WO2019016747A1 - Dispersions solides amorphes d'apalutamide et leur procédé de préparation - Google Patents

Dispersions solides amorphes d'apalutamide et leur procédé de préparation Download PDF

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WO2019016747A1
WO2019016747A1 PCT/IB2018/055371 IB2018055371W WO2019016747A1 WO 2019016747 A1 WO2019016747 A1 WO 2019016747A1 IB 2018055371 W IB2018055371 W IB 2018055371W WO 2019016747 A1 WO2019016747 A1 WO 2019016747A1
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Prior art keywords
apalutamide
solid dispersion
amorphous solid
preparation
amorphous
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PCT/IB2018/055371
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English (en)
Inventor
Amol Ashok Pawar
Peddi Reddy SUBBA REDDY
Vamsi Krishna Mudapaka
Shanmukha Prasad Gopi
K Rama Subba REDDY
Himanshu Verma
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Dr. Reddy's Laboratories Limited
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Publication of WO2019016747A1 publication Critical patent/WO2019016747A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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

Definitions

  • aspects of the present application relates to amorphous solid dispersions of apalutamide, coamorphous forms of apalutamide and process for the preparation of amorphous form of apalutamide.
  • the drug compound having the adopted name "Apalutamide” has chemical name: 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenza-mide as below.
  • US8445507B2 discloses apalutamide or a pharmaceutically acceptable salt thereof, method for treating prostrate cancer using apalutamide or a pharmaceutically acceptable salt thereof and pharmaceutical composition thereof.
  • US9884054B2 discloses method of treating non-metastatic castration-resistant prostate cancer with apalutamide.
  • WO20131 84681 A1 discloses crystalline Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I and Form J of apalutamide.
  • WO20161 24149A1 discloses crystalline Form I and Form II of apalutamide.
  • WO2016090098A1 discloses solid dispersion of apalutamide with HPMCAS.
  • WO2016090101 A1 discloses solid dispersion of apalutamide with a poly(meth)acrylate copolymer.
  • WO20160901 05A1 discloses solid dispersion of apalutamide with a poly(meth)actylate copolymer and HPMCAS.
  • US201 60346207A1 discloses solid pharmaceutical composition comprising apalutamide, carrier and surfactant.
  • An aspect of the invention particular solid pharmaceutical formulations for oral adminstration of apalutamide, where such formulations have an improved stability, a longer shelf life, or provide for a reduced pill burden for the patient, in particular the cancer patient can be reduced, and hence therapy adherence and therapy efficiency can be improved.
  • an amorphous form of a drug may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development.
  • the solubility of crystalline form is lower than its amorphous form in some instances, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have an amorphous form of a drug to meet the needs of drug development which is stable and also a reproducible process for their preparation. Hence, it is desirable to provide a stable amorphous solid dispersion apalutamide and coamorphous forms of apalutamide with coformer.
  • the present application provides an amorphous solid dispersion of apalutamide with a pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, prosolv, hydroxypropyl methylcellulose or mixtures thereof.
  • a pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, prosolv, hydroxypropyl methylcellulose or mixtures thereof.
  • the present application provides amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate, characterized by its X-ray powder diffractogram as substantially shown in Figures 4, 14,16,28,29 and 30
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with HPMC phthalate comprising the steps of:
  • the present application provides amorphous solid dispersion of apalutamide with copovidone, characterized by its X-ray powder diffractogram as substantially shown in figures 1 , 8, 1 5 and 1 7.
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with copovidone comprising the steps of:
  • the present application provides amorphous solid dispersion of apalutamide with cellulose acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 24 and 25.
  • PXRD powder X-ray diffraction
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with cellulose acetate phthalate comprising the steps of:
  • the present application provides amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 26 and 27.
  • PXRD powder X-ray diffraction
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate comprising the steps of:
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide, the process comprising the steps of:
  • the present application provides a process for the preparation of amorphous apalutamide, the process comprising the steps of:
  • the present application provides coamorphous form of apalutamide with L(+) tartaric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 20.
  • the present application provides a process for the preparation of coamorphous form of apalutamide with L(+) tartaric acid comprising the steps of:
  • the present application provides coamorphous form of apalutamide with citric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 21 .
  • the present application provides a process for the preparation of coamorphous form of apalutamide with citric acid comprising the steps of:
  • the present application provides coamorphous form of apalutamide with saccharin, characterized by its X-ray powder diffractogram as substantially shown in FIG. 22.
  • the present application provides a process for the preparation of coamorphous form of apalutamide with saccharin comprising the steps of:
  • the present application provides coamorphous form of apalutamide with sucralose, characterized by its X-ray powder diffractogram as substantially shown in FIG. 23.
  • the present application provides process for the preparation of coamorphous form of apalutamide with sucralose comprising the steps of:
  • the present application provides a pharmaceutical composition comprising amorphous form of apalutamide or coamorphous form of apalutamide or amorphous solid dispersion of apalutamide with atleast one pharmaceutically acceptable excipient.
  • Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with copovidone VA 64 prepared by the method of Example No 1 .
  • Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with ethyl cellulose prepared by the method of Example No 2.
  • Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinylpyrrolidone-K90 and hydroxypropyl cellulose prepared by the method of Example No 3.
  • Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate prepared by the method of Example No 4.
  • Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with methyl cellulose prepared by the method of Example No 5.
  • Figure 6 is an illustrative X-ray powder diffraction pattern of solid dispersion of apalutamide with prosolv HD 40 prepared by the method of Example No 6.
  • Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose prepared by the method of Example No 7.
  • Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous premix of apalutamide with copovidone VA 64 and syloid 244 NF prepared by the method of Example No 8.
  • Figure 9 is an illustrative X-ray powder diffraction pattern of amorphous premix of apalutamide with hydroxypropyl methylcellulose and syloid 244 prepared by the method of Example No 9.
  • Figure 1 0 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinylpyrrolidone-K90 prepared by the method of Example No 10.
  • Figure 1 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl cellulose prepared by the method of Example No 1 1 .
  • Figure 1 2 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 12.
  • Figure 1 3 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 13.
  • Figure 14 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate HP- 55 prepared by the method of Example No 14.
  • Figure 1 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with copovidone VA64NF prepared by the method of Example No 1 5.
  • Figure 1 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate HP- 55 prepared by the method of Example No 16.
  • Figure 1 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with copovidone VA64 prepared by the method of Example No 1 7.
  • Figure 1 8 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 18.
  • Figure 1 9 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 19.
  • Figure 20 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with L(+) tartaric acid prepared by the method of Example No 20.
  • Figure 21 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with citric acid prepared by the method of Example No 21 .
  • Figure 22 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with saccharin prepared by the method of Example No 22
  • Figure 23 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with sucralose prepared by the method of Example No 23
  • Figure 24 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with cellulose acetate phthalate in 1 :0.315 w/w ratio prepared by the method of Example No 24
  • Figure 25 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with cellulose acetate phthalate in 1 :3 w/w ratio prepared by the method of Example No 25
  • Figure 26 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate in 1 :0.16 w/w ratio prepared by the method of Example No 26
  • Figure 27 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate in 1 :3 w/w ratio prepared by the method of Example No 27
  • Figure 28 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with HPMC phthalate in 1 :3 w/w ratio prepared by the method of Example No 28
  • Figure 29 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with HPMC phthalate in 1 :4 w/w ratio prepared by the method of Example No 29
  • Figure 30 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with HPMC phthalate in 1 :0.6 w/w ratio prepared by the method of Example No 30
  • the present application provides an amorphous solid dispersion of apalutamide with a pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, prosolv, hydroxypropyl methylcellulose or mixtures thereof.
  • a pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, prosolv, hydroxypropyl methylcellulose or mixtures thereof.
  • the present application provides amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate, characterized by its X-ray powder diffractogram as substantially shown in Figures 4, 14,16,28,29 and 30
  • the present application provides amorphous solid dispersion of apalutamide with copovidone, characterized by its X-ray powder diffractogram as substantially shown in figures 1 , 8, 15 and 17
  • the present application provides amorphous solid dispersion of apalutamide with cellulose acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 24 and 25.
  • PXRD powder X-ray diffraction
  • the present application provides amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 26 and 27.
  • PXRD powder X-ray diffraction
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with HPMC phthalate comprising the steps of:
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with copovidone comprising the steps of:
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with cellulose acetate phthalate comprising the steps of:
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate comprising the steps of:
  • the solvent may be selected from acetone, methanol, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, ethanol, 2-propanol, 1 -butanol, 2- butanol, 1 -pentanol, 2-pentanol, 3-pentanol or mixtures thereof.
  • providing a solution at step a) may be carried out by taking the reaction mixture containing apalutamide and polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, directly or by dissolving apalutamide and polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
  • a solution of apalutamide and polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
  • a solution of apalutamide and polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate may be filtered to make it clear, free of unwanted particles.
  • the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
  • amorphous solid dispersion of Apalutamide may be carried out by any methods known in the art or procedures described in the present application.
  • amorphous solid dispersion of Apalutamide may be isolated by employing any of the techniques, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using rotavapor, spray drying, freeze drying, agitated thin film drying, melt-extrusion technique, filtration and the like.
  • the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 80°C or any other suitable temperatures.
  • Amorphous solid dispersion of apalutamide with polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate isolated at step b) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, or any other suitable temperatures.
  • the drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide, comprising the steps of:
  • the solvent at step a) of this aspect may be selected from halogenated hydrocarbons,Ci-C6 alcohols, C3-C6 ketones, Cs-Cs aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, water or mixtures thereof.
  • the solvent may be selected from the group consisting of dichloromethane, methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, water or mixtures thereof.
  • Atleast one pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), prosolv HD 40, syloid, syloid 244 NF, polyvinylpyrrolidone vinylacetate, polyvinylacetal diethylaminoacetate (AEA®), polysorbate 80, polyoxyethylene- polyoxypropylene copolymers (Poloxamer® 1 88), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 1 88, pluronic F-68,
  • providing a solution at step a) may be carried out by taking the reaction mixture containing apalutamide directly or by dissolving apalutamide and atleast one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
  • a solution of apalutamide and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
  • a solution of apalutamide and the excipient may be filtered to make it clear, free of unwanted particles.
  • the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
  • an adsorbent material such as carbon and/or hydrose, to remove colored components, etc., before filtration.
  • the isolation of amorphous solid dispersion of Apalutamide may be carried out by any methods known in the art or procedures described in the present application.
  • amorphous solid dispersion of Apalutamide may be isolated by employing any of the techniques, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using rotavapor, spray drying, freeze drying, agitated thin film drying, melt-extrusion technique, filtration and the like.
  • the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • Amorphous solid dispersion of apalutamide isolated at step b) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, or any other suitable temperatures.
  • the drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the application provides amorphous form of Apalutamide, characterized by its X-ray powder diffractogram as substantially shown in figures 1 2, 13, 1 8 and 1 9.
  • the present application provides a process for the preparation of amorphous Apalutamide, the process comprising the steps of:
  • step a) may be carried out by dissolving Apalutamide in a solvent selected from acetone, ethanol or mixtures thereof.
  • the solution may be provided by taking the reaction mixture containing Apalutamide in a solvent selected from acetone, ethanol or mixtures thereof.
  • the Apalutamide may be dissolved in a solvent selected from acetone, ethanol or mixtures thereof by heating the reaction mixture to obtain a homogenous solution.
  • the solution may be filtered to make it particle free.
  • amorphous Apalutamide may be carried out by any methods known in the art or procedures described in the present application.
  • amorphous Apalutamide may be isolated by employing any of the techniques, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using rotavapor, spray drying, freeze drying, agitated thin film drying, filtration and the like.
  • drying amorphous Apalutamide may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 30°C or above at which amorphous Apalutamide is stable and for any time period required for obtaining a desired quality, such as from about 15 minutes to 17 hours or longer.
  • the present application provides coamorphous form of apalutamide with L(+) tartaric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 20.
  • the present application provides a process for the preparation of coamorphous form of apalutamide with L(+) tartaric acid comprising the steps of:
  • the present application provides coamorphous form of apalutamide with citric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 21 .
  • the present application provides process for the preparation of coamorphous form of apalutamide with citric acid comprising the steps of:
  • the present application provides a coamorphous form of apalutamide with saccharin, characterized by its X-ray powder diffractogram as substantially shown in FIG. 22.
  • the present application provides a process for the preparation of coamorphous form of apalutamide with saccharin comprising the steps of:
  • the present application provides coamorphous form of apalutamide with sucralose, characterized by its X-ray powder diffractogram as substantially shown in FIG. 23.
  • the present application provides a process for the preparation of coamorphous form of apalutamide with sucralose comprising the steps of:
  • the solvent may be selected from methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3-pentanol, dichloromethane, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran or mixtures thereof.
  • providing a solution at step a) may be carried out by taking the reaction mixture containing apalutamide and coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose directly or by dissolving apalutamide and coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
  • a solution of apalutamide and coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
  • a solution of apalutamide and coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose may be filtered to make it clear, free of unwanted particles.
  • the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
  • the isolation of coamorphous form of apalutamide may be carried out by any methods known in the art or procedures described in the present application.
  • coamorphous form of apalutamide may be isolated by employing any of the techniques, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using rotavapor, spray drying, freeze drying, agitated thin film drying, melt-extrusion technique, filtration and the like.
  • the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 80°C, or any other suitable temperatures.
  • coamorphous form of apalutamide with coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose isolated at step b) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, or any other suitable temperatures.
  • the drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present application provides amorphous form of apalutamide or amorphous solid dispersion of apalutamide or coamorphous form of apalutamide comprising apalutamide having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
  • Starting materials used for the preparation of amorphous form of apalutamide or amorphous solid dispersion of apalutamide or coamorphous form of apalutamide may be any crystalline or amorphous in nature. Further, these starting materials may be purified according to any of the method known in the art such as recrystallization, slurrying, acid-base treatment i.e., salt making and breaking, chromatography, fractional distillation or any other separation methods, before using.
  • Apalutamide that may be used as the input for the process of the present invention may be obtained by the processes described in the art.
  • apalutamide may be prepared by the processes described in US8445507B2 and US8987452B2.
  • the present application provides a pharmaceutical composition comprising amorphous form of apalutamide or amorphous solid dispersion of apalutamide or coamorphous form of apalutamide and atleast one additional pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, coll
  • solid dispersion when used in the present application, denotes a state where most of the apalutamide, preferably 90%, 95% or all of the apalutamide of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix.
  • solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way.
  • the two components form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
  • the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer.
  • it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
  • C1 -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, 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.”
  • Cs-Csaliphatic or aromatic hydrocarbons include, but are not limited to, n-pentane, isopentane, neopentane, n- hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4- dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n- octane, iso
  • C3-C6esters include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl 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.
  • 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-C6Nitriles include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
  • Coamorphous when used in the present application, denotes “Co- amorphous mixtures consist of two (or more) types of small molecules which interact on molecular level without detectable crystallization” or "A co-amorphous system is characterized by the use of only low molecular weight components that are mixed into a homogeneous single-phase co-amorphous blend"
  • Example-1 Preparation of amorphous solid dispersion of apalutamide with copovidone VA 64
  • Apalutamide (500 mg), copovidone VA 64 (500 mg) and dichloromethane (50 imL) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 5 minutes at 25°C.
  • the reaction mass was filtered to remove any insoluble particles.
  • the reaction mass was evaporated under vacuum at 40°C for over 10 minutes.
  • Example-2 Preparation of amorphous solid dispersion of apalutamide with ethyl cellulose
  • Example-3 Preparation of amorphous solid dispersion of apalutamide with Polyvinylpyrrolidone-K90 and hydroxypropyl cellulose
  • Apalutamide (250 mg), polyvinylpyrrolidone-K90 (250 mg), hydroxypropyl cellulose (250 mg), dichloromethane (50 ml_) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 20 minutes at 35°C.
  • Methanol (5 imL) was added to the reaction mass at 25°C.
  • the reaction mass was stirred for 15 minutes at 25°C.
  • the reaction mass was filtered to remove any insoluble particles.
  • the reaction mass was evaporated under vacuum at 40°C for over 10 minutes.
  • Example-4 Preparation of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate
  • Apalutamide (500 mg), hydroxypropyl methylcellulose phthalate (500 mg), dichloromethane (50 imL) and methanol (5 imL) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 5 minutes at 25°C.
  • the reaction mass was filtered to remove any insoluble particles.
  • the reaction mass was evaporated under vacuum at 40°C for over 10 minutes.
  • Example-5 Preparation of amorphous solid dispersion of apalutamide with methyl cellulose
  • Apalutamide (500 mg), methyl cellulose (1 000 mg), dichloromethane (50 imL) and methanol (20 imL) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 60 minutes at 30°C.
  • the reaction mass was filtered to remove any insoluble particles.
  • the reaction mass was evaporated under vacuum at 50°C for over 25 minutes.
  • Example-6 Preparation of solid dispersion of apalutamide with prosolv HD 40
  • Apalutamide (200 mg), prosolv HD 40 (1 000 mg) and dichloromethane (50 imL) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 5 minutes at 25°C.
  • the reaction mass was evaporated under vacuum at 25°C for over 5 minutes.
  • Example-7 Preparation of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose
  • Apalutamide (500 mg), hydroxypropyl methylcellulose (500 mg), dichloromethane (50 imL) and methanol (5 imL) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 10 minutes at 25°C.
  • the reaction mass was filtered to remove any insoluble particles.
  • the reaction mass was evaporated under vacuum at 40°C for over 5 minutes.
  • the dried product was grinded into fine powder using mortar and pestle at 25°C.
  • Example-8 Preparation of amorphous premix of apalutamide with copovidone VA 64 and syloid 244 NF
  • Amorphous solid dispersion of apalutamide with copovidone VA 64 (800 mg), syloid 244 NF (400 mg) were charged into a mortar at 25°C.
  • the reaction mixture was physically mixed using mortar pestle for 5 minutes at 25°C.
  • Example-9 Preparation of amorphous premix of apalutamide with hydroxypropyl methylcellulose and syloid 244
  • Amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose (800 mg) and syloid 244 (400 mg) were charged into a mortar at 25°C.
  • the reaction mixture was physically mixed using mortar pestle for 5 minutes at 25°C.
  • Example-10 Preparation of amorphous solid dispersion of apalutamide with polyvinylpyrrolidone-K90
  • Apalutamide (500 mg), polyvinylpyrrolidone-K90 (500 mg), dichloromethane (100 mL) and Methanol (10 mL) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 5 minutes at 25°C.
  • the reaction mass was filtered to remove any insoluble particles.
  • the reaction mass was evaporated under vacuum at 50°C for over 10 minutes.
  • the dried product was grinded into fine powder using mortar and pestle.
  • Example-11 Preparation of amorphous solid dispersion of apalutamide with hydroxypropyl cellulose
  • Apalutamide (500 mg), hydroxypropyl cellulose (500 mg), dichloromethane (1 00 mL) and Methanol (10 mL) were charged into a round bottom flask at 25°C.
  • the reaction mass was stirred for 30 minutes at 30°C.
  • the reaction mass was filtered to remove any insoluble particles.
  • the reaction mass was evaporated under vacuum at 50°C for over 10 minutes.
  • Apalutamide (1 g) was dissolved in acetone (50 mL) at 75°C. The resulted solution was rotary evaporated under vacuum at 75°C. The solid was dried under vacuum at
  • Example-13 Preparation of amorphous form of Apalutamide
  • Apalutamide (35g) was dissolved in acetone (550 mL) at 55°C. The resulted solution was filtered under vacuum. The clear solution was subjected to spray drying under nitrogen at a feed solution RPM of 80 or 5g/min and feed solution temperature was 30°C. The inlet temperature was kept at 80°C and the outlet temperature was kept at 40°C. The product was dried under VTD at 40°C for 17 hours to obtain the title compound. Yield: 21 .0g
  • Example-14 Preparation of amorphous solid dispersion of Apalutamide with hydroxypropyl methylcellulose phthalate HP-55
  • Example-15 Preparation of amorphous solid dispersion of Apalutamide with copovidone VA64NF
  • Example-16 Preparation of amorphous solid dispersion of Apalutamide with hydroxypropyl methylcellulose phthalate HP-55
  • Example-17 Preparation of amorphous solid dispersion of Apalutamide with copovidone VA64
  • Apalutamide (18g), copovidone VA64 (18g) and methanol (500 mL) were charged into a round bottom flask at 25°C.
  • the reaction mixture was stirred for 15 minutes at 65°C.
  • the resulted solution was filtered under vacuum.
  • the clear solution was subjected to spray drying under nitrogen at a feed solution RPM of 80 or 5g/min.
  • the inlet temperature was kept at 90°C and the outlet temperature was kept at 42°C.
  • the product was dried under VTD at 60°C for 3 hours to obtain the title compound. Yield: 21 .7g
  • Apalutamide (0.5g) was dissolved in mixture of dichloromethane (9.5ml_) and ethanol (0.5ml_) at 40°C. The resulted solution was rotary evaporated under vacuum at 55°C to obtain the title compound. Yield: 0.41 g
  • Example-20 Preparation of coamorphous form of apalutamide with L(+) Tartaric acid.
  • Example-21 Preparation of coamorphous form of apalutamide with citric acid.
  • Apalutamide (0.8 g) and citric acid (0.322 g) were dissolved in methanol (50ml_) at 27°C.
  • the reaction mass was heated to 65°C.
  • the resulted solution was evaporated under vacuum at 65°C to obtain the title compound.
  • Example-22 Preparation of coamorphous form of apalutamide with saccharin.
  • Apalutamide (0.8 g) and saccharin (0.307 g) were dissolved in methanol (50ml_) at 26°C.
  • the reaction mass was heated to 66°C.
  • the resulted solution was evaporated under vacuum at 66°C, the isolated solid was further dried at 65°C for about 30 minutes to obtain the title compound.
  • Example-23 Preparation of coamorphous form of apalutamide with sucralose.
  • Apalutamide (0.8 g) and sucralose (0.667 g) were dissolved in methanol (50ml_) at 26°C.
  • the reaction mass was heated to 66°C.
  • the resulted solution was evaporated under vacuum at 67°C and the isolated solid was further dried at 65°C for about 1 .5 hours to obtain the title compound.
  • Example-24 Preparation of amorphous solid dispersion of apalutamide with cellulose acetate phthalate.
  • Apalutamide (0.5g) and cellulose acetate phthalate (0.158g) were dissolved in acetone (50ml_) at 65°C.
  • the clear solution was completely evaporated under vacuum at 65°C, the isolated solid was further dried at 65°C for about 30 minutes to obtain the title compound.
  • Example-25 Preparation of amorphous solid dispersion of apalutamide with cellulose acetate phthalate.
  • Apalutamide (0.25g) and celluloase acetate phthalate (0.75g) were dissolved in acetone (50ml_) at 65°C.
  • the clear solution was completely evaporated under vacuum at 65°C, the isolated solid was further dried at 65°C for about 45 minutes to obtain the title compound.
  • Example-26 Preparation of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate.
  • Apalutamide (0.5g) and polyvinyl acetate phthalate (0.08g) were dissolved in methanol (50ml_) at 65°C. The clear solution was completely evaporated under vacuum at 65°C to obtain the title compound.
  • Example-27 Preparation of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate.
  • Apalutamide (0.25g) and polyvinyl acetate phthalate (0.75g) were dissolved in methanol (50ml_) at 65°C. The clear solution was completely evaporated under vacuum at 66°C to obtain the title compound.
  • Example-28 Preparation of amorphous solid dispersion of apalutamide with HPMC phthalate.
  • Apalutamide (0.25g) and HPMC phthalate (0.75g) were dissolved in methanol (40ml_) and dichloromethane (10ml_) at 25°C. The reaction mass was heated to 65°C. The resulted solution was completely evaporated under vacuum at 66°C, the isolated solid was further dried at 65°C for about 40 minutes to obtain the title compound.
  • Example-29 Preparation of amorphous solid dispersion of apalutamide with HPMC phthalate.
  • Apalutamide (0.25g) and HPMC phthalate (1 g) were dissolved in methanol (40ml_) and dichloromethane (10ml_) at 26°C. The reaction mass was heated to 65°C. The resulted solution was completely evaporated under vacuum at 65°C to obtain the title compound.
  • Example-30 Preparation of amorphous solid dispersion of apalutamide with HPMC phthalate.
  • Apalutamide (0.5g) and HPMC phthalate (0.3g) were dissolved in methanol (40ml_) and dichloromethane (10ml_) at 25°C. The reaction mass was heated to 66°C. The resulted solution was completely evaporated under vacuum at 66°C, the isolated solid was further dried at 65°C for about 30 minutes to obtain the title compound.

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Abstract

Des aspects de la présente invention concernent des dispersions solides amorphes d'apalutamide comportant un excipient pharmaceutiquement acceptable choisi parmi le phtalate d'hydroxypropylméthylcellulose, la copovidone, le phtalate d'acétate de cellulose, le phtalate d'acétate de polyvinyle, l'éthylcellulose, l'hydroxypropylcellulose, la méthylcellulose, l'hydroxypropylméthylcellulose ou des mélanges correspondants, des formes co-amorphes d'apalutamide, un procédé de préparation de la forme amorphe d'apalutamide et des compositions pharmaceutiques correspondantes.
PCT/IB2018/055371 2017-07-20 2018-07-19 Dispersions solides amorphes d'apalutamide et leur procédé de préparation WO2019016747A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201900003839A1 (it) 2019-03-15 2020-09-15 Olon Spa Sintesi di apalutamide amorfa stabile
EP3811932A1 (fr) 2019-10-22 2021-04-28 Zentiva K.S. Forme posologique d'apalutamide
WO2023084545A1 (fr) * 2021-11-15 2023-05-19 Amerise Pharmaceuticals Pvt Ltd. Composition pharmaceutique stable d'antiandrogènes non stéroïdiens

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140100256A1 (en) * 2012-09-11 2014-04-10 Bend Research Formulations of enzalutamide
WO2015118015A1 (fr) * 2014-02-05 2015-08-13 Lek Pharmaceuticals D.D. Compositions pharmaceutiques solides d'antagonistes du récepteur des androgènes
WO2016192680A1 (fr) * 2015-06-03 2016-12-08 Triastek, Inc. Formes galéniques et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140100256A1 (en) * 2012-09-11 2014-04-10 Bend Research Formulations of enzalutamide
WO2015118015A1 (fr) * 2014-02-05 2015-08-13 Lek Pharmaceuticals D.D. Compositions pharmaceutiques solides d'antagonistes du récepteur des androgènes
WO2016192680A1 (fr) * 2015-06-03 2016-12-08 Triastek, Inc. Formes galéniques et leur utilisation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201900003839A1 (it) 2019-03-15 2020-09-15 Olon Spa Sintesi di apalutamide amorfa stabile
WO2020188399A1 (fr) * 2019-03-15 2020-09-24 Olon S.P.A. Synthèse d'apalutamide amorphe stable
EP3811932A1 (fr) 2019-10-22 2021-04-28 Zentiva K.S. Forme posologique d'apalutamide
WO2023084545A1 (fr) * 2021-11-15 2023-05-19 Amerise Pharmaceuticals Pvt Ltd. Composition pharmaceutique stable d'antiandrogènes non stéroïdiens

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