WO2018015974A1 - Formes polymorphes de sélexipag et dispersion solide amorphe de sélexipag - Google Patents

Formes polymorphes de sélexipag et dispersion solide amorphe de sélexipag Download PDF

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Publication number
WO2018015974A1
WO2018015974A1 PCT/IN2017/050298 IN2017050298W WO2018015974A1 WO 2018015974 A1 WO2018015974 A1 WO 2018015974A1 IN 2017050298 W IN2017050298 W IN 2017050298W WO 2018015974 A1 WO2018015974 A1 WO 2018015974A1
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Prior art keywords
selexipag
crystalline
powder
ray diffraction
diffraction pattern
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PCT/IN2017/050298
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English (en)
Inventor
Ramakoteswara Rao Jetti
Hemant Malhari MANDE
Anjaneyaraju Indukuri
Aggi Ramireddy Bommareddy
Narasimha Murty PILLI
Maheshkumar Gadakar
Ghanshyam WAGH
Ponpandian Thanasekaran
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Mylan Laboratories Limited
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Publication of WO2018015974A1 publication Critical patent/WO2018015974A1/fr

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    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present disclosure relates generally to active pharmaceutical ingredients and more specifically to novel crystalline forms of selexipag and processes for the preparation thereof.
  • the present disclosure also relates to amorphous solid dispersions of selexipag, process for the preparation thereof, premixes of selexipag, and processes for the preparation thereof.
  • IP prostacyclin I2 receptor
  • the present invention provides novel forms of crystalline selexipag Form IV, Form V, Form VI, Form VII, Form VII-1 , Form VIII, and Form IX.
  • crystalline selexipag Form IV may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values of 5.73, 17.68, 18.32, 19.16, 19.45, 20.59, 20.77, and 23.13 ⁇ 0.2 s .
  • crystalline selexipag Form IV may be characterized by the powder X-ray diffraction pattern in Figure 1 .
  • crystalline selexipag Form V may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values of 5.93, 1 1 .14, 19.73, 19.96, 20.98, 21 .15, 22.21 , and 23.34 ⁇ 0.2 s
  • crystalline selexipag Form V may be characterized by the powder X-ray diffraction pattern in Figure 2.
  • crystalline selexipag Form VI may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values of 6.38, 6.94, 10.69, 13.74, 18.44, 18.97, 19.43, 21 .32, 23.35, 24.01 , 24.71 , 25.23, and 26.25 ⁇ 0.2 s .
  • crystalline selexipag Form VI may be characterized by the powder X-ray diffraction pattern in Figure 3.
  • crystalline selexipag Form VII may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values of 5.76, 10.98, 13.2, 15.4, 17.6, 18.1 , 19.4, 19.6, 23.3, and 24.6 ⁇ 0.2 s .
  • crystalline selexipag Form VII may be characterized by the powder X-ray diffraction pattern in Figure 4.
  • crystalline selexipag Form VII-1 may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values of 6.29, 18.79, 19.31 , 23.3, 23.7, 24.5, and 25.0 ⁇ 0.2 s .
  • crystalline selexipag Form VII-1 may be characterized by the powder X-ray diffraction pattern in Figure 5.
  • crystalline selexipag Form VII-1 may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values of 6.21 , 10.65, 13.99, 15.39, 15.78, 18.34, 18.73, 19.10, 19.47, 20.12, 21 .36, 21 .86, 22.56, 23.12, 23.66, 24.10, 24.43, 24.91 , 26.59, 30.54, and 31 .26 ⁇ 0.2 s .
  • crystalline selexipag Form VII-1 may be characterized by the powder X-ray diffraction pattern in Figure 6.
  • crystalline selexipag Form IX may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values of 5.81 , 1 1 .19, 15.40, 17.77, 18.40, 19.34, 19.65, 19.85, 20.93, 22.47, 23.32, 23.83, 24.64, 25.87, 27.52, 27.72, 28.26, and 29.26 ⁇ 0.2 s .
  • crystalline selexipag Form IX may be characterized by the powder X-ray diffraction pattern in Figure 7.
  • the present invention provides a process for the preparation of selexipag Form IV, Form V, Form VI, Form VII, Form VII-1 , Form VIII, and Form IX.
  • selexipag Form IV may be prepared by a process that includes the steps of:
  • selexipag Form V may be prepared by a process that includes the steps of:
  • the anti-solvent may be an ether, a hydrocarbon, or a mixture thereof.
  • suitable ethers include diethyl ether, diisopropyl ether, methyl tert- butyl ether, and mixtures thereof.
  • suitable hydrocarbons include hexane, cyclohexane, methyl cyclohexane, heptane, pentane, and mixtures thereof.
  • selexipag Form VI may be prepared by a process that includes the steps of:
  • selexipag Form VII may be prepared by a process that includes the steps of:
  • selexipag Form VII-1 may be prepared by a process that includes the steps of:
  • selexipag Form VIII may be prepared by a process that includes the steps of:
  • the anti-solvent may be, but are not limited to, an ether, a hydrocarbon, or a mixture thereof.
  • suitable ethers include diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof.
  • suitable hydrocarbons include hexane, cyclohexane, methyl cyclohexane, heptane, pentane, and mixtures thereof.
  • selexipag Form IX may be prepared by a process that includes the steps of:
  • the present invention provides an amorphous solid dispersion of crystalline selexipag with a pharmaceutically acceptable carrier and methods for the preparation thereof.
  • solid dispersions of selexipag with pharmaceutically acceptable carriers may be prepared with any one of crystalline selexipag Form IV, V, VI, VII, VII- 1 , VIII, IX, or mixtures thereof.
  • the pharmaceutically acceptable carrier may be, for example, a copolymer of n-vinyl-2-pyrrolidone and vinyl acetate, povidone, and mixtures thereof.
  • the n-vinyl-2-pyrrolidone and vinyl acetate is Plasdone S-630.
  • povidone with a k- value of 30 is used.
  • an amorphous solid dispersion of selexipag with a pharmaceutically acceptable carrier may be prepared by a process that includes the steps of:
  • the solvent may be, for example (but not limited to), methanol, dichloromethane, acetone, water, or mixtures thereof.
  • the solvent may be removed by is achieved by methods well known in the art, for example (but not limited to), by evaporation, distillation, spray drying, filtration, lyophilization, agitated thin film drying, or a combination thereof.
  • the pharmaceutically acceptable carrier may be, for example, a co-polymer of n-vinyl-2-pyrrolidone and vinyl acetate, povidone, hydroxyl propyl ⁇ -cyclodextrin, hydroxypropyl methylcellulose, or mixtures thereof.
  • the n-vinyl-2-pyrrolidone and vinyl acetate is Plasdone S-630.
  • povidone with a k-value of 30 is used.
  • an amorphous solid dispersion of selexipag with a pharmaceutically acceptable carrier may be prepared by hot melt extrusion.
  • the present invention provides a premix crystalline selexipag with a pharmaceutically acceptable carrier and methods for the preparation thereof.
  • premixes of selexipag with pharmaceutically acceptable carriers may be prepared with any one of crystalline selexipag Form IV, V, VI, VII, VII-1 , VIII, IX, or mixtures thereof.
  • the pharmaceutically acceptable carrier may be, for example, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), or mixtures thereof.
  • the present invention provides a premix of crystalline selexipag Form V with L-HPC, which may be characterized by a powder X-ray diffraction pattern with substantial peaks at 29 values 5.91 , 1 1 .1 1 , 13.66, 15.71 , 16.42, 17.36, 17.78, 18.13, 18.45, 19.71 , 20.94, 22.19, 23.27, 24.81 , 26.05, and 26.24 ⁇ 0.2 s .
  • a premix of crystalline selexipag Form V with L-HPC may also be characterized by the powder X-ray diffraction pattern in Figure 14.
  • the present invention provides a premix of crystalline selexipag Form V with hydroxypropyl cellulose, which may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values 5.82, 10.98, 12.83, 13.53, 15.58, 16.30, 17.22, 17.98, 18.30, 19.55, 20.81 , 22.05, 23.15, 23.63, 24.05, 26.10, 26.66, and 31 .43 ⁇ 0.2 s .
  • a premix of crystalline selexipag Form V with HPC may also be characterized by the powder X-ray diffraction pattern in Figure 15.
  • the present invention provides a premix of crystalline selexipag Form VI with L-HPC, which may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values 6.21 , 6.77, 13.06, 13.56, 13.89, 14.96, 15.22, 15.47, 16.02, 18.27, 18.79, 19.26, 20.15, 21 .15, 22.26, 22.57, 23.13, 23.88, 24.59, 25.06, 25.94, and 26.07 ⁇ 0.2 s .
  • a premix of crystalline selexipag Form VI with L-HPC may also be characterized by the powder X-ray diffraction pattern in Figure 16.
  • the present invention provides a premix of crystalline selexipag Form VI with HPC, which may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values 6.30, 6.86, 13.65, 13.99, 15.06, 15.57, 16.13, 16.74, 17.88, 18.35, 18.89, 19.36, 20.24, 21 .22, 22.37, 22.64, 23.22, 23.97, 24.68, 25.12, 26.03, and 26.19 ⁇ 0.2 s .
  • a premix of crystalline selexipag Form VI with HPC may also be characterized by the powder X-ray diffraction pattern in Figure 17.
  • the present invention provides a premix of crystalline selexipag Form VII with L-HPC, which may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values 6.26, 6.87, 13.71 , 13.87, 14.95, 15.39, 16.07, 16.77, 18.24, 18.76, 19.28, 20.25, 21 .20, 22.46, 23.21 , 23.78, 24.51 , and 24.97 ⁇ 0.2 s .
  • a premix of crystalline selexipag Form VII with L-HPC may also be characterized by the powder X-ray diffraction pattern in Figure 19.
  • the present invention provides a premix of crystalline selexipag Form VII with HPC, which may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2 ⁇ values 6.24, 6.86, 13.69, 13.91 , 14.95, 15.39, 16.07, 16.73, 18.21 , 18.74, 19.28, 20.23, 20.53, 21 .15, 21 .72, 22.44, 22.65, 23.19, 23.74, 24.48, and 24.92 ⁇ 0.2 s .
  • a premix of crystalline selexipag Form VII with HPC may also be characterized by the powder X-ray diffraction pattern in Figure 18.
  • the present invention provides a process for the preparation of a premix of crystalline selexipag Form V.
  • a premix of crystalline selexipag Form V may be prepared by a process that includes the steps of:
  • the present invention provides a process for the preparation of a premix of crystalline selexipag Form VI.
  • a premix of crystalline selexipag Form VII may be prepared by a process that includes the steps of:
  • the present invention provides a process for the preparation of a premix of crystalline selexipag Form VII-1 .
  • a premix of crystalline selexipag Form VII-1 may be prepared by a process that includes the steps of:
  • the anti-solvent may be, for example, an ether, a hydrocarbon, or mixtures thereof.
  • suitable ethers include, but are not limited to, diethyl ether, di-isopropyl ether, methyl tert-butyl ether, and mixtures thereof.
  • suitable hydrocarbons include, but are not limited to, hexane, cyclohexane, methyl cyclohexane, heptane, pentane, and mixtures thereof.
  • pharmaceutically acceptable carriers include low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose, and mixtures thereof.
  • Figure 1 is a powder X-ray diffraction pattern of crystalline selexipag Form IV
  • Figure 2 is a powder X-ray diffraction pattern of crystalline selexipag Form V
  • Figure 3 is a powder X-ray diffraction pattern of crystalline selexipag Form VI;
  • Figure 4 is a powder X-ray diffraction pattern of crystalline selexipag Form VII;
  • Figure 5 is a powder X-ray diffraction pattern of crystalline selexipag Form VII-1 ;
  • Figure 6 is a powder X-ray diffraction pattern of crystalline selexipag Form VIII
  • Figure7 is a powder X-ray diffraction pattern of crystalline selexipag Form IX;
  • Figure8 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form I with 50% w/w Plasdone S-630;
  • Figure9 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form I with 50% w/w povidone K-30;
  • Figure " ! 0 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag with 50% w/w hydroxypropyl ⁇ -cyclodextrin;
  • Figurel 1 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipagwith 50% w/w hydroxypropyl methylcellulose;
  • Figurel 2 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form
  • Figurel 3 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form
  • Figurel 4 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form V with 50% w/w low-substituted hydroxypropyl cellulose (L-HPC, LH-1 1 );
  • Figure " ! 5 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form V with50% w/w hydroxypropyl cellulose (Klucel EXF);
  • Figure " ! 6 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VI with 50% w/w L-HPC (LH-1 1 );
  • Figure " ! 7 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VI with 50% w/w HPC (Klucel EXF);
  • Figure " ! 8 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VII-1 with 50% w/w HPC (Klucel EXF);
  • Figure " ! 9 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VII-1 with 50% w/w L-HPC (LH-1 1 ).
  • the present disclosure relates to novel crystalline forms of selexipag and their processes for preparation.
  • the present disclosure also relates to an amorphous solid dispersion of selexipag and its processes for their preparation as well as premix of crystalline selexipag and their process.
  • the polymorphs of the present disclosure may be are characterized by powder X-ray diffraction.
  • samples of the compounds and mixtures prepared according to methods disclosed herein were analyzed by powder X-ray diffraction on a BRUKER D-8 Discover powder diffractometer equipped with goniometer of ⁇ /2 ⁇ configuration and Lynx Eye detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0° 50.0° 0.030°step size and 0.4 seconds step time.
  • the present invention provides crystalline Form IV of selexipag.
  • selexipag Form IV may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 19.45, 20.59, and 23.13 ⁇ 0.2 s .
  • Selexipag Form IV may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.73, 17.68, 18.32, 19.16, 19.45, 20.59, 20.77, and 23.13 ⁇ 0.2 s .
  • Selexipag Form IV may also be characterized by the powder X-ray diffraction pattern in Figure 1 .
  • the term "about” when modifying an absolute measurement, such as time, mass, or volume, is meant to mean the recited value plus or minus 10% of that value (e.g., in certain embodiments, "about” includes plus or minus 5% or plus or minus 2%, or plus or minus 1 % of that value).
  • the term “about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees(e.g., in certain embodiments, "about” includes plus or minus 2%, or plus or minus 1 % of that value).
  • selexipag Form IV can be prepared by a process that includes the following steps: a) dissolving selexipag in o-xylene;
  • selexipag is dissolved in o-xylene. In particularly useful embodiments, this is carried out at an elevated temperature, for example, at about 60 "C - 80 ⁇ , to facilitate dissolution of the selexipag. In some particularly useful embodiments, after selexipag is dissolved in o-xylene, the reaction mixture is cooled, for example, to about -20 "C to about 15 "C and the temperature is held at this cooler te mperature for an extended period of time, for example, from about 15hours to about 20 hours.
  • seeds of selexipag Form IV may be added. Such seeds can be prepared according to the preceding method, if necessary.
  • the temperature is raised, for example, from about 15 °C to about 30 before optionally adding seeds of selexipag Form IV.
  • Selexipag Form IV may then be isolated. Isolation of the final selexipag Form IV may be carried out by methods well known in the art, for example, by filtering the solution to obtain a solid.
  • the reaction mixture is stirred for several days, for example, for 2-3 days, before isolating selexipag Form IV to facilitate precipitation of solid selexipag Form IV.
  • selexipag Form IV is a solvate. It is further believed that selexipag Form IV is a solvate of o-xylene with a ratio of selexipag to o-xylene of 1 :1 .
  • the present invention provides selexipag Form V.
  • selexipag Form V may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.93 and 23.34 ⁇ 0.2 s .
  • Selexipag Form V may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.93, 1 1 .14, 19.73, 19.96, 20.98, 21 .15, 22.21 , and 23.34 ⁇ 0.2 s .
  • Selexipag Form V may also be characterized by the powder X-ray diffraction pattern in Figure 2.
  • selexipag Form V may be prepared by a process that includes the following steps: a) dissolving selexipag in anisole;
  • selexipag is dissolved in anisole. In particularly useful embodiments, this is carried out at an elevated temperature, for example, from about 60 "Cto about 80 to facilitate dissolution of the selex ipag.
  • the reaction mixture is cooled, for example, to 10 "C to about 15 "C.
  • the reaction mixture may then be optionally seeded with selexipag Form IV or selexipag Form V.
  • an anti-solvent may then be added.
  • suitable anti-solvents include, but are not limited to, hexane, heptane, cyclohexane, and mixtures thereof.
  • selexipag Form V a ratio of 2:1 solvent to anti-solvent is used.
  • heptane is used as an anti-solvent.
  • Selexipag Form V may then be isolated. Isolation of the final selexipag Form V may be carried out by methods well known in the art, for example, by filtering the solution to obtain a solid.
  • the reaction mixture is stirred, for example, from about 30 to about 60 minutes at a lowered temperature (e.g., about 10 "C to about 20 " €) to facilitate formation of a precipitate.
  • a lowered temperature e.g., about 10 "C to about 20 " €
  • Seeds of selexipag Form V can be prepared according to the preceding method, if necessary, with or without use of a seed for selexipag Form IV to encourage crystallization.
  • selexipag Form Vis a solvent. It is further believed that selexipag Form V is a solvate of anisole with a ratio of selexipag to anisole of 1 :1 .
  • the present invention provides selexipag Form VI.
  • Selexipag Form VI may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.38, 18.97, 21 .32, and 25.23 ⁇ 0.2 s .
  • Selexipag Form VI may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.38, 6.94, 10.69, 13.74, 18.44, 18.97, 19.43, 21 .32, 23.35, 24.01 , 24.71 , 25.23, and 26.25 ⁇ 0.2 s .
  • Selexipag Form VI may also be characterized by the powder X-ray diffraction pattern in Figure 3.
  • selexipag Form VI may be prepared by a process that includes the following steps: a) dissolving selexipag in chlorobenzene;
  • selexipag may be dissolved in chlorobenzene. In particularly useful embodiments, this is carried out at an elevated temperature, for example, from about 60 "C to about 80 ⁇ , to facilitate dissoluti on of the selexipag. In such embodiments, after selexipag is dissolved in chlorobenzene, the reaction mixture is cooled, for example, from about 10 "C to about 15 Optionally, the reaction mix ture may be seeded with selexipag Form IV or selexipag Form VI.
  • Selexipag Form VI may then be isolated. Isolation of selexipag Form VI may be carried out by methods well known in the art, for example, by filtering the solution to obtain a solid.
  • the reaction mixture is stirred, for example, from about 30 to about 60 minutes at a lowered temperature (e.g., about 10 "C to about 20 " €) to facilitate formation of a precipitate.
  • a lowered temperature e.g., about 10 "C to about 20 " €
  • Seeds of selexipag Form VI can be prepared according to the preceding method, if necessary, with or without use of a seed for selexipag Form IV to encourage crystallization.
  • selexipag Form VI is a solvate. It is further believed that selexipag Form VI is a chlorobenzene solvate with a ratio of selexipag to chlorobenzene of 1 :1 .
  • the present invention provides selexipag Form VII.
  • Selexipag Form VII may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.76, 19.6, and 24.6 ⁇ 0.2 s .
  • Selexipag Form VII may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.76, 10.98, 13.2, 15.4, 17.6, 18.1 , 19.4, 19.6, 23.3, and 24.6 ⁇ 0.2 s .
  • Selexipag Form VII may also be characterized by the powder X-ray diffraction pattern in Figure 4.
  • the present invention provides a process for the preparation of selexipag Form VII.
  • selexipag Form VII may be prepared by a process that includes the following steps: a) dissolving selexipag in toluene;
  • selexipag may be dissolved in toluene. In particularly useful embodiments, this is carried out at an elevated temperature, for example, from at about 60 "C to about 80 to facilitate dissolution of the selexipag. In such embodiments, after selexipag is dissolved in toluene, the reaction mixture is cooled, for example, from about 10 "C to about 15 To facilitate formation of selexipag Form V II, the reaction mixture may be seeded with selexipag Form IV or selexipag Form V. Selexipag Form VII may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtering the solution to obtain a solid.
  • the reaction mixture is stirred, for example, from about 30 to about 60 minutes at a lowered temperature (e.g., about 10 "C to about 20 " €) to facilitate formation of a precipitate.
  • a lowered temperature e.g., about 10 "C to about 20 " €
  • selexipag Form VII is a solvate. It is further believed that selexipag Form VII is a toluene solvate with a ratio of selexipag to toluene of 1 :1 .
  • the present invention provides selexipag Form VI 1- .
  • Selexipag Form VII-1 may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.29, 18.79, and 25.0 ⁇ 0.2 s .
  • Selexipag Form VII-1 may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.29, 18.79, 19.31 , 23.3, 23.7, 24.5, and 25.0 ⁇ 0.2 s .
  • Selexipag Form VII-1 may also be characterized by the powder X-ray diffraction pattern in Figure 5.
  • selexipag Form VII-1 may be prepared by a process that includes the following steps: a) dissolving selexipag in toluene;
  • selexipag may be dissolved in toluene. In particularly useful embodiments, this is carried out at an elevated temperature, for example, from about 60 "C to about 80 to facilitate dissolution of the se lexipag. In such embodiments, after selexipag is dissolved in toluene, the reaction mixture is cooled, for example, from about 10 "C to about 15 To facilitation formation of selexipag Form VI 1-1 , the reaction mixture may then be seeded with selexipag Form VI.
  • Selexipag Form VII-1 may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtering the solution to obtain a solid.
  • the reaction mixture is stirred for an extended period of time, for example, from about 3 to about 4 hours at a lowered temperature (e.g., about 10 "C to about 20 ⁇ ) to facilitate fo rmation of a precipitate.
  • a lowered temperature e.g., about 10 "C to about 20 ⁇
  • selexipag Form VII-1 is a solvate. It is further believed that selexipag Form VII-1 is a toluene solvate with a ratio of selexipag to toluene of 1 :1 .
  • the present invention provides selexipag Form VIII.
  • Selexipag Form VIII may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.21 , 18.34, 19.47, and 23.66 ⁇ 0.2 s .
  • Selexipag Form VIII may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.21 , 10.65, 13.99, 15.39, 15.78, 18.34, 18.73, 19.10, 19.47, 20.12, 21 .36, 21 .86, 22.56, 23.12, 23.66, 24.10, 24.43, 24.91 , 26.59, 30.54, and 31 .26 ⁇ 0.2 s .
  • Selexipag Form VIII may also be characterized by the powder X-ray diffraction pattern in Figure 6.
  • selexipag Form VIII may be prepared by a process that includes the steps: a) dissolving selexipag in nitrobenzene;
  • selexipag may be dissolved in nitrobenzene. In particularly useful embodiments, this is carried out at an elevated temperature, for example, from about 60 "C to about 80 ⁇ , to facilitate dissoluti on of the selexipag.
  • the reaction mixture is cooled, for example, from about 10 "C to about 15
  • the reaction mix ture may be seeded with selexipag Form IV or selexipag Form VIII.
  • an anti-solvent may be added.
  • the anti-solvent may be, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, or mixtures thereof.
  • the anti-solvent is methyl tert-butyl ether.
  • a ratio of 10:3 solvent:anti-solvent is used.
  • Selexipag Form VIII may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtering the solution to obtain a solid.
  • the reaction mixture is stirred, for example, from about 30 to about 60 minutes at a lowered temperature (e.g., about 10 "C to about 20 " €) to facilitate formation of a precipitate.
  • a lowered temperature e.g., about 10 "C to about 20 " €
  • Seeds of selexipag Form VIII can be prepared according to the preceding method, if necessary, with or without use of a seed of selexipag Form IV to encourage crystallization.
  • selexipag Form VIII is a solvate. It is further believed that selexipag Form VIII is a nitrobenzene solvate with a ratio of selexipag to nitrobenzene of 1 :1 .
  • the present invention provides selexipag Form IX.
  • Selexipag Form IX may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.81 , 1 1 .19, and 23.32 ⁇ 0.2 s .
  • Selexipag Form IX may be further characterized by a powder X- ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.81 , 1 1 .19, 15.40, 17.77, 18.40, 19.34, 19.65, 19.85, 20.93, 22.47, 23.32, 23.83, 24.64, 25.87, 27.52, 27.72, 28.26, and 29.26 ⁇ 0.2 s .
  • Selexipag Form IX may also be characterized by the powder X-ray diffraction pattern in Figure 7.
  • selexipag Form IX may be prepared by a process that includes the following steps: a) dissolving selexipag in 1 ,2-dichlorobenzene;
  • selexipag may be dissolved in 1 ,2-dichlorobenzene. In particularly useful embodiments, this is carried out at an elevated temperature, for example, from about 60 "C to about 80 to facilitate dissoluti on of the selexipag.
  • the reaction mixture is cooled, for example, from about 10 "C to about 15 ⁇ .
  • the reacti on mixture may be seeded with selexipag Form V or selexipag Form IX. Selexipag Form IX may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtering the solution to obtain a solid.
  • the reaction is further cooled, for example, from about 0 " € to about 5 ⁇ before the optional step of seeding, after which the reaction mixture may be stirred for an extended period of time, for example, for about 3 hours, to facilitate formation of a precipitate.
  • selexipag Form IX is a solvate. It is further believed that selexipag Form IX isa 1 ,2-dichlorobenzene solvate with a ratio of selexipag to 1 ,2-dichlorobenzene of 1 :1 .
  • the starting selexipag material useful for making any of selexipag Forms IV, V, VI, VII, VII-1 , VIII, or IX can be any form, for example, any crystalline polymorphic form or amorphous.
  • the initial dissolution of selexipag in a suitable solvent e.g., dissolution of selexipag in o-xylene for preparing selexipag Form IV
  • a suitable solvent e.g., dissolution of selexipag in o-xylene for preparing selexipag Form IV
  • selexipag Form V may be prepared in situ, as depicted in the following synthetic Scheme-I:
  • Crude selexipag which, in the context of Scheme-I, is formed in situ in the conversion of formula III to formula I, may be prepared according to methods well known in the art, for example, by those disclosed in U.S. Pat. No. 7,205,302. While the in-situ conversion of selexipag to selexipag Form V is depicted in Scheme-I, crude selexipag may be used as the starting selexipag material in any one of the above disclosed processes for preparing any one of selexipag Forms IV, V, VI, VII, VII-1 , VIII, or IX.
  • the solubility of selexipag Form V was investigated in USP standard buffers adjusted to different pHs.
  • the buffer solution included 3.73 g of potassium chloride was dissolved in 100 ml_ of water which was mixed with 425 ml_ of 0.2 M hydrochloric acid. Water was added to bring the volume to 1000 ml_.
  • the buffer solution included 2.99 g of sodium acetate dissolved in 100 ml of water which was mixed with 14 mL of 2 N acetic acid. Water was added to bring the volume to 1000 mL.
  • the buffer preparation included 6.80 g of potassium phosphate dissolved in 100 mL of water which was mixed with 28 ml of 0.2 M sodium hydroxide.
  • the buffer preparation included 6.80 g of potassium phosphate dissolved in 100 mL of water which was mixed with 1 12 mL of 0.2 M sodium hydroxide. Water was added to a volume of 1000 mL.
  • the buffer preparation included 3.09 g of boric acid and 3.73 g of potassium chloride dissolved in 100 mL of water which was mixed with 19.5 mL of 0.2 M sodium hydroxide. Water was added to bring the volume to 1000 mL.
  • Table 4 shows the results of this solubility test. As shown in table 4, selexipag Form V is practically insoluble at most pH values, with the exception of pH 8, where it is slightly soluble. Further, selexipag Form V is practically insoluble in water alone.
  • the polymorphs of selexipag prepared by the methods disclosed herein may exhibit enhanced physical and chemical stability. Therefore, the stability of samples of selexipag Form IV, Form V, Form VI, and Form VII-1 was studied in various storage environments. In particular, the physical and chemical stability each sample of selexipag was determined by storing the samples at 40 ⁇ C/75% relative humidity (RH), at 25 ⁇ C/60% relative humidity (RH) and at 5 ⁇ 3 "C for 6 months. The product was analyzed by powder X-ray diffraction (PXRD) and HPLC to determine purity.
  • selexipag Form IV shows no significant chemical degradation and no change in powder X-ray diffraction pattern when stored for 6 months at 5 ⁇ 3 ⁇ RH.
  • selexipag Form V shows no significant chemical degradation and no change in powder X-ray diffraction pattern when stored for 6 months at 5 ⁇ 3 ⁇ RH.
  • selexipag Form VI shows no significant chemical degradation and no change in powder X-ray diffraction pattern when stored for 6 months at 5 ⁇ 3 ⁇ C RH.
  • selexipag Form VI 1-1 shows no significant chemical degradation and no change in powder X-ray diffraction pattern when stored for 6 months at 5 ⁇ 3 ⁇ C RH.
  • selexipag Form V (anisole solvate) has advantageous properties in comparison to prior art crystalline forms of selexipag such as improved processing and handling characteristics, for example, enhanced flowability, wettability, filterability, and the ability to purify it in a single step (as compared to prior art processes requiring multiple steps). It has improved physical properties such as higher bulk density and higher chemical and polymorphic purity.
  • aqueous solubility of selexipag Form V is comparable to the aqueous solubility of Form I, as disclosed in U.S. Patent No. 8,791 ,122.
  • the present invention provides an amorphous solid dispersion of selexipag together with one or more pharmaceutically acceptable carriers.
  • solid dispersions of selexipag and pharmaceutically acceptable carriers may be prepared about 5 % w/w (pharmaceutically acceptable carrier/total composition mass) to about 90 % w/w pharmaceutically acceptable carrier, which may be about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 10%-40%, 10%-30%, 10%-20%, 20%-50%, 20%-40%, 20%-30%, 30%-50%, 30%-40%, and 40%-50% w/w.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, polysaccharides, polyvinylpyrrolidone (povidone), polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, n-vinyl-2-pyrrolidone-vinyl acetate copolymers, C r C 6 polyalkylene glycols, and mixtures thereof.
  • Suitable polysaccharides include, but are not limited to, hydroxypropyl methyl cellulose, croscarmellose, carboxymethyl cellulose, a sodium salt of carboxymethyl cellulose, a calcium salt of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, optionally substituted a-cyclodextrins, optionally substituted ⁇ -cyclodextrins, optionally substituted ⁇ -cyclodextrins, and mixtures thereof.
  • the amorphous solid dispersion contains selexipag with a copolymer of n- vinyl-2-pyrrolidone and vinyl acetate.
  • the copolymer of n- vinyl-2-pyrrolidone and vinyl acetate is Plasdone S-630.
  • This solid dispersion can be characterized as amorphous by powder X-ray diffraction.
  • Figures8 and 12 show a powder X-ray diffraction pattern collected from an amorphous solid dispersion of selexipag with Plasdone S-630.
  • Figure 8 displays data collected from an amorphous solid dispersion of crystalline selexipag Form I with 50% w/w Plasdone S-630
  • Figure 12 displays data collected from an amorphous solid dispersion of crystalline selexipag Form V with 50% Plasdone S-630.
  • crystalline selexipag Form I may be prepared by processes in the prior art, for example, in International Patent Publication No. WO2010150865, which is incorporated by reference with respect to the processes it discloses for preparing selexipag Form I.
  • the amorphous solid dispersion contains selexipag with povidone K-30.
  • Figures 9 and 13 shows a powder X-ray diffraction pattern collected from an amorphous solid dispersion of selexipag with povidone K-30.
  • Figure 9 displays data collected from an amorphous solid dispersion of selexipag Form I with 50% povidone K-30 while
  • Figure 13 displays data collected from an amorphous solid dispersion of selexipag Form V with 50% w/w povidone K-30.
  • selexipag Form I may be prepared by processes in the prior art, for example, in International Patent Publication No. WO2010150865, which is incorporated by reference with respect to the processes it discloses for preparing selexipag Form I.
  • the amorphous solid dispersion contains selexipag with hydroxypropyl ⁇ -cyclodextrin.
  • Figure 10 shows a powder X-ray diffraction pattern collected from an amorphous solid dispersion of selexipag Form I with 50% w/w hydroxypropyl ⁇ - cyclodextrin.
  • the amorphous solid dispersion contains selexipag with hydroxypropyl methylcellulose.
  • Figure 1 1 shows a powder X-ray diffraction pattern collected from an amorphous solid dispersion of selexipag Form I with 50% w/w hydroxypropyl methylcellulose.
  • the present invention provides a process for the preparation of an amorphous solid dispersion of selexipag.
  • a solid dispersion of selexipag can be prepared by a process that includes the following steps: a) dissolving selexipag and one or more pharmaceutically acceptable carriers in a solvent; and
  • selexipag and one or more pharmaceutical acceptable carriers are dissolved in a suitable solvent.
  • the selexipag used to prepare the premix may be a crystalline, amorphous, or mixtures thereof.
  • suitable solvents include, but are not limited to, acetone, methanol, dichloromethane, water, and mixtures thereof.
  • this is carried out at a temperature of about 30 "C to about 80
  • the solvent may then be removed by methods well known in the art to isolate an amorphous solid dispersion of selexipag.
  • the solvent may be removed by evaporation, distillation, spray drying, filtration, lyophilization, agitated thin film drier (ATFD), or any combination thereof.
  • the present invention provides a method for the preparation of a solid dispersion of selexipag by a hot melt extrusion method.
  • a solid dispersion of selexipag may be prepared by passing selexipag and one or more pharmaceutically acceptable carriers through a 40-mesh sieve and subjecting the mixture to melt extrusion on a melt extrusion instrument.
  • the selexipag used to prepare the premix may be crystalline, amorphous, or mixtures thereof.
  • Zone-I temperature 1 10 ⁇ C - 135 ⁇ C
  • Zone-2 temperature 135 " € - 155 "C;
  • Zone-3 temperature 145 "C - 175 "C;
  • the resulting mixture may be further processed to create the final premix. For example, in some embodiments, milling is performed.
  • Zone-1 temperature 1 10 "C
  • Zone-3 temperature 145 and
  • milling the extruded mixture is particularly useful. This may be carried out, for example, at a temperature of 25 ⁇ 2 ⁇ C.
  • the obtained product may be characterized by powder X-ray diffraction and shown to be amorphous, as shown in Figures 12 and 13.
  • the present disclosure providespremixes of crystalline selexipag forms V, VI, and VII-1 .
  • the present invention provides premixes of crystalline selexipag with pharmaceutically acceptable excipients.
  • suitable pharmaceutical excipients include, but are not limited to, polysaccharides, polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, CrC 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® tradename), and mixtures thereof.
  • polysaccharides polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl a
  • Suitable polysaccharides include, for example, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), including low-substituted HPC, optionally substituted a-cyclodextrins, optionally substituted ⁇ -cyclodextrins (e.g., hydroxypropyl ⁇ - cyclodextrin), optionally substituted ⁇ -cyclodextrins (e.g., hydroxypropyl ⁇ -cyclodextrin), and mixtures thereof.
  • CMC carboxymethyl cellulose
  • HPC hydroxypropyl cellulose
  • substituted with respect to cyclodextrin means the addition of side chain groups, for example, hydroxyl, hydroxypropyl, C r C 6 alkyl, and other C r C 6 hydroxyalkyl.
  • the pharmaceutically acceptable excipient is hydroxypropyl cellulose (HPC) or low-substituted hydroxypropyl cellulose (L-HPC).
  • HPC and L- HPC are excipients well known to those in the art.
  • HPC and L-HPC can be characterized or distinguished from each other by the degree of hydroxyl substitution on the glucose ring, expressed as the number of hydroxypropoxy groups per glucose ring unit.
  • HPC typically has a higher molar substitution.
  • the Klucel EXF used in particular embodiments of this invention has a molar substitution of about 3.4 - 4.4.
  • low-substituted hydroxypropyl cellulose (L-HPC) typically has a lower molar substitution.
  • the LH-1 1 used in particular embodiments of this invention has a molar substitution of about 0.2 - 0.4.
  • the present invention provides premixes of each crystalline polymorphic form of selexipag disclosed herein (e.g., forms IV, V, VI, VII, VII-1 , VIII, and IX) with HPC.
  • premixes of selexipag and HPC may be prepared about 5 % w/w (HPC/total composition mass) to about 90 % w/w HPC, which may be about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 10%-40%, 10%-30%, 10%-20%, 20%-50%, 20%-40%, 20%-30%, 30%-50%, 30%-40%, and 40%-50% w/w.
  • the present invention provides premixes of each crystalline polymorphic form of selexipag disclosed herein (e.g., forms IV, V, VI, VII, VII-1 , VIII, and IX) with L-HPC.
  • premixes of selexipag and L- HPC may be prepared about 5 % w/w (L-HPC/total composition mass) to about 90 % w/w L-HPC, which may be about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 10%-40%, 10%-30%, 10%-20%, 20%-50%, 20%-40%, 20%-30%, 30%-50%, 30%-40%, and 40%-50% w/w.
  • the premix contains selexipag Form V and L-HPC.
  • the L-HPC is LH-1 1 .
  • a premix of selexipag Form V and L-HPC may be characterized by a powder X-ray diffraction pattern containingsubstantial peaks at 2 ⁇ angles of 5.91 , 1 1 .1 1 , 13.66, 15.71 , 16.42, 17.36, 17.78, 18.13, 18.45, 19.71 , 20.94, 22.19, 23.27, 24.81 , 26.05, and 26.24 ⁇ 0.2 s .
  • a premix of selexipag Form V and L-HPC may be characterized by the powder X-ray diffraction pattern in Figure 14.
  • the premix contains selexipag Form V and HPC.
  • the HPC is Klucel EXF.
  • a premix of selexipag Form V and HPC may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 5.82, 10.98, 12.83, 13.53, 15.58, 16.30, 17.22, 17.98, 18.30, 19.55, 20.81 , 22.05, 23.15, 23.63, 24.05, 26.10, 26.66, and 31 .43 ⁇ 0.2 s .
  • a premix of selexipag Form V and HPC may be characterized by the powder X-ray diffraction pattern in Figure15.
  • the premix contains selexipag Form VI and L-HPC.
  • the L-HPC is LH-1 1 .
  • a premix of selexipag Form VI and L-HPC may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.21 , 6.77, 13.06, 13.56, 13.89, 14.96, 15.22, 15.47, 16.02, 18.27, 18.79, 19.26, 20.15, 21 .15, 22.26, 22.57, 23.13, 23.88, 24.59, 25.06, 25.94, and 26.07 ⁇ 0.2 s .
  • a premix of selexipag Form VI and L-HPC may be characterized by the powder X-ray diffraction pattern in Figure 16.
  • the premix contains selexipag Form VI and HPC
  • the HPC is Klucel EXF.
  • a premix of selexipag Form VI and HPC may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.30, 6.86, 13.65, 13.99, 15.06, 15.57, 16.13, 16.74, 17.88, 18.35, 18.89, 19.36, 20.24, 21 .22, 22.37, 22.64, 23.22, 23.97, 24.68, 25.12, 26.03, and 26.19 ⁇ 0.2 s .
  • a premix of selexipag Form VI and HPC may be characterized by the powder X-ray diffraction pattern in Figure 17.
  • the premix contains selexipag Form VII-1 and HPC.
  • the HPC is Klucel EXF.
  • a premix of selexipag Form VII-1 and HPC may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.24, 6.86, 13.69, 13.91 , 14.95, 15.39, 16.07, 16.73, 18.21 , 18.74, 19.28, 20.23, 20.53, 21 .15, 21 .72, 22.44, 22.65, 23.19, 23.74, 24.48, and 24.92 ⁇ 0.2 s .
  • a premix of selexipag Form VII-1 and HPC may be characterized by the powder X-ray diffraction pattern in Figure 18.
  • the premix contains selexipag Form VII-1 and L-HPC.
  • the L-HPC is LH-1 1 .
  • a premix of selexipag Form VII-1 and L-HPC may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2 ⁇ angles of 6.26, 6.87, 13.71 , 13.87, 14.95, 15.39, 16.07, 16.77, 18.24, 18.76, 19.28, 20.25, 21 .20, 22.46, 23.21 , 23.78, 24.51 , and 24.97 ⁇ 0.2 s .
  • a premix of selexipag Form VII-1 and L-HPC may be characterized by the powder X-ray diffraction pattern in Figure 19.
  • the present invention provides a process for the preparation of premixes of selexipag with one or more pharmaceutically acceptable excipients.
  • a premix of selexipag Form V may be prepared by a process that includes the following steps: a) dissolving selexipag in anisole;
  • selexipag may be dissolved in anisole. In some embodiments, this may be carried out at an elevated temperature, for example, from about 70 "C to about 90 "C to facilitate dissolution of selexip ag in the anisole. In such embodiments, the solution may then be cooled, for example, from about 20 "C to 25
  • the reaction mixture may be seeded with selexipag Form V.
  • a pharmaceutically acceptable excipient may then be added, after which an anti-solvent may be optionally added.
  • anti-solvents include, but are not limited to, ethers, for example, diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof.
  • ethers for example, diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof.
  • methyl tert-butyl ether is used as an anti-solvent.
  • a premix of selexipag Form V may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtering and collecting a solid.
  • the reaction mixture is cooled, for example, to about 0 "C to about 5 "C after the pharmaceutically accep table excipient is added but before isolation. In some embodiments, it may be particularly useful to hold the reaction mixture at this temperature for an extended period of time, for example, about 3 hours, while stirring.
  • a premix of selexipag Form VI may be prepared by a process that includes the following steps: a) dissolving selexipag in chlorobenzene;
  • selexipag may be dissolved in chlorobenzene. In some embodiments, this may be carried out an elevated temperature, for example, at about 70 "C to about 90 to facilitate dissolution of the selex ipag in the chlorobenzene. In such embodiments, the reaction mixture may then be cooled, for example, to about 25 "C to about 30
  • the reaction mixture may be seeded with selexipag Form VI. In some embodiments, it may be particularly useful to stir the optionally seeded solution for an extended period of time, for example, from about 12 to about 18 hours.
  • a pharmaceutically acceptable excipient may then be added, followed by isolation of a premix of selexipag Form VI. This may be done by method well known in the art, for example, by filtering the reaction mixture to collect a solid.
  • a premix of selexipag Form VII-1 may be prepared by a process that includes the following steps: a) dissolving selexipag in toluene;
  • selexipag may be dissolved in toluene. In some embodiment's, this may be carried out at an elevated temperature, for example, at about 75 "C to about 100 to facilitate dissolution of the sele xipag in toluene. In such embodiments, the reaction mixture may then be cooled, for example, to about 25 "C to about 30 Optionally, the reaction mixture may then be seeded with selexipagForm VI. Next, a pharmaceutically acceptable excipientmay be added. In some particularly useful embodiments, this may be carried out at a decreased temperature, for example, from about 0 "C to about 5 A premix of selexipag Form VII-1 may then be isolated.
  • This may be done by method well known in the art, for example, by filtering the reaction mixture to collect a solid. In some embodiments, it may be particularly useful to stir the solution for an extended period of time, for example, for 3 hours, after adding the pharmaceutically acceptable excipient.
  • suitable pharmaceutical excipient include, but are not limited to, polysaccharides, polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, CrC 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® trade name), and mixtures thereof.
  • polysaccharides polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate
  • Suitable polysaccharides include, for example, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), including low-substituted HPC, optionally substituted a-cyclodextrins, optionally substituted ⁇ -cyclodextrins (e.g., hydroxypropyl ⁇ - cyclodextrin), optionally substituted ⁇ -cyclodextrins (e.g., hydroxypropyl ⁇ -cyclodextrin), and mixtures thereof.
  • CMC carboxymethyl cellulose
  • HPC hydroxypropyl cellulose
  • substituted with respect to cyclodextrin means the addition of side chain groups, for example, hydroxyl, hydroxypropyl, C r C 6 alkyl, and other C r C 6 hydroxyalkyl.
  • the pharmaceutically acceptable excipient is hydroxypropyl cellulose (HPC) or low-substituted hydroxypropyl cellulose (L-HPC).
  • the amorphous solid dispersions of selexipag prepared by the methods disclosed herein may exhibit enhanced physical and chemical stability. Therefore, the stability of samples of amorphous solid dispersions of selexipag was studied in various storage environments.
  • Table 3 Stability studies of amorphous solid dispersions of selexipag (50% w/w with Plasdone S-630) prepared by melt extrusion process
  • crystalline forms of selexipag, the premixes thereof, as well as the amorphous solid dispersion of selexipag disclosed herein may be used to formulate an oral dosage form, such as a tablet or a capsule.
  • an oral dosage form such as a tablet or a capsule.
  • selexipag When administered to patients, selexipag may be useful in therapy for the treatment of pulmonary arterial hypertension.
  • the crystalline forms of selexipag as well as the amorphous solid dispersion of selexipag disclosed herein may be formulated into a tablet which may contain additional inactive ingredients such as D-mannitol, corn starch, L-HPC, HPC, magnesium stearate, and mixtures thereof. Tablets may be coated with a coating that contains additional excipients, such as hydroxypropyl methylcellulose, propylene glycol, titanium dioxide, carnauba wax, iron oxide red, iron oxide yellow, iron oxide black, and mixtures thereof.
  • additional excipients such as hydroxypropyl methylcellulose, propylene glycol, titanium dioxide, carnauba wax, iron oxide red, iron oxide yellow, iron oxide black, and mixtures thereof.
  • the tablets may contain selexipag at an effective amount of between 200 meg (micrograms) and 1 .6 mg.
  • the tablets have 200 meg, 400 meg, 600 meg, 800 meg, 1 mg, 1 .2 mg, 1 .4 mg, or 1 .6 mg of effective selexipag.
  • an effective amount refers to the amount of active selexipag included within the dosage form.
  • Example 7 Preparation of crystalline selexipag Form VII
  • Selexipag 200mg was dissolved in toluene (3 mL) at 70 "C and the clear solution was filtered to remove any undissolved particulate. The clear solution was slowly cooled to 10-15 "C then seeds of Form IV (1 % w/w) were added. The reaction mixture was maintained under stirring at 10-15 "C for 30-60minutes. The solution was filter ed and the obtained solid was washed with cold toluene (1 ml_)then dried at 40 "C under vacuum for 3hours to yield novel crystalline selexipag Form VII.
  • Crude selexipag (6g) was dissolved in toluene (120 mL) at 60-70 The clear solution was filtered to remove any undissolved particulate; clear solution was washed with toluene (6 mL). The clear solution was gradually cooled to 10-15 "C then seeds of Form VI (2% w/w) were added and the reaction mixture was maintained for 3-4hours with slow agitation. The solution was filtered and the solid was washed with cold toluene (12 mL)] then dried at 30-40 "C under vacuum for 3 hours to yield crystalline selexipag Form VII-1 .
  • Example 14 Preparation of an amorphous solid dispersion of selexipag with Plasdone S- 630 (50% w/w)
  • Example 15 Preparation of an amorphous solid dispersion of selexipag with Plasdone S- 630 (50% w/w)
  • Example 16 Preparation of an amorphous solid dispersion of selexipag with povidone K30 (50% w/w) Selexipag (0.5 g) and povidone K30 (0.5 g) were dissolved in methanol (20 mL) and dichloromethane (5 mL) at 40 The clear solutio n was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then distilled using rotary evaporator at 40 "C to yield an amorphous solid dispersion of selexipag with povidone K30.
  • Example 17 Preparation of an amorphous solid dispersion of selexipag with povidone K30 (50% w/w)
  • Example 18 Preparation of an amorphous solid dispersion of selexipag with hydroxypropyl ⁇ -cyclodextrin (50% w/w)
  • Example 19 Preparation of an amorphous solid dispersion of selexipag with hydroxypropyl methylcellulose (50% w/w)
  • Example 20 Preparation of an amorphous solid dispersion of selexipag (50% w/w with Plasdone S-630)
  • Example 21 Preparation of an amorphous solid dispersion of selexipag (25% w/w with Plasdone S-630)
  • Example 22 Preparation of an amorphous solid dispersion of selexipag (50% w/wwith Povidone K-30)
  • Example 23 Preparation of a premix of crystalline selexipag Form V with L-HPC (50% w/w)
  • Example 24 Preparation of a premix of crystalline selexipag Form V with hydroxypropyl cellulose (HPC) (50% w/w) Selexipag (5 g) was dissolved in anisole (25 mL) at 70-75 The clear solution was filtered to remove any undissolved particulate, cooled to 20-25 seeded with selexipag Form V (50mg), and stirred at the same temperature for 15-30 minutes. Hydroxypropyl cellulose (5 g, Klucel EXF) was added and stirred for 30minutes at same temperature.
  • HPC hydroxypropyl cellulose
  • Methyl t-butyl ether was added and the reaction mixture was stirred at 20-25 "C for 30 -60 minutes, cooled to 0-5°C, and stirred at the same temperature for 3 hours.
  • the solution was filtered and the obtained solid was washed with methyl tert-butyl ether (5 mL) then dried at 30 "C under vacuum for 15hours to yield a premix of crystalline selexipag Form V with hydroxypropyl cellulose.
  • Example 25 Preparation of a premix of crystalline selexipag Form VI with L-HPC (50% w/w)
  • Example 26 Preparation of a premix of crystalline selexipag Form VI with hydroxypropyl cellulose (HPC) (50% w/w)
  • Example 27 Preparation of a premix of crystalline selexipag Form VII-1 with HPC (50% w/w)
  • Example 28 Preparation of a premix of crystalline selexipag Form VII-1 with L-HPC (50% w/w)
  • This reaction mixture was adjusted to pH 2.5-3.5with concentrated hydrochloric acid (60 ml_) and then extracted with dichloromethane (1 .500 L). The organic layers were combined and washed with water (2 * 600 ml_), the solvent was evaporated under reduced pressure, and a residue was formed. This residue was stirred with methyl tert-butyl ether (500 ml_) for 2hours and filtered to obtain a solid, which was washed with methyl tert-butyl ether (100 ml_) to form a crude product.
  • aqueous hydrochloric acid (300 m!_) was added to the reaction mixture and the organic and aqueous layers were separated.
  • the organic layer was concentrated under reduced pressure to get an oily residue which was then dissolved in ethyl acetate (1 .000 L).
  • the product was then extracted with water.
  • the pH of the aqueous extraction solution was then adjusted to 10-1 1 using 75 g sodium carbonate, then extracted with ethyl acetate.
  • the aqueous layer was then acidified using aqueous hydrochloric acid and the product was extracted with ethyl acetate.
  • the combined ethyl acetate layers were washed with water and 10% brine solution.
  • the organic layer was concentrated under reduced pressure to get an oily residue, which was dissolved In anisole (500 mL) at 60 "C, cooled and seeded (2%) with the aniso ie solvate of selexipag.
  • the reaction mixture was stirred at 20-25 for l Ohours, after which methyl tert-butylether (700 mL) was added, the reaction mixture was cooled to 0-5" €, and stirred f or 5hours.
  • the solution was filtered and the obtained solid was washed with methyl tert-butyl ether.
  • the wet cake was dried at reduced pressure at 20-25 "C to obtain the title compound.
  • the ethyl acetate layer was treated with activated carbon (ENO-PC) at 30-35 ⁇ a nd filtered through celite bed, washed the bed with ethyl acetate (140 mL). Charged the filtrates into a clean and dry round bottom flask. To the ethyl acetate layer was added n-hexane (2100 mL) at 20-30" €. Stirred the mixture at 20- 30" € for 4 hours. The obtained solid material was f iltered and washed with 1 :1 mixture of ethyl acetate and n-hexane (140 mL) at 20-30" €. Dried the solid compound at 50-55 ⁇ under vacuum for 4 hours to get the crude selexipag (103 g).
  • ENO-PC activated carbon
  • the reaction mixture was cooled to 0-1 ⁇ and slowly water (720 mL) was under stirring. Separated the layers and the aqueous layer washed twice with ethyl acetate (2 x 450 mL). The pH of the aqueous layer adjusted to 2 to 3 by using 1 :1 aqueous hydrochloride at 15- 20" € followed by extracted with ethyl acetate (1260 mL). The ethyl acetate layer was washed twice with water (2 x 540 mL). The ethyl acetate layer treated with activated carbon (ENO-PC) at 30-35" € and filtered through celite bed, washed the bed with ethyl acetate (90 mL).
  • ENO-PC activated carbon
  • a mixture of crude selexipag (80 g) and ethyl acetate (560 mL) was heated to 60-65 ⁇ . Stirred the reaction mixture at 60-65" € for 20 minutes. Fil tered the solution through 0.22 ⁇ membrane and washed with ethyl acetate (80 mL) at 60-65" €. T he filtrates were transferred into dry and clean round bottom flask. To the ethyl acetate solution was added pre-filtered n-hexane (80 mL) under stirring at 45-65 ⁇ . The mixture was heated t o 60-65" € and maintained for 10 minutes. Cooled the mixture gradually to 30-35" € and maintai ned for 1 hour.

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Abstract

La présente invention concerne des formes cristallines de sélexipag et leurs procédés de préparation. La présente invention concerne également une dispersion solide amorphe de sélexipag et ses procédés de préparation, ainsi qu'un prémélange de sélexipag cristallin et son procédé de préparation.
PCT/IN2017/050298 2016-07-20 2017-07-20 Formes polymorphes de sélexipag et dispersion solide amorphe de sélexipag WO2018015974A1 (fr)

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Cited By (3)

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WO2019098300A1 (fr) 2017-11-16 2019-05-23 日本新薬株式会社 Formulation à libération contrôlée
US10407396B2 (en) 2017-11-16 2019-09-10 Apotex Inc. Crystalline form of selexipag
EP3705115A1 (fr) 2019-03-07 2020-09-09 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition contenant du selexipag

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019098300A1 (fr) 2017-11-16 2019-05-23 日本新薬株式会社 Formulation à libération contrôlée
US10407396B2 (en) 2017-11-16 2019-09-10 Apotex Inc. Crystalline form of selexipag
EP3705115A1 (fr) 2019-03-07 2020-09-09 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition contenant du selexipag

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