DESC:The following specification particularly describes the invention and the manner in which it is to be performed (For Complete):
CRYSTALLINE FORMS OF RIBOCICLIB SUCCINATE

FIELD OF INVENTION
The present application relates to crystalline forms of ribociclib succinate and process for preparation thereof. Specifically, the present application relates to crystalline forms DR1, DR2, DR3, DR4, DR5, DR6, DR7 and DR8 of ribociclib succinate and process for preparation thereof.

BACKGROUND OF INVENTION
Ribociclib succinate is a cylcin-dependent kinase-4/6 inhibitor indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Ribociclib succinate is chemically known as Butanedioic acid-7-Cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7Hpyrrolo[2,3-d]pyrimidine-6-carboxamide and has following structural formula:

Ribociclib is first disclosed in PCT patent application, WO2010020675A1 (hereinafter referred as the WO’675 application). The US patent US9193732B2 discloses the polymorphic forms of succinate salt of ribociclib, characterized by XRD, DSC, TGA, post-DVS XRD, post-DVS DSC and post-DVS TGA figures (hereinafter referred as the US’ 732 patent). Another US application US2016039832A1 discloses both anhydrous and hydrated forms of succinate salt of ribociclib (hereinafter referred as the US’ 832 application). Further the Chinese application CN105085533A discloses a crystalline form I of mono-succinate salt of ribociclib, characterized by XRD peaks (hereinafter referred as the CN’ 533 application).
In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, “polymorphs” refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, “Tricky Business,” Science News, Vol. 166(8), August 2004.

Hence, there remains a need for alternate crystalline forms of ribociclib succinate and processes for preparing them.

SUMMARY OF INVENTION
First aspect of the present application relates to crystalline form DR1 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 4.84, 8.98, and 16.29 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR1 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at 10.74, 13.06, 14.28, 17.93, 18.46, 19.17, 20.09, 22.13 and 26.32 ± 0.2° 2?.
Second aspect of the present application relates to crystalline form DR1 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 1.
Third aspect of the present application provides a process for preparing crystalline form DR1 of ribociclib succinate comprising
a) keeping amorphous form of ribociclib succinate for a sufficient time; and
b) isolating crystalline form DR1 of ribociclib succinate.
Fourth aspect of the present application relates to a composition comprising crystalline form DR1 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Fifth aspect of the present application relates to crystalline form DR2 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 4.57, 6.30, 7.13, 11.25 and 24.14 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR2 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at 18.22, 19.62 and 26.11 ± 0.2° 2?.
Sixth aspect of the present application provides crystalline form DR2 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 2.
Seventh aspect of the present application provides a process for preparing crystalline form DR2 of ribociclib succinate comprising
a) providing a mixture of ribociclib succinate in a suitable solvent or mixtures thereof; and
b) isolating crystalline form DR2 of ribociclib succinate.
Eighth aspect of the present application relates to a composition comprising crystalline form DR2 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Ninth aspect of the present application relates to crystalline form DR3 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 6.43, 9.33, 11.09, 16.01 and 25.16 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR3 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 7.53, 12.52, 13.92, 14.70, 17.46 and 21.22 ± 0.2° 2?.
Tenth aspect of the present application relates to crystalline form DR3 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 3.
Eleventh aspect of the present application relates to a process for preparing crystalline form DR3 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a solvent comprising benzyl alcohol;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR3 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.
Twelfth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR3 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Thirteenth aspect of the present application relates to crystalline form DR4 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 6.38, 10.52, 13.50 and 25.31 ± 0.2° 2?. In embodiments, the present application relates to crystalline form DR4 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 6.91, 14.29, 16.25, 19.72 and 20.97 ± 0.2° 2?.
Fourteenth aspect of the present application relates to crystalline form DR4 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 4.
Fifteenth aspect of the present application relates to a process for preparing crystalline form DR4 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a solvent comprising benzyl alcohol;
b) optionally filtering the un-dissolved particles;
c) adding an anti-solvent comprising methyl tertiary butyl ether
d) isolating crystalline form DR4 of ribociclib succinate from the solution of step c); and
e) optionally, drying the isolated product at suitable temperature.
Sixteenth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR4 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Seventeenth aspect of the present application relates to crystalline form DR5 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.68, 8.12, and 10.40 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR5 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 12.44, 13.93, 14.84, 17.30, 20.39, 21.70 and 28.27 ± 0.2° 2?.
Eighteenth aspect of the present application relates to crystalline form DR5 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 5.
Nineteenth aspect of the present application relates to a process for preparing crystalline form DR5 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a suitable solvent;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR5 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.
Twentieth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR5 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Twenty-first aspect of the present application relates to crystalline form DR6 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.58, 9.06, 9.41, and 15.97 ± 0.2° 2?. In embodiments, the present application relates to crystalline form DR6 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 10.79, 12.90, 18.01, 19.88 and 21.93 ± 0.2° 2?.
Twenty-second aspect of the present application relates to crystalline form DR6 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 6.
Twenty-third aspect of the present application relates to a process for preparing crystalline form DR6 of ribociclib succinate comprising, drying crystalline form DR5 of ribociclib succinate at suitable temperature.
Twenty-fourth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR6 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Twenty-fifth aspect of the present application relates to crystalline form DR7 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.52, 10.74 and 13.05 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR7 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 14.0, 21.46 and 22.09 ± 0.2° 2?.
Twenty-sixth aspect of the present application relates to crystalline form DR7 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 7.
Twenty-seventh aspect of the present application relates to a process for preparing crystalline form DR7 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a suitable solvent;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR7 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.
Twenty-eighth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR7 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Twenty-ninth aspect of the present application relates to crystalline form DR8 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.84, 9.02, 10.19 and 16.29 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR8 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 10.76, 13.07, 14.04, 14.94, 18.46, 19.17, 20.10, 22.14 and 26.36 ± 0.2° 2?.
Thirtieth aspect of the present application relates to crystalline form DR8 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 8.
Thirty-first aspect of the present application relates to a process for preparing crystalline form DR8 of ribociclib succinate comprising
a) mixing ribociclib succinate with a suitable solvent or a mixture thereof;
b) isolating the resulting solid from the mixture of step a);
c) optionally, drying the isolated material at suitable temperature;
d) mixing the dried material of step c) with a suitable solvent or a mixture thereof;
e) isolating crystalline form DR8 of ribociclib succinate from the mixture of step d); and
f) optionally, drying the isolated product at suitable temperature.
Thirty-Second aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR8 of ribociclib succinate and one or more pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of crystalline form DR1 of ribociclib succinate.
Figure 2 is an illustration of a PXRD pattern of crystalline form DR2 of ribociclib succinate.
Figure 3 is an illustration of a PXRD pattern of crystalline form DR3 of Ribociclib succinate.
Figure 4 is an illustration of a PXRD pattern of crystalline form DR4 of Ribociclib succinate.
Figure 5 is an illustration of a PXRD pattern of crystalline form DR5 of Ribociclib succinate.
Figure 6 is an illustration of a PXRD pattern of crystalline form DR6 of Ribociclib succinate.
Figure 7 is an illustration of a PXRD pattern of crystalline form DR7 of Ribociclib succinate.
Figure 8 is an illustration of a PXRD pattern of crystalline form DR8 of Ribociclib succinate.

DETAILED DESCRIPTION OF INVENTION
First aspect of the present application relates to crystalline form DR1 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 4.84, 8.98, and 16.29 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR1 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at 10.74, 14.28, 13.06, 17.93, 18.46, 19.17, 20.09, 22.13 and 26.32 ± 0.2° 2?.
Second aspect of the present application relates to crystalline form DR1 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 1.
Third aspect of the present application provides a process for preparing crystalline form DR1 of ribociclib succinate comprising
a) keeping amorphous form of ribociclib succinate for a sufficient time; and
b) isolating crystalline form DR1 of ribociclib succinate.
The amorphous form of ribociclib succinate may be prepared by a process, as reported in the co-pending application, IN201641031408. The amorphous form may be kept in a suitable condition for a sufficient time to convert to crystalline form DR1 of ribociclib succinate. The suitable condition may include a temperature condition of about 0 °C to about 50 °C. Specifically, the suitable condition may include a temperature of about 0 °C to about 20 °C. More specifically, the suitable condition may include a temperature of about 0 °C to about 10 °C. The sufficient time may be 1 month to 6 months. Specifically, the sufficient time may be 3 months.
Isolation of crystalline form DR1 obtained in step b) may be performed by any technique known in the art. Optionally, the crystalline form DR1 may be dried under suitable condition.
The obtained crystalline form DR1 of ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form DR1 of ribociclib succinate. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form DR1 of ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The crystalline form DR1 of ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising ribociclib succinate.
Fourth aspect of the present application relates to a composition comprising crystalline form DR1 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Fifth aspect of the present application relates to crystalline form DR2 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 4.57, 6.30, 7.13, 11.25 and 24.14 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR2 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at 18.22, 19.62 and 26.11 ± 0.2° 2?.
Sixth aspect of the present application provides crystalline form DR2 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 2.
Seventh another aspect of the present application provides a process for preparing crystalline form DR2 of ribociclib succinate comprising
a) providing a mixture of ribociclib succinate in a suitable solvent or mixtures thereof; and
b) isolating crystalline form DR2 of ribociclib succinate.
The suitable solvent of step a) includes but not limited to aromatic hydrocarbon solvent such as toluene, xylene and the like, aliphatic hydrocarbon solvent such as hexane, cyclohexane and the like; ether solvent such as diisopropyl ether, diethyl ether and the like. Specifically, the solvent is aliphatic hydrocarbon solvent. More specifically, the solvent is hexane. In one embodiment, the mixture of ribociclib succinate and the suitable solvent may be heated to achieve complete dissolution of ribociclib succinate in the solvent.
In one of the embodiments of step a), any physical form of ribociclib succinate may be utilized, which may be crystalline or amorphous, for providing the mixture of ribociclib succinate in a suitable solvent or mixtures thereof. In another embodiment of step a), any physical form of ribociclib succinate may be utilized, which may be anhydrous or hydrate, for providing the mixture of ribociclib succinate in suitable solvent or mixtures thereof. In another embodiment, amorphous form of ribociclib succinate, as reported in the co-pending application IN201641031408 may be used in step a). In another embodiment, crystalline anhydrous form of ribociclib succinate, as reported in the WO’805 application may be used in step a).
In one embodiment of step a), the seed crystals of crystalline form DR2 of ribociclib succinate may be optionally added to the mixture of step a).
Isolation of crystalline form DR2 obtained in step b) may be performed by any technique known in the art. In one embodiment, crystalline form DR2 may be isolated from the mixture of step b) by evaporation. In another embodiment, crystalline form DR2 of ribociclib succinate may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form DR2 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The obtained crystalline form DR2 of ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form DR2 of ribociclib succinate. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form DR2 of ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The crystalline form DR2 of ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising ribociclib succinate.
Eighth aspect of the present application relates to a composition comprising crystalline form DR2 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Ninth aspect of the present application relates to crystalline form DR3 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 6.43, 9.33, 11.09, 16.01 and 25.16 ± 0.2° 2?. In embodiments, the present application relates to crystalline form DR3 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 7.53, 12.52, 13.92, 14.70, 17.46 and 21.22 ± 0.2° 2?.
Tenth aspect of the present application provides crystalline form DR3 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 3.
Eleventh aspect of the present application provides a process for preparing crystalline form DR3 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a solvent comprising benzyl alcohol;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR3 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.
In one embodiment crystalline Form DR3 of ribociclib succinate may be a benzyl alcohol solvate.
In embodiments of step a), the solvent may be a mixture of benzyl alcohol and an organic solvent. The organic solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like. In a specific embodiment, the solvent may be benzyl alcohol.
In one embodiment of step a), a mixture of ribociclib succinate and a solvent comprising benzyl alcohol may be heated to dissolve ribociclib succinate in the solvent. In a specific embodiment, a mixture of ribociclib succinate and a solvent comprising benzyl alcohol may be heated at about 40 °C to about 50 °C to dissolve ribociclib succinate in the solvent.
In one of the embodiments of step a), any physical form of ribociclib succinate may be utilized, which may be crystalline or amorphous, for providing the solution of ribociclib succinate in a solvent comprising benzyl alcohol. In another embodiment of step a), any physical form of ribociclib succinate may be utilized, which may be anhydrous or hydrate, for providing the solution of ribociclib succinate in a solvent comprising benzyl alcohol. Yet in another embodiment, any of the polymorphic form as reported in the US’ 732 patent may be used in step a). Still in another embodiment, crystalline form I of mono-succinate salt of ribociclib, as reported in the CN’ 533 application may be used in step a).
In one embodiment, the crystalline form DR3 of ribociclib succinate may optionally be added to the solution of ribociclib succinate in a solvent comprising benzyl alcohol as seed crystals.
Isolation of crystalline form DR3 of ribociclib succinate in step c) may be performed by any technique known in the art. Specifically, crystalline form DR3 of ribociclib succinate may be isolated from the mixture of step b) by filtration followed by cooling the solution to lower temperatures. Optionally, the crystalline form DR3 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 45 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 48 hours, or longer.
The crystalline form DR3 of ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form DR3 of ribociclib succinate. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form DR3 of ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The crystalline form DR3 of ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising Ribociclib succinate.
Twelfth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR3 of Ribociclib succinate and one or more pharmaceutically acceptable excipient.
Thirteenth aspect of the present application relates to crystalline form DR4 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 6.38, 10.52, 13.50 and 25.31 ± 0.2° 2?. In embodiments, the present application relates to crystalline form DR4 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 6.91, 14.29, 16.25, 19.72 and 20.97 ± 0.2° 2?.
Fourteenth aspect of the present application relates to crystalline form DR4 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 4.
Fifteenth aspect of the present application relates to a process for preparing crystalline form DR4 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a solvent comprising benzyl alcohol;
b) optionally filtering the un-dissolved particles;
c) adding an anti-solvent comprising methyl tertiary butyl ether
d) isolating crystalline form DR4 of ribociclib succinate from the solution of step c); and
e) optionally, drying the isolated product at suitable temperature.
In one embodiment crystalline Form DR4 of ribociclib succinate may be a benzyl alcohol solvate.
In embodiments of step a), the solvent may be a mixture of benzyl alcohol and an organic solvent. The organic solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like. In a specific embodiment, the solvent may be benzyl alcohol.
In one embodiment of step a), a mixture of ribociclib succinate and a solvent comprising benzyl alcohol may be heated to dissolve ribociclib succinate in the solvent. In a specific embodiment, a mixture of ribociclib succinate and a solvent comprising benzyl alcohol may be heated at about 40 °C to about 50 °C to dissolve ribociclib succinate in the solvent.
In one of the embodiments of step a), any physical form of ribociclib succinate may be utilized, which may be crystalline or amorphous, for providing the solution of ribociclib succinate in a solvent comprising benzyl alcohol. In another embodiment of step a), any physical form of ribociclib succinate may be utilized, which may be anhydrous or hydrate, for providing the solution of ribociclib succinate in a solvent comprising benzyl alcohol. Yet in another embodiment, any of the polymorphic form as reported in the US’ 732 patent may be used in step a). Still in another embodiment, crystalline form I of mono-succinate salt of ribociclib, as reported in the CN’ 533 application may be used in step a).
In embodiments of step c), the anti-solvent may be a mixture of methyl tertiary butyl ether and an organic solvent. The organic solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like. In a specific embodiment, the anti-solvent may be methyl tertiary butyl ether.
Isolation of crystalline form DR4 of ribociclib succinate in step d) may be performed by any technique known in the art. Specifically, crystalline form DR4 of ribociclib succinate may be isolated from the mixture of step b) by anti-solvent precipitation. Optionally, the crystalline form DR4 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 45 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The crystalline form DR4 of ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form DR4 of ribociclib succinate. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form DR4 of ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The crystalline form DR4 of ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising Ribociclib succinate.
Sixteenth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR4 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Seventeenth aspect of the present application relates to crystalline form DR5 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.68, 8.12, and 10.40 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR5 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 12.44, 13.93, 14.84, 17.30, 20.39, 21.70 and 28.27 ± 0.2° 2?.
Eighteenth aspect of the present application relates to crystalline form DR5 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 5.
Nineteenth aspect of the present application relates to a process for preparing crystalline form DR5 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a suitable solvent;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR5 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.
In embodiments of step a), the suitable solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like. In a specific embodiment, the solvent may be an alcohol solvent. More specifically, the alcohol solvent may be methanol.
In one embodiment of step a), mixture of ribociclib succinate and solvent may be heated to dissolve ribociclib succinate in the solvent. In a specific embodiment, a mixture of ribociclib succinate and a solvent may be heated at about 45 °C to about 55 °C to dissolve ribociclib succinate in the solvent.
In one of the embodiments of step a), any physical form of ribociclib succinate may be utilized, which may be crystalline or amorphous, for providing the solution of ribociclib succinate in a solvent. In another embodiment of step a), any physical form of ribociclib succinate may be utilized, which may be anhydrous or hydrate, for providing the solution of ribociclib succinate in a solvent. Yet in another embodiment, any of the polymorphic form as reported in the US’ 732 patent may be used in step a). Still in another embodiment, crystalline form I of mono-succinate salt of ribociclib, as reported in the CN’ 533 application may be used in step a).
Isolation of crystalline form DR5 of ribociclib succinate in step c) may be performed by any technique known in the art. Specifically, crystalline form DR5 of ribociclib succinate may be isolated from the solution of step b) by evaporation. Optionally, the crystalline form DR5 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 100 °C and more specifically less than about 80 °C and most specifically at 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 48 hours, or longer.
The crystalline form DR5 of ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form DR5 of ribociclib succinate. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form DR5 of ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The crystalline form DR5 of ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising Ribociclib succinate.
Twentieth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR5 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Twenty-first aspect of the present application relates to crystalline form DR6 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.58, 9.06, 9.41, and 15.97 ± 0.2° 2?. In embodiments, the present application relates to crystalline form DR6 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 10.79, 12.90, 18.01, 19.88 and 21.93 ± 0.2° 2?.
Twenty-second aspect of the present application relates to crystalline form DR6 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 6.
Twenty-Third aspect of the present application relates to a process for preparing crystalline form DR6 of ribociclib succinate comprising, drying crystalline form DR5 of ribociclib succinate at suitable temperature.
Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 170 °C and more specifically less than about 150 °C and most specifically at temperatures less than about 130 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
Twenty-fourth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR6 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Twenty-fifth of the present application relates to crystalline form DR7 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.52, 10.74 and 13.05 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR7 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 14.0, 21.46 and 22.09 ± 0.2° 2?.
Twenty-sixth of the present application relates to crystalline form DR7 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 7.
Twenty-seventh aspect of the present application relates to a process for preparing crystalline form DR7 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a suitable solvent;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR7 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.
In embodiments of step a), the suitable solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like. In a specific embodiment, the solvent may be an alcohol solvent. More specifically, the alcohol solvent may be methanol.
In one embodiment of step a), mixture of ribociclib succinate and solvent may be heated to dissolve ribociclib succinate in the solvent. In a specific embodiment, a mixture of ribociclib succinate and a solvent may be heated at about 60 °C to about 80 °C to dissolve ribociclib succinate in the solvent.
In one of the embodiments of step a), any physical form of ribociclib succinate may be utilized, which may be crystalline or amorphous, for providing the solution of ribociclib succinate in a solvent. In another embodiment of step a), any physical form of ribociclib succinate may be utilized, which may be anhydrous or hydrate, for providing the solution of ribociclib succinate in a solvent. Yet in another embodiment, any of the polymorphic form as reported in the US’ 732 patent may be used in step a). Still in another embodiment, crystalline form I of mono-succinate salt of ribociclib, as reported in the CN’ 533 application may be used in step a).
In embodiment of step c) isolation of crystalline form DR7 of ribociclib succinate may be performed by any technique known in the art. Specifically, crystalline form DR7 of ribociclib succinate may be isolated from the solution of step b) by filtration.
In embodiment of step c) the solution of ribociclib succinate in methanol was cooled to suitable temperature to precipitate crystalline form DR7 of ribociclib succinate. Specifically the solution was cooled to 0 °C. Optionally, the crystalline form DR7 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 45 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The crystalline form DR7 of ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form DR7 of ribociclib succinate. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form DR7 of ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The crystalline form DR7 of ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising ribociclib succinate.
Twenty-eighth aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR7 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Twenty-ninth aspect of the present application relates to crystalline form DR8 of ribociclib succinate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.84, 9.02, 10.19 and 16.29 ± 0.2° 2?. In embodiments, the present application provides crystalline form DR8 of ribociclib succinate characterized by its PXRD pattern having additional peaks located at about 10.76, 13.07, 14.04, 14.94, 18.46, 19.17, 20.10, 22.14 and 26.36 ± 0.2° 2?.
Thirtieth aspect of the present application relates to crystalline form DR8 of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in Figure 8.
Thirty-first aspect of the present application relates to a process for preparing crystalline form DR8 of ribociclib succinate comprising
a) mixing ribociclib succinate with a suitable solvent or a mixture thereof;
b) isolating the resulting solid from the mixture of step a);
c) optionally, drying the isolated material at suitable temperature;
d) mixing the dried material of step c) with a suitable solvent or a mixture thereof;
e) isolating the crystalline form DR8 of ribociclib succinate from the mixture of step d); and
f) optionally, drying the isolated product at suitable temperature.
In embodiments of step a), the suitable solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like. In a specific embodiment, the solvent may be an alcohol solvent. More specifically, the alcohol solvent may be methanol.
In one embodiment of step a), mixture of ribociclib succinate and solvent may be heated to dissolve ribociclib succinate in the solvent. In a specific embodiment, a mixture of ribociclib succinate and a solvent may be heated at about 45 °C to about 55 °C to dissolve ribociclib succinate in the solvent.
In one of the embodiments of step a), any physical form of ribociclib succinate may be utilized, which may be crystalline or amorphous, for providing the solution of ribociclib succinate in a solvent. In another embodiment of step a), any physical form of ribociclib succinate may be utilized, which may be anhydrous or hydrate, for providing the solution of ribociclib succinate in a solvent. Yet in another embodiment, any of the polymorphic form as reported in the US’ 732 patent may be used in step a). Still in another embodiment, crystalline form I of mono-succinate salt of ribociclib, as reported in the CN’ 533 application may be used in step a).
In embodiment of step b) isolation of resulting solid may be performed by any technique known in the art. Specifically, resulting the solid may be isolated from the mixture of step a) by filtration.
Optionally, the resulting solid of step b) may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
In embodiments of step d), the suitable solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; aliphatic hydrocarbons such as n-hexane, n-heptane and the like; esters such as ethyl acetate, propyl acetate and the like. In a specific embodiment, the solvent may be an aliphatic hydrocarbon solvent. More specifically, the aliphatic hydrocarbon solvent may be n-hexane.
In embodiment of step e) isolation of the crystalline form DR8 of ribociclib succinate may be performed by any technique known in the art. Specifically, the crystalline form DR8 of ribociclib succinate may be isolated from the mixture of step a) by filtration.
Optionally, the crystalline form DR8 of ribociclib succinate of step e) may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 46 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The crystalline form DR8 of ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form DR8 of ribociclib succinate. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form DR8 of ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The crystalline form DR8 of ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising ribociclib succinate.
Thirty-Second aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR8 of ribociclib succinate and one or more pharmaceutically acceptable excipient.
Yet another aspect of the present application relates to a pharmaceutical composition comprising crystalline form DR1 or crystalline form DR2 or crystalline form DR3, crystalline form DR4 or crystalline form DR5 or crystalline form DR6 or crystalline form DR7 or crystalline form DR8 of ribociclib succinate and one or more pharmaceutically acceptable excipient. Crystalline form DR1 or crystalline form DR2 or crystalline form DR3, crystalline form DR4 or crystalline form DR5 or crystalline form DR6 or crystalline form DR7 or crystalline form DR8 of ribociclib succinate with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
X-ray powder diffractograms of form DR1 and DR2 are recorded on Bruker X-ray Diffractometer equipped with Lynxeye XE detector using generator setting of 40 mA and 40 kV at room temperature with X-ray source of copper (1.5418 Å). The diffractograms were collected over a 2? range of 3-40 °.
X-ray powder diffractograms of form DR3 and DR4 are recorded on PANalytical X’Pert PRO diffractometer equipped with X’Celerator detector using generator setting of 40 mA and 45 kV at room temperature with X-ray source of copper (1.5406Å). The diffractograms were collected over a 2? range of 3-40 °.
X-ray powder diffractograms of form DR5, DR6 and DR8 are recorded on PANalytical X’Pert PRO diffractometer equipped with X’Celerator detector using generator setting of 40 mA and 45 kV at room temperature with X-ray source of copper (1.5406Å). The diffractograms were collected over a 2? range of 3-40 °.
X-ray powder diffractogram of form DR7 is recorded on BRUKER D8 DISCOVER diffractometer equipped with LYNEX EYE XE detector using generator setting of 40 mA and 40 kV at room temperature with X-ray source of copper (1.5406Å). The diffractograms were collected over a 2? range of 3-40 °.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
A name used herein to characterize a crystalline form should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
In general, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?±0.2º) of 19.6º" means "having a diffraction peak at a diffraction angle (2?) of 19.4º to 19.8º. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES
Example 1: Preparation of crystalline form DR1 of ribociclib succinate
Amorphous form of ribociclib succinate was stored in a capped transparent sample holder for 3 months at 2-8 °C to afford the desired compound.
Example 2: Preparation of crystalline form DR2 of ribociclib succinate
Ribociclib succinate (42.9) was mixed with n-hexane (400 mL). The mixture was stirred for 10 minutes at 27 °C and filtered. The solid was washed with n-hexane (2 x 60 mL). The solid was dried at 50 °C stirred for 4 hours to afford the desired compound.
Example 3: Preparation of crystalline form DR3 of Ribociclib succinate
Ribociclib succinate (2 g) was dissolved in benzyl alcohol (40 mL) at 45 °C. The solution was filtered to separate the unwanted particles. The resulting clear solution was kept in an easy max reactor at 5 °C for about 27 hours. Seed crystals were added to the above solution and the reaction mass was maintained in easy max reactor at 5 °C for about 45 hours. The precipitated solid was filtered under vacuum at 25 °C. The resulting wet solid was dried in Air Tray Dryer (ATD) at about 45 °C for about 2 days to provide the title compound.
Example 4: Preparation of crystalline form DR4 of Ribociclib succinate
Ribociclib succinate (1.5 g) was dissolved in benzyl alcohol (30 mL) at 40 °C. The solution was filtered to separate the unwanted particles. Methyl tertiary butyl ether (95 mL) was slowly added to the above clear solution at 5 °C. The reaction mass was maintained for about 2 hrs. The precipitated solid was filtered under vacuum at 25 °C. The resulting solid was dried in Air Tray Dryer (ATD) at 45 °C for about 20 hours to provide the title compound.
Example 5: Preparation of crystalline form DR5 of Ribociclib succinate
Ribociclib succinate (5 g) was dissolved in methanol (400 mL) at 50 °C. The solution was filtered to separate the unwanted particles. The resulting clear solution was evaporated under reduced pressure at 60 °C using buchi rotavapor. The residue was dried under reduced pressure at about 60 °C for about 5 hours. The resulting solid was further dried in Air Tray Dryer (ATD) at about 45 °C for about 26 hours to afford the title compound.
Example 6: Preparation of crystalline form DR6 of Ribociclib succinate
Crystalline form DR5 of ribociclib succinate (1.5 g) as obtained in the example 1 was further dried in Vacuum Tray Dryer (VTD) at 125 °C for about 2 hours to afford the title compound.
Example 7: Preparation of crystalline form DR7 of ribociclib succinate
Ribociclib succinate (5 g) was dissolved in methanol (300 mL) at 70 °C. The solution was filtered to separate the unwanted particles. The resulting solution was cooled to 0 °C and stirred for about 3 h at the same temperature. The reaction mass was slowly brought to 25 °C and precipitated solid was filtered at the same temperature. The resulting solid was dried in Vacuum Tray Dryer (VTD) at about 25 °C for about 90 hours and then dried at about 45 °C for about 22 h to afford the title compound.

Example 8: Preparation of crystalline form DR8 of ribociclib succinate
Ribociclib succinate (28 g) was mixed with methanol (750 mL) at 25 °C. The reaction mass was heated to 50 °C and stirred for about 24 hours at the same temperature. The reaction mass was then cooled to 25 °C. The precipitated solid was filtered and dried in Vacuum Tray Dryer (VTD) at about 40 °C for about 6 hours. The resulted solid was mixed with n-hexane (200 mL) at 25 °C and stirred for about 30 minutes at 30 °C. The reaction mass was then filtered and washed with n-hexane (120 mL) at the same temperature. The resulting solid was dried in Vacuum Tray Dryer (VTD) at about 46 °C for about 5 hours to afford the title compound.

,CLAIMS:We claim:
1. Crystalline form of ribociclib succinate wherein crystalline form is selected from a group consisting of:
i) crystalline form DR1 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at 4.84, 8.98, and 16.29 ± 0.2° 2?; or powder X-ray diffraction pattern having peaks located at 4.84, 8.98, 10.74, 13.06, 14.28, 16.29, 17.93, 18.46, 19.17, 20.09, 22.13 and 26.32 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 1.
ii) crystalline form DR2 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at 4.57, 6.30, 7.13, 11.25 and 24.14 ± 0.2° 2?; or powder X-ray diffraction pattern having peaks located at 4.57, 6.30, 7.13, 11.25, 18.22, 19.62, 24.14 and 26.11 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 2.
iii) crystalline form DR3 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at about 6.43, 9.33, 11.09, 16.01 and 25.16 ± 0.2° 2?; or powder X-ray diffraction pattern having peaks located at about 6.43, 7.53, 9.33, 11.09, 12.52, 13.92, 14.70, 16.01, 17.46 21.22 and 25.16 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 3.
iv) crystalline form DR4 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at about 6.38, 10.52, 13.50 and 25.31 ± 0.2° 2?; or powder X-ray diffraction pattern having peaks located at about 6.38, 6.91, 10.52, 13.50, 14.29, 16.25, 19.72, 20.97 and 25.31 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 4.
v) crystalline form DR5 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at about 4.68, 8.12, and 10.40 ± 0.2° 2?; or powder X-ray diffraction pattern having peaks located at about 4.68, 8.12, 10.40, 12.44, 13.93, 14.84, 17.30, 20.39, 21.70 and 28.27 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 5.
vi) crystalline form DR6 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at about 4.58, 9.06, 9.41, and 15.97 ± 0.2° 2?; or powder X-ray diffraction pattern having peaks located at about 4.58, 9.06, 9.41, 10.79, 12.90, 15.97, 18.01, 19.88 and 21.93 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 6.
vii) crystalline form DR7 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at about 4.52, 10.74 and 13.05 ± 0.2° 2?; or powder X-ray diffraction pattern having peaks located at about 4.52, 10.74, 13.05, 14.0, 21.46 and 22.09 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 7.
viii) crystalline form DR8 of ribociclib succinate characterized by its powder X-ray diffraction pattern having peaks at about 4.84, 9.02, 10.19 and 16.29 ± 0.2° 2?; or powder X-ray diffraction pattern having additional peaks located at about 4.84, 9.02, 10.19, 10.76, 13.07, 14.04, 14.94, 16.29, 18.46, 19.17, 20.10, 22.14 and 26.36 ± 0.2° 2?; or a powder X-ray diffraction pattern substantially as illustrated in Figure 8.

2. A process for preparing crystalline form DR2 of ribociclib succinate comprising:
a) providing a mixture of ribociclib succinate in a suitable solvent or mixtures thereof; and
b) isolating crystalline form DR2 of ribociclib succinate.

3. A process for preparing crystalline form DR3 of ribociclib succinate comprising:
a) dissolving ribociclib succinate in a solvent comprising benzyl alcohol;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR3 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.

4. A process for preparing crystalline form DR4 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a solvent comprising benzyl alcohol;
b) optionally filtering the un-dissolved particles;
c) adding an anti-solvent comprising methyl tertiary butyl ether
d) isolating crystalline form DR4 of ribociclib succinate from the solution of step c); and
e) optionally, drying the isolated product at suitable temperature.

5. A process for preparing crystalline form DR5 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a suitable solvent;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR5 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.

6. A process for preparing crystalline form DR6 of ribociclib succinate comprising, drying crystalline form DR5 of ribociclib succinate at suitable temperature.

7. A process for preparing crystalline form DR7 of ribociclib succinate comprising
a) dissolving ribociclib succinate in a suitable solvent;
b) optionally filtering the un-dissolved particles;
c) isolating crystalline form DR7 of ribociclib succinate from the solution of step b); and
d) optionally, drying the isolated product at suitable temperature.
8. A process for preparing crystalline form DR8 of ribociclib succinate comprising
a) mixing ribociclib succinate with a suitable solvent or a mixture thereof;
b) isolating the resulting solid from the mixture of step a);
c) optionally, drying the isolated material at suitable temperature;
d) mixing the dried material of step c) with a suitable solvent or a mixture thereof;
e) isolating the crystalline form DR8 of ribociclib succinate from the mixture of step d); and
f) optionally, drying the isolated product at suitable temperature.

9. A pharmaceutical composition comprising crystalline form of ribociclib succinate of claim 1 and one or more pharmaceutically acceptable excipient.