA, mDSC and DVS.
  • the amorphous selexipag obtained by this method was characterized by a broad X-ray powder diffraction (XRPD) peak between about 12 and about 30 [2 ⁇ °], characteristic of an amorphous powder ( Figure 1).
  • XRPD X-ray powder diffraction
  • a Thermogravimetric Analysis (TGA) profile characteristic profile of the amorphous selexipag of the invention illustrates a weight loss of about 0.76% between about 22 °C and about 120 °C, which indicates that the amorphous selexipag obtain by this method is anhydrous selexipag ( Figure 2).
  • Figure 4 demonstrates polarized light microscopy (PLM) images of a typical amorphous selexipag as obtained in the solid-thermal heating-cooling technique in panel A.
  • PLM polarized light microscopy
  • a Dynamic Vapor Sorption (DVS) analysis of the amorphous selexipag showed that the amorphous material was slightly hygroscopic, demonstrating 0.34% mass change (AW%) at 80% RH according to Table 1 hereinbelow and the humidity cycle as depicted on Figure 6.
  • Amorphous selexipag can be obtained by utilizing the solid-thermal heating- cooling technique preformed in an oil bath.
  • 2.09 g selexipag Form I were weighed out into a glass vial, and the sample was heated to 160°C using an oil bath, under vacuum conditions. The sample began to melt at 150°C and melted completely after heating for about 15 min. The sample was kept at 160°C for 5 minutes and then was transferred into a mixture of ice and water for 5 minutes under vacuum conditions.
  • Amorphous selexipag was obtained in high yield of 93.0% and was analyzed by PLM, XRPD, TGA, and mDSC.
  • the amorphous selexipag obtained by this method was characterized by a similar broad X-ray powder diffraction (XRPD) peak between about 12 and about 30 [2 ⁇ °], which is consistent with the amorphous form obtained by TGA as described hereinabove ( Figure 8).
  • XRPD broad X-ray powder diffraction
  • a Thermogravimetric Analysis (TGA) profile characteristic profile of the amorphous selexipag of the invention illustrates a weight loss of about 0.44% between about 23.3 °C and about 120 °C, which indicates that the amorphous selexipag obtain by this method is anhydrous selexipag, as previously demonstrated for the amorphous material obtained by the TGA method ( Figure 10).
  • Polarized light microscopy (PLM) images demonstrated typical characteristics of amorphous material for the selexipag as obtained in the solid-thermal heating- cooling oil bath technique, similar to the amorphous material obtained by the TGA method.
  • amorphous selexipag was weighed into an aluminum pan hermetically sealed with a lid with a pin hole. The sample was heated from 25°C to 160°C at the rate of the 10°C/min and kept at 160°C for 5 mins before cooling to the 0°C at the rate of 50°C/min, and kept at 0°C for 5 mins before heating to 200°C at the rate of 2°C/min. This experiment was repeated to confirm Tg of the test compound. The results are depicted in Figure 13 and 14, and both the two results show the Tg is 38.4 °C ⁇ 43.4 °C.
  • Figures 13 and 14 represent the in situ preparation of amorphous selexipag using melting method on DSC.
  • Panel B represents heating the compound to above its melting point and quickly cooling down to form the amorphous sample. The sample was then heated under mDSC conditions to obtain the glass transition temperature based on the reverse heat flow curve (Panel A).
  • Example 3 solid stability of amorphous Selexipag
  • the amorphous Selexipag of the present invention is further evaluated for its chemical stability. About 3 mg of the compound is weighted into a 20 ml clear glass vial and being stored under the following conditions: 40°C, 60°C, 40°C/RH 75%, 60°C/RH 75%, and light (25 °C), for 2 weeks. An additional sample which is being stored at -20°C is used as control. The results show that the amorphous form of the present invention is stable and does not convert to other forms under the experimental conditions.
  • amorphous selexipag 1 ⁇ 2 mg was added into a 1.5 mL glass vial followed by stepwise addition of selected solvents until the solid dissolved.
  • the solubility was calculated. The results are shown in Table 2. Based on the solubility tests, the amorphous material is substantially more soluble than Form I selexipag in the solvents tested.
  • Figure 15 show the precipitated solid is a crystal form (mixture of Formula I and II of selexipag).
  • Panels A and B depict, respectively, wet and dry mixtures of Form I and Form II selexipag.

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Abstract

The present invention provides a stable amorphous form of selexipag, pharmaceutical compositions comprising same, methods for its preparation and use thereof for treating pulmonary arterial hypertension.

Description

AMORPHOUS FORM OF SELEXIPAG
FIELD OF THE INVENTION
The present invention relates to a stable amorphous form of selexipag, methods for its preparation, pharmaceutical compositions comprising same, and use thereof in treating pulmonary arterial hypertension.
BACKGROUND OF THE INVENTION
Selexipag (ACT-293987, NS-304) is a prostacyclin receptor (IP receptor) antagonist indicated for the treatment of pulmonary arterial hypertension.
Selexipag is chemically named 2-{4-[(5, 6-diphenylpyrazin-2-yl) (propan-2- yl) amino] butoxy}-N-(methanesulfonyl) acetamide and is represented by the following chemical structure:
Figure imgf000002_0001
A new crystalline or amorphous form of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.
Selexipag and processes for its preparation are disclosed in WO 02/088084 and US 7,205,302, however no spectral information was provided regarding the physical form of the obtained material. WO 2010/150865 and US 8,791 ,122 disclose an amorphous form and three crystalline forms of selexipag: 1) Form I is characterized by diffraction peaks in the X-ray powder diffraction pattern at 9.4°, 9.8°, 17.2° and 19.4° degrees two-theta; 2) Form II is characterized by diffraction peaks in the X-ray powder diffraction pattern at 9°, 12.9°, 20.7° and 22.6° degrees two-theta; and 3) Form III is characterized by diffraction peaks in the X-ray powder diffraction pattern at 9.3°, 9.7°, 16.8° , 20.6° and 23.5° degrees two-theta. No spectral or physical data are denoted for the alleged amorphous form.
There remains an unmet need for stable solid state forms of selexipag having good physicochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.
SUMMARY OF THE INVENTION
The present invention provides a stable amorphous form of selexipag, pharmaceutical compositions comprising same, methods for its preparation and use thereof for the treatment of pulmonary arterial hypertension. The present invention is based in part on the unexpected finding that the new stable amorphous form of selexipag disclosed herein possesses advantageous physicochemical properties which render its processing as a medicament beneficial. The new form of the present invention has advantageous solubility properties as compared to the crystalline forms of WO 2010/150865. Consequently, the stable amorphous form of the present invention may possess improved bioavailability which would enable its easy formulation into a variety of solid dosage forms.
According to one aspect, the present invention provides a stable amorphous form of selexipag with a high glass transition temperature (Tg). In one embodiment, the amorphous form of selexipag is characterized by an X-ray powder diffraction (XRPD) profile substantially as shown in any one or more of Figure 1 , Figure 8 or Figure 11. In another embodiment, the present invention provides an amorphous form of selexipag characterized by a modulated Differential Scanning Calorimetry (mDSC) profile substantially as shown in Figure 9 or Figure 12. In another embodiment, the present invention provides an amorphous form of selexipag characterized by a Differential Scanning Calorimetry (DSC) profile substantially as shown in Figure 13 or Figure 14. In yet another embodiment, the amorphous form of selexipag has a glass transition temperature between about 25 °C and about 45 °C. In another embodiment, the amorphous selexipag of the present invention is further characterized by a glass transition temperature (Tg) of about 35.9 °C or about 38.7°C or about 38.4°C or about 43.4°C as depicted in Figures 9, 12, 13 and 14, respectively. In another embodiment, the amorphous form of selexipag is characterized by a Thermal Gravimetric Analysis (TGA) profile substantially as shown in Figure 2 or Figure 10. In another embodiment, the amorphous form of selexipag is characterized by a Dynamic Vapor Sorption (DVS) spectra substantially as depicted in Figure 6. In another embodiment, the amorphous form of selexipag is characterized by a Polarized Light Microscopy (PLM) spectra substantially as depicted in Figure 4A. In yet another embodiment, the stable amorphous selexipag is an anhydrous selexipag.
In certain embodiments, the present invention provides a pharmaceutical composition comprising the stable amorphous selexipag of the present invention as an active ingredient, and a pharmaceutically acceptable carrier. In a particular embodiment, the pharmaceutical composition is in the form of a tablet. In another embodiment, the present invention provides a process for preparing a stable amorphous selexipag, the process comprising the steps of:
(a) heating solid selexipag to a temperature between about 130 °C and about 200 °C;
(b) optionally, maintaining the selexipag obtained after step (a) at said temperature; and
(c) cooling down the resultant selexipag of step (a) or step (b) to obtain amorphous selexipag.
In another embodiment, the heating temperature in step (a) or optional step (b) is about 160 °C.
In yet another embodiment, the heating in step (a) occurs at a rate of about 10 "Crnin 1.
In another embodiment, the cooling in step (c) occurs at a rate of 50 °Cmin_1. In another embodiment, the cooling down is carried out under a nitrogen purge.
In a specific embodiment, the solid selexipag in step (a) is a crystalline form I selexipag.
In another embodiment, the heating in step (a) is carried out by TGA plate or an oil-bath. In yet another embodiment, the cooling in step (c) is carried out utilizing an ice bath. In some embodiments, the present invention provides a method of treating pulmonary arterial hypertension, by administering to a subject in need thereof an effective amount of the amorphous selexipag of the present invention, or a pharmaceutical composition comprising the amorphous selexipag of the present invention. In another embodiment, the subject is a human.
In other embodiments, the present invention is directed to the amorphous selexipag of the present invention or the pharmaceutical composition comprising amorphous selexipag, for use in treating pulmonary arterial hypertension.
In an additional embodiment, an effective amount of the amorphous selexipag of the present invention, administered alone or in a pharmaceutical composition, may be co- administered with at least one other drug useful for treating pulmonary arterial hypertension. Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus.
Figure 2 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus.
Figure 3 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag (panel A), obtained by heating selexipag Form I of US 8,791 ,122. X-ray diffraction pattern of Form I selexipag is shown in panel B. The heating of Form I selexipag was done utilizing TGA apparatus.
Figure 4 illustrates a characteristic Polarized Light Microscopy (PLM) image of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus (panel A). Also shown for comparison is the PLM image of crystalline selexipag Form I of US 8,791 ,122 (panel B).
Figure 5 Panel A depicts the Differential Scanning Calorimetry (DSC) profile and Panel B depicts the Thermogravimetric Analysis (TGA) profile of selexipag Form I of US 8,791,122. .
Figure 6 illustrates a dynamic vapor sorption (DVS) isotherm plot of the amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing TGA apparatus. Panel A: Sorption is represented by diamonds and desorption is represented by squares. Panel B illustrates the corresponding kinetics of change in mass during sorption and desorption. Figure 7 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag, obtained by heating selexipag Form I of US 8,791,122 using TGA method before (panel A) and after (panel B) exposure to 90% RH during DVS analysis.
Figure 8 illustrates a characteristic X-ray diffraction pattern of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath.
Figure 9 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath. Panel A depicts a heat flow curve, while Panel B depicts a reversing heat flow curve. Panel A demonstrates one exothermic and one endothermic peak at the onsets of 97.6°C and 131.6°C, respectively. Panel B demonstrates a glass transition temperature of 35.9 °C characterizing the amorphous material.
Figure 10 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath.
Figure 11 illustrates a characteristic X-ray diffraction pattern of the amorphous form of selexipag, obtained by the oil bath method after grinding in a ball grinder for 30 minutes.
Figure 12 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of selexipag obtained by solid thermal heating-cooling method utilizing an oil bath after grinding in a ball grinder for 30 minutes. Panel A depicts a heat flow curve, while Panel B depicts a reversing heat flow curve. Panel A demonstrates one exothermic and one endothermic peak at the onsets of 82.29°C and 121.14°C, respectively. Panel B demonstrates a glass transition temperature of 38.7 °C characterizing the ground amorphous material.
Figure 13 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous form of selexipag obtained in situ by solid thermal heating- cooling method by DSC. The results demonstrate a glass transition temperature of 38.4 °C characterizing the amorphous material. Panel B represents heating selexipag above its melting point and quickly cooling down to form amorphous selexipag. The sample was then heated under mDSC conditions to obtain the glass transition temperature based on the reverse heat flow curve (panel A).
Figure 14 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous form of selexipag obtained in situ by solid thermal heating- cooling method by DSC. The results demonstrate a glass transition temperature of 43.4 °C characterizing the amorphous material. Panel B represents heating selexipag above its melting point and quickly cooling down to form amorphous selexipag. The sample was then heated under mDSC conditions to obtain the glass transition temperature based on the reverse heat flow curve (panel A).
Figure 15 illustrates the X-ray diffraction pattern of selexipag, after solvent- thermal heating/cooling in trimethylbenzene according to the method of US 8,791 ,122. Panel A depicts a wet mixture and Panel B depicts a dry mixture of Form I and Form II selexipag.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a stable amorphous form of 2- {4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy} -N-(methanesulfonyl)acetamide (selexipag).
The present invention is further directed to pharmaceutical compositions comprising the stable amorphous form of selexipag and a pharmaceutically acceptable carrier and their use in treating pulmonary arterial hypertension.
The present invention is further directed to a method of preparing the stable amorphous form of selexipag of the present invention.
The present invention is further directed to the use of the stable amorphous form of selexipag, alone or in combination with other drugs, for the manufacture of a medicament for the treatment of pulmonary arterial hypertension.
Polymorphs are two or more solid state phases of the same chemical compound that possess different arrangement and/or conformation of the molecules. Polyamorphism is the ability of a substance to exist in several different amorphous forms. Different forms of amorphous pharmaceuticals with readily discernible physical and chemical characteristics and some marked differences in their pharmaceutical performance have been reported. Even though amorphous materials do not exhibit long-range periodic atomic ordering, different amorphous phases of the same chemical substance can exhibit significant structural differences in their short- range atomic arrangement. These differences may lead to different physical and chemical properties such as density, stability, processability, dissolution and even bioavailability. Polyamorphism in pharmaceuticals is reviewed in Hancock et al. {Journal of Pharmacy and Pharmacology 2002, 54: 1151-1152), the content of which is hereby incorporated by reference. The identification and characterization of various morphic or amorphic forms of a pharmaceutically active compound is of great significance in obtaining medicaments with desired properties including a specific dissolution rate, milling property, bulk density, thermal stability or shelf-life. The amorphous form of Selexipag disclosed herein possesses improved physicochemical properties including hygroscopicity, bulk density and advantageous solubility properties. Furthermore, the amorphous Selexipag of the present invention has improved chemical and solid state stability. Hence the amorphous form of the invention may be more stable when stored over prolonged period of time.
The term "stable" according to the present invention refers to a state of a solid phase of a material, which allows isolation of said phase, substantially without any phase transformations or degradation taking place during the isolation of the material or upon storage. For example, the amorphous material of the invention does not undergo any substantial polymorphic transition upon storage and does not convert to a crystalline form upon exposure up to about 80% RH. The term "stable amorphous form of selexipag" encompasses a solid form of amorphous selexipag that has less than about 10%, preferably less than about 5%, more preferably less than about 1 %, and most preferably does not contain any detectable crystalline form of selexipag.
WO 2010/150865 and US 8,791 ,122 disclose three crystalline forms of selexipag (Forms I, II, and III), and indicate that an amorphous form can be obtained by a slow cooling of a solution of selexipag dissolved in trimethylbenzene (US 8,791 ,122, Test Example 4, columns 14-15, Table 4, entry 30). No spectral or physical characterization was provided for the allegedly obtained amorphous solid. As described hereinbelow in Comparative Example 1, the Applicants have repeated the process of US 8,791 ,122 and have repeatedly failed to observe an amorphous form of selexipag. Instead, as depicted in Figure 15, repetition of the process of US 8,791,122 consistently yielded a mixture of selexipag Form I and Form II as described US 8,791 ,122.
In one embodiment, the present invention provides a stable amorphous form of selexipag which is characterized by an X-ray powder diffraction (XRPD) pattern having a single broad peak expressed between about 10 and about 30 degrees two theta [2Θ°], substantially as is shown in Figure 1. In another embodiment, the stable amorphous form of selexipag of the invention is characterized by an XRPD pattern substantially as is shown in Figure 8. In another embodiment, the stable amorphous form of selexipag of the invention is characterized by an XRPD pattern substantially as is shown in Figure 11.
In some embodiments, the amorphous form is further characterized by its glass transition temperature and by using various techniques including, but not limited to, polarized light microscopy (PLM), thermal analysis (e.g. thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), including modulated DSC (mDSC)).
In one embodiment, the stable amorphous form of selexipag of the present invention is characterized by a mDSC profile substantially as shown in Figure 9. The mDSC profile demonstrates that the glass transition temperature (Tg) was 35.9°C on the reverse heat flow curve. Further, one exothermic peak at the onset of 97.6°C, and one endothermic peak at the onset of 131.6°C were observed on the heat flow curve. In another embodiment, the stable amorphous form of selexipag of the present invention is characterized by a mDSC profile substantially as shown in Figure 12. The mDSC profile demonstrates the glass transition temperature (Tg) was 38.7 °C on the reverse heat flow curve. Further, one exothermic and one endothermic peak at the onsets of 82.29°C and 121.14°C, were observed on the heat flow curve. Without wishing to be bound by any theory or mechanism of action, it is believed that the exothermic peak corresponds to the transition of amorphous selexipag to crystalline form I selexipag which occurs upon heating, and that the endothermic peak correlates with the melting point of crystalline form I selexipag (Figure 5). According to Figure 5, DSC shows one endothermic peak with the onset temperature of 124.1 °C, which is related to the melting point of Form I selexipag.
In another embodiment, the stable amorphous form of selexipag of the present invention is characterized by a DSC profile substantially as shown in Figure 13. The glass transition temperature (Tg) was 38.4°C in this experiment. In another embodiment, the stable amorphous form of selexipag of the present invention is characterized by a DSC profile substantially as shown in Figure 14. The glass transition temperature (Tg) was 43.4°C in this experiment.
In another embodiment, the stable amorphous form of selexipag of the present invention is further characterized by a Thermal Gravimetric Analysis (TGA) profile substantially as shown in Figure 2 or Figure 10.
In other embodiments, the amorphous form has a glass transition temperature between about 25°C and about 45°C. In other embodiments, the amorphous form has a glass transition temperature between about 30°C and about 45°C. In other embodiments, the amorphous form has a glass transition temperature between about 35°C and about 45°C. In a specific embodiment, the glass transition temperature of amorphous selexipag is about 35.9% (i.e., about 36°C) as demonstrated in panel B of Figure 9. In another specific embodiment, the glass transition temperature of amorphous selexipag is about 38.7% (i.e., about 39°C) as demonstrated in panel B of Figure 12. In another specific embodiment, the glass transition temperature of amorphous selexipag is about 38.4% (i.e., about 38°C) as demonstrated in panel A of Figure 13. In another specific embodiment, the glass transition temperature of amorphous selexipag is about 43.4% (i.e., about 43°C) as demonstrated in panel A of Figure 14.
In another embodiment, the amorphous form of selexipag is characterized by a
Dynamic Vapor Sorption (DVS) spectra as depicted in Figure 6.
In another embodiment, the amorphous form of selexipag is characterized by a Polarized Light Microscopy (PLM) image as depicted in Figure 4A. The PLM image of crystalline Form I of selexipag is provided for comparison in Figure 4B.
In yet another embodiment, the amorphous selexipag is an anhydrous form of selexipag. In other embodiments, the present invention further provides a process for the preparation of a stable amorphous selexipag. In one embodiment, these processes involve the use of solid selexipag, such as crystalline selexipag as the starting material or any other selexipag prepared by any methods known in the art. According to one embodiment, the solid selexipag starting material is heated to a temperature between 130 °C and about 200 °C, the heated solid selexipag is optionally maintained at the target temperature, followed by cooling to afford the formation of amorphous selexipag. In one embodiment, the solid selexipag is being heated to about 160 °C. In yet another embodiment, the heating of the solid selexipag occurs at a rate of about 10 °Cmin_1. In another embodiment, the heating of the solid selexipag is carried out by TGA plate or an oil-bath. In another embodiment, the cooling of the solid selexipag occurs at a rate of about 50 "Crnin"1. In another embodiment, the cooling down is carried out under a nitrogen purge. In yet another embodiment, the cooling of the solid selexipag is carried out utilizing an ice bath. In a specific embodiment, the starting material is crystalline form I selexipag (US 8,791,122).
The stable amorphous form of the present invention is useful for the treatment of pulmonary arterial hypertension. The present invention thus provides pharmaceutical compositions comprising amorphous selexipag and a pharmaceutically acceptable carrier. The pharmaceuticals can be safely administered orally or non- orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual. Typically, the amorphous selexipag of the present invention is administered orally. The pharmaceutical compositions can be formulated as tablets (including e.g. film-coated tablets and orally disintegrating tablets), powders, granules, capsules (including soft capsules), and sustained-release preparations as is well known in the art.
Pharmacologically acceptable carriers that may be used in the context of the present invention include various organic or inorganic carriers including, but not limited to, excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts. The pharmaceutical compositions of the present invention may further include additives such as, but not limited to, preservatives, antioxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings.
Suitable excipients include e.g. lactose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride and titanium oxide. Suitable lubricants include e.g. magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc and stearic acid. Suitable binders include e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, a-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substitutional hydroxypropyl cellulose. Suitable disintegrants include e.g. crosslinked povidone (any crosslinked l-ethenyl-2- pyrrolidinone homopolymer including polyvinylpyrrolidone (PVP) and l-vinyl-2- pyrrolidinone homopolymer), crosslinked carmellose sodium, carmellose calcium, carboxymethyl starch sodium, low- substituted hydroxypropyl cellulose, cornstarch and the like. Suitable water-soluble polymers include e.g. cellulose derivatives such as hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like.
Suitable preservatives include e.g. sodium benzoate, benzoic acid, and sorbic acid. Suitable antioxidants include e.g. sulfites, ascorbic acid and ot-tocopherol. Suitable coloring agents include e.g. food colors such as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2 and the like. Suitable sweetening agents include e.g. dipotassium glycyrrhetinate, aspartame, stevia and thaumatin. Suitable souring agents include e.g. citric acid (citric anhydride), tartaric acid and malic acid. Suitable bubbling agents include e.g. sodium bicarbonate. Suitable flavorings include synthetic substances or naturally occurring substances, including e.g. lemon, lime, orange, menthol and strawberry.
The stable amorphous Selexipag of the present invention is particularly suitable for oral administration in the form of tablets including sublingual tablets and orally disintegrating tablets, capsules, pills, dragees, powders, granules, orally disintegrating wafers, and the like. A tablet may be made by compression or molding, optionally with one or more excipients as is known in the art. For example, molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices and the like. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above- described excipients.
The present invention provides a method of treating pulmonary arterial hypertension comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising amorphous selexipag as described herein. In a specific embodiment, the subject in a human.
A "therapeutically effective amount" as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject.
The present invention further provides the administration of the amorphous selexipag of the present invention in combination therapy with one or more other active ingredients, for example other drugs for treating pulmonary hypertension selected from the group consisting of angiotensin-converting-enzyme inhibitor (ACE inhibitor), anticoagulant, diuretic agent, calcium channel blocker, endothelin receptor antagonist, blood vessel dilator and beta-adrenergic blocking agent. Additionally, the amorphous selexipag of the present invention can be given in combination therapy with an oxygen treatment. The combination therapy may include the two or more active ingredients within a single pharmaceutical composition as well as the two or more active ingredients in two separate pharmaceutical compositions administered to the same subject simultaneously or at a time interval determined by a skilled artisan.
The principles of the present invention are demonstrated by means of the following non-limiting examples. EXAMPLES
Example 1: General Preparation Method of Amorphous Selexipag
1. Instruments
Sartorius CP 225D Balance
Mettler Toledo XP6 Balance
Mili-Q Direct 8 Water Purification Equipment
ShuMei KQ-250DB Ultrasonic Cleaning Scrubber
Nikon LV100 PLM (Polarized Light Microscopy)
TA Q2000 DSC
TA Q5000IR TGA
Bruker D8 advanced X-ray powder diffractometer
BoXun DZF-65050 Vacuum Drier
Rota vapor R-l 14
2. XRPD, DSC, TGA, FT-IR, and FT-Raman
2.1 XRPD method
Details of XRPD method used in the tests are mentioned below:
- X-ray Generator: Cu, ka, (λ^1.54179Α).
- Tube Voltage: 40 kV, Tube Current: 40 mA.
- Monochromator: Fixed Monochromator
- Scanning Scope: 4-40 deg.
-Sample rotation speed: 15 rpm
- Scanning Step: 10 deg/min 2.2 DSC and TGA methods
Details of DSC method used in the tests are mentioned below: - Heating from 25 °C to 300 °C at 10 °C /min
mDSC samples were heated from 0°C to 200°C at 2 °C /min
Details of TGA method used in the tests are mentioned below:
- Heating from room temperature to -300 °C at 10 °C /min
2.3 DVS method
Details of DVS method used in the tests are mentioned below: - Exposing the sample to a humidity cycle from 30% to 90% RH and return to
0% RH in steps of 10% RH with equilibrium criteria of 0.01 % weight change per minute over 10 minutes (for no longer than 180 minutes).
Example 2: Preparation and characterization of amorphous Selexipag
2.1 Solid-thermal heating-cooling by TGA method
Amorphous selexipag was prepared using a solid-thermal heating-cooling technique. 30 mg of form I selexipag were placed in a TGA pan, followed by heating of the solid sample from room temperature to 160 °C at a rate of 10 °C min"1. The sample was kept in 160 °C for 5 minutes, then rapidly cooled back to room temperature under nitrogen purge at a rate of 50 °C min"1. The resulted amorphous solid material was obtained in a quantitative yield and was analyzed by XRPD, PLM, TGA, mDSC and DVS.
The amorphous selexipag obtained by this method was characterized by a broad X-ray powder diffraction (XRPD) peak between about 12 and about 30 [2Θ°], characteristic of an amorphous powder (Figure 1). A comparison between the XRD pattern of the obtained amorphous selexipag of the invention and the XRD pattern of crystalline selexipag Form I which was used as the starting material is presented in Figure 3. A Thermogravimetric Analysis (TGA) profile characteristic profile of the amorphous selexipag of the invention illustrates a weight loss of about 0.76% between about 22 °C and about 120 °C, which indicates that the amorphous selexipag obtain by this method is anhydrous selexipag (Figure 2).
Figure 4 demonstrates polarized light microscopy (PLM) images of a typical amorphous selexipag as obtained in the solid-thermal heating-cooling technique in panel A. As a comparison, a PLM image of crystalline selexipag Form I which was used as the starting material is depicted in panel B.
A Dynamic Vapor Sorption (DVS) analysis of the amorphous selexipag showed that the amorphous material was slightly hygroscopic, demonstrating 0.34% mass change (AW%) at 80% RH according to Table 1 hereinbelow and the humidity cycle as depicted on Figure 6.
Table 1 : Hygroscopicity measurements (dynamic vapor sorption; DVS)
Figure imgf000017_0001
A comparison between the XRPD pattern of the material before and after DVS analysis confirmed that there was no change in structure as demonstrated in Figure 7. 2.2 Solid-thermal heating-cooling by Oil-bath method
Amorphous selexipag can be obtained by utilizing the solid-thermal heating- cooling technique preformed in an oil bath. 2.09 g selexipag Form I were weighed out into a glass vial, and the sample was heated to 160°C using an oil bath, under vacuum conditions. The sample began to melt at 150°C and melted completely after heating for about 15 min. The sample was kept at 160°C for 5 minutes and then was transferred into a mixture of ice and water for 5 minutes under vacuum conditions. Amorphous selexipag was obtained in high yield of 93.0% and was analyzed by PLM, XRPD, TGA, and mDSC.
The amorphous selexipag obtained by this method was characterized by a similar broad X-ray powder diffraction (XRPD) peak between about 12 and about 30 [2Θ°], which is consistent with the amorphous form obtained by TGA as described hereinabove (Figure 8).
Modulated Differential Scanning Calorimetry (mDSC) profile of the amorphous selexipag obtained by this method, demonstrated a glass transition temperature of 35.9 °C (Figure 9, reversing heat flow curve, Panel B). Additionally, one exothermic peak and one endothermic peak were observed at the onset temperatures of 97.6 °C and 131.6 °C, respectively (Figure 9, heat flow, Panel A). Without wishing to be bound to any particular theory, it is believed that the exothermic peak corresponds to the transition of the amorphous material to form I selexipag, which occurred during heating, and the endothermic peak corresponds to the melting point of form I selexipag, as demonstrated in Figure 5. According to Figure 5, DSC shows one endothermic peak with the onset temperature of 124.1 °C, which is related to the melting point of Form I selexipag.
A Thermogravimetric Analysis (TGA) profile characteristic profile of the amorphous selexipag of the invention illustrates a weight loss of about 0.44% between about 23.3 °C and about 120 °C, which indicates that the amorphous selexipag obtain by this method is anhydrous selexipag, as previously demonstrated for the amorphous material obtained by the TGA method (Figure 10). Polarized light microscopy (PLM) images demonstrated typical characteristics of amorphous material for the selexipag as obtained in the solid-thermal heating- cooling oil bath technique, similar to the amorphous material obtained by the TGA method.
2.2.1 Grinding study of amorphous Selexipag
Approximately 100 mg of amorphous materials was weighed and transferred into a ball grinder for 30 minutes. The resulting material was then characterized using XRPD, mDSC and ^-NMR.
The XRPD results confirmed that the ground amorphous material was stable and didn't convert to another polymorphic crystalline form as demonstrated in Figure 11. mDSC analysis (Figure 12) revealed Tg of 38.7°C, a close value to the one of the original amorphous material before grinding. ^-NMR demonstrated that there was no chemical degradation of the amorphous material after grinding.
Further heating of the ground amorphous selexipag (powder) from room temperature to 40 °C, resulted in the formation of a gel.
2.2.2 Solid-thermal heating/cooling study of the raw material by DSC
Approximately 0.5-1.0 mg of amorphous selexipag was weighed into an aluminum pan hermetically sealed with a lid with a pin hole. The sample was heated from 25°C to 160°C at the rate of the 10°C/min and kept at 160°C for 5 mins before cooling to the 0°C at the rate of 50°C/min, and kept at 0°C for 5 mins before heating to 200°C at the rate of 2°C/min. This experiment was repeated to confirm Tg of the test compound. The results are depicted in Figure 13 and 14, and both the two results show the Tg is 38.4 °C~43.4 °C.
Figures 13 and 14 represent the in situ preparation of amorphous selexipag using melting method on DSC. Panel B represents heating the compound to above its melting point and quickly cooling down to form the amorphous sample. The sample was then heated under mDSC conditions to obtain the glass transition temperature based on the reverse heat flow curve (Panel A). Example 3: solid stability of amorphous Selexipag
The amorphous Selexipag of the present invention is further evaluated for its chemical stability. About 3 mg of the compound is weighted into a 20 ml clear glass vial and being stored under the following conditions: 40°C, 60°C, 40°C/RH 75%, 60°C/RH 75%, and light (25 °C), for 2 weeks. An additional sample which is being stored at -20°C is used as control. The results show that the amorphous form of the present invention is stable and does not convert to other forms under the experimental conditions.
Example 4: Solubility Studies
1 ~2 mg of amorphous selexipag was added into a 1.5 mL glass vial followed by stepwise addition of selected solvents until the solid dissolved. The solubility was calculated. The results are shown in Table 2. Based on the solubility tests, the amorphous material is substantially more soluble than Form I selexipag in the solvents tested.
Table 2: Approximate solubility of raw selexipag (anhydrous Form I) and amorphous selexipag at room temperature
Figure imgf000020_0001
Methyl isobutyl ketone 16.4-32.8 5.9-11.7
Ethyl acetate 36.3-72.5 14.6-21.9
Isopropyl acetate 33.3-66.5 4.71 -9.42
Methyl t-butyl ether 15.6-31.3 < 1.0
THF 29.8-59.5 24.4-48.8
2-MeTHF 41.6-83.5 18.3-27.5
Toluene 31.0-62.0 <1
1,4-Dioxane 20.1-40.3 >41
Comparative Example 1: Preparation of selexipag by method of US 8.791.122
Selexipag was prepared according to the method described in US 8,791 ,122 Test Example 4, entry 30. -733 mg of selexipag Form I was weighed out into a glass vial, - 200.0 mL of tri-methyl-benzene was added step by step to make a suspension. The resulting suspension was stirred at 50°C at a rate of 1000 rpm for 60 minutes to dissolve the compound. Then, the resulting suspension was filtered quickly with a filter at 60°C. After filtration, the isolated mother liquor (dissolving -703 mg of API) was stirred at 60°C for 30 minutes, before cooling down to 5°C for over 11 hrs. After stirring at 5°C for 72 hours, the precipitated solid was collected and checked by XRPD. The solid was dried at 20 °C under reduced pressure condition, and the dried solid was -468 mg and also checked by XRPD. The results (Figure 15) show the precipitated solid is a crystal form (mixture of Formula I and II of selexipag). Figure 15 Panels A and B depict, respectively, wet and dry mixtures of Form I and Form II selexipag.
While the present invention has been particularly described, persons skilled in the art will appreciate that many variations and modifications can be made. Therefore, the invention is not to be construed as restricted to the particularly described embodiments, and the scope and concept of the invention will be more readily understood by reference to the claims, which follow.

Claims

1. A stable amorphous form of selexipag, characterized by an X-ray powder diffraction (XRPD) profile substantially as shown in Figure 1 , Figure 8 or Figure 11.
2. The stable amorphous selexipag according to claim 1, further characterized by a modulated Differential Scanning Calorimetry (mDSC) profile substantially as shown in Figure 9 or Figure 12.
3. The stable amorphous selexipag according to claim 1, further characterized by a Differential Scanning Calorimetry (DSC) profile substantially as shown in Figure 13 or Figure 14.
4. The stable amorphous selexipag according to claim 1, further characterized by a glass transition temperature between about 25 °C and about 45 °C.
5. The stable amorphous selexipag according to claim 4, having a glass transition temperature at about 35.9 °C or about 38.4°C or about 38.7°C, or about 43.4°C.
6. The stable amorphous selexipag according to claim 1, further characterized by a Thermal Gravimetric Analysis (TGA) profile substantially as shown in Figure 2 or 10.
7. The stable amorphous selexipag according to claim 1, further characterized by a Dynamic Vapor Sorption (DVS) spectra substantially as depicted in Figure 6.
8. The stable amorphous selexipag according to claim 1, further characterized by a Polarized Light Microscopy (PLM) image substantially as depicted in Figure 4A.
9. The stable amorphous selexipag according to any one of the preceding claims, wherein said amorphous form is anhydrous.
10. A pharmaceutical composition comprising as an active ingredient the stable amorphous selexipag according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition according to claim 10 in the form of a tablet.
12. The stable amorphous selexipag according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 10 or 11, for use in treating pulmonary arterial hypertension.
13. A method of treating pulmonary arterial hypertension comprising administering to a subject in need thereof an effective amount of the stable amorphous selexipag according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 10 or 11.
14. The method according to claim 13, wherein the subject is a human.
15. The method according to claim 13, comprising co-administering the stable amorphous form of selexipag in combination with at least one other drug useful for treating pulmonary arterial hypertension.
16. A process for preparing a stable amorphous selexipag according to any one of claims 1 to 9, comprising the steps of:
(a) heating solid selexipag to a temperature between about 130 °C and about 200 °C;
(b) optionally, maintaining the selexipag obtained after step (a) at said temperature; and
(c) cooling down the resultant selexipag of step (a) or step (b) to obtain amorphous selexipag.
17. The process according to claim 16, wherein the temperature in step (a) or optional step (b) is about 160 °C.
18. The process according to claim 16, wherein the heating in step (a) occurs at a rate of about 10 "Crnin"1.
19. The process of claim 16, wherein the cooling in step (c) occurs at a rate of about 50 "Crnin 1.
20. The process according to claim 16, wherein said cooling down is carried out under a nitrogen purge.
21. The process according to claim 16, wherein said solid selexipag in step (a) is crystalline form I selexipag.
22. The process of claim 16, wherein the heating in step (a) is carried out by TGA plate or an oil-bath.
23. The process of claim 16, wherein the cooling in step (c) is carried out utilizing an ice bath.
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