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WO2019135254A1 - Polymorphes d'apalutamide et leur préparation - Google Patents

Polymorphes d'apalutamide et leur préparation Download PDF

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Publication number
WO2019135254A1
WO2019135254A1 PCT/IN2018/050881 IN2018050881W WO2019135254A1 WO 2019135254 A1 WO2019135254 A1 WO 2019135254A1 IN 2018050881 W IN2018050881 W IN 2018050881W WO 2019135254 A1 WO2019135254 A1 WO 2019135254A1
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Prior art keywords
apalutamide
crystalline
solvent
steps
dissolving
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Inventor
Ramakoteswara Rao Jetti
Aggi Ramireddy Bommareddy
Sureshbabu JAYACHANDRA
Sonny Sebastian
Jagadeeshwar Rao
Lakshminaryana VEMULA
Mahesh Nagin PATEL
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention relates to novel polymorphs of Apalutamide and their preparation process thereof.
  • the present invention further relates to processes for the preparation of amorphous and amorphous solid dispersion of Apalutamide.
  • Apalutamide chemically known as 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8- oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide and represented by Formula-I, is approved for the treatment of prostate cancer. It is similar to enzalutamide both structurally and pharmacologically, acting as a selective competitive antagonist of the androgen receptor (AR), but shows some advantages, including greater potency and reduced central nervous system permeation.
  • AR androgen receptor
  • Apalutamide was first disclosed in US 8445507B2 patent.
  • US patent, 8,461,243 B2 disclosed the preparation and purification of Apalutamide.
  • US patent, US9481663B 1 disclosed crystalline Form B and amorphous forms along with their preparations thereof.
  • US patent, US 9994545B1 disclosed crystalline Form A and its preparation thereof.
  • the present inventors developed an economic and cost-effective process for the preparation of amorphous Apalutamide and amorphous solid dispersion of Apalutamide.
  • the inventors further developed novel polymorphic forms of Apalutamide with improved chemical purity which are stable and suitable for formulation development.
  • the novel polymorphic forms and their processes of current invention may provide single purification step to obtain desired product quality or purer product from crude Apalutamide thereby addressing the major industrial challenges in purification and can also be prepared conveniently at a low cost.
  • the present invention provides a process for the preparation of amorphous Apalutamide and amorphous solid dispersion of Apalutamide.
  • the present invention further provides novel crystalline forms of Apalutamide designated as Form Ml, Form M2, Form M3, Form M4, Form M5 and Form M6 and their preparation process thereof.
  • One aspect of the present invention provides a process for the preparation of amorphous Apalutamide comprising the steps of:
  • Another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of: a) dissolving Apalutamide and pharmaceutically acceptable excipient in organic solvent,
  • Yet another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
  • the present invention provides novel crystalline form of Apalutamide form Ml characterized by powder X-ray diffraction pattern shown having peaks at 4.7, 13.9, 16.1, 20.6, 21.4, 22.2, 22.7, 25.7, 26.5, 27.6, 28.5, 30.1 ⁇ 0.2° degrees 2Q.
  • the crystalline Apalutamide Form Ml of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 4.
  • the present invention provides a process for the preparation of crystalline Form Ml of Apalutamide comprising the steps of:
  • the present invention provides a novel crystalline form M2 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 6.9, 7.4, 7.6, 8.3, 12.0, 13.2 16.4, 20.1 ⁇ 0.2° degrees 20.
  • the crystalline Form M2 of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 5.
  • the present invention provides a process for the preparation of crystalline Form M2 of Apalutamide comprising the steps of: a) dissolving Apalutamide in a solvent,
  • the present invention provides a novel crystalline form M3 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 5.0, 6.9, 7.5, 9.1, 12.0, 13.6, 14.1, 15.2, 16.4, 17.4, 19.5, 20.9 ⁇ 0.2° degrees 2Q.
  • crystalline Form M3 of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 6.
  • the present invention provides a process for the preparation of crystalline Form M3 of Apalutamide comprising the steps of:
  • the present invention provides novel crystalline form M4 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.9, 6.9, 7.4, 8.0, 8.5, 16.5 ⁇ 0.2° degrees 2Q.
  • crystalline Form M4 of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 7.
  • the present invention provides a process for the preparation of crystalline Form M4 of Apalutamide comprising the steps of:
  • the present invention provides a novel crystalline form M5 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.6, 4.0, 7.3, 8.1, 10.1, 12.2, 17.2, 20.3, 21.1 ⁇ 0.2° degrees 2Q. Yet in another aspect, the present invention provides a crystalline Apalutamide Form M5.
  • crystalline Apalutamide Form M5 may be characterized by the powder X-ray diffraction pattern in Figure 8.
  • the present invention provides a process for the preparation of crystalline Form M5 of Apalutamide comprising the steps of:
  • the present invention provides a novel crystalline Apalutamide Form M6.
  • the crystalline Form M6 of Apalutamide is characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.7, 6.9, 7.2, 9.1, 9.4, 10.5,11.0,
  • the crystalline Form M6 of Apalutamide may be characterized by the powder X-ray diffraction pattern as given in Figure 9.
  • the present invention is to provide a process for the preparation of crystalline Form M6 of Apalutamide comprising the steps of:
  • the present invention provides crystalline premix of Apalutamide Form M6.
  • the crystalline premix of Apalutamide Form M6 may be characterized by the powder X-ray diffraction pattern as given in Figure 10. Yet in another aspect, the present invention provides a process for the preparation of crystalline premix of Apalutamide Form M6 comprising the steps of:
  • the present invention provides crystalline premix of Apalutamide Form Ml.
  • the crystalline premix of Apalutamide Form Ml may be characterized by the powder X-ray diffraction pattern as given in Figure 11.
  • the present invention provides a process for the preparation of crystalline premix of Apalutamide Form Ml comprising the steps of:
  • Figure 1 shows a powder X-ray diffraction (PXRD) pattern of amorphous Apalutamide.
  • Figure 2 shows a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Apalutamide as per example 5.
  • PXRD powder X-ray diffraction
  • Figure 3 shows a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Apalutamide as per example 6.
  • Figure 4 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form Ml.
  • Figure 5 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M2.
  • Figure 6 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M3.
  • Figure 7 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M4.
  • Figure 8 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M5.
  • Figure 9 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M6.
  • Figure 10 shows a powder X-ray diffraction (PXRD) pattern of Crystalline premix of Apalutamide Form M6 with 50%w/w Silicon dioxide.
  • Figure 11 shows a powder X-ray diffraction (PXRD) pattern of Crystalline premix of Apalutamide Form Ml with 50%w/w Silicon dioxide.
  • the present invention relates to an improved process for the preparation of amorphous Apalutamide and amorphous solid dispersion of Apalutamide.
  • the present invention further relates to novel crystalline forms of Apalutamide designated as Forms Ml, M2, M3, M4, Form M5 and M6 and their preparation thereof.
  • Apalutamide may be dissolved in a solvent selected from methanol, 2-butanol, 1, 4-dioxane, or mixtures thereof and the resulting solution may be removed by conventional technique such as evaporation, Spray drying, Lyophilization or agitated thin film drier (ATFD) to obtain Apalutamide in amorphous form.
  • a solvent selected from methanol, 2-butanol, 1, 4-dioxane, or mixtures thereof
  • ATFD agitated thin film drier
  • the amorphous form of Apalutamide may be obtained by evaporation or lyophilization.
  • the amorphous form of Apalutamide may be obtained by feeding the material into the spray dryer with feed rate of the solution at 5ml/min and inlet temperature at 70°C.
  • Another embodiment of the present invention relates to an improved process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of: a) dissolving Apalutamide and a pharmaceutically acceptable excipient in an organic solvent,
  • Apalutamide and a pharmaceutically acceptable excipient selected from Plasdone S-630, Povidone K-30 or Aeropril 300 may be dissolved in a sufficient amount of solvent selected from methanol, ethanol, isopropanol, n-butanol, acetone, ethyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl amyl ketone (MAK) to form a clear solution.
  • solvent may be removed by evaporation to obtain amorphous solid dispersion of Apalutamide.
  • the present invention relates to a process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of: a) dissolving Apalutamide in an organic solvent,
  • Apalutamide may be dissolved in a solvent selected from methanol, ethanol, isopropanol, n-butanol, acetone, ethyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl amyl ketone (MAK), and added with a pharmaceutically acceptable excipient selected from Plasdone S-630, Povidone K- 30 or Aeropril 300 and the like.
  • the solvent may be removed by conventional technique such as evaporation to obtain amorphous solid dispersion of Apalutamide.
  • the present invention relates to crystalline Form Ml of Apalutamide characterized by powder X-ray diffraction pattern having peaks at 4.7, 7.1, 9.3, 10.7, 11.7,13.1, 13.9, 14.9,16.1, 16.8, 18.5, 20.1, 20.6, 21.4, 22.2, 22.7, 23.9, 24.7, 25.1, 25.7, 26.5, 27.6, 28.5, 30.1, 31.1, 31.8, 32.1, 32.9, 34.1, 34.5, 35.3, 36.7, 37.6, 38.0, 38.9, 40.3, 43.5, 45.5 ⁇ 0.2° degrees 2Q.
  • the present invention relates to crystalline Form Ml of Apalutamide characterized by powder X-ray diffraction as depicted in Figure 4. Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form Ml of Apalutamide comprising the steps of:
  • Apalutamide may be dissolved in a suitable solvent preferably Toluene, 2-butanol, ethanol, methanol, 1 -butanol, 1 -propanol, 1- pentanol.
  • a suitable solvent preferably Toluene, 2-butanol, ethanol, methanol, 1 -butanol, 1 -propanol, 1- pentanol.
  • the clear solution may be cooled and the precipitated solid may be filtered and dried to obtain crystalline form-Ml of Apalutamide.
  • the present invention relates to crystalline form M2 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 5.0, 6.9, 7.4, 7.6, 8.3, 10.0, 12.0, 12.6, 13.2, 13.7, 14.2, 15.3, 16.0, 16.4, 16.6, 17.3,17.7, 19.2, 20.1, 21.3, 21.9, 22.0, 23.6, 23.9, 24.8, 25.5, 25.8, 27.8, 28.7, 30.2,
  • crystalline Form M2 of Apalutamide may be characterized by the powder X-ray diffraction pattern as depicted in Figure 5.
  • the present invention relates to a process for the preparation of crystalline Form M2 of Apalutamide comprising the steps of:
  • Apalutamide may be dissolved in a suitable solvent selected from the group consisting of Methyl isobutyl ketone, acetone, methyl butyl ketone, methyl ethyl ketone & isopropyl ether and slowly cooled.
  • the resultant solid may be filtered and dried to obtain crystalline Form M2 of Apalutamide.
  • the present invention relates to crystalline Form M3 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 5.0, 6.9, 7.5, 8.2, 9.1, 10.0, 12.0, 13.6, 14.1, 15.2, 15.9, 16.4, 16.6, 17.4, 17.7,
  • crystalline Form M3 of Apalutamide characterized by the powder X-ray diffraction pattern as depicted in Figure 6.
  • the present invention relates to a process for the preparation of crystalline Form M3 of Apalutamide comprising the steps of:
  • Apalutamide may be dissolved in an organic solvent selected from acetone, methyl butyl ketone or methyl ethyl ketone.
  • the clear solution may be added with a suitable antisolvent selected from ethers such as isopropyl ether, methyl tert-butyl ether, diethyl ether preferable isopropyl ether.
  • the solid precipitated may be filtered and dried to obtain crystalline Form M3 of Apalutamide
  • the present invention relates to crystalline form M4 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.9, 6.9, 7.4, 8.0, 8.5, 9.1, 9.8, 11.5, 12.1, 12.4, 13.0, 14.0, 14.2, 15.0, 15.8, 16.0, 16.5, 16.8, 17.1, 18.1, 19.1, 19.4, 19.8, 20.2, 21.0, 21.4, 22.3, 23.3, 23.7, 24.2, 24.8, 26.0, 26.8, 27.3, 28.4, 29.0,30.0, 30.4, 31.0, 31.6, 33.0, 34.5, 36.5 ⁇ 0.2° degrees 2Q.
  • crystalline Form M4 of Apalutamide may be characterized by the powder X-ray diffraction pattern as depicted in Figure 7.
  • the present invention relates to a process for the preparation of crystalline Form M4 of Apalutamide comprising the steps of:
  • Apalutamide may be dissolved in an organic solvent selected from Dimethylformamide.
  • the clear solution may be added with a suitable antisolvent selected from water, methyl tert-butyl ether, Isopropyl ether.
  • the solid precipitated may be filtered and dried to obtain crystalline Form M4 of Apalutamide.
  • the crystalline Form M4 of Apalutamide prepared according to the present invention is a dimethyl formamide hemi solvate.
  • the present invention relates to crystalline form M5 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.6, 4.0, 7.3, 8.1, 10.1, 11.0, 12.2, 13.0, 14.0, 14.7, 15.1, 15.9, 16.2, 16.7, 17.2, 17.5, 18.3, 19.2, 19.8, 20.3, 21.1, 21.5, 22.3, 23.7, 24.5, 25.8, 26.4, 28.5, 29.1, 30.1, 30.5 33.5, 36.3, 42.0 ⁇ 0.2° degrees 2Q.
  • crystalline Apalutamide Form M5 may be characterized by the powder X-ray diffraction pattern as depicted in Figure 8.
  • crystalline Apalutamide Form M5 may be prepared by a process comprising the steps of:
  • Apalutamide may be dissolved in Dimethylformamide and the clear solution may be allowed for slow evaporation or distilled completely to obtain of crystalline Form M5 of Apalutamide.
  • the crystalline Form M5 of Apalutamide prepared according to the present invention is a dimethyl formamide solvate.
  • the present invention relates to crystalline form of Apalutamide designated as Form M6. Yet in another embodiment, the present invention relates to crystalline Form M6 of Apalutamide is characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.7, 6.9, 7.2, 9.1, 9.4, 10.5,11.0, 11.8, 13.2, 13.7, 14.1, 14.8, 15.3, 15.9, 16.2, 16.50,
  • the crystalline Form M6 of Apalutamide may be characterized by the powder X-ray diffraction pattern as depicted in Figure 9.
  • the present invention relates to a process for the preparation of crystalline Form M6 of Apalutamide comprising the steps of:
  • Apalutamide may be suspended in a solvent such as water or 2-butanol at ambient temperature for 2-3 hours.
  • the resultant reaction mass may be filtered and the solid obtained may be dried under vacuum to isolate crystalline Form M6 of Apalutamide.
  • the present invention relates to a process for the preparation of crystalline Form M6 of Apalutamide comprising the steps of:
  • Apalutamide may be dissolved in a solvent such as 2-butanol and cooled slowly to room temperature.
  • the resultant reaction mass may be added with water, maintained under stirring for about an hour and filtered.
  • the solid obtained may be dried under vacuum to isolate crystalline Form M6 of Apalutamide.
  • the crystalline Form M6 of Apalutamide is a solvate. According to the present invention, the crystalline Form M6 of Apalutamide is a solvate hydrate.
  • the crystalline Form M6 of Apalutamide is a 2- butanol solvate hydrate.
  • crystalline Form M6 of Apalutamide may be prepared by placing Apalutamide in a petri-dish and exposed to 90% relative humidity for 24hours.
  • the present invention relates to crystalline premix of Apalutamide Form M6.
  • the crystalline premix of Apalutamide Form M6 may be characterized by the powder X-ray diffraction pattern as depicted in Figure 10.
  • the present invention relates to a process for the preparation of crystalline premix of Apalutamide Form M6 comprising the steps of: a) suspending Apalutamide in water,
  • Apalutamide may be suspended in water and added with a pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide, magnesium stearate or mixtures thereof preferably Silicon dioxide.
  • a pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide, magnesium stearate or mixtures thereof preferably Silicon dioxide.
  • the resultant reaction mass may be filtered and the solid obtained may be dried at 50°C under vacuum to isolate crystalline premix of Apalutamide Form M6.
  • the present invention relates to a process for the preparation of crystalline premix of Apalutamide Form M6 comprising the steps of: a) dissolving Apalutamide in an organic solvent, b) adding water and pharmaceutically acceptable excipient, and
  • Apalutamide may be dissolved in an organic solvent such as alcohols such as methanol, enthanol or 2-butanol and gradually cooled to room temperature.
  • Water may be added followed by addition of pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide, magnesium stearate or mixtures thereof preferably Silicon dioxide.
  • the resultant reaction mass may be filtered and the solid obtained may be dried at 50°C under vacuum to isolate crystalline premix of Apalutamide Form M6.
  • the present invention relates to crystalline premix of Apalutamide Form Ml.
  • the crystalline premix of Apalutamide Form Ml may be characterized by the powder X-ray diffraction pattern as given in Figure 11.
  • the present invention relates to a process for the preparation of crystalline premix of Apalutamide Form Ml comprising the steps of: a) dissolving Apalutamide in an organic solvent;
  • Apalutamide may be dissolved in an organic solvent such as 2-butanol and heated to about 70 to 90°C followed by cooling to room temperature.
  • an organic solvent such as 2-butanol
  • a pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide, magnesium stearate, and mixtures thereof preferably Silicon dioxide may be added and maintained for about an hour.
  • the resultant reaction mass may be filtered and the solid obtained may be dried at 50°C under vacuum to isolate crystalline premix of Form Ml of Apalutamide.
  • the present invention relates to a process for the preparation of amorphous form of apalutamide.
  • amorphous Apalutamide may be prepared by heating Apalutamide Form M6 using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from about 25-l40°C followed by slow cooling to 30°C.
  • making of amorphous form or amorphous solid dispersion by drying of Apalutamide Form-M6 or crystalline premix of Form M6 is more advantageous in scale up than the prior art process.
  • the present invention relates to a pharmaceutical composition wherein the composition comprises of amorphous apalutamide and at least one pharmaceutically acceptable excipient and/or a pharmaceutically acceptable carrier. Yet in another embodiment, the present invention relates to a pharmaceutical composition wherein the composition comprises of amorphous solid dispersion of apalutamide and at least one pharmaceutically acceptable excipient and/or a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition wherein the composition comprises of apalutamide crystalline forms Ml or M2 or M3 or M4 or M5 or M6 and at least one pharmaceutically acceptable excipient and/or a pharmaceutically acceptable carrier.
  • Apalutamide as prepared by the processes described herein, may be formulated into a pharmaceutical dosage form, for example, one for oral administration such as tablets or capsules.
  • Such tablets or capsules may include other pharmaceutically acceptable excipients such as colloidal silicon dioxide, microcrystalline cellulose, starch, sodium starch glycolate, stearic acid, ammonium chloride, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, povidone, hydroxypropyl methyl cellulose, mannitol, fumaric acid, sodium hydroxide, crospovidone, talc, and artificial colorings and flavorings.
  • excipients such as colloidal silicon dioxide, microcrystalline cellulose, starch, sodium starch glycolate, stearic acid, ammonium chloride, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, povidone, hydroxypropyl
  • Oral dosage forms containing the substantially pure Apalutamide as prepared by methods disclosed herein may be particularly useful in the treatment of prostate cancer.
  • Apalutamide (0.5g) was dissolved in 2-butanol (5mL) at 75 ⁇ 5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 65 ⁇ 5°C. The solid obtained was identified as apalutamide amorphous form.
  • Apalutamide (0.5g) was dissolved in 1, 4-dioxane (3mL) at 25 ⁇ 5°C.
  • the resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to Lyophilisation using Labocon lyophilizer (ModeLFD-BT-l04) to yield apalutamide amorphous form.Yield: 0.4g
  • Apalutamide (0.5g) and Plasdone S-630 (0.5g) were dissolved in methanol (5mL) at 25 ⁇ 5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 65 ⁇ 5°C. The solid obtained was identified as amorphous solid dispersion of apalutamide.
  • Apalutamide (0.5g) and Povidone K-30 (0.5g) were dissolved in methanol (5mL) at 25 ⁇ 5°C. Filtered through hyflo to remove undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 65 ⁇ 5°C. The solid obtained was identified as amorphous solid dispersion of apalutamide.
  • Apalutamide (0.5g) was dissolved in methanol (5mL) at 25 ⁇ 5°C.
  • the resulting clear solution was filtered through hyflo to remove any undissolved particulates.
  • the solid obtained was identified as amorphous solid dispersion of apalutamide. Yield: 0.7g
  • Example 7 Example 7:
  • Apalutamide (0.5g) was dissolved in Toluene (5 ml) at 95°C and the obtained clear solution was gradually cooled to 25 ⁇ 5°C and stirred for 30 min. The precipitated solid was filtered and washed with Toluene (4ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-Ml
  • Apalutamide (0.5g) was dissolved in 2-butanol (7.5 ml) at 65°C and the obtained clear solution was gradually cooled to 25 ⁇ 5°C and stirred for 60 min. The precipitated solid was filtered and washed with 2-butanol (2ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-Ml
  • Apalutamide (0.5g) was dissolved in Methyl isobutyl ketone (2.5 mL) at 35-40°C and stirred for 30 min and the solution was gradually cooled to 0-5°C. Stirred for lh at 0- 5°C, filtered the solid and washed the solid with chilled methyl isobutyl ketone (1 ml). The solid obtained was dried at 50°C under vacuum to get the apalutamide crystalline form- M2.
  • Apalutamide (0.5g) was dissolved in acetone (5mL) at 25 ⁇ 5°C.
  • Isopropyl ether (25 ml) was added slowly and stirred for 1 h.
  • the precipitated solid was filtered and washed with isopropyl ether (5ml).
  • the wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-M3.
  • Apalutamide (0.5g) was dissolved in dimethyl formamide (5 ml) at 80°C and water (5 ml) was added to the clear solution and stirred for 30 min. The mixture was cooled and stirred for lh to 25-30°C. The precipitated solid was filtered and washed with water (5ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-M4.
  • Example 12 Apalutamide (0.5g) was dissolved in dimethyl formamide (5 ml) at 80°C and water (5 ml) was added to the clear solution and stirred for 30 min. The mixture was cooled and stirred for lh to 25-30°C. The precipitated solid was filtered and washed with water (5ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-M4.
  • Example 12 Example 12:
  • Apalutamide (100 mg) was dissolved in Dimethyl formamide (lmL) at 25 ⁇ 5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 75 ⁇ 5°C. The solid obtained was identified as apalutamide crystalline Form M5.
  • Apalutamide (lg) was dissolved in Dimethyl formamide (lOmL) at 25 ⁇ 5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 75 ⁇ 5°C. The solid obtained was identified as apalutamide crystalline Form M5.
  • Example 15 Preparation of crystalline Form M6 of Apalutamide.
  • Apalutamide form Ml (1.0 g) was suspended in water (20 ml) and maintained under stirring at 25-30°C for 2-3 hours. The reaction mixture was filtered, washed with water (10 ml) and dried the wet material at 50-55°C under vacuum to obtain crystalline Form M6 of Aplutamide. Water content: 2.82%
  • Example 16 Preparation of crystalline Form M6 of Apalutamide.
  • Apalutamide form Ml (1.0 g) was suspended in 2-butanol (20 ml) and maintained under stirring at 25-30°C for 2-3 hours. The reaction mixture was filtered, washed with 2-butanol (5 ml) and dried the wet material at 50-55°C under vacuum to get crystalline Form M6 of Apalutamide. Water content: 2.51%
  • Example 17 Preparation of crystalline Form M6 of Apalutamide.
  • Apalutamide form Ml (1.0 g) was placed in a petri-dish and exposed to 90% relative humidity for 24h. The product obtained was tested by PXRD analysis and identified as crystalline Form M6 of Apalutamide.
  • Example 18 Preparation of crystalline premix of Apalutamide Form Ml.
  • Apalutamide (lg) was dissolved in 2-butanol (20 ml) at 85°C and the resulting clear solution was gradually cooled to 25 ⁇ 5°C and stirred for 60 min. Then added Silicon dioxide (lg) and stirred at 25 ⁇ 5°C for 60min. The reaction mass was filtered, washed with 2-butanol (2ml) and the wet solid was dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline premix of apalutamide Form Ml.
  • Apalutamide form Ml (lg) was suspended in water (10 ml) and maintained under stirring at 25-30°C for 2 hours. Then added Silicon dioxide (lg) and stirred at 25 ⁇ 5°C for lh. The reaction mass was filtered, washed with water (2ml) and the wet solid was dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline premix of apalutamide Form M6.
  • Apalutamide Form M6 (0.2g) was heated using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from 30-l30°C and followed by slow cooling to 30°C. The resulting solid was identified as Apalutamide amorphous form.
  • Apalutamide (lg) was dissolved in 2-butanol (20 ml) at 85°C and the resulting clear solution was gradually cooled to 25 ⁇ 5°C and stirred for 60 min. Then added water (lOml) and stirred at 25 ⁇ 5°C for 60min. The reaction mass was filtered and dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline Apalutamide Form M6.
  • Apalutamide Form M6 (0.5g) was dried at l20-l30°C for lh and followed by slow cooling to 30°C. The resulting solid was identified as Apalutamide amorphous Form.
  • Example 23 Preparation of Crystalline premix of Apalutamide Form M6
  • Apalutamide (lg) was dissolved in 2-butanol (20 ml) at 85°C and the resulting clear solution was gradually cooled to 25 ⁇ 5°C and stirred for 60 min. Then added water (lOml) and stirred at 25 ⁇ 5°C for 60min. Then added Silicon dioxide (lg) and stirred at 25 ⁇ 5°C for 60min. The reaction mass was filtered and dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline premix of apalutamide Form M6.

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Abstract

L'invention concerne de nouveaux polymorphes d'apalutamide et leur procédé de préparation. La présente invention concerne également des procédés de préparation d'apalutamide amorphe et d'une dispersion solide amorphe d'apalutamide.
PCT/IN2018/050881 2018-01-02 2018-12-26 Polymorphes d'apalutamide et leur préparation Ceased WO2019135254A1 (fr)

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WO2021033098A1 (fr) * 2019-08-22 2021-02-25 Dr. Reddy’S Laboratories Limited Procédé pour la préparation d'apalutamide
IT201900015974A1 (it) * 2019-09-10 2021-03-10 Olon Spa Apalutamide cristallina stabile in forma pura e processo per la sua preparazione
WO2021117062A1 (fr) * 2019-12-11 2021-06-17 Msn Laboratories Private Limited, R&D Center Procédé de préparation de 4-[7-(6-cyano-5-trifluorométhylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-n-méthylbenzamide et de ses polymorphes
WO2022049265A1 (fr) 2020-09-04 2022-03-10 Synthon B.V. Procédé amélioré pour la préparation d'apalutamide
CN116332907A (zh) * 2023-03-16 2023-06-27 奥锐特药业股份有限公司 一种无定形阿帕他胺的制备方法

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Publication number Priority date Publication date Assignee Title
WO2021033098A1 (fr) * 2019-08-22 2021-02-25 Dr. Reddy’S Laboratories Limited Procédé pour la préparation d'apalutamide
IT201900015974A1 (it) * 2019-09-10 2021-03-10 Olon Spa Apalutamide cristallina stabile in forma pura e processo per la sua preparazione
WO2021048067A1 (fr) * 2019-09-10 2021-03-18 Olon S.P.A. Apalutamide cristallin stable sous forme pure, et son procédé de préparation
WO2021117062A1 (fr) * 2019-12-11 2021-06-17 Msn Laboratories Private Limited, R&D Center Procédé de préparation de 4-[7-(6-cyano-5-trifluorométhylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-n-méthylbenzamide et de ses polymorphes
WO2022049265A1 (fr) 2020-09-04 2022-03-10 Synthon B.V. Procédé amélioré pour la préparation d'apalutamide
CN116034101A (zh) * 2020-09-04 2023-04-28 斯索恩有限公司 制备阿帕鲁胺的改进方法
EP4541786A2 (fr) 2020-09-04 2025-04-23 Synthon B.V. Procédé amélioré de préparation d'apalutamide
EP4541786A3 (fr) * 2020-09-04 2025-08-06 Synthon B.V. Procédé amélioré de préparation d'apalutamide
CN116332907A (zh) * 2023-03-16 2023-06-27 奥锐特药业股份有限公司 一种无定形阿帕他胺的制备方法

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