WO2017115315A1

WO2017115315A1 - Solid forms of palbociclib

Info

Publication number: WO2017115315A1
Application number: PCT/IB2016/058071
Authority: WO
Inventors: Vamsi Krishna Mudapaka; Vishweshwar Peddy; Latif Jafar SHAIKH; Satyanarayana THIRUNAHARI; Srividya Ramakrishnan
Original assignee: Dr Reddys Laboratories Ltd
Current assignee: Dr Reddys Laboratories Ltd
Priority date: 2015-12-30
Filing date: 2016-12-29
Publication date: 2017-07-06
Anticipated expiration: 2018-06-30

Abstract

The present application relates to amorphous form of palbociclib and process for preparation thereof. The present application also relates to amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient wherein the pharmaceutically acceptable excipient may be selected from a group of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, syloid, Soluplus, Eudragit and hydroxypropyl cellulose. The present application also relates to a process for preparation of amorphous solid dispersion of palbociclib. The present application further relates to crystalline forms M1, M2, M3, M4, M5 and M6 of palbociclib and processes for preparation thereof.

Description

SOLID FORMS OF PALBOCICLIB

INTRODUCTION

One aspect of the present application relates to amorphous form of palbociclib and process for preparation thereof. Another aspect of the present application relates to amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient and process for preparation thereof. Yet another aspect of the present application relates to crystalline forms Ml , M2, M3, M4, M5 and M6 of palbociclib and process 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-l -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 amorphous form of palbociclib.

Another aspect of the present application relates to amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient.

Yet another aspect of the present application relates to a process for preparing amorphous form of palbociclib comprising milling palbociclib.

Still another aspect of the present application relates to a process for preparing amorphous form of palbociclib comprising ball milling palbociclib.

Another aspect of the present application relates to a process for preparing amorphous form of palbociclib comprising:

a) dissolving palbociclib in a suitable solvent or mixture thereof;

b) optionally filtering the un-dissolved particles;

c) optionally adding an anti-solvent; d) removing the solvent from the filtrate of step b) or step c) by any suitable technique; and e) optionally, drying the product at suitable temperature.

Still another aspect of the present application relates to a process for preparing amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient comprising: a) dissolving palbociclib and a pharmaceutically acceptable excipient in a suitable solvent or mixture thereof;

b) optionally filtering the un-dissolved particles;

c) optionally adding an anti-solvent;

d) removing the solvent from the filtrate of step b) or step c) by any suitable technique; and e) optionally, drying the product at suitable temperature.

Another aspect of the present application relates to a process for preparing amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient comprising ball milling palbociclib in presence of a pharmaceutically acceptable excipient.

Yet another aspect of the present application provides pharmaceutical composition comprising amorphous form of palbociclib, together with one or more pharmaceutically acceptable excipients.

Still another aspect of the present application provides pharmaceutical composition comprising amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient, together with one or more pharmaceutically acceptable excipients.

One aspect of the present application relates to crystalline form Ml 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° 2Θ. In embodiments, the present application provides crystalline form Ml 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° 2Θ. Still in other embodiments, the present application provides crystalline form Ml of palbociclib characterized by its PXRD pattern having additional peaks located at about 6.24, 12.70, 13.78, 29.84 ± 0.2° 2Θ.

Another aspect of the present application provides crystalline form Ml of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 10.

Yet another aspect of the present application provides a process for preparing crystalline form Ml 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 Ml 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 11.

Still another aspect of the present application provides a process for preparing crystalline form M2 of palbociclib comprising drying crystalline form Ml 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° 2Θ. 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° 2Θ.

Yet another aspect of the present application provides crystalline form M3 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 12 or Figure 13.

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 14.

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 15. Still another aspect of the present application provides a process for preparing crystalline form M5 of palbociclib comprising slurring crystalline form Ml 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° 2Θ. 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° 2Θ.

Another aspect of the present application provides crystalline form M6 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 16.

Yet another aspect of the present application provides a process for preparing crystalline form M6 of palbociclib comprising:

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 amorphous solid dispersion of palbociclib obtained by the process of example 1.

Figure 2: The PXRD pattern of amorphous form of palbociclib obtained by the process of example 2.

Figure 3: The PXRD pattern of amorphous solid dispersion of palbociclib obtained by the process of example 3.

Figure 4: The PXRD pattern of amorphous form of palbociclib obtained by the process of example 4.

Figure 5: The PXRD pattern of amorphous form of palbociclib obtained by the example 5. Figure 6: The PXRD pattern of amorphous form of solid dispersion of palbociclib obtained by the example 6.

Figure 7: The PXRD pattern of amorphous form of solid dispersion of palbociclib obtained by the example 7.

Figure 8: The PXRD pattern of amorphous solid dispersion of palbociclib obtained by the process of example 8. Figure 9: The PXRD pattern of amorphous solid dispersion of palbociclib obtained by the process of example 14.

Figure 10: The PXRD pattern of crystalline form Ml of palbociclib.

Figure 11: The PXRD pattern of crystalline form M2 of palbociclib.

Figure 12: The PXRD pattern of crystalline form M3 of palbociclib obtained by the process of example 20.

Figure 13: The PXRD pattern of crystalline form M3 of palbociclib obtained by the process of example 21.

Figure 14: The PXRD pattern of crystalline form M4 of palbociclib.

Figure 15: The PXRD pattern of crystalline form M5 of palbociclib.

Figure 16: The PXRD pattern of crystalline form M6 of palbociclib.

Figure 17: The comparative FT-IR spectra of amorphous solid dispersion of palbociclib with Eudragit EPO with crystalline form A of palbociclib.

Figure 18: The comparative FT-IR spectra of amorphous solid dispersion of palbociclib with HPMC 3 CPS with crystalline form A of palbociclib.

DETAILED DESCRIPTION

One aspect of the present application relates to amorphous form of palbociclib.

Another aspect of the present application relates to amorphous form of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 2 as prepared by the process of example 2. Another embodiment of the present application relates to amorphous form of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 4 as prepared by the process of example 4. Still another embodiment of the present application relates to amorphous form of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 5 as prepared by the process of example 5.

Yet another aspect of the present application relates to process for preparing amorphous form of palbociclib comprising milling palbociclib. Milling of palbociclib may be performed by techniques known in the art. In one embodiment, palbociclib may be ball milled. In another embodiment, palbociclib may be wet milled. In yet another embodiment, palbociclib may be bead milled.

Any crystalline form of palbociclib or mixture thereof may be used as starting material for preparing amorphous form of palbociclib. Specifically, crystalline form A or crystalline form B of palbociclib may be used as starting material for preparing amorphous form of palbociclib. Palbociclib may be charged into a ball-milling vessel and milled for about 30 minutes to about 20 hours at about 50 rpm to about 1000 rpm. Specifically, a crystalline form of palbociclib may be subjected to ball-milling for about 2 hours to about 8 hours at about 200 rpm to about 800 rpm. More specifically, a crystalline form of palbociclib may be subjected to ball-milling for about 6 hours to about 8 hours at about 400 rpm to about 500 rpm. The resulting solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous form of palbociclib.

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. 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 dried product 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 the product. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.

Still another aspect of the present application relates to a process for preparing amorphous form of palbociclib comprising:

a) dissolving palbociclib in a suitable solvent or mixture thereof;

b) optionally filtering the un-dissolved particles;

c) optionally adding an anti-solvent;

Suitable solvents of step a) for dissolving palbociclib include, but are not limited to dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; and mixtures thereof. Specifically, the suitable solvent form step a) is a mixture of dichloromethane and methanol.

In embodiments of step c), the suitable anti-solvent may be added to the solution of step a) or step b). The suitable anti-solvent includes but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; and mixture thereof.

Suitable techniques that may be used for the removal of solvent in step d) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure. Another embodiment of the present application relates to removal of solvent in step d) by filtration.

The isolation of solid may be performed by using techniques such as by scraping, or by shaking the container or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous form of palbociclib.

The steps of the above aspects may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, palbociclib may be dissolved in a suitable solvent at a temperature of about 25 °C to about 110 °C.

The amorphous form of palbociclib obtained in the present invention may contain water in between 5-10% w/w, specifically about 7.8% w/w.

It was found that the amorphous form of palbociclib is stable and has excellent physico- chemical properties. The amorphous form of palbociclib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.

The amorphous form of palbociclib of the present application may be stored at 25 °C under nitrogen atmosphere and packed in a double polythene bag tied with a thread, keeping primary packing containing amorphous palbociclib thereof inside a black color polyethylene bag containing oxygen busters and sealing it, placing above the double polyethylene bag inside a triple laminated bag optionally containing oxygen busters and sealing it, and placing the sealed triple laminated bag inside a closed high 30 density polyethylene (HDPE) container and storing in controlled environment chamber at about 25 °C and/or 40 °C.

Another aspect of the present application provides pharmaceutical composition comprising amorphous form of palbociclib, together with one or more pharmaceutically acceptable excipients. Amorphous form 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, chew able, 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, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

One of the aspects of the present application relates to amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient.

Another aspect of the present application relates to amorphous solid dispersion of palbociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 1 as prepared by the process of example 1. One embodiment of the present application relates to amorphous solid dispersion of palbociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 3 as prepared by the process of example 3. Yet another embodiment of the present application relates to amorphous form of palbociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 6 as prepared by the process of example 6. Still another embodiment of the present application relates to amorphous form of palbociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 7 as prepared by the process of example 7. Another embodiment of the present application relates to amorphous form of palbociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 8 as prepared by the process of example 8. Still another embodiment of the present application relates to amorphous form of palbociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 9 as prepared by the process of example 14.

The pharmaceutically acceptable excipient may include but not limited to methyl cellulose, ethyl cellulose, Soluplus, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinylalcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), syloid, copovidone, methacrylic acid, silicon dioxide, Eudragit, copovidone, methacrylic acid; mixtures of two or more thereof; copolymers thereof and derivatives thereof.

One specific aspect of the present application relates to amorphous solid dispersion of palbociclib with hydroxypropyl methylcellulose phthalate. Another specific aspect of the present application relates to amorphous solid dispersion of palbociclib with hydroxypropyl methylcellulose acetate succinate. Yet another specific aspect of the present application relates to amorphous solid dispersion of palbociclib with hydroxypropyl methylcellulose. Still another specific aspect of the present application relates to amorphous solid dispersion of palbociclib with Soluplus. Yet another specific aspect of the present application relates to amorphous solid dispersion of palbociclib with Eudragit. Another specific aspect of the present application relates to amorphous solid dispersion of palbociclib with hydroxypropyl cellulose.

Another aspect of the present application relates to amorphous solid dispersion of palbociclib with syloid (silicon dioxide). Specifically, the present application relates to amorphous solid dispersion of palbociclib with syloid.

The weight/weight ratio of palbociclib and pharmaceutically acceptable excipient in amorphous solid dispersion may be about 5 :95, or about 10:90, or about 15:85, or about 20:80, or about 25:75, or about 30:70, or about 35:65, or about 40:60, or about 45:55, or about 50:50 and vice versa.

Another aspect of the present application relates to process for preparing amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient comprising:

a) dissolving palbociclib and a pharmaceutically acceptable excipient in a suitable solvent or mixture thereof; b) optionally filtering the un-dissolved particles;

c) optionally adding an anti-solvent;

Any crystalline form of palbociclib or mixture thereof or amorphous form of palbociclib may be used as starting material for preparing amorphous solid dispersion of palbociclib. In one embodiment, crystalline form A or crystalline form B of palbociclib may be used as starting material for preparing amorphous solid dispersion of palbociclib. In another embodiment, amorphous form of palbociclib may be used as starting material for preparing amorphous solid dispersion of palbociclib.

Suitable solvents for dissolving palbociclib and pharmaceutically acceptable excipient include, but are not limited to dimethylformamide; dimethylacetamide; dimethyl sulphoxide; ketones such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane, anisole; esters such as ethyl acetate, isopropyl acetate; halogenated hydrocarbons such as dichloromethane; alcohols such as methanol, ethanol, propanol, isopropanol; acidic solvent such as acetic acid, propionic acid; mixtures thereof. In one embodiment, the solvent is selected from a group of tetrahydrofuran; dioxane; anisole; dichloromethane; methanol; dimethylformamide; dimethylacetamide; dimethyl sulphoxide; acetic acid and mixture thereof. In another embodiment, the solvent may be a mixture of dichloromethane and methanol. In another embodiment, the solvent may be acetic acid. In yet another embodiment, a solution of palbociclib may be added to a solution of pharmaceutically acceptable excipient. Specifically, a solution of palbociclib in acetic acid may be added to an aqueous solution of pharmaceutically acceptable excipient. Alternatively, an aqueous solution of pharmaceutically acceptable excipient may be added to a solution of palbociclib in acetic acid.

The step a) may be performed at a temperature of about 10 °C to about the boiling point of the solvent. Specifically, the step a) may be performed at a temperature of about 20 °C to about 40 °C. More specifically, the step a) may be performed at about 30 °C.

The solution of step a) may be filtered by methods known in the art to remove any particulate matter from the solution.

One embodiment of step c) includes addition of a suitable anti-solvent or mixture thereof to the solution of step a) or step b). Another embodiment of step b) includes addition of the solution of step a) or step b) to a suitable anti-solvent or mixture thereof. Suitable anti- solvent includes but are not limited to aliphatic hydrocarbon solvent such as heptane, hexane, cyclohexane and the like; aromatic hydrocarbons such as toluene, xylene and mixture thereof.

Suitable techniques that may be used for the removal of solvent in step d) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure. Another embodiment of the present application relates to removal of solvent in step d) by filtration. Specifically, the suitable technique for the removal of solvent in step d) may be spray-drying technique.

The resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may optionally be further dried to afford amorphous solid dispersion of palbociclib. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fiuidized 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. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.

The dried product 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 the product. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.

Another aspect of the present application relates to process for preparing amorphous solid dispersion of palbociclib comprising ball milling palbociclib in presence of a pharmaceutically acceptable excipient. Any crystalline form of palbociclib or mixture thereof may be used as starting material for preparing amorphous solid dispersion of palbociclib. Specifically, crystalline form A or crystalline form B of palbociclib may be used as starting material for preparing amorphous solid dispersion of palbociclib. Palbociclib and a pharmaceutically acceptable excipient may be charged into a ball-milling vessel and milled for about 30 minutes to about 20 hours at about 50 rpm to about 1000 rpm. Specifically, a crystalline form of palbociclib and a pharmaceutically acceptable excipient may be subjected to ball-milling for about 2 hours to about 8 hours at about 200 rpm to about 800 rpm. More specifically, a crystalline form of palbociclib and a pharmaceutically acceptable excipient may be subjected to ball-milling for about 3 hours to about 6 hours at about 400 rpm to about 500 rpm. The resulting solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous solid dispersion of palbociclib. The dried product 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 the product. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.

It was found that the amorphous solid dispersion of palbociclib is stable and has excellent physico-chemical properties. The comparative FT-IR spectra of amorphous solid dispersion (with Eudragit EPO) against crystalline form A of palbociclib and Eudragit EPO is shown in Figure 17. The comparative FT-IR spectra of amorphous solid dispersion (with HPMC 3 cps) against crystalline form A of palbociclib and HPMC 3 cps is shown in Figure 18. These figures demonstrate that amorphous solid dispersion (with HPMC 3 cps and Eudragit EPO) is stable due to high inter-molecular interaction. The amorphous solid dispersion of palbociclib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.

The amorphous solid dispersion of palbociclib of the present application may be stored at 25 °C under nitrogen atmosphere and packed in a double polythene bag tied with a thread, keeping primary packing containing amorphous palbociclib thereof inside a black color polyethylene bag containing molecular seives and/or oxygen busters and sealing it, placing above the double polyethylene bag inside a triple laminated bag optionally containing molecular seives and/or oxygen busters and sealing it, and placing the sealed triple laminated bag inside a closed high 30 density polyethylene (HDPE) container and storing in controlled environment chamber at about 25 °C and/or 40 °C.

Another aspect of the present application provides pharmaceutical composition comprising amorphous solid dispersion of palbociclib, together with one or more pharmaceutically acceptable excipients. Amorphous solid dispersion 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, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

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 Ml of palbociclib may be optionally added to the mixture of step a) or step b).

Isolation of crystalline form Ml of palbociclib from the mixture of step b) may be performed by any technique known in the art. Specifically, crystalline form Ml of palbociclib may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form Ml 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 Ml 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 Ml 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 Ml of palbociclib of the present application is stable and has excellent physico-chemical properties. The crystalline form Ml 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 Ml of palbociclib and one or more pharmaceutically acceptable excipient.

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° 2Θ. 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° 2Θ.

Yet another aspect of the present application provides crystalline form M3 of palbociclib characterized by a PXRD pattern substantially as illustrated in Figure 12 or Figure 13. Still another aspect of the present application provides a process for preparing crystalline form M3 of palbociclib comprising:

b) combining the mixture of step a) with a suitable anti-solvent or mixtures thereof; and c) isolating crystalline form M3 of palbociclib.

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.

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 15.

Still another aspect of the present application provides a process for preparing crystalline form M5 of palbociclib comprising slurring crystalline form Ml 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.

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;

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.

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 Ml 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 Ml 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 Ml , M3 and M6 of palbociclib of the present application are as follows:

Range: 3° 2Θ to 40° 2Θ 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° 2Θ to 40° 2Θ 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 (2Θ) 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 Θ ±0.2°) of 19.6°" means "having a diffraction peak at a diffraction angle (2Θ) of 19.4° to 19.8°. 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 amorphous solid dispersion of palbociclib with syloid

Syloid (0.5 g) and palbociclib (0.5 g) were charged in a ball mill bowl at 28 °C. The ball milling was performed for 5 hours at 500 RPM (Time interval for reverse rotation is 10 mins). The amorphous solid dispersion of palbociclib was scraped off the ball mill bowl. Yield: 34.6 %

EXAMPLE 2: Preparation of amorphous form of palbociclib

Palbociclib (1 g) were charged in a ball mill bowl at 28 °C. The ball milling was performed for 17 hours at 500 RPM (Time interval for reverse rotation is 10 mins). The amorphous form of palbociclib was scraped off the ball mill bowl.

Yield: 87.0 %

EXAMPLE 3: Preparation of amorphous solid dispersion of palbociclib with PVP K30

Palbociclib (1 g) and PVP K-30 (1 g) was dissolved at 110 °C in N,N-dimethylformamide (240 mL) and filtered to make the solution particle-free. The solution was spray-dried to provide amorphous solid dispersion of palbociclib with PVP K-30. The parameters of the spray-drier were as follows:

Nitrogen: 5 Kg/cm²

Inlet Temperature: 160 °C

Outlet Temperature: 89-90 °C

Pump: 5% (1.5 mL/min).

Yield: 1 g

EXAMPLE 4: Preparation of amorphous form of palbociclib

Palbociclib (3 g) was charged in a ball mill bowl at 30 °C. The ball milling was performed for 5 hours at 400 RPM (Time interval for reverse rotation is 10 minutes). The ball milling was then stopped for about 1 hour. The material was scrapped and the ball milling was continued with the same parameter for another 5 hours. The amorphous form of palbociclib was scraped off the ball mill bowl. Example 5: Preparation of amorphous form of Palbociclib

Palbociclib (2 g) was dissolved in a mixture of dichloromethane and methanol (80:20, 120 mL) at 28 °C and filtered the solution to make it particle free. The clear solution was spray dried to obtain the title compound.

Parameters for the spray drier of the above experiment:

Inlet temperature: 80 °C

Outlet temperature: 55 °C

Aspirator %: 70% (approx. 28 m /hour)

Feed rate: 5.1 mL/min (17%)

Example 6: Preparation of amorphous solid dispersion of Palbociclib with PVP K30

Palbociclib (10 g) and PVP K30 (10 g) mixed together and dissolved in a mixture of dichloromethane and methanol (80:20, 600 mL) mixture at 28 °C and filtered the

solution to make it particle free. The clear solution was spray dried to obtain the

title compound.

Parameters for the spray drier of the above experiment:

Inlet temperature: 75 °C

Outlet temperature: 48 °C

Aspirator %: 70% (approx. 28 mVhour)

Feed rate: 4.5 mL/min (15%)

Example 7: Preparation of amorphous solid dispersion of Palbociclib with PVP K30

Palbociclib (20 g) and of PVP K30 (20 g) mixed together and dissolved in a mixture of dichloromethane: methanol (80:20, 1200 mL) mixture at 28 °C and filtered the solution to make it particle free. The clear solution was spray dried to obtain the

title compound.

Parameters for the spray drier of the above experiment:

Inlet temperature: 80 °C

Outlet temperature: 54 °C

Aspirator %: 70% (approx. 28 m /hour)

Feed rate: 4.5 mL/min (15%)

EXAMPLE 8: Preparation of amorphous solid dispersion of palbociclib with HPMC phthalate

Palbociclib (5 g) was dissolved in a mixture of dichloromethane and methanol (300 mL, 4: 1). HPMC phthalate (5 g) was charged in the above solution at 28 °C. The solution was filtered to make particle-free and spray-dried with following conditions: Inlet temperature: 80 °C

Outlet temperature: 57 °C

Aspirator %: 70% (approx. 28 m³/hour)

Feed rate: 6 mL/min (20%)

The solid was dried in a vacuum tray drier for about 10 hours at 28-30 °C to provide the title compound.

EXAMPLE 9: Preparation of amorphous solid dispersion of palbociclib with HPMC acetate succinate

Palbociclib (5 g) was dissolved in a mixture of dichloromethane and methanol (300 mL, 4: 1). HPMC acetate succinate (5 g) was charged in the above solution at 28 °C. The solution was filtered to make particle-free and spray-dried with following conditions:

Inlet temperature: 80 °C

Outlet temperature: 56 °C

Aspirator %: 70% (approx. 28 mVhour)

Feed rate: 6 mL/min (20%)

EXAMPLE 10: Preparation of amorphous solid dispersion of palbociclib with HPMC 15 cps

Palbociclib (5 g) and HPMC 15 cps (5 g) were dissolved in a mixture of dichloromethane and methanol (250 mL, 4:1) at 28 °C. The solution was spray-dried with following conditions:

Inlet temperature: 80 °C

Outlet temperature: 56 °C

Aspirator %: 70% (approx. 28 mVhour)

Feed rate: 6 mL/min (20%)

The solid was dried in a vacuum tray drier for about 12 hours at 35 °C to provide the title compound.

EXAMPLE 11: Preparation of amorphous solid dispersion of palbociclib with HPMC 5 cps

Palbociclib (10 g) and HPMC 5 cps (10 g) were dissolved in a mixture of dichloromethane and methanol (400 mL, 4:1) at 28 °C. The solution was spray-dried with following conditions:

Inlet temperature: 80 °C

Outlet temperature: 50 °C

Aspirator %: 70% (approx. 28 mVhour) Feed rate: 6 mL/min (20%)

The solid was dried in a vacuum tray drier for about 12 hours at 37 °C to provide the title compound.

EXAMPLE 12: Preparation of amorphous solid dispersion of palbociclib with HPMC 3 cps 2910 grade

Palbociclib (10 g) and HPMC 3 cps (10 g) were dissolved in a mixture of dichloromethane and methanol (700 mL, 5:2) at 28 °C. The solution was spray-dried with following conditions:

Inlet temperature: 80 °C

Outlet temperature: 50-51 °C

Aspirator %: 70% (approx. 28 mVhour)

Feed rate: 6 mL/min (20%)

The solid was dried in a vacuum tray drier for about 9 hours at 37 °C to provide the title compound.

EXAMPLE 13: Preparation of amorphous solid dispersion of palbociclib with Soluplus

Palbociclib (5 g) and Soluplus (5 g) were dissolved in a mixture of dichloromethane and methanol (200 mL, 4:1) at 28 °C. The solution was spray-dried with following conditions:

Inlet temperature: 85 °C

Outlet temperature: 50 °C

Inlet gas flow rate: 0.5 m /min

Feed rate: 5-6 g/min

EXAMPLE 14: Preparation of amorphous solid dispersion of palbociclib with HPMC 3 cps 2208 grade

HPMC 3 cps 2208 grade (30 g) was dissolved in a mixture of dichloromethane (700 mL) and methanol (300 mL). Palbociclib (30 g) and dichloromethane (50 mL) were added to the above solution. The solution was spray-dried with following conditions:

Inlet temperature: 85 °C

Outlet temperature: 47 °C

Inlet gas flow rate: 0.5 m³/min

Feed rate: 5-6 g/min

The solid was dried in a vacuum tray drier for about 4 hours at 37 °C to provide the title compound. EXAMPLE 15: Preparation of amorphous solid dispersion of palbociclib with Eudragit EPO

Eudragit EPO (5 g) and palbociclib (5 g) were dissolved in a mixture of dichloromethane and methanol (200 mL, 4:1). The solution was filtered to remove any particulate matter and spray-dried with following conditions:

Inlet temperature: 85 °C

Outlet temperature: 47 °C

Inlet gas flow rate: 0.5 m /min

Feed rate: 5-6 g/min

EXAMPLE 16: Preparation of amorphous solid dispersion of palbociclib with UPC

Palbociclib (5 g) and HPC (5 g) were dissolved in a mixture of dichloromethane and methanol (200 mL, 4:1) at 28 °C. The solution was spray-dried with following conditions:

Inlet temperature: 85 °C

Outlet temperature: 50 °C

Inlet gas flow rate: 0.5 m³/min

Feed rate: 5-6 g/min

EXAMPLE 17: Preparation of amorphous solid dispersion of palbociclib with HPMC 3cps 2208 grade

HPMC 3cps 2208 grade (5g) was dissolved in water (lOOmL). Palbociclib (5 g) charged to above solution at 28 °C and then added acetic acid (5mL). The solution was filtered to remove any extraneous matter and was spray-dried with following conditions:

Inlet temperature: 120 °C

Outlet temperature: 80 °C

Aspirator %: 70% (approx. 28 m /hour)

Feed rate: 6 mL/min (20%)

The solid was dried in a vacuum tray drier at 50-70 °C for about 25 hours to provide the title compound.

Example 18: Preparation of crystalline form Ml 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 19: 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 20: 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 21: 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 22: 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 23: Preparation of crystalline form M5 of palbociclib

Crystalline form Ml 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 24: 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 25: 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

CLAIMs:

1. An amorphous form of palbociclib.

2. The amorphous form of palbociclib of claim 1, characterized by a PXRD pattern substantially as illustrated in Figure 2 or Figure 4 or Figure 5.

3. A process for preparation of amorphous form of palbociclib comprising:

a) dissolving palbociclib in a suitable solvent or mixture thereof;

b) optionally filtering the un-dissolved particles;

c) optionally adding an anti-solvent;

4. An amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient.

5. The amorphous solid dispersion of palbociclib of claim 5, characterized by a PXRD pattern substantially as illustrated in Figure 1 or Figure 3 or Figure 6 or Figure 7 or Figure 8 or Figure 9.

6. The amorphous solid dispersion of palbociclib wherein the pharmaceutically acceptable excipient is selected from a group of hydroxypropyl methylcellulose phthalate, syloid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, Soluplus, Eudragit and hydroxypropyl cellulose.

7. A process for preparing amorphous solid dispersion of palbociclib comprising:

a) dissolving palbociclib and a pharmaceutically acceptable excipient in a suitable solvent or mixture thereof;

b) optionally filtering the un-dissolved particles;

c) optionally adding an anti-solvent;

8. The process of claim 8, wherein the suitable solvent of step a) is a mixture of dichloromethane and methanol.

9. The process of claim 8, wherein the suitable solvent of step a) is a mixture of acetic acid and water.

10. The process of claim 8, wherein removal of solvent in step d) is performed by spray- drying.

11. 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° 2Θ.

12. 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° 2Θ.

13. 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;

14. The process of claim 13, wherein the suitable solvent of step a) is benzyl alcohol.

15. The process of claim 14, wherein the suitable anti-solvent of step b) is methyl isopropyl ketone.