DESC:he following specification particularly describes the invention and the manner in which it is to be performed:

CRYSTALLINE FORMS OF PALBOCICLIB

INTRODUCTION
One aspect of the present application relates to crystalline forms M1, M2, M3, M4, M5 and M6 of palbociclib and processes for preparation thereof.
Palbociclib is a cylcin-dependent kinase-4 inhibitor indicated for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. Palbociclib is chemically known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2yl]amino}-pyrido[2,3-d]pyrimidin-7(8H)-one and has following structural formula:

PCT patent application, WO2014128588A1 (hereinafter referred as the WO’588 application) discloses crystalline form A and crystalline form B of palbociclib.

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 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.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. Typically, the more crystalline the pharmaceutical agent, the lower is its bioavailability or vice varsa, reducing the degree of crystallinity has a positive effect on bioavailability. Amorphous material generally offers interesting properties such as higher dissolution rate and solubility than crystalline forms, typically resulting in improved bioavailability. An amorphous form of cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.
Hence, there remains a need for alternate solid forms of palbociclib and processes for preparing them.
SUMMARY
One aspect of the present application relates to crystalline form M1 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 3.42, 3.88, 9.56, 11.80 and 16.60 ± 0.2° 2?. In embodiments, the present application provides crystalline form M1 of palbociclib characterized by its PXRD pattern having additional peaks located at about 7.40, 7.66, 20.82, 24.04, 25.47 and 27.01 ± 0.2° 2?. Still in other embodiments, the present application provides crystalline form M1 of palbociclib characterized by its PXRD pattern having additional peaks located at about 6.24, 12.70, 13.78, 29.84 ± 0.2° 2?.
Another aspect of the present application provides crystalline form M1 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 1.
Yet another aspect of the present application provides a process for preparing crystalline form M1 of palbociclib comprising:
a) providing a mixture of palbociclib in a suitable solvent or mixtures thereof;
b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and
c) isolating crystalline form M1 of palbociclib.
Another aspect of the present application relates to crystalline form M2 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern substantially as illustrated in Figure 2.
Still another aspect of the present application provides a process for preparing crystalline form M2 of palbociclib comprising drying crystalline form M1 of palbociclib under suitable condition.

Yet another aspect of the present application relates to crystalline form M3 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 3.49, 3.95, 4.88, 9.62, 11.85 and 16.67 ± 0.2° 2?. In embodiments, the present application provides crystalline form M3 of palbociclib characterized by its PXRD pattern having additional peaks located at about 6.28, 12.80, 13.83, 19.56, 24.12 and 25.54 ± 0.2° 2?.
Yet another aspect of the present application provides crystalline form M3 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 3 or Figure 4.
Still another aspect of the present application provides a process for preparing crystalline form M3 of palbociclib comprising:
a) providing a mixture of palbociclib in a suitable solvent or mixtures thereof;
b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and
c) isolating crystalline form M3 of palbociclib.
Another aspect of the present application relates to crystalline form M4 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern substantially as illustrated in Figure 5.
Still another aspect of the present application provides a process for preparing crystalline form M4 of palbociclib comprising slurring crystalline form M3 of palbociclib in a suitable solvent under suitable conditions.
Another aspect of the present application relates to crystalline form M5 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern substantially as illustrated in Figure 6.
Still another aspect of the present application provides a process for preparing crystalline form M5 of palbociclib comprising slurring crystalline form M1 of palbociclib in a suitable solvent under suitable conditions.
One aspect of the present application relates to crystalline form M6 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.44, 8.64, 11.57, 13.36, 17.30 and 19.00 ± 0.2° 2?. In embodiments, the present application provides crystalline form M6 of palbociclib characterized by its PXRD pattern having additional peaks located at about 7.73, 9.96 and 27.00 ± 0.2° 2?.
Another aspect of the present application provides crystalline form M6 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 7.
Yet another aspect of the present application provides a process for preparing crystalline form M6 of palbociclib comprising:
a) providing a mixture of palbociclib in a suitable solvent or mixtures thereof;
b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and
c) isolating crystalline form M6 of palbociclib.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1: The PXRD pattern of crystalline form M1 of palbociclib.
Figure 2: The PXRD pattern of crystalline form M2 of palbociclib.
Figure 3: The PXRD pattern of crystalline form M3 of palbociclib obtained by the process of example 20.
Figure 4: The PXRD pattern of crystalline form M3 of palbociclib obtained by the process of example 21.
Figure 5: The PXRD pattern of crystalline form M4 of palbociclib.
Figure 6: The PXRD pattern of crystalline form M5 of palbociclib.
Figure 7: The PXRD pattern of crystalline form M6 of palbociclib.
DETAILED DESCRIPTION
One aspect of the present application relates to crystalline form M1 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 3.42, 3.88, 9.56, 11.80 and 16.60 ± 0.2° 2?. In embodiments, the present application provides crystalline form M1 of palbociclib characterized by its PXRD pattern having additional peaks located at about 7.40, 7.66, 20.82, 24.04, 25.47 and 27.01 ± 0.2° 2?. Still in other embodiments, the present application provides crystalline form M1 of palbociclib characterized by its PXRD pattern having additional peaks located at about 6.24, 12.70, 13.78, 29.84 ± 0.2° 2?.
Another aspect of the present application provides crystalline form M1 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 1.
Yet another aspect of the present application provides a process for preparing crystalline form M1 of palbociclib comprising:
a) providing a mixture of palbociclib in a suitable solvent or mixtures thereof;
b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and
c) isolating crystalline form M1 of palbociclib.
The suitable solvent of step a), includes but not limited to, alcoholic solvent such as methanol, ethanol, benzyl alcohol, and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like or mixture thereof. Specifically, the solvent of step a) may be an alcoholic solvent. More specifically, the solvent of step a) may be benzyl alcohol. In another embodiment of step a), any physical form of palbociclib may be utilized, which may be crystalline or amorphous, for providing the mixture of palbociclib in suitable solvent or mixtures thereof. In yet another embodiment of step a), any physical form of palbociclib may be utilized, which may be anhydrous or hydrate, for providing the mixture of palbociclib in suitable solvent or mixtures thereof. The suitable anti-solvent of step b) includes but not limited to aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as n-heptane, n-hexane, cyclohexane, methyl cyclohexane, cyclohexanone and mixture thereof. Specifically, the suitable anti-solvent of step b) may be aliphatic hydrocarbon solvent. More specifically, the suitable anti-solvent of step b) may be a mixture of methyl cyclohexane and cyclohexanone.
In one embodiment of step b), the suitable anti-solvent or mixture thereof may be added to the mixture of step a). Alternatively, the mixture of step a) may be added to the suitable anti-solvent or mixture thereof.
Optionally, a suitable solvent of step a) may be added to the resulting mixture of step b). The resulting mixture of step b) may be stirred for suitable time at a suitable temperature. Specifically, the resulting mixture of step b) may be stirred for about 30 minutes to about 5 days at about 0 °C to about boiling point of the solvent. More specifically, the resulting mixture of step b) may be stirred for about 45 minutes at about 20 °C to about 30 °C.
In one embodiment, the seed crystals of crystalline form M1 of palbociclib may be optionally added to the mixture of step a) or step b).
Isolation of crystalline form M1 of palbociclib from the mixture of step b) may be performed by any technique known in the art. Specifically, crystalline form M1 of palbociclib may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form M1 of palbociclib 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 M1 of palbociclib 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 M1 of palbociclib. 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 M1 of palbociclib of the present application is stable and has excellent physico-chemical properties. The crystalline form M1 of palbociclib of the present application may be easily formulated into a pharmaceutical composition comprising palbociclib.
Still another aspect of the present application relates to a composition comprising crystalline form M1 of palbociclib and one or more pharmaceutically acceptable excipient.
Another aspect of the present application relates to crystalline form M2 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern substantially as illustrated in Figure 2.
Still another aspect of the present application provides a process for preparing crystalline form M2 of palbociclib comprising drying crystalline form M3 of palbociclib under suitable conditions.
In one embodiment, crystalline form M3 of palbociclib may be dried in an air tray drier or vacuum tray drier for about 30 minutes to about 72 hours at a temperature from about 25 °C to about 200 °C. Specifically, crystalline form M3 of palbociclib may be dried in an air tray drier for about 30 minutes to 5 hours at a temperature from about 60 °C to about 180 °C. More specifically, crystalline form M3 of palbociclib may be dried in an air tray drier for about 1 hour at a temperature from about 150 °C to about 160 °C.
The obtained crystalline form M2 of palbociclib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. 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 M2 of palbociclib of the present application is stable and has excellent physico-chemical properties. The crystalline form M2 of palbociclib of the present application may be easily formulated into a pharmaceutical composition comprising palbociclib.
Yet another aspect of the present application relates to a composition comprising crystalline form M2 of palbociclib and one or more pharmaceutically acceptable excipient.
Another aspect of the present application relates to crystalline form M3 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 3.49, 3.95, 4.88, 9.62, 11.85 and 16.67 ± 0.2° 2?. In embodiments, the present application provides crystalline form M3 of palbociclib characterized by its PXRD pattern having additional peaks located at about 6.28, 12.80, 13.83, 19.56, 24.12 and 25.54 ± 0.2° 2?.
Yet another aspect of the present application provides crystalline form M3 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 3 or Figure 4.
Still another aspect of the present application provides a process for preparing crystalline form M3 of palbociclib comprising:
a) providing a mixture of palbociclib in a suitable solvent or mixtures thereof;
b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and
c) isolating crystalline form M3 of palbociclib.
The suitable solvent of step a), includes but not limited to, alcoholic solvent such as methanol, ethanol, benzyl alcohol, and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like or mixture thereof. Specifically, the solvent of step a) may be an alcoholic solvent. More specifically, the solvent of step a) may be benzyl alcohol. In another embodiment of step a), any physical form of palbociclib may be utilized, which may be crystalline or amorphous, for providing the mixture of palbociclib in suitable solvent or mixtures thereof. In yet another embodiment of step a), any physical form of palbociclib may be utilized, which may be anhydrous or hydrate, for providing the mixture of palbociclib in suitable solvent or mixtures thereof. The suitable anti-solvent of step b) includes but not limited to aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as n-heptane, n-hexane, cyclohexane, methyl cyclohexane, cyclohexanone and mixture thereof. Specifically, the suitable anti-solvent of step b) may be aliphatic hydrocarbon solvent. More specifically, the suitable anti-solvent of step b) may be a mixture of methyl cyclohexane and cyclohexanone.
In one embodiment of step b), the suitable anti-solvent or mixture thereof may be added to the mixture of step a). Alternatively, the mixture of step a) may be added to the suitable anti-solvent or mixture thereof.
Optionally, a suitable solvent of step a) may be added to the resulting mixture of step b). The resulting mixture of step b) may be stirred for suitable time at a suitable temperature. Specifically, the resulting mixture of step b) may be stirred for about 30 minutes to about 5 days at about 0 °C to about boiling point of the solvent. More specifically, the resulting mixture of step b) may be stirred for about 1 hour to about 6 hours at about 20 °C to about 30 °C.
In one embodiment of step a) or step b), the seed crystals of crystalline form M3 of palbociclib may be optionally added to the mixture of step a) or step b).
Isolation of crystalline form M3 of palbociclib from the mixture of step b) may be performed by any technique known in the art. Specifically, crystalline form M3 of palbociclib may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form M3 of palbociclib 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 M3 of palbociclib 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 M3 of palbociclib. 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 M3 of palbociclib of the present application is stable and has excellent physico-chemical properties. The crystalline form M3 of palbociclib of the present application may be easily formulated into a pharmaceutical composition comprising palbociclib.
Yet another aspect of the present application relates to a composition comprising crystalline form M3 of palbociclib and one or more pharmaceutically acceptable excipient.

Another aspect of the present application relates to crystalline form M4 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern substantially as illustrated in Figure 5.
Still another aspect of the present application provides a process for preparing crystalline form M4 of palbociclib comprising slurrying crystalline form M3 of palbociclib in a suitable solvent under suitable condition.
The suitable solvent includes but not limited to aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as n-heptane, n-hexane, cyclohexane, methyl cyclohexane, cyclohexanone and the like; water and mixture thereof. More specifically, the suitable solvent is water. The reaction mass may be stirred for about 30 minutes to about 50 hours at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction mass may be stirred for about 45 minutes to about 5 hours at a temperature of about 20 °C to about 100 °C. More specifically, the reaction mass may be stirred for about 1 hour to about 2 hours at a temperature of about 60 °C to about 80 °C.
Isolation of crystalline form M4 of palbociclib from the reaction mixture may be performed by any technique known in the art. Specifically, crystalline form M4 of palbociclib may be isolated from the reaction mixture by filtration. Optionally, the crystalline form M4 of palbociclib 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 M4 of palbociclib 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 M4 of palbociclib. 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 M4 of palbociclib of the present application is stable and has excellent physico-chemical properties. The crystalline form M4 of palbociclib of the present application may be easily formulated into a pharmaceutical composition comprising palbociclib.
Yet another aspect of the present application relates to a composition comprising crystalline form M4 of palbociclib and one or more pharmaceutically acceptable excipient.
Another aspect of the present application relates to crystalline form M5 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern substantially as illustrated in Figure 6.
Still another aspect of the present application provides a process for preparing crystalline form M5 of palbociclib comprising slurring crystalline form M1 of palbociclib in a suitable solvent under suitable conditions.
The suitable solvent includes but not limited to aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as n-heptane, n-hexane, cyclohexane, methyl cyclohexane, cyclohexanone and mixture thereof. More specifically, the suitable solvent is toluene. The reaction mass may be stirred for about 30 minutes to about 50 hours at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction mass may be stirred for about 45 minutes to about 10 hours at a temperature of about 20 °C to about 100 °C. More specifically, the reaction mass may be stirred for about 4 hours to about 6 hours at a temperature of about 80 °C to about 100 °C. The reaction mixture may be kept aside for few days at ambient temperature to facilitate the formation of crystalline form M5 of palbociclib. Specifically, the reaction mixture may be kept aside for 1-25 days at ambient temperature to facilitate the formation of crystalline form M5 of palbociclib.
Isolation of crystalline form M5 of palbociclib from the reaction mixture may be performed by any technique known in the art. Specifically, crystalline form M5 of palbociclib may be isolated from the reaction mixture by filtration. Optionally, the crystalline form M5 of palbociclib 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 M5 of palbociclib 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 M5 of palbociclib. 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 M5 of palbociclib of the present application is stable and has excellent physico-chemical properties. The crystalline form M5 of palbociclib of the present application may be easily formulated into a pharmaceutical composition comprising palbociclib.
Yet another aspect of the present application relates to a composition comprising crystalline form M5 of palbociclib and one or more pharmaceutically acceptable excipient.
One aspect of the present application relates to crystalline form M6 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.44, 8.64, 11.57, 13.36, 17.30 and 19.00 ± 0.2° 2?. In embodiments, the present application provides crystalline form M6 of palbociclib characterized by its PXRD pattern having additional peaks located at about 7.73, 9.96 and 27.00 ± 0.2° 2?.
Another aspect of the present application provides crystalline form M6 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 7.
Yet another aspect of the present application provides a process for preparing crystalline form M6 of palbociclib comprising:
a) providing a mixture of palbociclib in a suitable solvent or mixtures thereof;
b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and
c) isolating crystalline form M6 of palbociclib.
The suitable solvent of step a), includes but not limited to, alcoholic solvent such as methanol, ethanol, benzyl alcohol, and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like or mixture thereof. Specifically, the solvent of step a) may be an alcoholic solvent. More specifically, the solvent of step a) may be benzyl alcohol. In another embodiment of step a), any physical form of palbociclib may be utilized, which may be crystalline or amorphous, for providing the mixture of palbociclib in suitable solvent or mixtures thereof. In yet another embodiment of step a), any physical form of palbociclib may be utilized, which may be anhydrous or hydrate, for providing the mixture of palbociclib in suitable solvent or mixtures thereof. In still another embodiment of step a), the mixture of palbociclib and the solvent may be heated from about 40 °C to about boiling point of the solvent. Specifically, the mixture of palbociclib and the solvent may be heated to about 90 °C.
The suitable anti-solvent of step b) includes but not limited to aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as n-heptane, n-hexane, cyclohexane, methyl cyclohexane, cyclohexanone; a ketone solvent such as methyl isopropyl ketone, acetone and the like; and mixture thereof. Specifically, the suitable anti-solvent of step b) may be ketone solvent. More specifically, the suitable anti-solvent of step b) may be methyl isopropyl ketone.
In one embodiment of step b), the suitable anti-solvent or mixture thereof may be added to the mixture of step a). Alternatively, the mixture of step a) may be added to the suitable anti-solvent or mixture thereof.
The resulting mixture of step b) may be stirred for suitable time at a suitable temperature. Specifically, the resulting mixture of step b) may be stirred for about 30 minutes to about 5 days at about 0 °C to about boiling point of the solvent. More specifically, the resulting mixture of step b) may be stirred for about 30 minutes at about 0 °C to about 30 °C.
In one embodiment, the seed crystals of crystalline form M6 of palbociclib may be optionally added to the mixture of step a) or step b).
Isolation of crystalline form M6 of palbociclib from the mixture of step b) may be performed by any technique known in the art. Specifically, crystalline form M6 of palbociclib may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form M6 of palbociclib 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 M6 of palbociclib 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 M6 of palbociclib. 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 M6 of palbociclib of the present application is stable and has excellent physico-chemical properties. The crystalline form M6 of palbociclib of the present application may be easily formulated into a pharmaceutical composition comprising palbociclib.
Still another aspect of the present application relates to a composition comprising crystalline form M6 of palbociclib and one or more pharmaceutically acceptable excipient.
One aspect of the present application provides pharmaceutically acceptable dosage form comprising crystalline form M1 or crystalline form M2 or crystalline form M3 or crystalline form M4 or crystalline form M5 of palbociclib or crystalline form M6 of palbociclib and one or more pharmaceutically acceptable excipients. Crystalline forms M1 or M2 or M3 or M4 or M5 or M6 of palbociclib together 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.

The PXRD conditions for the measurement of PXRD peaks of crystalline forms M1, M3 and M6 of palbociclib of the present application are as follows:
Range: 3° 2? to 40° 2? in conventional reflection mode
Instrument: PANalytical X-ray Diffractometer
Detector: X’celerator
Source: Copper K-alpha radiation (1.5418 Angstrom).
The PXRD conditions for the measurement of PXRD peaks of crystalline forms M2, M4 and M5 of palbociclib of the present application are as follows:
Range: 3° 2? to 40° 2? in conventional reflection mode
Instrument: Bruker AXS D8 Discovery X-ray Diffractometer
Detector: LYNXEYE XE
Source: Copper K-alpha radiation (1.5418 Angstrom).

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.
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 ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. 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 ± 0.2°. 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 PXRD 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 M1 of palbociclib
Palbociclib (1 g) was dissolved in benzyl alcohol (15 mL) at 60 °C. The solution was added to methyl cyclohexane (300 mL), taken in a separate vessel. A gummy material was formed at the bottom. The mixture was stirred for 15 minutes and cyclohexanone (50 mL) was added. Still the gummy material observed at the bottom of the flask. Methanol (50 mL) was added to the reaction mass so that gummy material became free flowing. The mixture was filtered to afford the desired compound.
Example 2: Preparation of crystalline form M2 of palbociclib
Crystalline form M3 of palbociclib (300 mg) was dried in an air tray drier for about 60 minutes at 160 °C to afford the desired compound.
Example 3: Preparation of crystalline form M3 of palbociclib
Palbociclib (1 g) was dissolved in benzyl alcohol (10 mL) by sonication of the mixture for 1-2 minutes. The solution was filtered under vacuum and washed with benzyl alcohol (5 mL). The solution was added to methyl cyclohexane (300 mL). Two immiscible layers were formed. Cyclohexanone (50 mL) was added to the above mixture. Further methanol (50 mL) was added to the above mixture and the resulting mixture was stirred for about 45 minutes. The solid was filtered to afford the desired compound.
Example 4: Preparation of crystalline form M3 of palbociclib
Palbociclib (1 g) was dissolved in benzyl alcohol (15 mL) by sonication of the mixture for 5 minutes. The solution was filtered under vacuum and washed with benzyl alcohol (5 mL). The solution was added to methyl cyclohexane (300 mL). Two immiscible layers were formed. Cyclohexanone (70 mL) was added to the above mixture. Further methanol (50 mL) was added to the above mixture and the resulting mixture was stirred for 1 hour. The solid was filtered to afford the desired compound.
Example 5: Preparation of crystalline form M4 of palbociclib
Crystalline form M3 of palbociclib (250 mg) was slurried in water (5 mL) at 70 °C for 1 hour and filtered to afford the desired compound.
Example 6: Preparation of crystalline form M5 of palbociclib
Crystalline form M1 of palbociclib (300 mg) was slurried in toluene (14 mL) at 87-95 °C for about 5 hours. The mixture was cooled to 25 °C and kept aside for 23 days. The solid was filtered to afford the title compound.
Example 7: Preparation of crystalline form M6 of palbociclib
Palbociclib (1 g) was dissolved in benzyl alcohol (20 mL) at 90 °C and filtered. The solution was cooled to 0 °C. Methyl isopropyl ketone (150 mL) was added slowly to the above reaction mixture over a period of about 5 minutes. The reaction mass was stirred at the same temperature for about 20 minutes and the precipitated solid was filtered. The solid was dried at 79 °C for about 1 hour to provide the desired compound.
Example 8: Preparation of crystalline form M6 of palbociclib
Palbociclib (1 g) was dissolved in benzyl alcohol (20 mL) at 90 °C. The solution was cooled to 10 °C. Methyl isopropyl ketone (150 mL) was added slowly to the above reaction mixture over a period of about 5 minutes. The reaction mass was stirred at about 5-15 °C for about 20 minutes and the precipitated solid was filtered to provide the title compound.
,CLAIMS:WE CLAIM:
1. A crystalline form M6 of palbociclib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.44, 8.64, 11.57, 13.36, 17.30 and 19.00 ± 0.2° 2?.
2. The crystalline form M6 of palbociclib of claim 11, characterized by its PXRD pattern having peaks located at about 4.44, 7.73, 8.64, 9.96, 11.57, 13.36, 17.30, 19.00 and 27.00 ± 0.2° 2?.
3. A process for preparation of crystalline form M6 of palbociclib of claim 1 comprising:
a) providing a mixture of palbociclib in a suitable solvent or mixtures thereof;
b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and
c) isolating crystalline form M6 of palbociclib.
4. The process of claim 13, wherein the suitable solvent of step a) is benzyl alcohol.
5. The process of claim 14, wherein the suitable anti-solvent of step b) is methyl isopropyl ketone.
6. A pharmaceutically acceptable dosage form comprising crystalline form crystalline form M6 of palbociclib and one or more pharmaceutically acceptable excipients.