DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian provisional patent application no. IN201641024794 filed on July 20, 2017, IN201641029167 filed on August 26, 2016, and IN201741003838 filed on February 02, 2017, each of which are hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
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.
BACKGROUND
Selexipag is an agonist of the prostacyclin I2 receptor (IP) and is chemically known as 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butyloxy}-N-(methanesulfonyl) acetamide and is represented formula I below:

formula I
Selexipag is marketed in the United States as UPTRAVITM by Actelion.
International patent publication WO2002088084A1 describes compounds and pharmaceutical compositions for the treatment of pulmonary arterial hypertension.
International patent publication WO2010150865A1 discloses novel crystalline forms of selexipag Forms I, II, and III, each characterized by powder X-ray diffraction.

The inventors of the present disclosure have developed crystalline forms of selexipag, premixes of crystalline forms of selexipag with pharmaceutically acceptable carriers, and solid dispersions of amorphous selexipag with pharmaceutically acceptable carriers.
SUMMARY OF THE INVENTION
In one aspect, 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.
Within the context of the present invention, 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 º.
Within the context of the present invention, crystalline selexipag Form IV may be characterized by the powder X-ray diffraction pattern in Figure 1.
Within the context of the present invention, crystalline selexipag Form V may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2? values of 5.93, 11.14, 19.73, 19.96, 20.98, 21.15, 22.21, and 23.34 ± 0.2º
Within the context of the present invention, crystalline selexipag Form V may be characterized by the powder X-ray diffraction pattern in Figure 2.
Within the context of the present invention, 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 º.
Within the context of the present invention, crystalline selexipag Form VI may be characterized by the powder X-ray diffraction pattern in Figure 3.
Within the context of the present invention, 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 º.
Within the context of the present invention, crystalline selexipag Form VII may be characterized by the powder X-ray diffraction pattern in Figure 4.
Within the context of the present invention, 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 º.
Within the context of the present invention, crystalline selexipag Form VII-1 may be characterized by the powder X-ray diffraction pattern in Figure 5.
Within the context of the present invention, 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 º.
Within the context of the present invention, crystalline selexipag Form VII-1 may be characterized by the powder X-ray diffraction pattern in Figure 6.
Within the context of the present invention, crystalline selexipag Form IX may be characterized by a powder X-ray diffraction pattern with substantial peaks at 2? values of 5.81, 11.19, 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 º.
Within the context of the present invention, crystalline selexipag Form IX may be characterized by the powder X-ray diffraction pattern in Figure 7.
In another aspect, 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.
In one embodiment, selexipag Form IV may be prepared by a process that includes the steps of:
1. dissolving selexipag in o-xylene;
2. optionally seeding with selexipag Form IV; and
3. isolating selexipag Form IV.
In one embodiment, selexipag Form V may be prepared by a process that includes the steps of:
1. dissolving selexipag in anisole;
2. optionally seeding with selexipag Form IV or selexipag Form V;
3. optionally adding an anti-solvent; and
4. isolating selexipag Form V.
Within the context of this embodiment, the anti-solvent may be an ether, a hydrocarbon, or a mixture thereof. Examples of suitable ethers include diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof. Examples of suitable hydrocarbons include hexane, cyclohexane, methyl cyclohexane, heptane, pentane, and mixtures thereof.
In one embodiment, selexipag Form VI may be prepared by a process that includes the steps of:
1. dissolving selexipag in chlorobenzene;
2. optionally seeding with selexipag Form IV or selexipag Form VI; and
3. isolating selexipag Form VI.
In one embodiment, selexipag Form VII may be prepared by a process that includes the steps of:
1. dissolving selexipag in toluene;
2. seeding with Form IV or selexipag Form V; and
3. isolating selexipag Form VII.
In one embodiment, selexipag Form VII-1 may be prepared by a process that includes the steps of:
1. dissolving selexipag in toluene;
2. seeding with selexipag Form VI; and
3. isolating selexipag Form VII-1.
In one embodiment, selexipag Form VIII may be prepared by a process that includes the steps of:
1. dissolving selexipag in nitrobenzene;
2. optionally seeding with selexipag Form IV or selexipag Form VIII;
3. optionally adding an anti-solvent; and
4. isolating selexipag Form VIII.
Within the context of this embodiment, the anti-solvent may be, but are not limited to, an ether, a hydrocarbon, or a mixture thereof. Examples of suitable ethers include diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof. Examples of suitable hydrocarbons include hexane, cyclohexane, methyl cyclohexane, heptane, pentane, and mixtures thereof.
In one embodiment, selexipag Form IX may be prepared by a process that includes the steps of:
1. dissolving selexipag in 1,2-dichlorobenzene;
2. optionally seeding with selexipag Form V or selexipag Form IX; and
3. isolating selexipag Form IX.
In another aspect, the present invention provides an amorphous solid dispersion of crystalline selexipag with a pharmaceutically acceptable carrier and methods for the preparation thereof. Within the context of the invention, 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. Within the context of the invention, the pharmaceutically acceptable carrier may be, for example, a copolymer of n-vinyl-2-pyrrolidone and vinyl acetate, povidone, and mixtures thereof. In particularly useful embodiments, the n-vinyl-2-pyrrolidone and vinyl acetate is Plasdone S-630. In other particularly useful embodiments, povidone with a k-value of 30 is used.
In one embodiment, an amorphous solid dispersion of selexipag with a pharmaceutically acceptable carrier may be prepared by a process that includes the steps of:
1. dissolving selexipag and a pharmaceutically acceptable carrier in a solvent; and
2. removing the solvent to obtain an amorphous solid dispersion of selexipag.
Within the context of this embodiment, the solvent may be, for example (but not limited to), methanol, dichloromethane, acetone, water, or mixtures thereof. Within the context of this embodiment, 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 ß-cyclodextrin, hydroxypropyl methylcellulose, or mixtures thereof. In particularly useful embodiments, the n-vinyl-2-pyrrolidone and vinyl acetate is Plasdone S-630. In other particularly useful embodiments, povidone with a k-value of 30 is used.
In another embodiment, an amorphous solid dispersion of selexipag with a pharmaceutically acceptable carrier may be prepared by hot melt extrusion.
In another aspect, the present invention provides a premix crystalline selexipag with a pharmaceutically acceptable carrier and methods for the preparation thereof. Within the context of the invention, 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. Within the context of the invention, the pharmaceutically acceptable carrier may be, for example, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), or mixtures thereof.
In one embodiment, 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 2? values 5.91, 11.11, 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 º. A premix of crystalline selexipag Form V with L-HPC may also be characterized by the powder X-ray diffraction pattern in Figure 14.
In one embodiment, 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 º. A premix of crystalline selexipag Form V with HPC may also be characterized by the powder X-ray diffraction pattern in Figure 15.
In another embodiment, 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± 0.2º. A premix of crystalline selexipag Form VI with L-HPC may also be characterized by the powder X-ray diffraction pattern in Figure 16.
In one embodiment, 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 º. A premix of crystalline selexipag Form VI with HPC may also be characterized by the powder X-ray diffraction pattern in Figure 17.
In another embodiment, 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 º. A premix of crystalline selexipag Form VII with L-HPC may also be characterized by the powder X-ray diffraction pattern in Figure 19.
In one embodiment, 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 º. A premix of crystalline selexipag Form VII with HPC may also be characterized by the powder X-ray diffraction pattern in Figure 18.
In another aspect, the present invention provides a process for the preparation of a premix of crystalline selexipag Form V. In one embodiment, a premix of crystalline selexipag Form V may be prepared by a process that includes the steps of:
1. dissolving selexipag in anisole;
2. optionally seeding with selexipag Form V;
3. adding pharmaceutically acceptable carrier;
4. optionally adding an anti-solvent;
5. isolating a premix of crystalline selexipag Form V.
In another aspect, the present invention provides a process for the preparation of a premix of crystalline selexipag Form VI. In one embodiment, a premix of crystalline selexipag Form VII may be prepared by a process that includes the steps of:
1. dissolving selexipag in chlorobenzene;
2. optionally seeding with selexipag Form VI;
3. adding pharmaceutically acceptable carrier; and
4. isolating a premix of crystalline selexipag Form VI.
In another aspect, the present invention provides a process for the preparation of a premix of crystalline selexipag Form VII-1. In one embodiment, a premix of crystalline selexipag Form VII-1 may be prepared by a process that includes the steps of:
1. dissolving selexipag in toluene;
2. optionally seeding with selexipag Form VI;
3. adding pharmaceutically acceptable carrier; and
4. isolating a premix of crystalline selexipag Form VII-1.
Within the context of this embodiment, the anti-solvent may be, for example, an ether, a hydrocarbon, or mixtures thereof. Examples of suitable ethers include, but are not limited to, diethyl ether, di-isopropyl ether, methyl tert-butyl ether, and mixtures thereof. Examples of suitable hydrocarbons include, but are not limited to, hexane, cyclohexane, methyl cyclohexane, heptane, pentane, and mixtures thereof. Examples of pharmaceutically acceptable carriers include low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose, and mixtures thereof.
BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
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;
Figure 7 is a powder X-ray diffraction pattern of crystalline selexipag Form IX;
Figure 8 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form I with 50% w/w Plasdone S-630;
Figure 9 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form I with 50% w/w povidone K-30;
Figure 10 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag with 50% w/w hydroxypropyl ß-cyclodextrin;
Figure 11 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag with 50% w/w hydroxypropyl methylcellulose;
Figure 12 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form V with 50% w/w Plasdone S-630;
Figure 13 is a powder X-ray diffraction pattern of an amorphous solid dispersion of selexipag Form V with 25% w/w povidone K-30;
Figure 14 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-11);
Figure 15 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form V with 50% w/w hydroxypropyl cellulose (Klucel EXF);
Figure 16 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VI with 50% w/w L-HPC (LH-11);
Figure 17 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VI with 50% w/w HPC (Klucel EXF);
Figure 18 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VII-1 with 50% w/w HPC (Klucel EXF); and
Figure 19 is a powder X-ray diffraction pattern of premix of crystalline selexipag Form VII-1 with 50% w/w L-HPC (LH-11).

DETAILED DESCRIPTION OF THE INVENTION
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. Thus, 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 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
In one aspect, the present invention provides crystalline Form IV of selexipag.
In one embodiment, 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 º. 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 º. Selexipag Form IV may also be characterized by the powder X-ray diffraction pattern in Figure 1.
Within the context of the invention, 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). Within the context of the invention, 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).

In another aspect, the present invention provides a process for the preparation for selexipag Form IV. In one embodiment, selexipag Form IV can be prepared by a process that includes the following steps:
a) dissolving selexipag in o-xylene;
b) optionally seeding with selexipag Form IV; and
c) isolating selexipag Form IV.
Within the context of this embodiment, 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 °C, 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 temperature for an extended period of time, for example, from about 15 hours to about 20 hours. Optionally, seeds of selexipag Form IV may be added. Such seeds can be prepared according to the preceding method, if necessary. In such embodiments, where the temperature was cooled after dissolving selexipag in o-xylene, the temperature is raised, for example, from about 15 °C to about 30 °C, 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.
In some embodiments, 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.
It is believed that 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.
In another aspect, the present invention provides selexipag Form V.
In one embodiment, 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 º. Selexipag Form V may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2? angles of 5.93, 11.14, 19.73, 19.96, 20.98, 21.15, 22.21, and 23.34 ± 0.2 º. Selexipag Form V may also be characterized by the powder X-ray diffraction pattern in Figure 2.
In another aspect, of the present invention provides a process for the preparation of selexipag Form V. In one embodiment, selexipag Form V may be prepared by a process that includes the following steps:
a) dissolving selexipag in anisole;
b) optionally seeding with selexipag Form IV or selexipag Form V;
c) optionally adding an anti-solvent; and
d) isolating selexipag Form V.
According to the present embodiment, selexipag is dissolved in anisole. In particularly useful embodiments, this is carried out at an elevated temperature, for example, from about 60 °C to about 80 °C, to facilitate dissolution of the selexipag. In such embodiments, after selexipag is dissolved in anisole, 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. Optionally, an anti-solvent may then be added. Examples of suitable anti-solvents include, but are not limited to, hexane, heptane, cyclohexane, and mixtures thereof. One of skill in the art will recognize or be able to determine without undue experimentation the volume of anti-solvent required to facilitate formation of selexipag Form V. For example, in some embodiments, a ratio of 2:1 solvent to anti-solvent is used. In particularly useful embodiments, 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.
In some embodiments, after an anti-solvent is added, 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 °C) to facilitate formation of a precipitate.
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.
It is believed that selexipag Form V is 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.
In another aspect, 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 º. 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 º. Selexipag Form VI may also be characterized by the powder X-ray diffraction pattern in Figure 3.
In another aspect, the present invention provides a process for the preparation of selexipag Form VI. In one embodiment, selexipag Form VI may be prepared by a process that includes the following steps:
a) dissolving selexipag in chlorobenzene;
b) optionally seeding with selexipag Form IV or selexipag Form VI; and
c) isolating selexipag Form VI.
According to the present embodiment, 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 °C, to facilitate dissolution 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 °C. Optionally, the reaction mixture 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.
In some embodiments, after an anti-solvent is added, 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 °C) to facilitate formation of a precipitate.
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.
It is believe that 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.
In another aspect, 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 º. 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 º. Selexipag Form VII may also be characterized by the powder X-ray diffraction pattern in Figure 4.
In another aspect, the present invention provides a process for the preparation of selexipag Form VII. In one embodiment, selexipag Form VII may be prepared by a process that includes the following steps:
a) dissolving selexipag in toluene;
b) seeding with selexipag Form IV or selexipag Form V; and
c) isolating selexipag Form VII.
According to the present embodiment, 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 °C, 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 °C. To facilitate formation of selexipag Form VII, 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.
In some embodiments, after an anti-solvent is added, 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 °C) to facilitate formation of a precipitate.
It is believe that 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.
In another aspect, the present invention provides selexipag Form VII-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 º. 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 º. Selexipag Form VII-1 may also be characterized by the powder X-ray diffraction pattern in Figure 5.
In another aspect, the present invention provides a process for the preparation of selexipag Form VII-1. In one embodiment, selexipag Form VII-1 may be prepared by a process that includes the following steps:
a) dissolving selexipag in toluene;
b) seeding with selexipag Form VI; and
c) isolating selexipag Form VII-1.
According to the present embodiment, 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 °C, 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 °C. To facilitation formation of selexipag Form VII-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.
In some embodiments, after an anti-solvent is added, 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 °C) to facilitate formation of a precipitate.
It is believed that 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.
In another aspect, 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 º. 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 º. Selexipag Form VIII may also be characterized by the powder X-ray diffraction pattern in Figure 6.
In another aspect, the present invention provides a process for the preparation of selexipag Form VIII. In one embodiment, selexipag Form VIII may be prepared by a process that includes the steps:
a) dissolving selexipag in nitrobenzene;
b) optionally seeding with selexipag Form IV or selexipag Form VIII;
c) optionally adding an anti-solvent; and
d) isolating selexipag Form VIII.
According to the present embodiment, 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 °C, to facilitate dissolution of the selexipag. In such embodiments, after selexipag is dissolved in nitrobenzene, the reaction mixture is cooled, for example, from about 10 °C to about 15 °C. Optionally, the reaction mixture may be seeded with selexipag Form IV or selexipag Form VIII. Optionally, an anti-solvent may be added. Within the context of this embodiment, the anti-solvent may be, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, or mixtures thereof. In particularly useful embodiments, the anti-solvent is methyl tert-butyl ether. One of skill in the art will recognize or be able to determine without undue experimentation the volume of anti-solvent required to facilitate formation of selexipag Form V. For example, in some embodiments, 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.
In some embodiments, after an anti-solvent is added, 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 °C) to facilitate formation of a precipitate.
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.
It is believed that 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.
In another aspect, 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, 11.19, and 23.32 ± 0.2 º. Selexipag Form IX may be further characterized by a powder X-ray diffraction pattern containing substantial peaks at 2? angles of 5.81, 11.19, 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 º. Selexipag Form IX may also be characterized by the powder X-ray diffraction pattern in Figure 7.
In another aspect, the present invention provides a process for the preparation of selexipag Form IX. In one embodiment, selexipag Form IX may be prepared by a process that includes the following steps:
a) dissolving selexipag in 1,2-dichlorobenzene;
b) optionally seeding with selexipag Form V or selexipag Form IX; and
c) isolating selexipag Form IX.
According to the present embodiment, 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 °C, to facilitate dissolution of the selexipag. In such embodiments, after selexipag is dissolved in 1,2-dichlorobenzene, the reaction mixture is cooled, for example, from about 10 °C to about 15 °C. Optionally, the reaction 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.
In some embodiments, the reaction is further cooled, for example, from about 0 °C to about 5 °C 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.
It is believed that selexipag Form IX is a solvate. It is further believed that selexipag Form IX is a 1,2-dichlorobenzene solvate with a ratio of selexipag to 1,2-dichlorobenzene of 1:1.
Within the context of the invention, 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. Further, the initial dissolution of selexipag in a suitable solvent (e.g., dissolution of selexipag in o-xylene for preparing selexipag Form IV) may be carried out in situ after selexipag is synthesized.
For example, 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.
To summarize the processes disclosed herein, a summary of the solvents useful to prepare each of selexipag Forms IV, V, VI, VII, VII-1, VIII, and IX are shown below in Table 1.
Table 1
Solvent Selexipag form
o-xylene Form IV
Anisole Form V
Chlorobenzene Form VI
Toluene Form VII
Toluene Form VII-1
Nitrobenzene Form VIII
1,2-dichlorobenzene Form IX

The solubility of selexipag Form V was investigated in USP standard buffers adjusted to different pHs. For pH 1.2, 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. For pH 4.5, 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. For pH 6.0, 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. Water was added to bring the volume to 1000 mL. For pH 6.8, the buffer preparation included 6.80 g of potassium phosphate dissolved in 100 mL of water which was mixed with 112 mL of 0.2 M sodium hydroxide. Water was added to a volume of 1000 mL. For pH 8.0, 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 below 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.
Table 4: Solubility profile of selexipag Form V (Anisole solvate) in USP buffers at 37 °C
(USP) Buffer pH Solubility
pH 1.2 Practically insoluble (<0.1 mg/ mL)
pH 4.5 Practically insoluble (<0.1 mg/ mL)
pH 6.0 Practically insoluble (<0.1 mg/ mL)
pH 6.8 Practically insoluble (<0.1 mg/ mL)
pH 8.0 Very slightly soluble
Water Practically insoluble (<0.1 mg/ mL)

Solid State Stability data:
Within the context of the invention, 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.
Chromatographic conditions:
Column : Symmetry C18, 150 x 4.6 mm, 3.5µm
Detector : UV at 260 nm
Flow rate : 1.0 mL/minute
Injection volume : 20.0 µL
Column oven temperature : 45°C
Sample temperature : 10°C
Run time : 30 minutes
Acquisition time : 25 minutes
Diluent: Water: Acetonitrile (80:20) %v/v
Table 2 below shows the results of this study.
Table 2
ConditionPolymorph Form IV Form V Form VI Form VII-1
HPLC Purity (%) PXRD HPLC Purity (%) PXRD HPLC Purity (%) PXRD HPLC Purity (%) PXRD
at 5 ± 3 °C
Initial 99.85 Form IV 99.71 Form V 99.85 Form VI 99.82 Form VII-1
15 days 99.84 Stable 99.72 Stable 99.85 Stable 99.82 Stable
1 months 99.87 Stable 99.76 Stable 99.92 Stable 99.80 Stable
2 months 99.87 Stable 99.76 Stable 99.80 Stable 99.76 Stable
3 months 99.88 Stable 99.79 Stable 99.80 Stable 99.81 Stable
6 months 99.84 Stable 99.81 Stable 99.78 Stable - -

From the data collected as shown in Table 2 above, 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 °C RH.
From the data collected as shown in Table 2 above, 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 °C RH.
From the data collected as shown in Table 2 above, 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.
From the data collected as shown in Table 2 above, selexipag Form VII-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.
From the data collected as shown in Table 2 above, selexipag solvates Form IV, Form V, Form VI, and Form VII-1 were found to be physically unstable when stored at 40 °C/75% RH and at 25 °C/60% RH.
It has surprisingly been found that 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.
It is believed that some of these improved characteristics stem from the elongated rod shape morphology of the selexipag Form V crystal. It is believed that with this morphology improves filtration speed when compared to prior art crystals with plate-like morphology. Improved filtration may, in turn, lead to higher chemical and polymorphic purity achievable single step. The improved qualities as outlined above are combined with advantageous properties of polymorphic forms in the prior art. For example, the 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.
In another aspect, the present invention provides an amorphous solid dispersion of selexipag together with one or more pharmaceutically acceptable carriers.
Within the context of this embodiment, 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. Examples of 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, C1-C6 polyalkylene glycols, and mixtures thereof.
Examples of 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 ß-cyclodextrins, optionally substituted ?-cyclodextrins, and mixtures thereof.
In one embodiment, the amorphous solid dispersion contains selexipag with a copolymer of n-vinyl-2-pyrrolidone and vinyl acetate. In particularly useful embodiments, 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. For example, Figures 8 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, while Figure 12 displays data collected from an amorphous solid dispersion of crystalline selexipag Form V with 50% Plasdone S-630. Within the context of this embodiment, 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.
In another embodiment, the amorphous solid dispersion contains selexipag with povidone K-30. For example, 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. Within the context of this embodiment, 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.
In yet another embodiment, the amorphous solid dispersion contains selexipag with hydroxypropyl ß-cyclodextrin. For example, Figure 10 shows a powder X-ray diffraction pattern collected from an amorphous solid dispersion of selexipag Form I with 50% w/w hydroxypropyl ß-cyclodextrin.
In yet another embodiment, the amorphous solid dispersion contains selexipag with hydroxypropyl methylcellulose. For example, Figure 11 shows a powder X-ray diffraction pattern collected from an amorphous solid dispersion of selexipag Form I with 50% w/w hydroxypropyl methylcellulose.
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of selexipag. In one embodiment, 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
b) removing the solvent to obtain an amorphous solid dispersion of selexipag.
According to the present embodiment, selexipag and one or more pharmaceutical acceptable carriers are dissolved in a suitable solvent. Within the context of the present embodiment, the selexipag used to prepare the premix may be a crystalline, amorphous, or mixtures thereof. Within the context of this embodiment, examples of suitable solvents include, but are not limited to, acetone, methanol, dichloromethane, water, and mixtures thereof.
In particularly useful embodiments, this is carried out at a temperature of about 30 °C to about 80 °C. The solvent may then be removed by methods well known in the art to isolate an amorphous solid dispersion of selexipag. For example, the solvent may be removed by evaporation, distillation, spray drying, filtration, lyophilization, agitated thin film drier (ATFD), or any combination thereof.
In another aspect, the present invention provides a method for the preparation of a solid dispersion of selexipag by a hot melt extrusion method.
In one embodiment, 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. Within the context of the present embodiment, the selexipag used to prepare the premix may be crystalline, amorphous, or mixtures thereof.
One of skill in the art will be able to determine the proper instrument parameters for carrying out the extrusion process. In particular, useful embodiments, the following instrument parameters are used to accomplish melt extrusion:
Zone-I temperature: 110 °C – 135 °C;
Zone-2 temperature: 135 °C – 155 °C;
Zone-3 temperature: 145 °C – 175 °C; and
Exit zone temperature: 160 °C – 200 °C.
After the extrusion process, the resulting mixture may be further processed to create the final premix. For example, in some embodiments, milling is performed.
In other particularly useful embodiments, the following instrument parameters are used to accomplish melt extrusion:
Zone-1 temperature: 110 °C,
Zone-2 temperature: 135 °C,
Zone-3 temperature: 145 °C; and
Exit zone temperature: 160 °C.
In some embodiments, 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.
In another embodiment, the present disclosure provides premixes of crystalline selexipag forms V, VI, and VII-1.
In another aspect, the present invention provides premixes of crystalline selexipag with pharmaceutically acceptable excipients.
Within the context of the invention, examples of 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, C1-C6 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. 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 ß-cyclodextrins (e.g., hydroxypropyl ß-cyclodextrin), optionally substituted ?-cyclodextrins (e.g., hydroxypropyl ?-cyclodextrin), and mixtures thereof. As used herein, the term "substituted" with respect to cyclodextrin means the addition of side chain groups, for example, hydroxyl, hydroxypropyl, C1-C6 alkyl, and other C1-C6 hydroxyalkyl.
In particularly useful embodiments, the pharmaceutically acceptable excipient is hydroxypropyl cellulose (HPC) or low-substituted hydroxypropyl cellulose (L-HPC).
As used herein, hydroxypropyl cellulose (HPC) and low-substituted hydroxypropyl cellulose (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. For example, the Klucel EXF used in particular embodiments of this invention has a molar substitution of about 3.4 – 4.4. In contrast, low-substituted hydroxypropyl cellulose (L-HPC) typically has a lower molar substitution. For example, the LH-11 used in particular embodiments of this invention has a molar substitution of about 0.2 – 0.4.
In one embodiment, 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.
Within the context of this embodiment of the present disclosure, 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.
In one embodiment, 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.
Within the context of this embodiment of the present disclosure, 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.
In one embodiment, the premix contains selexipag Form V and L-HPC. In particularly useful embodiments, the L-HPC is LH-11. Within the context of this embodiment, a premix of selexipag Form V and L-HPC may be characterized by a powder X-ray diffraction pattern containing substantial peaks at 2? angles of 5.91, 11.11, 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 º. In another embodiment, a premix of selexipag Form V and L-HPC may be characterized by the powder X-ray diffraction pattern in Figure 14.
In another embodiment, the premix contains selexipag Form V and HPC. In particularly useful embodiments, the HPC is Klucel EXF. Within the context of this embodiment, 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± 0.2º. In another embodiment, a premix of selexipag Form V and HPC may be characterized by the powder X-ray diffraction pattern in Figure 15.
In one embodiment, the premix contains selexipag Form VI and L-HPC. In particularly useful embodiments, the L-HPC is LH-11. Within the context of this embodiment, 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 º. In another embodiment, a premix of selexipag Form VI and L-HPC may be characterized by the powder X-ray diffraction pattern in Figure 16.
In another embodiment, the premix contains selexipag Form VI and HPC In particularly useful embodiments, the HPC is Klucel EXF. Within the context of this embodiment, 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 º. In another embodiment, a premix of selexipag Form VI and HPC may be characterized by the powder X-ray diffraction pattern in Figure 17.
In another embodiment, the premix contains selexipag Form VII-1 and HPC. In particularly useful embodiments, the HPC is Klucel EXF. Within the context of this embodiment, 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 º. In another embodiment, a premix of selexipag Form VII-1 and HPC may be characterized by the powder X-ray diffraction pattern in Figure 18.
In one embodiment, the premix contains selexipag Form VII-1 and L-HPC. In particularly useful embodiments, the L-HPC is LH-11. Within the context of this embodiment, 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 º. In another embodiment, a premix of selexipag Form VII-1 and L-HPC may be characterized by the powder X-ray diffraction pattern in Figure 19.
In another aspect, the present invention provides a process for the preparation of premixes of selexipag with one or more pharmaceutically acceptable excipients.
In one embodiment, a premix of selexipag Form V may be prepared by a process that includes the following steps:
a) dissolving selexipag in anisole;
b) optionally seeding with selexipag Form V;
c) adding a pharmaceutically acceptable excipient;
d) optionally adding an anti-solvent; and
e) isolating a premix of selexipag Form V.
According to the present embodiment, 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 selexipag in the anisole. In such embodiments, the solution may then be cooled, for example, from about 20 °C to 25 °C. Optionally, 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. Within the context of this embodiment, examples of suitable anti-solvents include, but are not limited to, ethers, for example, diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof. In particularly useful embodiments, 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.
In some particularly useful embodiments, the reaction mixture is cooled, for example, to about 0 °C to about 5 °C after the pharmaceutically acceptable 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.
In another embodiment, a premix of selexipag Form VI may be prepared by a process that includes the following steps:
a) dissolving selexipag in chlorobenzene;
b) optionally seeding with selexipag Form VI;
c) adding a pharmaceutically acceptable excipient; and
d) isolating a premix of selexipag Form VI.
According to the present embodiment, 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 °C, to facilitate dissolution of the selexipag in the chlorobenzene. In such embodiments, the reaction mixture may then be cooled, for example, to about 25 °C to about 30 °C. Optionally, 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.
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.
In another embodiment, a premix of selexipag Form VII-1 may be prepared by a process that includes the following steps:
a) dissolving selexipag in toluene;
b) optionally seeding with selexipag Form VI;
c) adding a pharmaceutically acceptable excipient; and
d) isolating a premix of selexipag Form VII-1.
According to the present embodiment, 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 °C, to facilitate dissolution of the selexipag in toluene. In such embodiments, the reaction mixture may then be cooled, for example, to about 25 °C to about 30 °C. Optionally, the reaction mixture may then be seeded with selexipag Form VI. Next, a pharmaceutically acceptable excipient may 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 °C. 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.
Within the context of the invention, examples of 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, C1-C6 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. 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 ß-cyclodextrins (e.g., hydroxypropyl ß-cyclodextrin), optionally substituted ?-cyclodextrins (e.g., hydroxypropyl ?-cyclodextrin), and mixtures thereof. As used herein, the term "substituted" with respect to cyclodextrin means the addition of side chain groups, for example, hydroxyl, hydroxypropyl, C1-C6 alkyl, and other C1-C6 hydroxyalkyl.
In particularly useful embodiments, the pharmaceutically acceptable excipient is hydroxypropyl cellulose (HPC) or low-substituted hydroxypropyl cellulose (L-HPC).
Solid State Stability data:
Within the context of the invention, 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.
In particular, the physical and chemical stability of an amorphous solid dispersions of selexipag and 50% w/w Plasdone S-630, prepared by the hot melt extrusion methods disclosed herein, 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. HPLC analysis was performed by the parameters listed below:
Chromatographic conditions:
Column : Symmetry C18, 150 x 4.6 mm, 3.5µm
Detector : UV at 260 nm
Flow rate : 1.0 mL/minute
Injection volume : 20.0 µL
Column oven temperature : 45°C
Sample temperature : 10°C
Run time : 30 minutes
Acquisition time : 25 minutes
Diluent: Water: Acetonitrile (80:20) %v/v
Table 3 below shows the results of this study.
Table 3: Stability studies of amorphous solid dispersions of selexipag (50% w/w with Plasdone S-630) prepared by melt extrusion process
Condition\ Polymorph HPLC Purity (%) PXRD
at 40 ± 2 °C / 75 ± 5 %RH
Initial 99.83 Amorphous
15 days 99.63 Stable
1 months 99.66 Stable
2 months 99.61 Stable
3 months 99.61 Stable
6 months 99.68 Stable
at 25± 2 °C / 60 ± 5 %RH
Initial 99.83 Amorphous
15 days 99.62 Stable
1 months 99.67 Stable
2 months 99.61 Stable
3 months 99.63 Stable
6 months 99.68 Stable

From the data collected as shown in Table 3 above, the physical and chemical stability of the amorphous selexipag premix prepared by melt extrusion process shows no significant chemical degradation and no change in powder X-ray diffraction pattern when stored for 6 months at 25 °C/60% and 40 °C/75% RH.
The 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. 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. One of skill in the art will be familiar with a variety of excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
In some embodiments, the tablets may contain selexipag at an effective amount of between 200 mcg (micrograms) and 1.6 mg. In particularly useful embodiments, the tablets have 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1 mg, 1.2 mg, 1.4 mg, or 1.6 mg of effective selexipag. Within the context of this invention, an effective amount refers to the amount of active selexipag included within the dosage form.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.
Examples
Example 1: Preparation of crystalline selexipag Form IV
Selexipag (50 mg) was dissolved in o-xylene (2 mL) at 70 °C. The clear solution was cooled to - 20 °C and maintained at that temperature for 16 hours. The temperature was raised to 25-30 °C and maintained under stirring at 25-30 °C for 2 days. The solution was filtered and suck-dried under vacuum for 15 minutes to yield crystalline selexipag Form IV.
Example 2: Preparation of crystalline selexipag Form IV
Selexipag (2.0 g) was dissolved in o-xylene (30 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 solution was maintained under stirring at 25-30 °C for 30-60 minutes. The solution was filtered and the obtained solid was washed with o-xylene (6 mL) and dried at 40 °C under vacuum for 3 hours to yield crystalline selexipag Form IV.
Example 3: Preparation of crystalline selexipag Form V
Selexipag (2.0 g) was dissolved in anisole (10 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 selexipag Form IV (1% w/w) were added. The solution was maintained under stirring at 25-30 °C for 30-60 minutes. The solution was then filtered and the obtained solid was washed with anisole (4 mL) and dried at 40 °C under vacuum for 3 hours to yield crystalline selexipag Form V.
Example 4: Preparation of crystalline selexipag Form V
Selexipag (10.0 g) was dissolved in anisole (40 mL) at 70 °C and the solution was filtered through Hyflo to remove any undissolved particulate. The clear solution was slowly cooled to 10-15 °C then seeds of selexipag Form V (1% w/w) were added before further cooling the solution to 0 to 5 °C and maintaining the solution while stirring for 30-60 minutes. To the reaction mixture, heptane (50 mL) was added and the solution was maintained under stirring at 0 to-5 °C for 30-60 minutes. The obtained solution was filtered and the solid was washed with heptane (20 mL) and dried at 40 °C under vacuum for 3 hours to yield crystalline selexipag Form V.
Example 5: Preparation of crystalline selexipag Form VI
Selexipag (200 mg) was dissolved in chlorobenzene (2 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 30-60 minutes. The solution was filtered and the solid obtained was washed with chlorobenzene (1 mL) then dried at 40 °C under vacuum for 3 hours to yield crystalline selexipag Form VI of selexipag.
Example 6: Preparation of crystalline selexipag Form VI
Selexipag (1 g) was dissolved in chlorobenzene (10 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 VI (1% w/w) were added. The reaction mixture was maintained under stirring at 10-15 °C for 30-60 minutes. The solution was filtered and the solid was washed with chlorobenzene (2 mL) then dried at 40 °C under vacuum for 3 hours to yield crystalline selexipag Form VI.
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 30-60 minutes. The solution was filtered and the obtained solid was washed with cold toluene (1 mL) then dried at 40 °C under vacuum for 3 hours to yield novel crystalline selexipag Form VII.
Example 8: Preparation of crystalline selexipag Form VII
Crude selexipag (6 g) was dissolved in toluene (120 mL) at 60-70 °C. The clear solution was filtered to remove any undissolved particulate then was washed with toluene (6 mL). The clear solution was gradually cooled to 10-15 °C then seeds of Form V (2% w/w) were added. The reaction mixture was maintained under stirring at 10-15 °C for 15 hours with slow agitation. The solution was filtered and the obtained solid was washed with cold toluene (12 mL) then dried at 30-40 °C under vacuum for 3 hours to yield selexipag Form VII.
Example 9: Preparation of crystalline of selexipag Form VII-1
Crude selexipag (6 g) was dissolved in toluene (120 mL) at 60-70 °C. 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 3-4 hours 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 10: Preparation of crystalline selexipag Form VIII
Selexipag (200 mg) was dissolved in nitrobenzene (2 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 and the solution was maintained under stirring at 10-15 °C for 30-60 minutes. Tert-butyl methyl ether (3 mL) was added into the reaction mixture and maintained under stirring at 10-15 °C for 30-60 minutes. The solution was filtered and the solid was washed with tert-butyl methyl ether (2 mL) and dried at 40 °C under vacuum for 3 hours to yield crystalline selexipag Form VIII.
Example 11: Preparation of crystalline selexipag Form VIII
Selexipag (1 g) was dissolved in nitrobenzene (10 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 VIII (1% w/w) were added and the reaction mixture was maintained under stirring at 10-15 °C for 30-60 minutes. T-butyl methyl ether (3 mL) was added into the reaction mixture and maintained under stirring at 10-15 °C for 30-60 minutes. The solution was filtered and the obtained solid was washed with t-butyl methyl ether (5 mL) then dried at 40 °C under vacuum for 3 hours to yield crystalline selexipag Form VIII.
Example 12: Preparation of crystalline selexipag Form IX
Selexipag (100 mg) was dissolved in 1,2-dichlorobenzene (1 mL) at 75-80 °C. The clear solution was slowly cooled to 10-15 °C then seeds of Form V (1% w/w) were added. The reaction mixture was maintained under stirring at 0-5 °C for 3 hours. The solution was filtered and the solid was dried at 30 °C under vacuum for 3 hours to yield crystalline Form IX.
Example 13: Preparation of crystalline selexipag Form IX
Selexipag (2 g) was dissolved in 1,2-dichlorobenzene (6 mL) at 75-80 °C. The clear solution was slowly cooled to 10-15 °C then seeds of Form IX (1% w/w) were added. The reaction mixture was maintained under stirring at 0-5 °C for 16 hours. The solution was filtered and the solid was dried at 30 °C under vacuum for 3 hours to yield crystalline selexipag Form IX.
Example 14: Preparation of an amorphous solid dispersion of selexipag with Plasdone S-630 (50% w/w)
Selexipag (0.5 g) and Plasdone-S630 (0.5 g) were dissolved in methanol (20 mL) and dichloromethane (5 mL) at 40 °C. The clear solution 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 Plasdone S-630.
Example 15: Preparation of an amorphous solid dispersion of selexipag with Plasdone S-630 (50% w/w)
Selexipag (6.0 g) and Plasdone-S630 (6.0 g) were dissolved in methanol (360 mL) at 65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 15 mL/min and inlet temperature of 40 °C with 100% aspiration to yield an amorphous solid dispersion of selexipag with Plasdone S-630.
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 °C. The clear solution 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)
Selexipag (6.0 g) and povidone K30 (6.0 g) were dissolved in methanol (360 mL) at 65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 15 mL/min and inlet temperature of 40 °C with 100% aspiration to yield an amorphous solid dispersion of selexipag with povidone K30.
Example 18: Preparation of an amorphous solid dispersion of selexipag with hydroxypropyl ß-cyclodextrin (50% w/w)
Selexipag (6.0 g) and hydroxypropyl ß-cyclodextrin (6.0 g) were dissolved in methanol (270 mL) at 60-65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 15 mL/min and inlet temperature of 50 °C with 100% aspiration to yield an amorphous solid dispersion of selexipag with hydroxypropyl ß-cyclodextrin.
Example 19: Preparation of an amorphous solid dispersion of selexipag with hydroxypropyl methylcellulose (50% w/w)
Selexipag (5.0 g) and hydroxypropyl methylcellulose (5.0 g) were dissolved in acetone (150 mL) and water (50 mL) at 60-65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 15 mL/min and inlet temperature of 60 °C with 100% aspiration to yield an amorphous solid dispersion of selexipag with hydroxypropyl methylcellulose.
Example 20: Preparation of an amorphous solid dispersion of selexipag (50% w/w with Plasdone S-630)
Selexipag Form V (12.2 g) and Plasdone S-630 (10 g) were passed through a 40 mesh sieve and subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nano16) with the following experimental conditions: Zone-1 temperature: 110 °C, Zone-2 temperature: 135 °C, Zone-3 temperature: 145 °C and exit zone temperature of 160 °C. The extruded product was milled at 25±2 °C. The obtained product was characterized by PXRD and shown to be an amorphous solid dispersion of selexipag.
Example 21: Preparation of an amorphous solid dispersion of selexipag (25% w/w with Plasdone S-630)
Selexipag Form V (15 g) and Plasdone S-630 (6.2 g) were passed through a 40 mesh sieve and subjected to melt extrusion on hot melt extruder instrument (Leistritz, model: Nano 16) with the following experimental conditions: Zone-1 temprature:110 °C, Zone-2 temperature: 135 °C, Zone-3 temperature: 145 °C and exit zone temperature of 160 °C. The extruded product was milled at 25±2 °C. The obtained product was characterized by PXRD and was shown to be an amorphous solid dispersion of selexipag.
Example 22: Preparation of an amorphous solid dispersion of selexipag (50% w/w with Povidone K-30)
Selexipag Form V (12.2 g) and Povidone K-30 (10 g) were passed through a 40 mesh sieve and subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nano16) with the following experimental conditions: Zone-1 temperature: 135 °C, Zone-2 temperature: 155 °C, Zone-3 temperature: 175 °C and exit zone temperature of 200 °C. The extruded product was milled at 25 ± 2 °C. The obtained product was characterized by powder X-ray diffraction and was shown to be an amorphous solid dispersion of selexipag.
Example 23: Preparation of a premix of crystalline selexipag Form V with L-HPC (50% w/w)
Selexipag (5 g) was dissolved in anisole (25 mL) at 70-75 °C. The clear solution was filtered to remove any undissolved particulate then cooled to 20-25 °C and seeded with selexipag Form V (50 mg). The solution was stirred at the same temperature for 15-30 minutes. L-HPC (5 g, LH 11) was added and stirred for 30 minutes at the same temperature. Methyl tert-butyl ether was then added and the reaction mixture was stirred at 20-25 °C for 30-60 minutes, cooled to 0-5 °C, and then 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 15 hours to yield a premix of crystalline selexipag Form V with L-HPC.
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 °C. The clear solution was filtered to remove any undissolved particulate, cooled to 20-25 °C, seeded with selexipag Form V (50 mg), and stirred at the same temperature for 15-30 minutes. Hydroxypropyl cellulose (5 g, Klucel EXF) was added and stirred for 30 minutes at same temperature. 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 15 hours 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)
Selexipag (6 g) was dissolved in chlorobenzene (48 mL) at 70-75 °C. The clear solution was filtered to remove any undissolved particulate, cooled to 25-30 °C, seeded with selexipag Form VI (60 mg), and stirred at same temperature. After 3 hours, a sample was checked under a microscope and the crystal morphology is not comparable to that expected of Form VI. The reaction mixture was reheated to 70-75 °C to get a clear solution, then cooled to 25-30 °C, seeded with selexipag Form VI (60 mg), and stirred at the same temperature for 15 hours. After 15 hours, a sample was checked under a microscope and the crystal morphology is comparable with Form VI. L-HPC (6 g, LH-11 was added and the solution was stirred at 25-30 °C for 3 hours. The solution was filtered and the solid was washed with methyl tert-butyl ether (6 mL) and dried at 30 °C under vacuum for 15 hours to yield a premix of crystalline selexipag Form VI with L-HPC.
Example 26: Preparation of a premix of crystalline selexipag Form VI with hydroxypropyl cellulose (HPC) (50% w/w)
Selexipag (6 g) was dissolved in chlorobenzene (48 mL) at 70-75 °C. The clear solution was filtered to remove any undissolved particulate, cooled to 25-30 °C, seeded with selexipag Form VI (60 mg), and stirred at the same temperature for 18 hours. The product obtained was checked under a microscope and the sample morphology is comparable with Form VI. Hydroxypropyl cellulose (6 g, Klucel EXF) was added and stirred at 25-30 °C for 3 hours. The solution was filtered and the resulting solid was washed with methyl tert-butyl ether (6 mL), then dried at 30 °C under vacuum for 15 hours to yield a premix of crystalline selexipag Form VI with HPC.
Example 27: Preparation of a premix of crystalline selexipag Form VII-1 with HPC (50% w/w)
Selexipag (6 g) was dissolved in toluene (150 mL) at 80-85 °C. The clear solution was filtered to remove any undissolved particulate, cooled to 25-30 °C, seeded with selexipag Form VI (60 mg), and stirred at the same temperature for 15-30 minutes. Then slowly cooled to 5 °C and stirred at the same temperature for 30 minutes. Hydroxypropyl cellulose (6 g, Klucel EXF) was added and stirred at 0-5 °C for 3 hours. The solution was filtered and the obtained solid was dried at 30 °C under vacuum for 15 hours to yield a premix of crystalline selexipag Form VII-1 with hydroxy propyl cellulose.
Example 28: Preparation of a premix of crystalline selexipag Form VII-1 with L-HPC (50% w/w)
Selexipag (6 g) was dissolved in toluene (150 mL) at 80-85 °C. The clear solution was filtered to remove any undissolved particulate, cooled to 25-30 °C, seeded with selexipag Form VI (60 mg), and stirred at the same temperature for 15-30 minutes. The reaction mixture was slowly cooled to 5 °C and stirred at the same temperature for 30 minutes. Low- substituted hydroxypropyl cellulose (6 g, LH-11) was added and stirred at 0-5 °C for 3 hours. The solution was filtered and the obtained solid was dried at 30 °C under vacuum for 15 hours to yield a premix of crystalline selexipag Form VII-1 with L-HPC.
Example 29: Preparation of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butanol hydrate (formula VI)
2-Chloro-5,6-diphenylpyrazine (formula VIII, 100 g) in N-methyl-2-pyrrolidone (200 mL) was mixed with 4-(isopropylamino)-1-butanol (formula VII, 200 g) and the reaction mixture was then heated with stirring at 170-190 °C for 12-14 hours. The reaction mixture was cooled, poured into toluene (1.000 L), washed with water (1.000 L), and then further extracted with toluene (2*250 mL). The toluene layers are combined and washed with water (500 mL), 5% Sodium hydroxide solution (300 mL), and brine solution (500 mL). After washing, the reaction mixture was concentrated under vacuum to obtain crude solids (125 g) isolated as a residue. Toluene (300 mL) and n-heptane (1.000 L) were added. The precipitated product was cooled to 25-30 °C and stirred for 4-5 hours. The solution was filtered and the product was washed with n-heptane. The crude product was then purified from mixture of acetonitrile (1.000 L) and water (850 mL). The precipitated product was cooled to 5-10 °C, stirred for 4-5 hours, filtered, and the solid was washed with water. The wet product was dried under vacuum at 40 °C for 6-8 hours to give 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butanol hydrate (formula VI).
Example 30: Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid (formula IV)
4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butanol hydrate (formula VI, 100 g) was dissolved in toluene (1.000 L). Tetra-n-butylammonium hydrogen sulfate (23.5 g) and potassium hydroxide solution (820 mL) was added to the solution while stirring. The reaction mixture was cooled to 0-10 °C and tert-butyl bromoacetate (formula V, 165 g) was added dropwise maintaining the temperature between 5-10 °C. After stirring at 5-10 °C, the temperature was raised to 20-25 °C and the reaction mixture was further stirred for 1-3 hours. The aqueous and organic layers were separated with the aqueous layer at pH 8-10 and the aqueous layer was extracted with toluene (2*250 mL). The combined toluene layers were washed with water and concentrated to get oily 2-{4-[N-(5,6-diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester (formula IV).
8% sodium hydroxide solution (800 mL) was charged to a stirred solution of crude 2-{4-[N-(5,6-diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester taken in methanol (1.300 L). The reaction mixture was heated to 60-65 °C for 2-3 hours. The solvent was evaporated under reduced pressure to get a residue. This residue was dissolved in water (2.500 L) and washed with mixture of ethyl acetate and methyl tert-butyl ether. This reaction mixture was adjusted to pH 2.5-3.5 with 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 2 hours and filtered to obtain a solid, which was washed with methyl tert-butyl ether (100 mL) to form a crude product. The crude product was dissolved in isopropyl alcohol (800 mL) at 70-75 °C and the solution was cooled to 0-5 °C to precipitate a solid, which was washed with chilled isopropyl alcohol (100 mL). The solid was then dried to get 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (formula III).
Example 31: Preparation of Form V of selexipag
2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid (formula III, 100 g) was taken in dichloromethane (2000 mL). Methane sulfonamide (51 g), 4-dimethylamino pyridine (204 g), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (228 g) were added and the reaction mixture was stirred at 20-25 °C for 15-20 hours. After completion of the reaction, 15% aqueous hydrochloric acid (300 mL) 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 10-11 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 anisole solvate of selexipag. The reaction mixture was stirred at 20-25 °C for 10 hours, after which methyl tert-butyl ether (700 mL) was added, the reaction mixture was cooled to 0-5 °C, and stirred for 5 hours. 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.
Example 32: Preparation of crystalline selexipag
2-{4-[N-(5,6-diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (140 g) was taken in dichloromethane (2800 mL). Methane sulfonamide (71.4g) and N, N-dimethylaminopyridine (285.6g) were added to the reaction mixture at 20-30°C for 15 minutes. To this reaction mixture 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(319.2g) was added and stirred the resulting mixture at 20-30°C for 24 hours. The resulting mixture was cooled to 0-10°C and water (84 mL) added followed by dropwise addition of 1:1 aqueous hydrochloride (490 mL). Separated the organic layer and washed with 30% aqueous sodium chloride solution (980 mL). Distilled out the organic layer to obtain the residue and this residue was dissolved in ethyl acetate (1400 mL) and cooled to 12-18°C and washed with 4% aqueous hydrochloride solution (980 mL) followed by 20% aqueous sodium chloride solution for two times (2 x 700 mL). Extracted the product with 4% aqueous sodium carbonate solution (1750 mL) from the ethyl acetate layer. The basic aqueous layer washed twice with ethyl acetate (1260 mL). The pH of aqueous layer adjusted to 2 to 3 by using 1:1 aqueous hydrochloride (336 mL) followed by extracted with ethyl acetate (1960 mL). The ethyl acetate layer was washed twice with water (2 x 840 mL). The ethyl acetate layer was treated with activated carbon (ENO-PC) at 30-35°C and 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°C. Stirred the mixture at 20-30°C for 4 hours. The obtained solid material was filtered and washed with 1:1 mixture of ethyl acetate and n-hexane (140 mL) at 20-30°C. Dried the solid compound at 50-55°C under vacuum for 4 hours to get the crude selexipag (103 g).
Example 33: Preparation of crystalline selexipag
2-{4-[N-(5,6-diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (90 g.) was taken in ethyl acetate (900 mL) added carbonyl diimidazole (55.7 g) under stirring. The mixture was stirred at 20-30°C for 60 minutes. The mixture was heated to 60-65°C and stirred for 2 hours. The resulting solution cooled to 20-30°C and charged methane sulfonamide (47 g). Stirred the mixture at 20-30°C for 15 minutes. Added DBU (49 g, 0.32 mol.) dropwise at 20-30°C and maintained for 15 hours. The reaction mixture was cooled to 0-10°C 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°C 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°C and filtered through celite bed, washed the bed with ethyl acetate (90 mL). Charged the filtrates into a clean and dry round bottom flask. To the ethyl acetate layer was added n-hexane (1350 mL) at 20-30°C under stirring. Stirred the mixture at 20-30°C for 2.5 hours and 5-10°C for 1 hour. The obtained solid material was filtered and washed with 1:1 mixture of ethyl acetate and n-hexane (90 mL). Dried the solid compound at 50-55°C under vacuum for 3hours to get the crude selexipag (90 g)

Purification of selexipag:
A mixture of crude selexipag (80 g) and ethyl acetate (560 mL) was heated to 60-65°C. Stirred the reaction mixture at 60-65°C for 20 minutes. Filtered the solution through 0.22 µ membrane and washed with ethyl acetate (80 mL) at 60-65°C. The 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°C. The mixture was heated to 60-65°C and maintained for 10 minutes. Cooled the mixture gradually to 30-35°C and maintained for 1 hour. The mixture cooled to 20-30°C and stirred for 3 hours. The obtained solid material was filtered and washed with 8:1 ratio of pre-filtered ethyl acetate and n-hexane (80 mL). Dried the solid compound at 50-55°C under vacuum for 3 hours to get the crystalline selexipag Form III (63 g) containing small amount of Form II.
,CLAIMS:We claim:
1. A process for the preparation of selexipag Form V comprising the steps of:
a) dissolving selexipag in anisole;
b) optionally seeding with selexipag Form V;
c) optionally adding an anti-solvent; and
d) isolating selexipag Form V.
2. A process for the preparation of crystalline Form VII-1 of selexipag comprising the steps of:
a) dissolving selexipag in toluene;
b) seeding with selexipag Form VI; and
c) isolating selexipag Form VII-1.
3. Crystalline selexipag Form V.
4. Crystalline selexipag Form V of claim 3, characterized by a powder x-ray diffraction pattern with substantial peaks at 2? values of 5.93, 11.14, 19.73, 19.96, 20.98, 21.15, 22.21, and 23.34 ± 0.2º as shown in Figure 2.
5. Crystalline selexipag VII-1.
6. Crystalline selexipag Form VII-1 of claim 5, 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 º as shown in Figure 5.
7. The process according to claims 1, wherein the anti-solvent is selected from ether solvents such as without limitation, diethyl ether, diisopropylether, methyl tert-butyl ether and the hydrocarbon solvents is selected from hexane, cyclohexane, methyl cyclohexane, heptane and pentane and mixtures thereof.
8. The amorphous solid dispersion of selexipag and a pharmaceutically acceptable carrier prepared by hot-melt extrusion.
9. The solid dispersion of claim 8, wherein the selexipag is selected from crystalline selexipag Form IV, V, VI, VII-1 and mixtures thereof.
10. The solid dispersion of claim 8, wherein the pharmaceutically acceptable carrier is selected from the group consisting of Plasdone S-630, povidone K-30, and mixtures thereof.