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WO2019102492A1 - Polymorphes cristallins d'abémaciclib - Google Patents

Polymorphes cristallins d'abémaciclib Download PDF

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Publication number
WO2019102492A1
WO2019102492A1 PCT/IN2018/050775 IN2018050775W WO2019102492A1 WO 2019102492 A1 WO2019102492 A1 WO 2019102492A1 IN 2018050775 W IN2018050775 W IN 2018050775W WO 2019102492 A1 WO2019102492 A1 WO 2019102492A1
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WIPO (PCT)
Prior art keywords
solvent
abemaciclib
mixtures
process according
group
Prior art date
Application number
PCT/IN2018/050775
Other languages
English (en)
Inventor
Ramakoteswara Rao Jetti
Anjaneyaraju Indukuri
Aggi Ramireddy Bommareddy
Attanti Veera Venkata SRINIVASARAO
Rathinapandian JEBARAJ
Shivakumar CHANDUPATLA
Ramesh BATHARAJU
Sunil Kunamneni
Original Assignee
Mylan Laboratories Limited
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Filing date
Publication date
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Publication of WO2019102492A1 publication Critical patent/WO2019102492A1/fr

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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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure generally relates to the field of pharmaceutical sciences and more specifically relates to novel polymorphic forms of abemaciclib.
  • the present disclosure provides polymorphic forms of abemaciclib designated as crystalline form-Ml, form-M2, form-M3, form- M4, form-M5, and provides an amorphous solid dispersion of abemaciclib with pharmaceutically acceptable excipients.
  • the disclosure further provides processes for the preparation thereof.
  • the present disclosure also provides processes for the preparation of form-I of abemaciclib and amorphous abemaciclib.
  • the present disclosure further provides a process for the preparation of abemaciclib.
  • Abemaciclib chemically known as N- [5- [(4-ethyl- l-piperazinyl)methyl]-2-pyridinyl] -5-fluoro-4- [4-fluoro-2-methyl- 1 -( 1 -methylethyl)- 1 H-benzimidazol-6-yl] -2-pyrimidinamine, has the structure shown in Formula-I.
  • Abemaciclib is a kinase inhibitor, marketed in the U.S. under the tradename VERZENIOTM by Lilly USA, and is indicated for use in combination with fulvestrant for treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • Abemaciclib also is indicated for use as a monotherapy for the treatment of adult patients with HR positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
  • U.S. Patent No. 7,855,211 discloses abemaciclib and its pharmaceutically acceptable salts, and discloses abemaciclib crystalline form I, crystalline form III, amorphous abemaciclib, and processes for the preparation thereof.
  • Chinese patent application CN106008468 discloses abemaciclib crystalline form-A, form-B, form-C, and processes for the preparation thereof.
  • PCT patent publication WO 2017108781 discloses abemaciclib crystalline form- IV and process for the preparation thereof.
  • the present disclosure provides polymorphic forms of abemaciclib and processes for the preparation thereof.
  • the present disclosure also provides processes for the preparation of abemaciclib crystalline form I and amorphous abemaciclib.
  • the present invention provides crystalline form-Ml of abemaciclib.
  • crystalline form-Ml of abemaciclib may be characterized by a powder X-ray diffraction pattern having significant peaks at 5.0, 5.6, 11.2, 12.6, 15.8, 18.4, 19.0, and 25.4 ( ⁇ ) 0.2 °2Q.
  • the present invention provides crystalline form-M2 of abemaciclib.
  • crystalline form-M2 of abemaciclib may be characterized by a powder X-ray diffraction pattern having significant peaks at 4.9, 5.9, 9.0, 11.1, 11.9, 5.5, and 26.4 ( ⁇ ) 0.2 °2Q.
  • the present invention provides crystalline form-M3 of abemaciclib.
  • crystalline form-M3 of abemaciclib may be characterized by a powder X-ray diffraction pattern having significant peaks at 5.0, 5.5, 7.0, 11.3, 12.6, and 16.3 ( ⁇ ) 0.2 °2Q.
  • the present invention provides crystalline form-M4 of abemaciclib.
  • crystalline form-M4 of abemaciclib may be characterized by a powder X-ray diffraction pattern having significant peaks at 5.1, 7.1, 11.3, 11.9, 16.2, 20.8, and 26.2 ( ⁇ ) 0.2 °2Q.
  • the present invention provides crystalline form-M5 of abemaciclib.
  • the present invention provides an amorphous solid dispersion of abemaciclib.
  • the present invention provides a process for the preparation of crystalline form- Ml of abemaciclib that includes the steps of: a) providing abemaciclib in anisole solvent;
  • the present invention provides a process for the preparation of crystalline form- Ml of abemaciclib that includes the steps of: a) dissolving abemaciclib in anisole and methanol solvent mixture;
  • the present invention provides a process for the preparation of crystalline form- Ml of abemaciclib that includes the steps of: a) dissolving abemaciclib in anisole solvent;
  • the present invention provides a process for the preparation of crystalline form- M2 of abemaciclib that includes the steps of: a) drying crystalline form-Ml, form-M3, or form-M4 of abemaciclib; and
  • the present invention provides a process for the preparation of crystalline form- M3 of abemaciclib comprising the steps of: a) dissolving abemaciclib in a polar solvent; b) adding the above solution to a hydrocarbon solvent;
  • the present invention provides a process for the preparation of crystalline form- M3 of abemaciclib that includes the steps of: a) dissolving abemaciclib in a first solvent;
  • the present invention provides a process for the preparation of crystalline form- M3 of abemaciclib that includes the steps of: a) dissolving abemaciclib in a solvent;
  • the present invention provides a process for the preparation of crystalline form- M4 of abemaciclib that includes the steps of: a) dissolving abemaciclib in a polar solvent;
  • the present invention provides a process for the preparation of crystalline form- M5 of abemaciclib that includes the steps of: a) dissolving abemaciclib in a polar solvents;
  • the present invention provides a process for the preparation of crystalline form- M5 of abemaciclib that includes the steps of: a) dissolving abemaciclib in a polar solvent; b) adding the above solution to a non-polar solvent;
  • the present invention provides a process for the preparation of crystalline form- M5 of abemaciclib that includes the steps of: a) dissolving abemaciclib in a polar solvent;
  • the present invention provides a process for the preparation of crystalline form- M5 of abemaciclib that includes the steps of: a) dissolving abemaciclib in a solvent;
  • the present invention provides a process for the preparation of amorphous abemaciclib that includes the steps of: a) dissolving abemaciclib in a solvent; and
  • the present invention provides a process for the preparation of an amorphous solid dispersion of abemaciclib comprising the steps of: a) dissolving abemaciclib and a pharmaceutical excipient in a polar solvent; and
  • the present invention provides a process for the preparation of crystalline form- I of abemaciclib that includes the steps of: a) dissolving abemaciclib in ketone solvent; and
  • the present invention provides a process for the preparation of abemaciclib of formula (I) that includes reacting 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l -isopropyl-2- methyl- lH-benzoimidazole of formula (II) with 5-(4-ethyl-piperazin-lylmethyl)-pyridin-2- ylamine of formula (III) in the presence of palladium acetate to produce abemaciclib of formula (I)
  • the present invention provides a process for the preparation of abemaciclib intermediate 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro- 1 -isopropyl-2-methyl- 1H- benzoimidazole of formula (II) that includes the steps of: a) reacting 4-bromo-2,6-difluoro-phenylamine of formula (IV) with N-isopropyl acetamide of formula (V) in the presence of dehydrating agent and a first base in a first solvent to produce N-(4-bromo-2,6-difluoro-phenyl)-N'-isopropyl-acetamidine of formula (VI)
  • Formula (IV) Formula (V) Formula (VI) b) reacting the compound of formula (VI) with a second base in a second solvent without isolating to get 6-bromo-4-fluoro- 1 -isoprop yl-2-methyl-lH-benzoimidazole of formula
  • Formula (VI) Formula (VII) c) reacting the compound of formula (VII) with bis(pinacolato)diborane, triphenyl phosphine, in presence of a first palladium catalyst in a third solvent to produce the compound of formula (VIII)
  • Formula (VII) Formula (VIII) d) reacting the compound of formula (VIII) with 2,4-dichloro-5-fluoro pyrimidine of formula (IX) in the presence of a third base, a second palladium catalyst, and a fourth solvent to produce 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl- lH-benzoimidazole of formula (II)
  • Figure 1 shows a powder X-ray diffraction pattern of crystalline form-Ml of abemaciclib
  • Figure 2 shows a powder X-ray diffraction pattern of crystalline form-M2 of abemaciclib
  • Figure 3 shows a powder X-ray diffraction pattern of crystalline form-M3 of abemaciclib
  • Figure 4 shows a powder X-ray diffraction pattern of crystalline form-M4 of abemaciclib
  • Figure 5 shows a powder X-ray diffraction pattern of crystalline form-M5 of abemaciclib
  • Figure 6 shows a powder X-ray diffraction pattern of amorphous abemaciclib
  • Figure 7 shows a powder X-ray diffraction pattern of an amorphous solid dispersion of abemaciclib with a 60:40 linear random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (PLASDONE ® S-630, 50% w/w);
  • Figure 8 shows a powder X-ray diffraction pattern of an amorphous solid dispersion of abemaciclib with colloidal silicon dioxide (AERO PERL ® 300, 50% w/w);
  • Figure 9 shows a powder X-ray diffraction pattern of an amorphous solid dispersion of abemaciclib with microcrystalline cellulose grade 101 (AVICEL® PH 101, 50% w/w); and
  • Figure 10 shows a powder X-ray diffraction pattern of an amorphous solid dispersion of abemaciclib with microcrystalline cellulose grade 102 (AVICEL® PH 102, 50% w/w).
  • the present disclosure provides novel polymorphic forms of abemaciclib, designated as crystalline form-Ml, form- M2, form-M3, form-M4, and form-M5 as well as amorphous solid dispersions of abemaciclib.
  • the present disclosure also provides processes for the preparation of the same.
  • the present invention also provides methods for the preparation of crystalline form I of abemaciclib and amorphous abemaciclib.
  • the crystalline abemaciclib polymorphic forms and dispersions disclosed herein were characterized by powder X-ray diffraction (PXRD) measured on a BROKER D-8 Discover powder diffractometer equipped with a goniometer of Q/2Q configuration and Lynx Eye detector.
  • the Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size, and 0.4 seconds step time.
  • the present invention provides crystalline form-Ml of abemaciclib.
  • crystalline form-Ml of abemaciclib base may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.0, 5.6, 11.2, 12.6, 15.8, 18.4, 19.0, and 25.4 ( ⁇ ) 0.2 ° .
  • crystalline form-Ml of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.0, 5.6, 6.4, 8.4, 9.8, 11.2, 12.6, 13.6, 14.1, 14.7, 15.1, 15.8, 16.9, 17.4, 18.4, 19.0, 19.7, 20.2, 20.8, 22.1, 22.9, 23.6, 24.1, 24.7, 25.4, 26.4, 27.0, and 29.0 ( ⁇ ) 0.2 °.
  • crystalline form-Ml of abemaciclib may be characterized by the PXRD pattern in Figure 1.
  • the present invention provides a process for the preparation of crystalline form- Ml of abemaciclib.
  • abemaciclib may be prepared by a process that includes the steps of: a) dissolving or suspending abemaciclib in anisole; and
  • abemaciclib may be dissolved or suspended in anisole.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • dissolution of abemaciclib in anisole may be facilitated by heating the mixture, for example, to a temperature of about 40 °C to about reflux. In some embodiments, heating to a temperature of about 50 °C to about 80 °C was found to be particularly useful for dissolving abemaciclib in anisole.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may be cooled to precipitate form-Ml of abemaciclib.
  • the solution is cooled to 20 °C to 30 °C and the mixture is stirred for about 1 hour to about 3 hours.
  • amorphous abemaciclib may be suspended in anisole to form a suspension.
  • the suspension may be stirred for about 2 hours to about 4 hours at a temperature of about 20 °C to about 30 °C.
  • Crystalline form-Ml of abemaciclib may then be isolated from the mixture of abemaciclib in anisole. Isolation may be carried out by methods well known in the art, for example, by filtration. The solid may be further dried, if necessary, at a temperature of about 50 °C to about 55 °C to remove residual solvent.
  • crystalline form-Ml of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a mixture of anisole and methanol;
  • abemaciclib may be dissolved in a mixture of methanol and anisole.
  • the mixture may be about 1:9 methanol to anisole.
  • Dissolution may be carried out at a temperature of about 25 °C to 30 °C.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • solvent may be removed to concentrate the solution. This may be carried out by methods well known in the art, such as distillation.
  • a hydrocarbon solvent may be added to the reaction mass.
  • suitable hydrocarbon solvents include but are not limited to toluene, n-heptane, n-hexane, and mixtures thereof. This may be carried out at a temperature of about 25 °C to 30 °C.
  • the mixture may be stirred to facilitate precipitation of crystalline form-Ml of abemaciclib. In some embodiments, the mixture is stirred for about 1 hour to about 3 hours.
  • Crystalline form-Ml of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration. The solid may be further dried, if necessary, at a temperature of about 50 °C to about 55 °C to remove residual solvent.
  • crystalline form-Ml of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in anisole;
  • abemaciclib may be dissolved in anisole. Dissolution of abemaciclib may be facilitated by heating the mixture, for example, to a temperature of about 40 °C to about reflux. In some embodiments the mixture is heated to a temperature of about 50 °C to about 80 °C.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • the abemaciclib solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may then be cooled, for example, to a temperature of about 20 °C to 30 °C.
  • a hydrocarbon solvent may then be added to the reaction mixture.
  • suitable hydrocarbon solvents include, but are not limited to, toluene, n-heptane, n- hexane, and mixtures thereof. This may be carried out at a temperature of about 25 °C to about 30 °C.
  • the mixture may be stirred to facilitate formation of a solid which is identifiable as form-Ml of abemaciclib.
  • the mixture is stirred for about 1 hour to about 3 hours.
  • Crystalline form-Ml of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, filtration. The solid may be further dried, if necessary, at a temperature of about 50 °C to about 55 °C to remove residual solvent. In another aspect, the present invention provides crystalline form- M2 of abemaciclib.
  • crystalline form-M2 of abemaciclib base may be characterized by a PXRD pattern having significant peaks at 2Q angles of 4.9, 5.9, 9.0, 11.1, 11.9, 25.5, and 26.4 ( ⁇ ) 0.2 °.
  • crystalline form-M2 of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 4.9, 5.9, 9.0, 9.8, 11.1, 11.9, 12.3, 13.3, 14.1, 15.1, 15.6, 15.9, 16.7, 18.0, 18.5, 19.0, 19.6, 20.2, 20.5, 21.4, 22.0, 22.6, 23.2, 23.6, 24.7, 25.5 26.4, 28.5, 29.1, and 30.2 ( ⁇ ) 0.2 °.
  • crystalline form-M2 of abemaciclib may be characterized by the PXRD pattern in Figure 2.
  • the present invention provides a process for the preparation of crystalline form- M2 of abemaciclib.
  • crystalline form- M2 of abemaciclib may be prepared by a process that includes the step of drying crystalline form-Ml of abemaciclib, form-M3 of abemaciclib, or form-M4 of abemaciclib. Drying may be carried out by methods well known in the art, for example, drying under vacuum. Drying may be carried out at a temperature of about 100 °C to about 180 °C for about 10 hours to about 15 hours. In particularly useful embodiments, drying may be carried out at a temperature of about 140 °C to about 180 °C for about 30 minutes to about 60 minutes.
  • crystalline form-M2 of abemaciclib may be prepared by a process that includes the step of vacuum drying form-Ml of abemaciclib, form-M3 of abemaciclib, or form- M4 of abemaciclib at a temperature of about 80 °C to about 120 °C for about 12 hours to about 16 hours.
  • the present invention provides crystalline form-M3 of abemaciclib.
  • crystalline form-M3 of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.0, 5.5, 7.0, 11.3, 12.6, and 16.3 ( ⁇ ) 0.2 °.
  • crystalline form-M3 of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.0, 5.5, 7.0, 10.1, 11.3, 12.6, 13.9, 14.7, 15.3, 16.3, 18.6, 19.3, 20.3, 20.9, 22.0, 22.8, 24.2, 24.7, 26.4, 27.9, 29.0, 30.3, 32.9, and 36.9 ( ⁇ ) 0.2 °.
  • crystalline form-M3 of abemaciclib may be characterized by the PXRD pattern in Figure 3.
  • crystalline form-M3 is a hydrated form of abemaciclib.
  • the present invention provides a process for the preparation of crystalline form- M3 of abemaciclib.
  • crystalline form-M3 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent to form a solution; b) adding the solution to a hydrocarbon solvent to form a second solution;
  • abemaciclib may be dissolved in a polar solvent.
  • the polar solvent may be, for example, an alcohol solvent, an ester solvent, or mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, 1 -propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2- pentanol, or mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • abemaciclib is dissolved in a mixture of ethyl acetate and methanol.
  • Heating may facilitate dissolution.
  • the mixture is heated to a temperature of about 40 °C to about reflux.
  • the mixture is heated to a temperature of about 50 °C to about 80 °C.
  • the abemaciclib solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may then be cooled, for example, to a temperature of about 20 °C to about 30 °C.
  • the solution may be added to a hydrocarbon solvent.
  • a hydrocarbon solvent include, but are not limited to, toluene, n-heptane, n-hexane, cyclohexane, methyl cyclohexane, and mixtures thereof.
  • the hydrocarbon solvent is n-heptane.
  • the solution may be then added to a mixture of seeds of crystalline form-M3 of abemaciclib in a third solvent at a temperature of about 25 °C to about 30 °C.
  • the third solvent may be a hydrocarbon solvent, for example, toluene, n-heptane, n-hexane, cyclohexane, methyl cyclohexane, or mixtures thereof.
  • the second and third solvents may be same or may be different.
  • the reaction mixture may be stirred, for example, for about 1 hour to about 3 hours to facilitate precipitation of a solid identifiable as crystalline form-M3 of abemaciclib.
  • Crystalline form-M3 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration. The obtained solid may be dried, for example, under vacuum at 100 °C, for 2 hours.
  • crystalline form-M3 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a first solvent to form a first solution;
  • abemaciclib may be dissolved in a first solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • the first solvent may be a polar solvent.
  • suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, 1- propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, 1- pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • abemaciclib is dissolved in methanol.
  • the first solution may be heated, for example, to a temperature of about 40 °C to about reflux. In some embodiments, the first solution is heated to a temperature of about 50 °C to about 70 °C.
  • the first solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may then be concentrated. This may be carried out by methods well known in the art, for example, by distillation. In particularly useful embodiments, the solution is concentrated by distilling at atmospheric pressure or under vacuum at a temperature of about 25 °C to about 35
  • seeds of crystalline form-M3 of abemaciclib may then be added at the same temperature.
  • the solution may be stirred for about 5 minutes to about 10 minutes to facilitate the addition of seeds.
  • a second solvent may be added to form a second solution.
  • the second solvent may be a polar solvent, a non-polar solvent, or a mixture thereof.
  • suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, 1 -propanol, isopropanol, 1- butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • suitable non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof.
  • ether solvents include, but are not limited to, anisole, isopropyl ether, l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert- butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents include, but are not limited to, toluene, hexane, n-heptane, and mixtures thereof.
  • the second solvent can be the same or different from the first solvent. In particularly useful embodiments, a mixture of ethyl acetate and n-heptane is used as a second solvent.
  • the resulting second solution may be stirred to facilitate formation of solid crystalline form-M3 of abemaciclib.
  • the solution may be stirred for about 1 hour to about 24 hours.
  • Crystalline form-M3 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration.
  • the collected solid may then be dried under vacuum at 50 °C for about 15 to about 24 hours.
  • crystalline form-M3 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a solvent;
  • abemaciclib may be dissolved in a solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • the solvent may be a polar solvent, a non-polar solvent, or a mixture thereof. Examples of suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, 1 -propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof.
  • ether solvents include, but are not limited to, anisole, isopropyl ether, l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents include, but are not limited to, toluene, hexane, n-heptane, and mixtures thereof. In particularly useful embodiments, a mixture of ethyl acetate and n-heptane is used as a solvent.
  • seeds of form-M3 may be added to the solution at temperature of 25 °C to 35 °C.
  • the solution may be stirred for up to about 1 hour to about 24 hours to facilitate precipitation of solid crystalline form-M3 of abemaciclib.
  • Crystalline form-M3 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration. The collected solid may then be dried under vacuum at 50 °C for about 15 to about 24 hours.
  • the present invention provides crystalline form-M4 of abemaciclib.
  • crystalline form-M4 of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.1, 7.1, 11.3, 11.9, 16.2, 20.8, and 26.2 ( ⁇ ) 0.2 °.
  • crystalline form-M4 of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 5.1, 5.6, 7.1, 8.7, 9.3, 10.3, 11.3, 11.9, 12.2, 12.7, 13.0, 13.4, 14.0, 14.4, 15.1, 15.8, 16.2, 16.7, 17.5, 18.2, 18.6, 19.4, 19.9, 20.3, 20.8, 21.4, 21.8, 22.6, 23.0, 23.8, 24.3, 24.7, 25.5, 26.2, 27.3, 27.9, and 28.3( ⁇ ) 0.2 °.
  • crystalline form-M4 of abemaciclib may be characterized by the PXRD pattern in Figure 4. It is believed that crystalline form-M4 of abemaciclib is a methanol solvate of abemaciclib.
  • the present invention provides a process for the preparation of crystalline form- M4 of abemaciclib.
  • crystalline form-M4 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent;
  • abemaciclib may be dissolved in a polar solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • abemaciclib is dissolved in methanol.
  • Dissolution may be facilitated by heating, for example, heating to a temperature of about 40 °C to about reflux. In some embodiments, the solution is heated to a temperature of about 50 °C to about 80 °C.
  • the solution may then be cooled.
  • the solution may be cooled to a temperature of about -20 °C to about -5 °C.
  • the solution may be stirred for about 10 to 30 minutes.
  • an ether solvent may be added. This may be carried out at a temperature of about -10 °C to about -15 °C over a period of about 10 to 15 minutes.
  • ether solvents include, but are not limited to, l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • methyl tert- butyl ether is used.
  • the solution may be stirred to facilitate precipitation of solid form-M4 of abemaciclib. For example, in some embodiments, the solution is stirred for about 1-3 hours. Crystalline form-M4 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration. The solid may be further dried, if necessary, to remove residual solvent.
  • the present invention provides crystalline form-M5 of abemaciclib.
  • crystalline form-M5 of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 4.9, 13.8, 18.5, 21.9, 24.3, 25.1, and 25.9 ( ⁇ ) 0.2
  • crystalline form-M5 of abemaciclib may be characterized by a PXRD pattern having significant peaks at 2Q angles of 4.9, 6.8, 7.9, 10.0, 10.6, 11.6, 13.8, 14.5, 16.1, 17.5, 18.5, 19.8, 20.3, 21.9, 23.7, 24.3, 25.1, 25.9, 29.2, 30.2, 32.5, 34.0, and 35.4 ( ⁇ ) 0.2 °.
  • crystalline form-M5 of abemaciclib may be characterized by the PXRD pattern in Figure 5.
  • the present invention provides a process for the preparation of crystalline form- M5 of abemaciclib.
  • crystalline form-M5 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent;
  • abemaciclib may be dissolved in a polar solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • abemaciclib is dissolved in a mixture of ethyl acetate and methanol.
  • Heating may facilitate dissolution.
  • the mixture is heated to a temperature of about 40 °C to about reflux.
  • the mixture is heated to a temperature of about 50 °C to about 80 °C.
  • the abemaciclib solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may then be cooled, for example, to a temperature of about 20 °C to about 30 °C.
  • the solution may be added to a hydrocarbon solvent.
  • a hydrocarbon solvent This may be carried out slowly, for example, dropwise, at a temperature of about 0 °C to about 5 °C.
  • hydrocarbon solvents include, but are not limited to, toluene, n-heptane, n-hexane, and mixtures thereof.
  • the hydrocarbon solvent is n-heptane.
  • the solution may be added to a mixture of seeds of crystalline form-M5 of abemaciclib in a solvent at the same temperature of about 0 °C to about 5 °C.
  • the solvent may be a hydrocarbon solvent., for example, toluene, n-heptane, n-hexane, and mixtures thereof.
  • the reaction mixture may be stirred, for example, for about 1 hour to about 3 hours to facilitate precipitation of a solid identifiable as crystalline form-M5 of abemaciclib.
  • Crystalline form-M5 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration. The obtained solid may be dried, for example, under vacuum at about 30 °C to about 35 °C, for about 12 hours to about 16 hours.
  • crystalline form-M5 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent to form a solution;
  • abemaciclib may be dissolved in a polar solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • abemaciclib is dissolved in methanol. Dissolution may be facilitated by heating, for example, to temperature of about 40 °C to about reflux. In some embodiments, the solution is heated to a temperature of about 50 °C to about 70 °C.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may be cooled to about 20 °C to about 30 °C.
  • the solution may be added to a non-polar solvent. This may be carried out slowly, for example, dropwise, at a temperature of about 25 °C to 30 °C.
  • the non-polar solvent may contain seeds of crystalline form-M5 of abemaciclib.
  • non-polar solvents examples include ether solvents, hydrocarbon solvents, and mixtures thereof.
  • ether solvents include, but are not limited to, anisole, isopropyl ether, l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert- butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents include, but are not limited to, toluene, hexane, n-heptane, and mixtures thereof.
  • the non-polar solvent is methyl tert-butyl ether.
  • the solution may be stirred for about 1 hour to about 15 hours to facilitate formation of solid crystalline form-M5 of abemaciclib.
  • Crystalline form-M5 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration. The solid may be dried, for example, under vacuum at about 30 °C to about 35 °C for about 15 to about 20 hours.
  • crystalline form-M5 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent;
  • abemaciclib may be dissolved in a polar solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • abemaciclib is dissolved in methanol. Dissolution may be facilitated by heating, for example, to a temperature of about 40 °C to about reflux. In some embodiments, the solution is heated to a temperature of about 50 °C to about 70 °C.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may be cooled to about 20 °C to about 30 °C.
  • a non-polar solvent may then be added at a temperature of about 25 °C to 30 °C.
  • the non-polar solvent may contain seeds of crystalline form-M5 of abemaciclib.
  • suitable non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof.
  • ether solvents include, but are not limited to, anisole, isopropyl ether, l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents include, but are not limited to, toluene, hexane, n-heptane, and mixtures thereof.
  • the non-polar solvent is methyl tert-butyl ether.
  • the resulting solution may be stirred for about 1 hour to about 15 hours, to facilitate precipitation of a solid that is form-M5 of abemaciclib.
  • Crystalline form-M5 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration. The obtained solid may be dried, for example, under vacuum at about 30 °C to about 35 °C, for about 15 hours to about 20 hours.
  • crystalline form-M5 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a solvent,
  • abemaciclib may be dissolved in a solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • the solvent may be a polar solvent, a non-polar solvent, or a mixture thereof. Examples of suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, 1 -propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and mixtures thereof.
  • non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof.
  • ether solvents include, but are not limited to, anisole, isopropyl ether, l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents include, but are not limited to, toluene, hexane, n-heptane, and mixtures thereof. In particularly useful embodiments, a mixture of methyl tert-butyl ether and methanol is used as a solvent.
  • Dissolution may be facilitated by heating, for example, to a temperature of about 40 °C to about reflux. In some embodiments, the solution is heated to a temperature of about 50 °C to about 70 °C.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may be cooled to about 20 °C to about 30 °C.
  • seeds of crystalline form-M5 of abemaciclib may be added at a temperature of about 25 °C to about 30 °C.
  • the solution may be stirred for about 1 hour to about 15 hours to facilitate formation of solid crystalline form-M5 of abemaciclib. Crystalline form-M5 of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration.
  • the obtained solid may be dried, for example, under vacuum at about 30 °C to about 35 °C, for about 15 hours to about 20 hours.
  • the present invention provides an amorphous form of abemaciclib.
  • amorphous abemaciclib may be characterized as amorphous by the PXRD pattern in Figure 6.
  • amorphous abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a solvent; and
  • abemaciclib may be dissolved in a solvent.
  • the abemaciclib starting material may be of a variety of different forms, for example, any crystalline form, an amorphous form, or any solvated form.
  • abemaciclib starting material may be any polymorphic form.
  • the solvent may be, for example, an alcohol solvent, a ketone solvent, a halogenated solvent, or any mixture thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • chlorinated solvent examples include, but are not limited to, dichloromethane, l,l-dichloroethane, l,2-dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
  • abemaciclib is dissolved in methanol or dichloromethane at a temperature of about 25 °C to about 40 °C.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • solvent may be removed to isolate amorphous abemaciclib.
  • This may be carried out by well-known techniques, for example, evaporation, distillation, spray drying, lyophilization, agitated thin film drying, or combinations thereof.
  • spray drying or distillation is used to remove the solvent.
  • the polymorphs of abemaciclib disclosed herein exhibit physical stability.
  • the physical stability of each polymorph, including amorphous abemaciclib, crystalline form-M2, form-M3, and form-M5 samples were assessed by storing samples of each polymorph at 40 °C/75% relative humidity (RH) and at 25 °C/60% relative humidity (RH) conditions for 6 months. The samples were analyzed by PXRD for polymorphic purity after storage.
  • Amorphous abemaciclib also exhibited no change in PXRD pattern when stored for 6 months at 25 °C/60% relative humidity (RH) conditions. This data is tabulated below in Table 1.
  • the present invention provides solid dispersions of abemaciclib with pharmaceutically acceptable excipients.
  • the solid dispersion may be prepared with amorphous, crystalline, or any solvate of abemaciclib and one or more pharmaceutically acceptable excipients.
  • the present invention provides methods for preparing solid dispersions of abemaciclib with a pharmaceutically acceptable excipient.
  • an amorphous solid dispersion of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib and a pharmaceutical excipient in a solvent; and
  • abemaciclib and a pharmaceutical excipient may be first dissolved in a solvent.
  • abemaciclib starting material may be of a variety of different forms, for example, any polymorph or any solvated form.
  • solvent may be, for example, an alcohol solvent, a ketone solvent, and ether solvent, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, l-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • Suitable pharmaceutical excipients include polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, silicon dioxide (e.g., AEROPERL ® 300 sold by Evonik), polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., those sold under the PLASDONE ® tradename), Ci-C 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC ® tradename), and mixtures thereof.
  • PVAC polyvinylpyrrolidone
  • PVAC polyvinyl acetate
  • PVA polyvinyl alcohol
  • acrylic acid and their salts silicon dioxide
  • Suitable polysaccharides include, for example, microcrystalline cellulose, microcrystalline cellulose grade 101 (e.g., AVICEL® PH- 101), microcrystalline cellulose grade 102 (e.g., AVICEL® PH 102), hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), optionally substituted a-cyclodextrins, optionally substituted b-cyclodextrins (e.g., hydroxypropyl b-cyclodextrin), optionally substituted g- cyclodextrins (e.g., hydroxypropyl g-cyclodextrin) and mixtures thereof.
  • microcrystalline cellulose grade 101 e.g., AVICEL® PH- 101
  • substituted with respect to cyclodextrin means the addition of side chain groups such as hydroxyl, hydroxypropyl, or other Ci-C 6 alkyl and Ci-C 6 hydroxyalkyl groups.
  • vinylpyrrolidone-vinyl acetate copolymers e.g., PLASDONE S-630
  • granulated silicon dioxide e.g., AEROPERL ® 300
  • microcrystalline cellulose grade 101 e.g., AVICEL® PH- 101
  • microcrystalline cellulose grade 102 e.g., AVICEL® PH 102
  • these excipients are incorporated into the solid dispersion at a weight percent of 50% w/w with respect to the total weight of the composition.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solvent may be removed to isolate an amorphous solid dispersion of abemaciclib. This may be carried out by techniques well-known in the art, for example, by evaporation, distillation, spray drying, or agitated thin film drying, or any combination thereof.
  • an amorphous solid dispersion of abemaciclib may be isolated, for example, by filtering the solution to obtain a solid.
  • the solid may then be dried under vacuum.
  • the present invention provides methods for preparing crystalline form I of abemaciclib.
  • crystalline form I of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in ketone solvent; and
  • abemaciclib may be dissolved in a ketone solvent.
  • ketone solvents include, but are not limited to, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • the abemaciclib starting material may be any form, for example, any crystalline form, amorphous form, or any solvated form.
  • abemaciclib is dissolved in methyl isobutyl ketone. Dissolution may be facilitated by heating, for example, to a temperature of about 40 °C to about reflux. In some embodiments, the solution is heated to a temperature of about 50 °C to about 80 °C.
  • the solution may be filtered, for example, through a material such as HYFLO ® , to remove any undissolved particulates.
  • the solution may be cooled to about 20 °C to about 30 °C and stirred for about 1 hour to about 3 hours to facilitate precipitation of crystalline form I of abemaciclib.
  • Crystalline form I of abemaciclib may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtration followed by suck-drying.
  • the present invention provides a method for preparing abemaciclib of formula (I).
  • abemaciclib may be prepared by a process that includes the step of reacting 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl-lH-benzoimidazole of formula (II) with 5-(4-ethyl-piperazin-l-ylmethyl)-pyridin-2-ylamine of formula (III) in the presence of palladium acetate to produce abemaciclib of formula (I).
  • 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l- isopropyl-2-methyl-lH-benzoimidazole of formula (II) may be reacted with 5-(4-ethyl- piperazin-lylmethyl)-pyridin-2-ylamine of formula (III) in the presence of palladium acetate.
  • This may be done in the presence of base, for example, potassium carbonate, a suitable reagent, such as xantphos, and in a solvent, such as tert-amyl alcohol.
  • the present invention provides a method for preparing the intermediate 6- (2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro- l-isopropyl-2-methyl- lH-benzoimidazole of formula (P)
  • 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl- lH- benzoimidazole of formula (II) may be prepared by a process that includes the steps of: a) reacting 4-bromo-2,6-difluoro-phenylamine of formula (IV) with N-isopropyl
  • Formula (IV) Formula (V) Formula (VI) b) reacting the compound of formula (VI) with a base in a solvent to get 6-bromo-4- fluoro-l -isoprop yl-2-methyl-lH-benzoimidazole of formula (VII);
  • Formula (VII) c) reacting a compound of formula (VII) with bis(pinacolato)diborane, triphenyl phosphine in the presence of a palladium catalyst in a solvent to produce the compound of formula (VIII); and
  • 4-bromo-2,6-difluoro-phenylamine of formula (IV) may be reacted with N-isopropyl acetamide of formula (V) in the presence of dehydrating agent and base in a solvent to produce N-(4-bromo-2,6-difluoro-phenyl)-N'-isopropyl-acetamidine of formula (VI).
  • the dehydrating agent may be, for example, sulfuric acid, phosphorous oxychloride phosphoryl chloride, phosphorus pentoxide, orthoformic acid, aluminium phosphate, or any mixture thereof.
  • the base may be an organic base, an inorganic base, or mixtures thereof.
  • Suitable organic bases include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine, and mixtures thereof.
  • Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • the solvent may be a non-polar solvent, a polar aprotic solvent, or mixtures thereof.
  • Suitable non-polar solvents include, but are not limited to, l,4-dioxane, toluene, benzene, xylene, methyl tert-butyl ether (MTBE), dichloromethane, and mixtures thereof.
  • Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N- methylpyrrolidinone (NMP), dimethylsulf oxide (DMSO), l,2-dimethoxyethane, and mixtures thereof.
  • Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, toluene is used as a solvent.
  • the compound of formula (VI) may be reacted with base in solvent to get 6-bromo-4- fluoro-l -isoprop yl-2-methyl-lH-benzoimidazole of formula (VII). As noted above, the compound of formula (VI) need not be isolated at this step.
  • the base may be an organic base, an inorganic base, or mixtures thereof.
  • Suitable organic bases include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine, and mixtures thereof.
  • Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • potassium hydroxide was found to be a particularly effective base.
  • the solvent may be a non-polar solvent, a polar aprotic solvent, or mixtures thereof.
  • Suitable non-polar solvents useful within this reaction include, but are not limited to, l,4-dioxane, toluene, benzene, xylene, methyl tert-butyl ether (MTBE), dichloromethane, and mixtures thereof.
  • Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2- dimethoxyethane and mixtures thereof.
  • Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some embodiments, dimethylsulfoxide was found to be a particularly effective solvent.
  • the compound of formula (VII) may be isolated. This may be done by methods well known in the art without undue experimentation.
  • the reaction mass is cooled to about 25 °C to about 30 °C.
  • water may be slowly added into the reaction mixture which is then stirred at about 30 °C to about 35 °C for about 15 minutes to about 20 minutes.
  • the aqueous and organic layers may be separated.
  • the organic layer may be washed, for example, with an aqueous solution of sodium chloride.
  • the organic layer may be concentrated under vacuum to obtain a residue, to which a solvent (e.g., a mixture of toluene and hexanes) may be added.
  • the mixture may be stirred, for example, for about 2 to about 3 hours at room temperature.
  • a solid may be isolated by filtering the mixture and drying the collected solid under vacuum at about 50 °C to about 55 °C.
  • the compound of formula (VII) may be reacted with bis(pinacolato)diborane, in the presence of a palladium catalyst, triphenylphosphine, and a base in a solvent to produce a compound of formula (VIII).
  • the solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or a mixture thereof.
  • Suitable non-polar solvents include, but are not limited to, l,4-dioxane, toluene, benzene, xylene, methyl tert-butyl ether (MTBE), dichloromethane, and mixtures thereof.
  • Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2- dimethoxyethane and mixtures thereof.
  • Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, propyl acetate, isopropyl acetate, and mixtures thereof.
  • the base may be an organic base, an inorganic base, or mixtures thereof.
  • Suitable organic bases include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine, and mixtures thereof.
  • Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • potassium carbonate was found to be a particularly effective base.
  • the palladium catalyst may be palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) chloride, or
  • the compound of formula (VIII) may be reacted with 2,4-dichloro-5-fluoro pyrimidine of formula (IX) in the presence of a palladium catalyst and a base in a solvent to produce 6-(2- chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl-lH-benzoimidazole of formula (II).
  • the base may be an organic base, an inorganic base, or mixtures thereof.
  • Suitable organic bases include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine, and mixtures thereof.
  • Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • potassium carbonate was found to be a particularly effective base.
  • the palladium catalyst may be palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) chloride, or [1,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloride.
  • bis(triphenylphosphine)palladium(II)chloride was found to be a particularly effective catalyst.
  • the solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof.
  • Suitable non-polar solvents include, but are not limited to, l,4-dioxane, toluene, benzene, xylene, methyl tert-butyl ether (MTBE), dichloromethane, and mixtures thereof.
  • Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2- dimethoxyethane and mixtures thereof.
  • Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, propyl acetate, isopropyl acetate, and mixtures thereof.
  • abemaciclib may be incorporated into a pharmaceutically acceptable dosage form, for example, an oral dosage form such as a tablet or capsule.
  • abemaciclib is formulated into a tablet.
  • tablets contain 50 mg to 200 mg abemaciclib, which includes 50 mg, 100 mg, 150 mg, and 200 mg abemaciclib.
  • the tablet or capsule may have additional pharmaceutically acceptable excipients, such as microcrystalline cellulose 101 or 102 (including or additional to any that may be part of a solid dispersion), lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide, polyvinyl alcohol, polyethylene glycol, talc, as well as artificial colorings, such as iron oxide red, iron oxide yellow, and titanium dioxide.
  • excipients such as microcrystalline cellulose 101 or 102 (including or additional to any that may be part of a solid dispersion), lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide, polyvinyl alcohol, polyethylene glycol, talc, as well as artificial colorings, such as iron oxide red, iron oxide yellow, and titanium dioxide.
  • compositions that incorporate abemaciclib polymorphs or solid dispersions disclosed herein may be useful in the treatment of HR -positive, HER-2 negative advanced, or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
  • Pharmaceutical dosage forms that incorporate abemaciclib polymorphs or solid dispersion disclosed herein may also be useful when combined with fulvestrant for the treatment of women with HR -positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
  • Amorphous abemaciclib (0.5 g) was suspended in anisole (4 mL) and stirred at 25 ⁇ 5 °C for 3 hours. The resulting reaction mass was filtered to yield crystalline form-Ml of abemaciclib.
  • Abemaciclib (0.1 g) was dissolved in anisole (1 mL) at 60-70 °C to get a clear solution. The resulting clear solution was filtered through HYFLO® to remove any undissolved particulates, cooled to 25 ⁇ 5 °C, stirred for 1-2 hours, and filtered to yield crystalline form-Ml of abemaciclib.
  • Abemaciclib (0.5 g) was dissolved in anisole (3.5 mL) at 60-70 °C to get a clear solution. The resulting clear solution was filtered through HYFLO ® to remove any undissolved particulates, cooled to 25 ⁇ 5 °C, and n-heptane (3.5 mL) was added. The mixture was stirred for 1 - 2 hours then filtered to yield crystalline form-Ml of abemaciclib.
  • Abemaciclib form-Ml (0.25 g) was dried at about 160 °C for 30 minutes. The resulting solid was identified as crystalline form-M2 of abemaciclib.
  • Crystalline form-M3 of abemaciclib (0.50 g) was dried at 100 °C under vacuum for 15 hours. The resulting solid was identified as crystalline form-M2 of abemaciclib.
  • Crystalline form-M4 of abemaciclib (0.50 g) was dried at 100 °C under vacuum for 15 hours. The resulting solid was identified as crystalline form-M2 of abemaciclib.
  • Abemaciclib (1.0 g) was dissolved in a mixture of ethyl acetate (15 mL) and methanol (2 mL) at 70-75 °C. The resulting clear solution was filtered through HYFLO ® to remove any undissolved particulate. The clear solution was added dropwise to n-heptane (30 mL) at 25-30 °C over 20 minutes. The mixture was stirred for 15 hours at 25 ⁇ 5 °C, filtered, and the obtained solid was dried under vacuum at 100 °C for 2 hours. The resulting solid was identified as crystalline form- M3 of abemaciclib.
  • Abemaciclib (1.0 g) was dissolved in mixture of ethyl acetate (15 mL) and methanol (2 mL) at 70-75 °C. The resulting clear solution was filtered through HYFLO ® to remove any undissolved particulate. The clear solution was added dropwise to the mixture of n-heptane (30 mL) and seeds of crystalline form-M3 of abemaciclib at 25-30 °C over 5-10 minutes. The mixture was stirred for 15 hours at 25 ⁇ 5 °C, filtered, and the resulting solid was dried under vacuum at 100 °C for 2 hours. The resulting solid was identified as crystalline form-M3 of abemaciclib.
  • Abemaciclib (6.5 g) was dissolved in methanol (60 mL) at 25 ⁇ 5 °C. The resulting clear solution was filtered through HYFLO ® to remove any undissolved particulates and the clear solution was subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with a solution feed rate of 5 mL/minute and an inlet temperature at 70 °C to yield amorphous abemaciclib.
  • Abemaciclib (0.5 g) and PLASDONE ® S-630 (0.5 g) were dissolved in methanol (15 mL) at 50 ⁇ 5 °C.
  • the resulting clear solution was filtered through HYFLO ® to remove any undissolved particulates.
  • the solvent was distilled off completely under vacuum using a BLICHI Rotavapor ® rotary evaporator at 55-60 °C.
  • the solid obtained was identified as an amorphous solid dispersion of abemaciclib.
  • Example 18 Preparation of an amorphous solid dispersion of abemaciclib with colloidal silicon dioxide (AEROPERL ® 300 (50% w/w))
  • Abemaciclib (0.5 g) was dissolved in methanol (5 mL) at 25 ⁇ 5 °C. The resulting clear solution was filtered through HYFLO ® to remove any undissolved particulates. AEROPERL ® 300 (0.5 g) was added and the solvent distilled off completely under vacuum using a BLICHI Rotavapor ® rotary evaporator at 55-60 °C. The solid obtained was identified as an amorphous solid dispersion of abemaciclib.
  • Example 19 Preparation of an amorphous solid dispersion of abemaciclib with microcrystalline cellulose grade 101 (50% w/w)
  • Abemaciclib (0.5 g) was dissolved in methanol (15 mL) at 25 ⁇ 5 °C. The resulting clear solution was filtered through HYFLO ® to remove any undissolved particulates and microcrystalline cellulose grade 101 (AVICEL® PH-101, 0.5 g) was added. The solvent was distilled off completely under vacuum using a BLICHI Rotavapor ® at 55-60 °C. The solid obtained was identified as an amorphous solid dispersion of abemaciclib with microcrystalline cellulose.
  • Example 20 Preparation of an amorphous solid dispersion of abemaciclib with microcrystalline cellulose grade 102 (50% w/w)
  • Amorphous abemaciclib (0.1 g) was suspended in acetone (1 mL) and stirred at 25 ⁇ 5 °C for 16 hours. The mixture was filtered and the obtained solid was identified crystalline form I of abemaciclib.
  • Abemaciclib (5 g) was dissolved in methanol (50 mL) at 60 °C in a round bottom flask (RBF). The clear solution was filtered through HYFLO ® to remove any undissolved particulates. The reaction mass was distilled under atmospheric pressure up to 2 volumes of reaction mass present in the RBF. The reaction mixture was then cooled to 30 °C and a vacuum was applied at 30-35 °C to remove solvent until syrupy liquid mass was observed. Seeds of crystalline form-M3 of abemaciclib (50 mg) were added at 30-35 °C and the reaction mass was stirred for 5-10 minutes.
  • the pH of the reaction mass was adjusted to 7.5-8.0 with a sodium hydroxide solution, stirred for 30 minutes at 30-35 °C, and the layers were separated. The organic layer was washed with water and the layers were again separated. Potassium hydroxide (161.5 g, 2.88 mol) and dimethylsulfoxide 400 mL at 30-35 °C were charged to the organic layer.
  • the reaction mixture was heated to reflux and water was added azeotropic ally for 2-4 hours at reflux temperature.
  • the reaction mass was cooled to 25-30 °C and water was slowly added into the reaction mixture.
  • the reaction mixture was stirred at 30- 35 °C for 15-20 minutes and the layers were separated.
  • the organic layer was washed with an aqueous sodium chloride solution. The organic layer was concentrated under vacuum.
  • Example 28 Preparation of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2- methyl-lH-benzoimidazole.
  • Argon/Nitrogen was bubbled into a mixture of 6-bromo-4-fluoro-l-isopropyl-2-methyl-lH- benzoimidazole (20 g, 0.0737 mol), bis(pinacolato)diborane (22.5 g, 0.0886 mol), triphenyl phosphine (0.193 g, 0.00073 mol), and potassium acetate (21.72 g, 0.2213 moles) in isopropyl acetate (60 mL).
  • Bis(triphenylphosphine)palladium(II) dichloride (2.07 g, 0.00294 mol) was added to the reaction mixture which was then heated to 85-90 °C for 2-4 hours.
  • the completion of the reaction was monitored by TLC/HPLC.
  • the reaction mass was cooled to 30-35 °C.
  • 2,4- Dichloro-5-fluoro pyrimidine (13.54 g, 0.0811 mol), potassium carbonate solution, and isopropyl acetate 60 mL were charged to the reaction mass at 30-35 °C and bubbled with organ/nitrogen for 30 minutes.
  • the reaction mixture was heated to 80-85 °C and maintained for 3-4 hours.
  • the completion of the reaction was monitored by TLC/HPLC.
  • the reaction mass was cooled to 30-35 °C and stirred for 3-4 hours, filtered, and the solid product was washed with isopropyl acetate.
  • the wet material was then dissolved in methylene dichloride and treated with N-acetyl-L- cysteine at 40-45 °C for 2 hours.
  • the pH of the reaction mass was adjusted to 11.0-12.0 with a sodium hydroxide solution, stirred for 30 minutes at 30-35 °C, and the layers were separated.
  • the organic layer was washed with water and distilled under vacuum at 40-45 °C. Isopropyl acetate was charged to the residue and the temperature was raised to 60-65 °C for 30 minutes.
  • the reaction mass was cooled to 30-35 °C, stirred for 1-2 hours, then filtered.
  • Example 29 Preparation of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2- methyl-lH-benzoimidazole.
  • Argon/Nitrogen was bubbled into a mixture of 6-bromo-4-fluoro-l-isopropyl-2-methyl-lH- benzoimidazole (20 g, 0.0737 mol), bis(pinacolato)diborane (22.5 g, 0.0886 mol), triphenylphosphine (0.193 g, 0.00073 mol), and potassium acetate (21.72 g, 0.2213 moles) in toluene (60 mL).
  • Bis(triphenylphosphine)palladium(II)chloride (1.035 g, 0.00147 mol) was added and the mixture was heated to 85-90 °C for 2-4 hours.
  • the solid product was washed with isopropyl acetate.
  • the wet material was then dissolved in methylene dichloride and treated with N-acetyl-L-cysteine at 40-45 °C for 2 hours.
  • the pH of the reaction mass was adjusted to 11.0-12.0 with sodium hydroxide solution, stirred for 30 minutes at 30-35 °C, and the layers were separated.
  • the organic layer was washed with water and distilled under vacuum at 40-45 °C. Isopropyl acetate was charged to the residue and the temperature was raised to 60-65 °C for 30 minutes.
  • the reaction mass was cooled to 30-35 °C, stirred for 1-2 hours, and filtered.
  • Argon/Nitrogen was bubbled into a mixture of 6-bromo-4-fluoro-l-isopropyl-2-methyl-lH- benzoimidazole (10 g, 0.0309 mol), 5-(4-ethyl-piperazin-lylmethyl)-pyridin-2-ylamine (6.89 g, 0.0312 mol), potassium carbonate (8.65 g), and xantphos (1.07 g, 0.0018 mole) in tert-amyl alcohol (50 mL). Palladium acetate (0.2 g, 0.00089 mole) was added and the reaction mass was heated to 98-100 °C for 2-4 hours. The completion of the reaction was monitored by TLC/HPLC.
  • the reaction mass was cooled to 30-35 °C., then diluted with dichloromethane (80 mL) and water (30 mL) and filtered through a HYFLO ® bed.
  • the compound was extracted from the organic layer using hydrochloric acid diluted in water (1:1) (2 x 30 mL).
  • the pH of the combined aqueous layers was adjusted to 11-12 with a sodium hydroxide solution and the compound was extracted using dichloromethane.
  • the organic layer was treated with N-acetyl-L-cysteine and the pH of the solution was adjusted to 11.0-12.0 with a sodium hydroxide solution. The mixture was stirred for 30 minutes at 30-35 °C and the layers were separated.

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Abstract

La présente invention concerne de nouveaux polymorphes d'abémaciclib, des dispersions solides d'abémaciclib avec des excipients pharmaceutiques, et des procédés pour leur préparation. L'invention concerne en outre des procédés de préparation de la forme I d'abémaciclib cristallin, de l'abémaciclib amorphe et des procédés de synthèse de l'abémaciclib.
PCT/IN2018/050775 2017-11-23 2018-11-23 Polymorphes cristallins d'abémaciclib WO2019102492A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2021030843A1 (fr) 2019-08-13 2021-02-18 Johnson Matthey Public Limited Company Formes solides d'abemaciclib, leur utilisation et leur préparation
CN117510471A (zh) * 2022-07-29 2024-02-06 江苏天士力帝益药业有限公司 一种阿贝西利的合成方法
US12011442B2 (en) 2018-04-05 2024-06-18 Macfarlan Smith Limited Solid-state forms of Abemaciclib, their use and preparation

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12011442B2 (en) 2018-04-05 2024-06-18 Macfarlan Smith Limited Solid-state forms of Abemaciclib, their use and preparation
WO2021030843A1 (fr) 2019-08-13 2021-02-18 Johnson Matthey Public Limited Company Formes solides d'abemaciclib, leur utilisation et leur préparation
CN117510471A (zh) * 2022-07-29 2024-02-06 江苏天士力帝益药业有限公司 一种阿贝西利的合成方法
CN117510471B (zh) * 2022-07-29 2025-02-25 江苏天士力帝益药业有限公司 一种阿贝西利的合成方法

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