WO2017029594A1 - Processes for preparation of selexipag and its amorphous form - Google Patents

Processes for preparation of selexipag and its amorphous form Download PDF

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Publication number
WO2017029594A1
WO2017029594A1 PCT/IB2016/054858 IB2016054858W WO2017029594A1 WO 2017029594 A1 WO2017029594 A1 WO 2017029594A1 IB 2016054858 W IB2016054858 W IB 2016054858W WO 2017029594 A1 WO2017029594 A1 WO 2017029594A1
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Prior art keywords
selexipag
isopropylamino
butanol
pharmaceutically acceptable
solid dispersion
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PCT/IB2016/054858
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French (fr)
Inventor
Srinivas ORUGANTI
Bhaskar KANDAGATLA
Vilas Hareshwar Dahanukar
Krishnarao CHINTADA
Latif Jafar SHAIKH
Sesha Reddy Yarraguntla
Subba Reddy Peddireddy
Mohan Kumar KOTTUR
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Dr. Reddy's Laboratories Limited
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Publication of WO2017029594A1 publication Critical patent/WO2017029594A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines

Definitions

  • the present application relates to processes for preparation of Selexipag, its amorphous form, amorphous solid dispersion and pharmaceutical composition thereof.
  • the drug compound having the adopted name Selexipag has a chemical name 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)-N-(methylsulfonyl)acetamide, and is represented by structure of formula I.
  • Selexipag brand name Uptravi® is a drug developed by Actelion for the treatment of pulmonary arterial hypertension (PAH).
  • PH pulmonary arterial hypertension
  • Selexipag and its synthesis methods are described in US Patent No. 7,205,302 B2 (US '302), in which 2-chloro-5,6- diphenylpyrazine is reacted with 4-(isopropylamino)-1 -butanol to yield 4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol, then the product is reacted with tertiary butyl bromoacetate to form 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]butyloxy ⁇ acetic acid tertiary butyl ester.
  • the tertiary butyl ester is hydrolyzed to yield 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid, then the acid is reacted with methane sulfonamide in presence of CDI and DABCO to form Selexipag.
  • the selexipag was isolated from a mixture of diethyl ether and THF as residue and is purified by silica gel column chromatography.
  • the Selexipag preparative method described in US '302 is schematically represented below.
  • US Patent No. 8,791 ,122 B2 (US ⁇ 22) also describes a synthetic scheme for preparation of selexipag, in which 2-chloro-5,6-diphenylpyrazine is reacted with Sodium iodide to form 2-iodo-5,6-diphenylpyrazine, then the iodopyrazine is reacted with 4- (isopropylamino)-l -butanol to yield 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol, and the product is reacted with 2-chloro-N-(methylsulfonyl)acetamide to form Selexipag.
  • the Selexipag synthetic scheme described in US ⁇ 22 is schematically represented below.
  • amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline forms. For some therapeutic indications one bioavailability pattern may be favored over another.
  • the present application provides processes for preparation of Selexipag its amorphous form and pharmaceutical compositions thereof.
  • the present application provides a process for preparation of Selexipag comprising:
  • step (c) optionally, purifying the Selexipag obtained in step (b).
  • the present application provides a process for preparation of 2-halo-N-(methylsulfonyl)acetamide comprising reacting methane sulfonamide with haloacetyl chloride to form 2-halo-N-(methylsulfonyl)acetamide
  • the present application provides a process for preparation of Selexipag comprising:
  • step (d) optionally, purifying the Selexipag obtained in step (c).
  • the present application provides amorphous form of Selexipag.
  • the present application provides amorphous form of Selexipag characterized by powder X-ray diffraction (PXRD) substantially as depicted in Figure 1 .
  • PXRD powder X-ray diffraction
  • the present application provides a process for preparing amorphous form of Selexipag, which comprises;
  • the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
  • the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as depicted in Figure 2 to Figure 6.
  • PXRD powder X-ray diffraction
  • the present application provides a process for preparing an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers, which comprises;
  • Figure 1 is X-ray power diffraction pattern of an amorphous form of Selexipag prepared according to Example 9.
  • Figure 2 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag and HPMC Phthalate prepared according to Example 10.
  • Figure 3 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag and PVP-K30 prepared according to Example 1 1 .
  • Figure 4 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag, PVP-K30 and syloid (1 :1 :1 w/w/w) prepared according to Example 14.
  • Figure 5 is X-ray power diffraction pattern of amorphous solid dispersion comprising Selexipag and Copovidone prepared according to Example 15.
  • Figure 6 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag and HPMC-AS prepared according to Example 16.
  • the present application provides a process for preparation of Selexipag and its intermediates thereof.
  • the present application provides a process for preparation of Selexipag comprising:
  • step (c) optionally, purifying the Selexipag obtained in step (b).
  • the step (a) involves reaction of 2-chloro-5,6-diphenylpyrazine and 4- (isopropylamino)-l -butanol to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol.
  • the compounds 2-chloro-5,6-diphenylpyrazine and 4-(isopropylamino)-1 -butanol are known compounds and may be obtained by any process including processes described in the art, or by a process described in this application. These starting materials may be purified by the processes known in the art to get the desired purity before proceeding for the reaction
  • the reaction is carried out in the presence of a suitable base and an organic solvent.
  • the base to be used is for example lithium hydroxide, sodium hydroxide potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or their mixed base.
  • the solvent to be used is for example N-methylpyrrolidine, toluene, dimethylformamide and dimethylsulfoxide; or the reaction may be carried out without using any solvent.
  • the amount of 4-(isopropylamino)-1 -butanol to be used may be generally within a range of 0.8 to 3.0 molar ratio relative to 2-chloro-5,6-diphenylpyrazine.
  • the reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from about 30°C to about 200°C.
  • the reaction time varies depending on the kinds of the solvent and the base used and on the reaction temperature, but may be generally within a range of from about 1 hour to about 20 hours. After completion of the reaction, the reaction mass may be poured into water and the aqueous mass is extracted with a suitable water immiscible solvent to isolate the compound.
  • reaction mass of step (a), without isolation of the product may directly be used in step (b).
  • the step (b) involves reaction of 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]-1 -butanol with 2-chloro-N-(methylsulfonyl)acetamide or 2-bromo-N- (methylsulfonyl)acetamide to form Selexipag.
  • the reaction is carried out in the presence of a suitable base and a suitable solvent.
  • the base to be used is for example lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, potassium methoxide, potassium tertiary butoxide or a mixture thereof.
  • the solvent to be used is for example dimethylsulfoxide, dimethylformamide, toluene and the like.
  • the amount of 2-chloro-N-(methylsulfonyl)acetamide or 2-bromo-N- (methylsulfonyl)acetamide to be used may be generally within a range of from about 0.8 to 2.0 molar ratio relative to 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol.
  • the reaction temperature varies depending on the kinds of the solvent and the base used, but may be generally within a range of from about 20°C to about 50°C.
  • the reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from about 1 hour to about 20 hours.
  • reaction is carried out in presence of a phase transfer catalyst such as tetra butyl ammonium bromide, tetra butyl ammonium sulfate and the like or in presence of a adduct such as sodium iodide, potassium iodide, sodium bromide potassium bromide and the like.
  • a phase transfer catalyst such as tetra butyl ammonium bromide, tetra butyl ammonium sulfate and the like
  • a adduct such as sodium iodide, potassium iodide, sodium bromide potassium bromide and the like.
  • reaction mass may be poured into water and pH of the aqueous mass may be adjusted to acidic and extracted with a suitable solvent to isolate the crude Selexipag.
  • the crude Selexipag may be purified by recrystallizing it in a suitable solvent.
  • the obtained Selexipag may be dried.
  • the drying of solid material may be carried out under suitable conditions to afford Selexipag, substantially free of residual solvents. Drying may be carried out at reduced pressures, such as more than about 500 mm Hg, at temperatures such as about 0°C to about 60°C, or higher. Drying may be suitably carried out using equipment such as a rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof.
  • the synthetic scheme described in US ⁇ 22 involves conversion of 2-chloro-5,6- diphenylpyrazine to 2-iodo-5,6-diphenylpyrazine by reacting the former with sodium iodide.
  • the 2-iodo-5,6-diphenylpyrazine is reacted with 4-(isopropylamino)-1 -butanol to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol and reacting the product with 2-chloro-N-(methylsulfonyl)acetamide to form selexipag, thereby increasing one step and time cycle.
  • the process of the present application involves reaction of 2-chloro-5,6-diphenylpyrazine directly with 4- (isopropylamino)-l -butanol to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol and reacting the product with 2-chloro-N-(methylsulfonyl)acetamide to form selexipag, thereby synthesizing selexipag in two steps with high yields and purity and decreasing time cycle.
  • the present application provides Selexipag prepared by the process of the present invention is at least about 99% purity.
  • the present application provides Selexipag prepared by the process of the present invention is at least about 99.5% purity.
  • the present application provides Selexipag prepared by the process of the present invention is at least about 99.8% purity.
  • the present application provides a process for preparation of 2-halo-N-(methylsulfonyl)acetamide comprising reacting methane sulfonamide with haloacetyl chloride to form 2-chloro-N-(methylsulfonyl)acetamide
  • the process involves reaction of methane sulfonamide with chloroacetyl chloride, bromoacetyl chloride, etc. to form 2-chloro-N-(methylsulfonyl)acetamide, 2- bromo-N-(methylsulfonyl)acetamide, etc.
  • the compounds methane sulfonamide, chloroacetyl chloride and bromoacetyl chloride are known compounds and may be obtained by any process described in the art.
  • the reaction is carried out using a suitable solvent such as toluene, dimethylformamide, acetonitrile, tetrahydrofuran, ethylacetate, n-butylacetate or a mixture thereof. In one aspect the reaction is carried out using n-butylacetate solvent.
  • a suitable solvent such as toluene, dimethylformamide, acetonitrile, tetrahydrofuran, ethylacetate, n-butylacetate or a mixture thereof.
  • the reaction is carried out using n-butylacetate solvent.
  • the reaction temperature varies depending on the solvent used, but may be generally within a range of from about 20°C to about 150°C.
  • the reaction time varies depending on the solvent and on the reaction temperature, but may be generally within a range of from about 1 hour to about 20 hours.
  • the product may be isolated by filtering the reaction mass.
  • the present application provides use of 2-chloro-N- (methylsulfonyl)acetamide and 2-bromo-N-(methylsulfonyl)acetamide prepared by the process described above in the preparation of Selexipag.
  • the present application provides a process for preparation of Selexipag comprising:
  • step (d) optionally, purifying the Selexipag obtained in step (c).
  • Steps (a) to (d) of the present aspect are carried out according to the processes described in the present invention.
  • Selexipag obtained by any of the processes described in this application can be purified to obtain the required purity.
  • the purification can be done using any of the known methods such as crystallization, slurry washing, column chromatography, etc.
  • the obtained Selexipag may be crystalline or amorphous product.
  • the present application provides amorphous form of Selexipag. In another embodiment, the present application provides amorphous form of Selexipag characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 1 .
  • PXRD powder X-ray diffraction
  • the present application provides a process for preparing amorphous form of Selexipag, comprising
  • Selexipag used as the input in the process for preparation of amorphous form of Selexipag and its solid dispersion of the present application can be prepared by any process known in the art.
  • Providing a solution in step (a) includes direct use of a reaction mixture containing Selexipag that is obtained in the course of its synthesis or dissolving Selexipag in a solvent.
  • Any physical form of Selexipag may be utilized for providing the solution of Selexipag in step (a).
  • Suitable solvents which can be used for dissolving Selexipag include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n- propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as aceton
  • the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art.
  • the solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite.
  • the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
  • Step (b) involves removing solvent from the solution of Selexipag.
  • Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
  • Step (c) involves recovering an amorphous form of Selexipag.
  • the said recovery can be achieved by using the processes known in the art.
  • the resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Selexipag is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
  • the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
  • Solid dispersion refers to the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in finely crystalline, solubilized or amorphous state (Sareen et al., 2012 and Kapoor et al., 2012).
  • Solid dispersion consists of two or more than two components, generally a carrier polymer and drug optionally along with stabilizing agent (and/or surfactant or other additives).
  • the most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage.
  • the increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve.
  • the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figures 2 to 6.
  • PXRD powder X-ray diffraction
  • the present application provides a process for preparing an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers, comprising;
  • Providing a solution in step (a) includes direct use of a reaction mixture containing Selexipag that is obtained in the course of its synthesis or dissolving Selexipag and pharmaceutically acceptable carrier in a solvent.
  • Any physical form of Selexipag may be utilized for providing the solution of Selexipag in step (a).
  • Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium ste
  • Suitable solvents which can be used for dissolving the Selexipag include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n- propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as ace
  • step (a) After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques.
  • the solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • Step (b) involves removing solvent from a solution obtained in step (a);
  • Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, filtration or any other technique known in the art.
  • Step (c) involves recovering an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
  • the said recovery can be achieved by using the processes known in the art.
  • the resulting compound obtained in step (c) may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Selexipag is not degraded in its quality.
  • the drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
  • the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient
  • a hygroscopic ingredient and to increase the stability of the amorphous form addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous selexipag or solid dispersion to control hygroscopicity and to improve stability.
  • the present application provides Selexipag having particle sizes less than about 150 ⁇ , or less than about 100 ⁇ , or less than about 50 ⁇ , or less than about 20 ⁇ , or less than about 10 ⁇ .
  • the present application provides Selexipag having a particle size distribution wherein the 10 th volume percentile particle size (D 0 ) is less than about 5 ⁇ , the 50 th volume percentile particle size (D 50 ) is less than about 10 ⁇ , and/or the 90 in volume percentile particle size (Dg 0 ) is less than about 20 ⁇ .
  • particle size distributions of Selexipag particles may be measured using light scattering equipment, such as, for example, a Malvern Master Sizer 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom (helium neon laser source, Selexipag suspended in light liquid paraffin, size range: 0.01 ⁇ to 3000 ⁇ ).
  • light scattering equipment such as, for example, a Malvern Master Sizer 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom (helium neon laser source, Selexipag suspended in light liquid paraffin, size range: 0.01 ⁇ to 3000 ⁇ ).
  • the present invention further encompasses 1 ) a pharmaceutical composition comprising Selexipag prepared by the process described above, and at least one pharmaceutically acceptable excipient; and 2) the use of Selexipag prepared by the process described above, in the manufacture of a pharmaceutical composition, and 3) a method of treating arteriosclerosis, thrombosis, hypertension, pulmonary hypertension, ischemic disorder, angina comprising administration of an effective amount of a pharmaceutical composition comprising Selexipag prepared by the process described above.
  • Amorphous form refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
  • An "alcohol” is an organic compound containing a carbon bound to a hydroxyl group.
  • Ci-C 6 alcohols include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
  • aliphatic hydrocarbon is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds.
  • a liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.”
  • C 5 -C 8 aliphatic or aromatic hydrocarbons include, but are not limited to, isopentane, neopentane, isohexane, 3- methylpentane, 2,3-dimethylbutane, neohexane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3- ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane
  • C 3 -C 6 esters include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
  • ether is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms.
  • C 2 -C 6 ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, or the like.
  • halogenated hydrocarbon is an organic compound containing a carbon bound to a halogen.
  • Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
  • C 3 -C 6 ketones include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
  • a “nitrile” is an organic compound containing a cyano -(C ⁇ N) bonded to another carbon atom.
  • C 2 -C 6 Nitriles include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
  • Methane sulfonamide (10 gm) and n-butylacetate (80 mL) were charged into a 250 mL round bottom flask at 30°C.
  • Chloroacetylchloride (21 .37 gm) was added slowly over a period of 10 minutes at 30°C.
  • Temperature of the reaction mass was raised to 125°C and maintained reflux for 16 hours.
  • Progress of the reaction was monitored by TLC and after completion of the reaction the mass was cooled to 20°C and stirred for 1 hour at 20°C. Reaction mass was filtered and the wet solid was washed with n- butylacetate (10 mL).
  • the wet solid was taken into another 100 mL round bottom flask and n-butylacetate (50 mL) was added and stirred for 30 minutes at 20°C. The precipitation was filtered and the solid was suck dried. The material was dried at 45° under vacuum for 5 hours to yield 14 gm of title compound.
  • Methane sulfonamide (100 gm) and n-butylacetate (800 mL) were charged into a 2000 mL round bottom flask at 30°C.
  • Chloroacetylchloride (213.7 gm) was added slowly over a period of 10 minutes at 30°C.
  • Temperature of the reaction mass was raised to 125°C and maintained reflux for 16 hours.
  • Progress of the reaction was monitored by TLC and after completion of the reaction the mass was cooled to 20°C and stirred for 1 hour at 20°C. Reaction mass was filtered and the wet solid was washed with n-butylacetate (100 mL).
  • Methane sulfonamide (2 gm) was dissolved in 70 mL dry Toluene and stirred at room temperature.
  • Bromoacetyl bromide (4.5 mL) was added dropwise to the reaction mixture and it was refluxed for 5 hours.
  • the reaction mixture was cooled to room temperature and then placed on an ice bath.
  • the product crystallized out of the toluene and was collected by vacuum filtration and rinsed with 10 mL cold toluene. The white solid was collected, and dried in vacuo overnight to get 2.03 gm of the title compound.
  • Example 4 Preparation of 2-bromo-N-(methylsulfonyl)acetamide Methane sulfonamide (100 gm) was dissolved in 2000 mL of dry Toluene and stirred at room temperature. Bromoacetyl bromide (225 mL) was added dropwise to the reaction mixture and was refluxed for 5 hours. The reaction mixture was cooled to room temperature and then placed on an ice bath. The product crystallized out of the toluene and was collected by vacuum filtration and rinsed with 300 mL cold toluene. The white solid was collected, and dried in vacuo overnight to get 102 gm of the title compound.
  • Example 5 Preparation of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1- butanol.
  • Example 9 Preparation of amorphous form of Selexipag.
  • Example 10 Preparation of amorphous solid dispersion of Selexipag and hydroxy propyl methyl cellulose phthalate (HPMC-Phthalate).
  • Example 11 Preparation of amorphous solid dispersion of Selexipag and PVP- K30.
  • Example 12 Preparation of amorphous solid dispersion of Selexipag and PVP- K30.
  • Example 13 Preparation of amorphous solid dispersion of Selexipag and PVP- K30.
  • Example 14 Preparation of amorphous solid dispersion of Selexipag, PVP-K30 and Syloid (1 :1 :1).
  • Amorphous solid dispersion of Selexipag and PVP-K30 prepared in example 13 was blended vigorously with syloid (125 mg) and exposed to air at 60% RH for 23 hours.
  • Example 15 Preparation of amorphous solid dispersion of Selexipag and Copovidone.
  • Example 16 Preparation of amorphous solid dispersion of Selexipag and hydroxy propyl methyl cellulose phthalate - Acetyl Succinate (HPMC-AS).
  • Example 17 Preparation of amorphous solid dispersion of Selexipag and hydroxy propyl methyl cellulose phthalate (HPMC-Phthalate).

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Abstract

The present application relates to processes for preparation of Selexipag, its amorphous form, amorphous solid dispersion and pharmaceutical composition thereof. Formula (I):

Description

PROCESSES FOR PREPARATION OF SELEXIPAG AND ITS AMORPHOUS FORM
FIELD OF THE INVENTION
The present application relates to processes for preparation of Selexipag, its amorphous form, amorphous solid dispersion and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION
The drug compound having the adopted name Selexipag, has a chemical name 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)-N-(methylsulfonyl)acetamide, and is represented by structure of formula I.
Figure imgf000003_0001
Formula I
Selexipag (brand name Uptravi®) is a drug developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its synthesis methods are described in US Patent No. 7,205,302 B2 (US '302), in which 2-chloro-5,6- diphenylpyrazine is reacted with 4-(isopropylamino)-1 -butanol to yield 4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol, then the product is reacted with tertiary butyl bromoacetate to form 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]butyloxy}acetic acid tertiary butyl ester. The tertiary butyl ester is hydrolyzed to yield 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, then the acid is reacted with methane sulfonamide in presence of CDI and DABCO to form Selexipag. The selexipag was isolated from a mixture of diethyl ether and THF as residue and is purified by silica gel column chromatography. The Selexipag preparative method described in US '302 is schematically represented below.
Figure imgf000004_0001
Selexipag
US Patent No. 8,791 ,122 B2 (US Ί 22) also describes a synthetic scheme for preparation of selexipag, in which 2-chloro-5,6-diphenylpyrazine is reacted with Sodium iodide to form 2-iodo-5,6-diphenylpyrazine, then the iodopyrazine is reacted with 4- (isopropylamino)-l -butanol to yield 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol, and the product is reacted with 2-chloro-N-(methylsulfonyl)acetamide to form Selexipag. The Selexipag synthetic scheme described in US Ί 22 is schematically represented below.
Figure imgf000004_0002
Selexipag
The prior-art processes herein described above suffer from drawbacks such as more process steps, low yield and purity. Hence there is a continuing need to develop simplified and improved process for preparing Selexipag which is suitable for commercial manufacturing in high purity and yield. US Ί 22 also describes crystalline Form I, Form II and Form III of Selexipag and their use in the treatment of pulmonary arterial hypertension.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline forms. For some therapeutic indications one bioavailability pattern may be favored over another.
There remains a need to provide stable, commercially viable and advantageous solid state forms of Selexipag.
SUMMARY OF THE INVENTION
The present application provides processes for preparation of Selexipag its amorphous form and pharmaceutical compositions thereof.
In one embodiment, the present application provides a process for preparation of Selexipag comprising:
(a) reacting 2-chloro-5,6-diphenylpyrazine with 4-(isopropylamino)-1 -butanol in presence of a base to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]- -butanol.
Figure imgf000005_0001
(b) reacting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol with 2- halo-N-(methylsulfonyl)acetamide in presence of dimethylsulfoxide to form Selexipag.
Figure imgf000005_0002
Selexipag
(c) optionally, purifying the Selexipag obtained in step (b). In the second embodiment, the present application provides a process for preparation of 2-halo-N-(methylsulfonyl)acetamide comprising reacting methane sulfonamide with haloacetyl chloride to form 2-halo-N-(methylsulfonyl)acetamide
Figure imgf000006_0001
In the third embodiment, the present application provides a process for preparation of Selexipag comprising:
(a) reacting methane sulfonamide with haloroacetyl chloride to form 2-halo-N- (methylsulfonyl)acetamide
Figure imgf000006_0002
(b) reacting 2-chloro-5,6-diphenylpyrazine with 4-(isopropylamino)-1 -butanol in presence of a base to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]-1 -butanol.
Figure imgf000006_0003
(c) reacting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol with 2- halo-N-(methylsulfonyl)acetamide in presence of dimethylsulfoxide to form Selexipag.
Figure imgf000006_0004
Selexipag
(d) optionally, purifying the Selexipag obtained in step (c).
In the fourth embodiment, the present application provides amorphous form of Selexipag. In the fifth embodiment, the present application provides amorphous form of Selexipag characterized by powder X-ray diffraction (PXRD) substantially as depicted in Figure 1 .
In the sixth embodiment, the present application provides a process for preparing amorphous form of Selexipag, which comprises;
a) providing a solution of Selexipag in a solvent or a mixture of two or more solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous form of Selexipag.
In the seventh embodiment, the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
In the eighth embodiment, the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as depicted in Figure 2 to Figure 6.
In the ninth embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution comprising Selexipag and one or more pharmaceutically acceptable carriers,
b) removing solvent from the solution obtained in step (a), and
c) recovering an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is X-ray power diffraction pattern of an amorphous form of Selexipag prepared according to Example 9.
Figure 2 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag and HPMC Phthalate prepared according to Example 10.
Figure 3 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag and PVP-K30 prepared according to Example 1 1 . Figure 4 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag, PVP-K30 and syloid (1 :1 :1 w/w/w) prepared according to Example 14.
Figure 5 is X-ray power diffraction pattern of amorphous solid dispersion comprising Selexipag and Copovidone prepared according to Example 15.
Figure 6 is X-ray power diffraction pattern of an amorphous solid dispersion comprising Selexipag and HPMC-AS prepared according to Example 16.
DETAILED DESCRIPTION
The present application provides a process for preparation of Selexipag and its intermediates thereof.
In one embodiment, the present application provides a process for preparation of Selexipag comprising:
(a) reacting 2-chloro-5,6-diphenylpyrazine with 4-(isopropylamino)-1 -butanol in presence of a base to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol.
Figure imgf000008_0001
(b) reacting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol with 2-halo- -(methylsulfonyl)acetamide in presence of dimethylsulfoxide to form Selexipag.
Figure imgf000008_0002
Selexipag
(c) optionally, purifying the Selexipag obtained in step (b).
The step (a) involves reaction of 2-chloro-5,6-diphenylpyrazine and 4- (isopropylamino)-l -butanol to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol.
The compounds 2-chloro-5,6-diphenylpyrazine and 4-(isopropylamino)-1 -butanol are known compounds and may be obtained by any process including processes described in the art, or by a process described in this application. These starting materials may be purified by the processes known in the art to get the desired purity before proceeding for the reaction
The reaction is carried out in the presence of a suitable base and an organic solvent. The base to be used is for example lithium hydroxide, sodium hydroxide potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or their mixed base. The solvent to be used is for example N-methylpyrrolidine, toluene, dimethylformamide and dimethylsulfoxide; or the reaction may be carried out without using any solvent.
The amount of 4-(isopropylamino)-1 -butanol to be used may be generally within a range of 0.8 to 3.0 molar ratio relative to 2-chloro-5,6-diphenylpyrazine. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from about 30°C to about 200°C. The reaction time varies depending on the kinds of the solvent and the base used and on the reaction temperature, but may be generally within a range of from about 1 hour to about 20 hours. After completion of the reaction, the reaction mass may be poured into water and the aqueous mass is extracted with a suitable water immiscible solvent to isolate the compound.
In one embodiment, the reaction mass of step (a), without isolation of the product, may directly be used in step (b).
The step (b) involves reaction of 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]-1 -butanol with 2-chloro-N-(methylsulfonyl)acetamide or 2-bromo-N- (methylsulfonyl)acetamide to form Selexipag. The reaction is carried out in the presence of a suitable base and a suitable solvent. The base to be used is for example lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, potassium methoxide, potassium tertiary butoxide or a mixture thereof. The solvent to be used is for example dimethylsulfoxide, dimethylformamide, toluene and the like.
The amount of 2-chloro-N-(methylsulfonyl)acetamide or 2-bromo-N- (methylsulfonyl)acetamide to be used may be generally within a range of from about 0.8 to 2.0 molar ratio relative to 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol. The reaction temperature varies depending on the kinds of the solvent and the base used, but may be generally within a range of from about 20°C to about 50°C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from about 1 hour to about 20 hours.
Optionally the reaction is carried out in presence of a phase transfer catalyst such as tetra butyl ammonium bromide, tetra butyl ammonium sulfate and the like or in presence of a adduct such as sodium iodide, potassium iodide, sodium bromide potassium bromide and the like.
After completion of the reaction, the reaction mass may be poured into water and pH of the aqueous mass may be adjusted to acidic and extracted with a suitable solvent to isolate the crude Selexipag. The crude Selexipag may be purified by recrystallizing it in a suitable solvent.
The obtained Selexipag may be dried. The drying of solid material may be carried out under suitable conditions to afford Selexipag, substantially free of residual solvents. Drying may be carried out at reduced pressures, such as more than about 500 mm Hg, at temperatures such as about 0°C to about 60°C, or higher. Drying may be suitably carried out using equipment such as a rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof.
The synthetic scheme described in US Ί 22 involves conversion of 2-chloro-5,6- diphenylpyrazine to 2-iodo-5,6-diphenylpyrazine by reacting the former with sodium iodide. The 2-iodo-5,6-diphenylpyrazine is reacted with 4-(isopropylamino)-1 -butanol to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol and reacting the product with 2-chloro-N-(methylsulfonyl)acetamide to form selexipag, thereby increasing one step and time cycle. Unlike the synthetic scheme of US Ί 22, the process of the present application involves reaction of 2-chloro-5,6-diphenylpyrazine directly with 4- (isopropylamino)-l -butanol to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol and reacting the product with 2-chloro-N-(methylsulfonyl)acetamide to form selexipag, thereby synthesizing selexipag in two steps with high yields and purity and decreasing time cycle.
In another embodiment, the present application provides Selexipag prepared by the process of the present invention is at least about 99% purity.
In another embodiment, the present application provides Selexipag prepared by the process of the present invention is at least about 99.5% purity.
In another embodiment, the present application provides Selexipag prepared by the process of the present invention is at least about 99.8% purity.
In another embodiment, the present application provides a process for preparation of 2-halo-N-(methylsulfonyl)acetamide comprising reacting methane sulfonamide with haloacetyl chloride to form 2-chloro-N-(methylsulfonyl)acetamide
Figure imgf000011_0001
The process involves reaction of methane sulfonamide with chloroacetyl chloride, bromoacetyl chloride, etc. to form 2-chloro-N-(methylsulfonyl)acetamide, 2- bromo-N-(methylsulfonyl)acetamide, etc. The compounds methane sulfonamide, chloroacetyl chloride and bromoacetyl chloride are known compounds and may be obtained by any process described in the art.
The reaction is carried out using a suitable solvent such as toluene, dimethylformamide, acetonitrile, tetrahydrofuran, ethylacetate, n-butylacetate or a mixture thereof. In one aspect the reaction is carried out using n-butylacetate solvent.
The reaction temperature varies depending on the solvent used, but may be generally within a range of from about 20°C to about 150°C. The reaction time varies depending on the solvent and on the reaction temperature, but may be generally within a range of from about 1 hour to about 20 hours.
After completion of the reaction the product may be isolated by filtering the reaction mass.
In another embodiment, the present application provides use of 2-chloro-N- (methylsulfonyl)acetamide and 2-bromo-N-(methylsulfonyl)acetamide prepared by the process described above in the preparation of Selexipag. In another embodiment, the present application provides a process for preparation of Selexipag comprising:
(a) reacting methane sulfonamide with haloacetyl chloride to form 2-halo-N- (methylsulfonyl)acetamide
Figure imgf000012_0001
(b) reacting 2-chloro-5,6-diphenylpyrazine with 4-(isopropylamino)-1 -butanol in presence of a base to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]-1 -butanol.
Figure imgf000012_0002
(c) reacting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol with 2- halo-N-(methylsulfonyl)acetamide in presence of dimethylsulfoxide to form Selexipag.
Figure imgf000012_0003
Selexipag
(d) optionally, purifying the Selexipag obtained in step (c).
Steps (a) to (d) of the present aspect are carried out according to the processes described in the present invention.
Selexipag obtained by any of the processes described in this application can be purified to obtain the required purity. The purification can be done using any of the known methods such as crystallization, slurry washing, column chromatography, etc. The obtained Selexipag may be crystalline or amorphous product.
In another embodiment, the present application provides amorphous form of Selexipag. In another embodiment, the present application provides amorphous form of Selexipag characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 1 .
In another embodiment, the present application provides a process for preparing amorphous form of Selexipag, comprising
a) providing a solution of Selexipag in a solvent or a mixture solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous form of Selexipag.
Selexipag used as the input in the process for preparation of amorphous form of Selexipag and its solid dispersion of the present application can be prepared by any process known in the art.
Providing a solution in step (a) includes direct use of a reaction mixture containing Selexipag that is obtained in the course of its synthesis or dissolving Selexipag in a solvent.
Any physical form of Selexipag may be utilized for providing the solution of Selexipag in step (a).
Suitable solvents which can be used for dissolving Selexipag include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n- propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removing solvent from the solution of Selexipag.
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
Step (c) involves recovering an amorphous form of Selexipag. The said recovery can be achieved by using the processes known in the art.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Selexipag is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another embodiment, the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in finely crystalline, solubilized or amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more than two components, generally a carrier polymer and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve.
In another embodiment, the present application provides an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figures 2 to 6.
In another embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers, comprising;
a) providing a solution of Selexipag and pharmaceutically acceptable carrier in a solution,
b) removing solvent from the solution obtained in step (a); and
c) recovering an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carrier.
Providing a solution in step (a) includes direct use of a reaction mixture containing Selexipag that is obtained in the course of its synthesis or dissolving Selexipag and pharmaceutically acceptable carrier in a solvent.
Any physical form of Selexipag may be utilized for providing the solution of Selexipag in step (a).
Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Suitable solvents which can be used for dissolving the Selexipag include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n- propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from a solution obtained in step (a);
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, filtration or any other technique known in the art.
Step (c) involves recovering an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers. The said recovery can be achieved by using the processes known in the art. The resulting compound obtained in step (c) may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Selexipag is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous selexipag or solid dispersion to control hygroscopicity and to improve stability.
In another embodiment, the present application provides Selexipag having particle sizes less than about 150 μιτι, or less than about 100 μιτι, or less than about 50 μιη, or less than about 20 μηη, or less than about 10 μιτι.
For example, the present application provides Selexipag having a particle size distribution wherein the 10th volume percentile particle size (D 0) is less than about 5 μπΊ, the 50th volume percentile particle size (D50) is less than about 10 μηι, and/or the 90in volume percentile particle size (Dg0) is less than about 20 μηη. The "10th volume percentile" as used herein, unless otherwise defined refers to the size of particles, below which 10% of the measured particle volume lies; "50i!l volume percentile" as used herein, unless otherwise defined refers to the size of particles, below which 50% of the measured particle volume lies, and "90th volume percentile" as used herein, unless otherwise defined refers to the size of particles, below which 90% of the measured particle volume lies. Particle size distributions of Selexipag particles may be measured by any technique known in the art. For example, particle size distributions of Selexipag particles may be measured using light scattering equipment, such as, for example, a Malvern Master Sizer 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom (helium neon laser source, Selexipag suspended in light liquid paraffin, size range: 0.01 μηι to 3000 μιη).
The present invention further encompasses 1 ) a pharmaceutical composition comprising Selexipag prepared by the process described above, and at least one pharmaceutically acceptable excipient; and 2) the use of Selexipag prepared by the process described above, in the manufacture of a pharmaceutical composition, and 3) a method of treating arteriosclerosis, thrombosis, hypertension, pulmonary hypertension, ischemic disorder, angina comprising administration of an effective amount of a pharmaceutical composition comprising Selexipag prepared by the process described above.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 .
"Amorphous form" as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%. An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "Ci-C6 alcohols" include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic." Examples of "C5-C8 aliphatic or aromatic hydrocarbons" include, but are not limited to, isopentane, neopentane, isohexane, 3- methylpentane, 2,3-dimethylbutane, neohexane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3- ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An "ester" is an organic compound containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "C3-C6 esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An "ether" is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms. "C2-C6 ethers" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, or the like.
A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A "ketone" is an organic compound containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "C3-C6 ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A "nitrile" is an organic compound containing a cyano -(C≡N) bonded to another carbon atom. "C2-C6 Nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
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 application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention. EXAMPLES
Example 1 : Preparation of 2-chloro-N-(methylsulfonyl)acetamide
Methane sulfonamide (10 gm) and n-butylacetate (80 mL) were charged into a 250 mL round bottom flask at 30°C. Chloroacetylchloride (21 .37 gm) was added slowly over a period of 10 minutes at 30°C. Temperature of the reaction mass was raised to 125°C and maintained reflux for 16 hours. Progress of the reaction was monitored by TLC and after completion of the reaction the mass was cooled to 20°C and stirred for 1 hour at 20°C. Reaction mass was filtered and the wet solid was washed with n- butylacetate (10 mL). The wet solid was taken into another 100 mL round bottom flask and n-butylacetate (50 mL) was added and stirred for 30 minutes at 20°C. The precipitation was filtered and the solid was suck dried. The material was dried at 45° under vacuum for 5 hours to yield 14 gm of title compound.
Example 2: Preparation of 2-chloro-N-(methylsulfonyl)acetamide
Methane sulfonamide (100 gm) and n-butylacetate (800 mL) were charged into a 2000 mL round bottom flask at 30°C. Chloroacetylchloride (213.7 gm) was added slowly over a period of 10 minutes at 30°C. Temperature of the reaction mass was raised to 125°C and maintained reflux for 16 hours. Progress of the reaction was monitored by TLC and after completion of the reaction the mass was cooled to 20°C and stirred for 1 hour at 20°C. Reaction mass was filtered and the wet solid was washed with n-butylacetate (100 mL). The wet solid was taken into another 1000 mL round bottom flask and n- butylacetate (500 mL) was added and stirred for 30 minutes at 20°C. The precipitation was filtered and the solid was suck dried. The material was dried at 45° under vacuum for 5 hours to yield 141 gm of title compound as off white solid. Purity: 99.5% by HPLC. Example 3: Preparation of 2-bromo-N-(methylsulfonyl)acetamide
Methane sulfonamide (2 gm) was dissolved in 70 mL dry Toluene and stirred at room temperature. Bromoacetyl bromide (4.5 mL) was added dropwise to the reaction mixture and it was refluxed for 5 hours. The reaction mixture was cooled to room temperature and then placed on an ice bath. The product crystallized out of the toluene and was collected by vacuum filtration and rinsed with 10 mL cold toluene. The white solid was collected, and dried in vacuo overnight to get 2.03 gm of the title compound. Example 4: Preparation of 2-bromo-N-(methylsulfonyl)acetamide Methane sulfonamide (100 gm) was dissolved in 2000 mL of dry Toluene and stirred at room temperature. Bromoacetyl bromide (225 mL) was added dropwise to the reaction mixture and was refluxed for 5 hours. The reaction mixture was cooled to room temperature and then placed on an ice bath. The product crystallized out of the toluene and was collected by vacuum filtration and rinsed with 300 mL cold toluene. The white solid was collected, and dried in vacuo overnight to get 102 gm of the title compound. Example 5: Preparation of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1- butanol.
2-chloro-5,6-diphenylpyrazine (10 gm), 4-(isopropylamino)-1 -butanol (44 gm) and N-methylpyrrolidine (50 mL) were charged into a 250 mL round bottom flask at 30°C. The reaction mass was heated to 190°C and stirred for 10 hours. The reaction mass was cooled to 30°C and poured into cold water, extracted with ethylacetate, dried over anhydrous magnesium sulphate and then concentrated to get 9 gm of the title compound.
Example 6: Preparation of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1- butanol.
2-chloro-5,6-diphenylpyrazine (100 gm), 4-(isopropylamino)-1 -butanol (440 gm) and N-methylpyrrolidine (500 mL) were charged into a 2000 mL round bottom flask at 30°C. The reaction mass was heated to 190°C and stirred for 10 hours. The reaction mass was cooled to 30°C and poured into cold water, extracted with ethylacetate (200 mLx 3), The organic layer was dried over anhydrous magnesium sulphate and then concentrated to get 92 gm of the title compound.
Example 7: Preparation of Selexipag
Potassium tertiary butoxide (700 mg) and dimethylsulfoxide (50 mL) were charged into a 100 mL round bottom flask at 30°C. 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]-1 -butanol (1 gm) at 28 °C and the resulted mixture was stirred for 15 minutes. 2-chloro-N-(methylsulfonyl)acetamide (1 .2 gm) was added at the resulted was added at the resulted mixture was stirred at 30°C for 16 hours. Progress of the reaction was monitored by TLC and after completion of the reaction the reaction mass was poured into cold water and pH was adjusted to 6.5 with 1 N hydrochloric acid (-15 mL). The aqueous layer was extracted with ethylacetate, dried over anhydrous magnesium sulphate and then concentrated. The residue was purified by silica gel column chromatography using 2% Methanol in DCM as eluent to obtain 890 mg of Selexipag. Example 8: Preparation of Selexipag
Potassium tertiary butoxide (130.2 gm) and dimethylsulfoxide (910 ml_) were charged into a 2000 imL round bottom flask at 28°C. 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]-1 -butanol (70 gm) was added at the resulted mixture was stirred for 15 minutes. 2-chloro-N-(methylsulfonyl)acetamide (83 gm) was added at the resulted mixture was stirred for at 20°C for 5 hours. Progress of the reaction was monitored by TLC and after completion of the reaction the reaction mass was poured into cold water (2100 ml_)and the resulted solution was washed with MTBE (3X500 ml_) and pH of the aqueous layer was adjusted to 5.5 with 1 N hydrochloric acid (-150 ml_). The aqueous layer was extracted with MTBE (4X700 ml_) and the organic layer was washed with cold water (2X700 ml_) and the organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The crude was triturated with MTBE (500 ml_) for 30 minutes at 28°C and the solid was filtered. The wet solid was washed with MTBE (140 ml_) and dried under vacuum at 28°C for 3 hours to give 76.4 g of Selexipag as pale yellow solid. Purity: 99.08% by HPLC.
Example 9: Preparation of amorphous form of Selexipag.
Selexipag (1 .0 gm) was dissolved in 25 ml_ of acetone at 28°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was distilled under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 28°C for 3 hours to get 750 mg of amorphous Selexipag.
PXRD pattern: Fig. 1 .
Example 10: Preparation of amorphous solid dispersion of Selexipag and hydroxy propyl methyl cellulose phthalate (HPMC-Phthalate).
Selexipag (1 .0 g) was dissolved in 25 ml_ of acetone at 28°C and a solution of HPMC Phthalate (1 .0 g of HPMC Phthalate dissolved in 30 ml_ of acetone) was added and the resulted mixture was stirred for 10 min at 28°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was completely evaporated under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 28°C for 3 hours to get 1 .5 gm of amorphous solid dispersion of Selexipag and HPMC Phthalate. PXRD pattern: Fig. 2.
Example 11 : Preparation of amorphous solid dispersion of Selexipag and PVP- K30.
Selexipag (1 .0 g) was dissolved in 25 mL of acetone at 28°C and a solution of PVP K-30 (1 .0 g of PVP K-30 dissolved in 60 mL of acetone) was added and the resulted mixture was stirred for 10 min at 28°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was completely evaporated under reduced pressure at 50°C. The solid was dried under vacuum at 28°C for 3 hours to get 1 .6 gm of amorphous solid dispersion of Selexipag and PVP K-30. PXRD pattern: Fig. 3.
Example 12: Preparation of amorphous solid dispersion of Selexipag and PVP- K30.
Selexipag (10.0 g) and PVP K-30 (10.0 g) were charged into a 2 L round bottom flask and Acetone (1000 mL) was added and the resulted mixture was stirred for 15 minutes at 28°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was transferred into a 2 L Buchi flask. The solution was completely concentrated using a rotavapor under reduced pressure at 50°C. The solid was dried under vacuum at 30°C for an hour to get 1 6.5 gm of amorphous solid dispersion of Selexipag and PVP K-30. PXRD pattern: Fig. 3.
Example 13: Preparation of amorphous solid dispersion of Selexipag and PVP- K30.
Selexipag (12.0 g) and PVP K-30 (12.0 g) were charged into a 2 L round bottom flask and Acetone (1 100 mL) was added and the resulted mixture was stirred for 15 minutes at 28°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was transferred into a 2 L Buchi flask. The solution was completely concentrated using a rotavapor under reduced pressure at 53°C. The solid was dried under vacuum at 30°C for an hour to get 1 8.5 gm of amorphous solid dispersion of Selexipag and PVP K-30. PXRD pattern: Fig. 3.
Example 14: Preparation of amorphous solid dispersion of Selexipag, PVP-K30 and Syloid (1 :1 :1). Amorphous solid dispersion of Selexipag and PVP-K30 prepared in example 13 (250 mg) was blended vigorously with syloid (125 mg) and exposed to air at 60% RH for 23 hours. PXRD pattern: Fig. 4.
Example 15: Preparation of amorphous solid dispersion of Selexipag and Copovidone.
Selexipag (500 mg) and Copovidone (500 mg) were charged into a 100 mL round bottom flask and Acetone (25 mL) was added and the resulted mixture was stirred for 5 minutes at 28°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was transferred into a 100 mL Buchi flask and the solution was completely evaporated under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 28°C for 3 hours to get 800 mg of amorphous solid dispersion of Selexipag and Copovidone. PXRD pattern: Fig. 5.
Example 16: Preparation of amorphous solid dispersion of Selexipag and hydroxy propyl methyl cellulose phthalate - Acetyl Succinate (HPMC-AS).
Selexipag (500 mg) and HPMC-AS (500 mg) were charged into a 100 mL round bottom flask and Acetone (25 mL) was added and the resulted mixture was stirred for 5 minutes at 28°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was transferred into a 100 mL Buchi flask and the solution was completely evaporated under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 28°C for 3 hours to get 800 mg of amorphous solid dispersion of Selexipag and HPMC-AS. PXRD pattern: Fig. 6.
Example 17: Preparation of amorphous solid dispersion of Selexipag and hydroxy propyl methyl cellulose phthalate (HPMC-Phthalate).
Selexipag (1 .0 g) and HPMC Phthalate (1 .0 g) were charged into a 100 mL round bottom flask and Acetone (25 mL) was added and the resulted mixture was stirred for 10 min at 28°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was completely evaporated under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 28°C for 3 hours to get 1 .5 gm of amorphous solid dispersion of Selexipag and HPMC Phthalate. PXRD pattern: Fig. 2.

Claims

1 . A process for preparation of Selexipag, comprising
(a) reacting 2-chloro-5,6-diphenylpyrazine with 4-(isopropylamino)-1 -butanol in presence of a base to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol.
Figure imgf000026_0001
(b) reacting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol with 2-halo- N-(methylsulfonyl)acetamide in presence of dimethylsulfoxide to form Selexipag.
Figure imgf000026_0002
Selexipag
(c) optionally, purifying the Selexipag obtained in step (b).
2. A process for preparation of 2-halo-N-(methylsulfonyl)acetamide, comprising reacting methane sulfonamide with haloacetyl chloride to form 2-halo-N- (methylsulfonyl)acetamide
Figure imgf000026_0003
3. A process for preparation of Selexipag, comprising:
(a) reacting methane sulfonamide with haloacetyl chloride to form 2-halo-N- (methylsulfonyl)acetamide
Figure imgf000026_0004
(b) reacting 2-chloro-5,6-diphenylpyrazine with 4-(isopropylamino)-1 -butanol in presence of a base to form 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 - butanol.
Figure imgf000027_0001
(c) reacting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1 -butanol with 2-halo- -(methylsulfonyl)acetamide in presence of dimethylsulfoxide to form Selexipag.
Figure imgf000027_0002
Selexipag
(d) optionally, purifying the Selexipag obtained in step (c).
4. Amorphous form of Selexipag
5. Amorphous form of Selexipag characterized by powder X-ray diffraction (PXRD) as depicted in Figure 1 .
6. A process for preparing amorphous form of Selexipag, comprising
a) providing a solution of Selexipag in a solvent or a mixture of solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous form of Selexipag.
7. Amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
8. The solid dispersion of Selexipag according to claim 7, wherein the pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, copovidone, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate.
9. Amorphous solid dispersion comprising selexipag and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) as depicted in any of figure 2 to figure 6.
10. A process for preparing an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers, comprising
a) providing a solution comprising Selexipag and one or more pharmaceutically acceptable carriers, b) removing solvent from the solution obtained in step (a), and
c) recovering an amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.
1 1 . A pharmaceutical composition comprising Selexipag according to any of claims 1 to 10 and one or more pharmaceutically acceptable carriers.
12. Use of Selexipag according to any of claims 1 to 10 together with at least one pharmaceutically acceptable carrier, for the treatment of pulmonary artery hypertension.
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US10815204B2 (en) 2016-04-01 2020-10-27 Honour (R&D) Process for the preparation of diphenylpyrazine derivatives
WO2017168401A1 (en) * 2016-04-01 2017-10-05 Honour (R&D) Process for the preparation of diphenylpyrazine derivatives
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WO2018078383A1 (en) * 2016-10-27 2018-05-03 Cipla Limited Pharmaceutical composition comprising amorphous selexipag
KR102593075B1 (en) 2017-03-08 2023-10-23 액테리온 파마슈티칼 리미티드 Pharmaceutical composition containing selexipag
KR20190122803A (en) * 2017-03-08 2019-10-30 액테리온 파마슈티칼 리미티드 Pharmaceutical compositions comprising selecifag
WO2019023605A1 (en) 2017-07-27 2019-01-31 Allergan, Inc. Prostacyclin receptor agonists for reduction of body fat
WO2019034094A1 (en) * 2017-08-17 2019-02-21 东莞东阳光药物研发有限公司 Method for preparing alcoholic compound
CN111065627A (en) * 2017-08-17 2020-04-24 东莞东阳光药物研发有限公司 Preparation method of alcohol compound
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WO2019098300A1 (en) 2017-11-16 2019-05-23 日本新薬株式会社 Controlled release formulation
EP3705115A1 (en) 2019-03-07 2020-09-09 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition containing selexipag
CN110128358A (en) * 2019-04-08 2019-08-16 河北科技大学 4 [(5,6 diphenyl pyrazine, 2 base) (isopropyl) amino] butyl 2 (sulfonyloxy methyl amino) acetic acid esters preparation methods
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