CRYSTALLINE POLYMORPHS OF ABEMACICLIB

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of earlier Indian provisional patent application IN 201741042091 filed on November 23, 2017 which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

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.

DESCRIPTION OF RELATED ART

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.

Formula-I

Abemaciclib is a kinase inhibitor, marketed in the U.S. under the tradename VERZENIO™ 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. 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.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides crystalline form-Ml of abemaciclib.

In one embodiment, 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.

In another aspect, the present invention provides crystalline form-M2 of abemaciclib.

In one embodiment, 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.

In another aspect, the present invention provides crystalline form-M3 of abemaciclib.

In one embodiment, 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.

In another aspect, the present invention provides crystalline form-M4 of abemaciclib. In one embodiment, 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.

In another aspect, the present invention provides crystalline form-M5 of abemaciclib.

In another aspect, the present invention provides an amorphous solid dispersion of abemaciclib.

In another aspect, 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;

b) isolating crystalline form-Ml of abemaciclib.

In another aspect, 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;

b) removing the solvent;

c) adding a hydrocarbon solvent; and

d) isolating crystalline form-Ml of abemaciclib.

In another aspect, 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;

b) adding a hydrocarbon solvent; and

c) isolating crystalline form-Ml of abemaciclib.

In another aspect, 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

b) isolating crystalline form- M2 of abemaciclib.

In another aspect, 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;

c) optionally seeding with crystalline form-M3 of abemaciclib; and

d) isolating crystalline form-M3 of abemaciclib.

In another aspect, 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;

b) concentrating the reaction mass;

c) optionally seeding with crystalline form-M3 of abemaciclib;

d) adding a second solvent; and

e) isolating crystalline form-M3 of abemaciclib.

In another aspect, 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;

b) seeding with crystalline form-M3 of abemaciclib; and

c) isolating crystalline form-M3 of abemaciclib.

In another aspect, 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;

b) adding an ether solvent; and

c) isolating crystalline form-M4 of abemaciclib.

In another aspect, 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;

b) adding the above solution to a hydrocarbon solvent at a temperature of 0-5 °C;

c) optionally seeding with crystalline form-M5 of abemaciclib; and

d) isolating crystalline form-M5 of abemaciclib.

In another aspect, 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;

c) optionally seeding with crystalline form-M5 of abemaciclib; and

d) isolating crystalline form-M5 of abemaciclib.

In another aspect, 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 non polar solvent;

c) optionally seeding with crystalline form-M5 of abemaciclib; and

d) isolating crystalline form-M5 of abemaciclib.

In another aspect, 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;

b) seeding with crystalline form-M5 of abemaciclib; and

c) isolating crystalline form-M5 of abemaciclib.

In another aspect, the present invention provides a process for the preparation of amorphous abemaciclib that includes the steps of: a) dissolving abemaciclib in a solvent; and

b) removing the solvent to isolate amorphous abemaciclib.

In another aspect, 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

b) removing the solvent to isolate an amorphous solid dispersion of abemaciclib.

In another aspect, 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

b) isolating crystalline form I of abemaciclib.

In another aspect, 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)·

Fonnula (II) Formula (III) Formula (I) In another aspect, 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

(VII)

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)

In this reaction scheme, intermediate compounds of formula (VI), formula (VII), or formula (VIII) need not be isolated before proceeding to the next recited step. In some embodiments, compounds of formula (VI) and formula (VIII) are not isolated. BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure 1 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).

DETAILED DESCRIPTION OF THE INVENTION

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.

Various measurements and values, including mass, volume, moles, and time, are disclosed herein and modified by the word“about.” As used herein, unless otherwise defined, the term“about” means 10% above or below the value recited. With respect to temperature, unless otherwise defined, the term“about” means the value recited plus or minus 5 degrees.

In one aspect, the present invention provides crystalline form-Ml of abemaciclib.

In one embodiment, 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 ° . In another embodiment, 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 °.

In another embodiment, crystalline form-Ml of abemaciclib may be characterized by the PXRD pattern in Figure 1.

It is believed that crystalline form-Ml of abemaciclib is an anisole hemi-solvate of abemaciclib.

In another aspect, the present invention provides a process for the preparation of crystalline form- Ml of abemaciclib.

In one embodiment, abemaciclib may be prepared by a process that includes the steps of: a) dissolving or suspending abemaciclib in anisole; and

b) isolating crystalline form-Ml of abemaciclib.

According to this embodiment, 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.

In some embodiments, 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.

In some embodiments, the solution may be filtered, for example, through a material such as HYFLO ^® , to remove any undissolved particulates. Within the context of this embodiment, the solution may be cooled to precipitate form-Ml of abemaciclib. In some embodiments, the solution is cooled to 20 °C to 30 °C and the mixture is stirred for about 1 hour to about 3 hours.

In other embodiments, 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.

In another embodiment, 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;

b) removing the solvent mixture;

c) adding a hydrocarbon solvent; and

d) isolating crystalline form-Ml of abemaciclib.

According to this embodiment, abemaciclib may be dissolved in a mixture of methanol and anisole. In particularly useful embodiments, 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.

In some embodiments, the solution may be filtered, for example, through a material such as HYFLO ^® , to remove any undissolved particulates.

Next, solvent may be removed to concentrate the solution. This may be carried out by methods well known in the art, such as distillation.

Next, a hydrocarbon solvent may be added to the reaction mass. Examples of 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.

In another embodiment, crystalline form-Ml of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in anisole;

b) adding a hydrocarbon solvent; and c) isolating crystalline form-Ml of abemaciclib.

According to this embodiment, 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.

In some embodiments, 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. Examples of 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. For example, 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, 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.

In one embodiment, 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 °.

In another embodiment, 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 °.

In another embodiment, crystalline form-M2 of abemaciclib may be characterized by the PXRD pattern in Figure 2. In another aspect, the present invention provides a process for the preparation of crystalline form- M2 of abemaciclib.

In one embodiment, 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.

It is believed that crystalline form-M2 of abemaciclib is anhydrous.

In another embodiment, 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.

In another aspect, the present invention provides crystalline form-M3 of abemaciclib.

In one embodiment, 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 °.

In another embodiment, 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 °.

In another embodiment, crystalline form-M3 of abemaciclib may be characterized by the PXRD pattern in Figure 3.

It is believed that crystalline form-M3 is a hydrated form of abemaciclib.

In another aspect, the present invention provides a process for the preparation of crystalline form- M3 of abemaciclib.

In one embodiment, 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;

c) optionally adding the second solution to seeds of crystalline form-M3 of abemaciclib in a third solvent; and

d) isolating crystalline form-M3 of abemaciclib.

According to this embodiment, abemaciclib may be dissolved in a polar solvent. The polar solvent may be, for example, an alcohol solvent, an ester solvent, or mixtures thereof. Specific examples of 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. Specific examples of 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.

In particularly useful embodiments, abemaciclib is dissolved in a mixture of ethyl acetate and methanol.

Heating may facilitate dissolution. For example, in some embodiments, the mixture is heated 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.

Once dissolved, 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.

Next, the solution may be added to a hydrocarbon solvent. This may be carried out slowly, for example, dropwise, at a temperature of about 25 °C to about 30 °C. Specific examples of hydrocarbon solvent include, but are not limited to, toluene, n-heptane, n-hexane, cyclohexane, methyl cyclohexane, and mixtures thereof. In particularly useful embodiments, the hydrocarbon solvent is n-heptane.

Optionally, 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.

In another embodiment, 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;

b) concentrating the solution;

c) optionally seeding the solution with crystalline form-M3 of abemaciclib;

d) adding a second solvent to form a second solution; and

e) isolating crystalline form-M3 of abemaciclib.

According to this embodiment, 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. Examples of suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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.

In particularly useful embodiments, 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.

In some embodiments, 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

°C.

Optionally, 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.

Next, a second solvent may be added to form a second solution. This may be carried out at the same temperature of about 25 °C to 35 °C. Within the context of this embodiment, the second 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. Specific examples of 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. Specific examples of 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. Examples of suitable non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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. For example, 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.

In another embodiment, crystalline form-M3 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a solvent;

b) adding seeds of crystalline form-M3 of abemaciclib;

c) isolating crystalline form-M3 of abemaciclib. According to this embodiment, 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. Specific examples of 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. Specific examples of 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. Examples of non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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.

Next, 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.

In another aspect, the present invention provides crystalline form-M4 of abemaciclib.

In one embodiment, 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 °.

In another embodiment, 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 °.

In another embodiment, 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.

In another aspect, the present invention provides a process for the preparation of crystalline form- M4 of abemaciclib.

In one embodiment, crystalline form-M4 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent;

b) adding an ether solvent; and

c) isolating crystalline form-M4 of abemaciclib.

According to this embodiment, 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. Examples of suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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.

In particularly useful embodiments, 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. For example, 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.

Next, 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.

Specific examples of 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. In particularly useful embodiments, 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.

In another aspect, the present invention provides crystalline form-M5 of abemaciclib.

In one embodiment, 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

In another embodiment, 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 °.

In another embodiment, crystalline form-M5 of abemaciclib may be characterized by the PXRD pattern in Figure 5.

It is believed that crystalline form-M5 of abemaciclib is anhydrous.

In another aspect, the present invention provides a process for the preparation of crystalline form- M5 of abemaciclib.

In one embodiment, crystalline form-M5 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent;

b) adding a hydrocarbon solvent at a temperature of 0 °C to 5 °C;

c) optionally seeding with crystalline form-M5 of abemaciclib; and

d) isolating crystalline form-M5 of abemaciclib.

According to this embodiment, 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. Examples of suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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.

In particularly useful embodiments, abemaciclib is dissolved in a mixture of ethyl acetate and methanol.

Heating may facilitate dissolution. For example, in some embodiments, the mixture is heated 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.

Once dissolved, 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.

Next, the solution may be added to a hydrocarbon solvent. This may be carried out slowly, for example, dropwise, at a temperature of about 0 °C to about 5 °C. Specific examples of hydrocarbon solvents include, but are not limited to, toluene, n-heptane, n-hexane, and mixtures thereof. In particularly useful embodiments, the hydrocarbon solvent is n-heptane.

Optionally, 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.

In another embodiment, 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;

b) combining the solution and a non-polar solvent;

c) optionally seeding with crystalline form-M5 of abemaciclib; and

d) isolating crystalline form-M5 of abemaciclib. According to this embodiment, 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. Examples of suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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.

In particularly useful embodiments, 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. Optionally, the non-polar solvent may contain seeds of crystalline form-M5 of abemaciclib.

Examples of suitable non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof. Specific examples of 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. Specific examples of hydrocarbon solvents include, but are not limited to, toluene, hexane, n-heptane, and mixtures thereof. In particularly useful embodiments, 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.

In another embodiment, crystalline form-M5 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a polar solvent;

b) adding a non-polar solvent;

c) optionally seeding with crystalline form-M5 of abemaciclib; and

d) isolating crystalline form-M5 of abemaciclib.

According to this embodiment, 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. Examples of suitable polar solvents include alcohol solvents, ester solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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.

In particularly useful embodiments, 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. Optionally, the non-polar solvent may contain seeds of crystalline form-M5 of abemaciclib. Examples of suitable non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof. Specific examples of 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. Specific examples of hydrocarbon solvents include, but are not limited to, toluene, hexane, n-heptane, and mixtures thereof. In particularly useful embodiments, 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. In another embodiment, crystalline form-M5 of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a solvent,

b) seeding with crystalline form-M5 of abemaciclib; and

c) isolating crystalline form-M5 of abemaciclib.

According to this embodiment, 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. Specific examples of 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. Specific examples of 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. Examples of non-polar solvents include ether solvents, hydrocarbon solvents, and mixtures thereof. Specific examples of 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. Specific examples of 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.

Next, 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.

In another aspect, the present invention provides an amorphous form of abemaciclib.

In one embodiment, amorphous abemaciclib may be characterized as amorphous by the PXRD pattern in Figure 6.

In another aspect, the present invention provides a process for preparing amorphous abemaciclib. In one embodiment, amorphous abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in a solvent; and

b) removing the solvent to isolate amorphous abemaciclib.

According to this embodiment, 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. Within the context of the present disclosure, abemaciclib starting material may be any polymorphic form. Within the context of this embodiment, the solvent may be, for example, an alcohol solvent, a ketone solvent, a halogenated solvent, or any mixture thereof. Specific examples of 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. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. Examples of suitable chlorinated solvent include, but are not limited to, dichloromethane, l,l-dichloroethane, l,2-dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof. In particularly useful embodiments, 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.

Next, 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. In certain embodiments, spray drying or distillation is used to remove the solvent. In some embodiments, the polymorphs of abemaciclib disclosed herein exhibit physical stability. Thus, 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.

When analyzed, crystalline form-M2, form-M3, and form-M5 of abemaciclib exhibit no change in PXRD pattern when stored for 6 months at 40°C/75% relative humidity (RH) and at 25 °C/60% relative humidity (RH) conditions. This data is tabulated below in Table 1.

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.

Table 1

In another aspect, the present invention provides solid dispersions of abemaciclib with pharmaceutically acceptable excipients. Within the context of the invention, the solid dispersion may be prepared with amorphous, crystalline, or any solvate of abemaciclib and one or more pharmaceutically acceptable excipients. In another aspect, the present invention provides methods for preparing solid dispersions of abemaciclib with a pharmaceutically acceptable excipient.

In one embodiment, 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

b) removing the solvent to isolate an amorphous solid dispersion of abemaciclib.

According to the present embodiment, abemaciclib and a pharmaceutical excipient may be first dissolved in a solvent. Within the context of this embodiment, abemaciclib starting material may be of a variety of different forms, for example, any polymorph or any solvated form. Within the context of this embodiment, solvent may be, for example, an alcohol solvent, a ketone solvent, and ether solvent, or mixtures thereof.

Examples of 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. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.

Examples of 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.

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. As used herein, the term “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.

In particularly useful embodiments of the present disclosure, 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), or microcrystalline cellulose grade 102 (e.g., AVICEL® PH 102) is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, 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.

Next, 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.

Next, 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.

In another aspect, the present invention provides methods for preparing crystalline form I of abemaciclib.

In one embodiment, crystalline form I of abemaciclib may be prepared by a process that includes the steps of: a) dissolving abemaciclib in ketone solvent; and

b) isolating crystalline form I of abemaciclib.

According to this embodiment, abemaciclib may be dissolved in a ketone solvent. Specific examples of 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.

In particularly useful embodiments, 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.

In yet another aspect, the present invention provides a method for preparing abemaciclib of formula (I).

Formula (I)

In one embodiment, 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).

Formula (II) Formula (III)

According to the present embodiment, 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. This may be carried out at an increased temperature, for example, about 80 °C to about 120 °C for about 1 hour to about 6 hours to produce abemaciclib of formula (I). In yet another aspect, 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)

Fonnula (II) In one embodiment, 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

acetamide of formula (V) in the presence of a dehydrating agent and a base in a 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 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

Formula (VIII) d) reacting the compound of formula (VIII) with 2,4-dichloro-5-fluoro pyrimidine of formula (IX) in the presence of a base and a solvent to produce 6-(2-chloro-5-fluoro- pyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl-lH-benzoimidaz ole of formula (II).

Formula (IX) Formula (II)

In this reaction scheme, intermediate compounds of formula (VI), formula (VII), or formula (VIII) need not be isolated before proceeding to the next recited step. In some embodiments, compounds of formula (VI) and formula (VIII) are not isolated.

According to the present embodiment, 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.

Next, 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. In some embodiments, 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.

After the completion of reaction, the compound of formula (VII) may be isolated. This may be done by methods well known in the art without undue experimentation. For example, in some embodiments, the reaction mass is cooled to about 25 °C to about 30 °C. In some embodiments, 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.

Next, according to the present embodiment, 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. In some embodiments, 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

[l,r-bis(diphenylphosphino)ferrocene]palladium (II) dichloride. In some embodiments, bis(triphenylphosphine)palladium(II)chloride was found to be a particularly effective catalyst. As noted above, isolation of formula (VIII) is not necessary at this point.

Next, 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-methy l-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. In some embodiments, 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. In some embodiments, 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.

The polymorphs of abemaciclib, including forms Ml, M2, M3, M4, M5 and amorphous as well as the solid dispersions disclosed herein may be incorporated into a pharmaceutically acceptable dosage form, for example, an oral dosage form such as a tablet or capsule. In particularly useful embodiments, abemaciclib is formulated into a tablet. In particularly useful embodiments, 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.

Pharmaceutical dosage forms 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.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure. EXAMPLES

Example 1: Preparation of crystalline form-Ml of abemaciclib

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.

Example 2: Preparation of 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.

Example 3: Preparation of crystalline form-Ml of abemaciclib

Abemaciclib (0.5 g) was dissolved in methanol (2 mL) and anisole (5 mL) at 25 ± 5 °C. The resulting clear solution was filtered through HYFLO® to remove any undissolved particulates. Approximately one third of the initial volume of the reaction mass was distilled off under vacuum by using a BLICHI Rotavapor ^® rotary evaporator at 55 - 60 °C. n-heptane (5 mL) was then added to the reaction mass at 25 ± 5 °C, stirred for 1 hour, and filtered. The solid obtained was identified as crystalline form-Ml of abemaciclib.

Example 4: Preparation of 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.

Example 5: Preparation of crystalline form-M2 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.

Example 6: Preparation of crystalline form-M2 of abemaciclib

Abemaciclib form-M3 (0.25 g) was dried at about 160 °C for 30 minutes. The resulting solid was identified as crystalline form-M2 of abemaciclib. Example 7: Preparation of 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.

Example 8: Preparation of 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.

Example 9: Preparation of crystalline form-M3 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.

Example 10: Preparation of 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.

Example 11: Preparation of crystalline form-M4 of abemaciclib

Abemaciclib (1.0 g) was dissolved in methanol (4 mL) at 60-65 °C. The resulting clear solution was cooled to -10 to -15 °C and stirred for 10-15 minutes. Methyl tert-butyl ether (10 mL) was added to this clear solution at -10 to -15 °C over 5-10 minutes. The reaction mixture was stirred for 3 hours at -10 to -15 °C, filtered, and the obtained solid was dried under vacuum at 30-35 °C for 1 hour. The resulting solid was identified as crystalline form-M4 of abemaciclib. Example 12: Preparation of crystalline form-M5 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 0-5 °C over 5-10 minutes and stirred at 0-5 °C for 15 hours. The product obtained was filtered and the collected solid dried under vacuum at 30-35 °C for 15 hours. The resulting solid was identified as crystalline form-M5 of abemaciclib.

Example 13: Preparation of crystalline form-M5 of abemaciclib

Abemaciclib (2.0 g) was dissolved in a mixture of ethyl acetate (30 mL) and methanol (8 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 a mixture of n-heptane (60 mL) and seeds of form-M5 at 0-5 °C for 5-10 minutes and stirred at 0-5 °C for 1-2 hours. The product obtained was filtered and the obtained solid was dried under vacuum at 30-35 °C for 15 hours. The resulting solid was identified as crystalline form-M5 of abemaciclib.

Example 14: Preparation of amorphous 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.

Example 15: Preparation of amorphous abemaciclib

Abemaciclib (10 g) was dissolved in methanol (80 mL) at 25 ± 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 BLTCHI Rotavapor ^® rotary evaporator at 55-60 °C to get a foamy solid. The solid obtained was identified as amorphous abemaciclib.

Example 16: Preparation of amorphous abemaciclib

Abemaciclib (1.5 g) was dissolved in dichloromethane (30 mL) at 30 ± 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 BLTCHI Rotavapor ^® rotary evaporator at 55-60 °C to get a foamy solid. The solid obtained was identified as amorphous abemaciclib. Example 17: Preparation of an amorphous solid dispersion of abemaciclib with a vinylpyrrolidone- vinyl acetate copolymer (PLASDONE ^® S-630 (50% w/w))

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)

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 102 (AVICEL® PH- 102, 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 21: Preparation of crystalline form I of abemaciclib

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.

Example 22: Preparation of crystalline form I of abemaciclib

Abemaciclib (5 g) was dissolved in methyl isobutyl ketone (75 mL) at 75 ± 5 °C. The resulting clear solution was filtered through HYFLO ^® to remove any undissolved particulates, cooled to 25 + 5 °C, stirred for 1-2 hours, filtered, and the solid was suck-dried. The solid obtained was identified as crystalline form I of abemaciclib.

Example 23: Preparation of crystalline form-M3 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. A mixture of ethyl acetate (25 mL) and n-heptane (50 mL) was then added at 30-35 °C over 10- 15 minutes and stirred at 30 °C for 1-24 hours. The presence of crystalline form-M3 of abemaciclib was detected by PXRD. Upon satisfactory PXRD results, the reaction mass was filtered, washed with n-heptane (10 mL), and dried under vacuum at 50 °C for 15-24 hours. If the PXRD was not satisfactory, stirring was continued until PXRD results are satisfactory.

Example 24: Preparation of crystalline form-M5 of abemaciclib

Abemaciclib (10 g) was dissolved in methanol (30 mL) at 55-58 °C. The resulting clear solution was filtered through HYFLO ^® to remove any undissolved particulates. The clear solution was charged to a mixture of methyl tert-butyl ether (120 mL) and seeds of crystalline form-M5 of abemaciclib (100 mg) at 25-30 °C. The resulting mixture was stirred at 20-30 °C for 1-15 hours. The reaction mass was filtered and the solid was washed with methyl tert-butyl ether (10 mL). The material was dried under vacuum at 30-35 °C for 15-20 hours. Example 25: Preparation of crystalline form-M5 of abemaciclib

Abemaciclib (10 g) was dissolved in methanol (30 mL) at 55-58 °C. The resulting clear solution was filtered through HYFLO ^® to remove any undissolved particulates. Methyl tert-butyl ether (120 mL) was charged to the reaction mass with seeds of crystalline form-M5 of abemaciclib (lOOmg) at 25-30 °C and the resulting mixture was stirred at 20-30 °C for 1-15 hours The reaction mass was filtered and the solid was washed with methyl tert-butyl ether (10 mL). The material was dried under vacuum at 30-35 °C for 15-20 hours.

Example 26: Preparation of crystalline form-M5 of abemaciclib

Abemaciclib (10 g) was dissolved in a methyl tert-butyl ether (50 mL) and methanol (30 mL) mixture at 52-55 °C. The resulting clear solution was filtered to remove any undissolved particulates. The filtrate was heated to 52-55 °C and stirred for 60 minutes at 52-55 °C. The reaction mass was cooled to 25-30 °C and seeds of crystalline form-M5 of abemaciclib were added at 25-30 °C. The resulting mixture was stirred at 23-25 °C for 1-15 hours. The reaction mass was filtered, and then washed with methyl tert-butyl ether (10 mL). The material was dried under vacuum at 30-35 °C for 15-20 hours.

Example 27: Preparation of crystalline form-M5 of abemaciclib

Abemaciclib (2 g) was dissolved in methanol (8 mL) at 60-65 °C. The resulting clear solution was filtered through HYFLO ^® to remove any undissolved particulate. The clear solution was added dropwise to a solution of methyl tert-butyl ether (20 mL) with seeds of crystalline form- M5 of abemaciclib (20 mg) at 25-30 °C over 5-10 minutes, and then stirred for 15 hours. The mixture obtained was filtered and the collected solid was dried under vacuum at 30-35 °C for 15- 20 hours.

Example 28: Preparation of 6-bromo-4-fluoro-l-isopropyl-2-methyl-lH-benzoimidazole

4-Bromo-2,6-difluoro- N-Isopropyl N-(4-Bromo-2,6-difluoro-phenyl)- 6-Bromo-4-fluoro- 1 -isopropyl- phenylamine acetamide N'-isopropyl-acetamidine 2-methyl- 1 H-benzoimidazole

4-Bromo-2,6-difluoro-phenylamine (200 g, 0.961 mol) and N-isopropyl acetamide (107 g, 1.057 mol) in toluene (1000 mL) were stirring at 10-15 °C. Phosphoryl chloride (177 g, 1.154 mol) and triethylamine (117 g, 1.156 moles) were slowly added. The reaction mixture was heated to reflux for 2-3 hours. The reaction mass was cooled to 10-15 °C and water was slowly added into the reaction mixture which was stirred at 30-35 °C for 15-20 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. Toluene (160 mL) and hexanes (1000 mL) were charged to the residue and the resulting mixture was stirred for 2-3 hours at room temperature. The mixture was filtered and the collected solid was washed with hexanes and dried at 50-55 °C to yield 215 g (82.3%) of 6-bromo-4-fluoro-l- isopropyl-2-methyl-lH-benzoimidazole with a purity of 99.70%.

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. The solid product was washed with isopropyl acetate and dried at 50-55 °C to yield 18 g (75.63 %) of 6-(2-chloro-5- fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl-lH-benz oimidazole with a purity of 99.40%.

Example 29: Preparation of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2- methyl-lH-benzoimidazole.

o uene , water

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 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), bis(triphenylphosphine)palladium(II)chloride (1.035 g 0.00147 mol), potassium carbonate solution, and toluene 60 mL at 30-35 °C were charged to the reaction mass and organ/nitrogen was bubbled into the mixture 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, stirred for 3-4 hours, and filtered. 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. The solid product was washed with isopropyl acetate and dried at 50-55 °C to give 17 g (yield = 71.42%) of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2- methyl-lH-benzoimidazole (purity 99.74%). Example 30: Preparation of abemaciclib

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. The organic layer was washed with water and distilled under vacuum at 40-45 °C. Acetone (100 mL) was charged to the residue and the temperature was raised to reflux for 30 minutes, and then cooled to 30-35 °C. The mixture was filtered and the solid product was washed with acetone and dried at 50-55 °C to give 13 g (82.85%) of abemaciclib with purity of 99.79%.