WO2018073574A1

WO2018073574A1 - Polymorphic forms of palbociclib

Info

Publication number: WO2018073574A1
Application number: PCT/GB2017/053133
Authority: WO
Inventors: Dharmaraj Ramachandra Rao; Geena Malhotra; Srinivas Laxminarayan Pathi; Chandrasekaran Ramasubbu; Rajesh RADHAMANALAN; Manish Gopaldas Gangrade; Jennet JAYACHANDRAN
Original assignee: Cipla Limited; King, Lawrence
Priority date: 2016-10-20
Filing date: 2017-10-17
Publication date: 2018-04-26

Abstract

The present invention relates to polymorphic forms of palbociclib and processes for preparation thereof,to pharmaceutical compositions comprising palbociclib,and to the use of such compositions for the treatment of cancer.

Description

Polymorphic forms of palbociclib

FIELD OF INVENTION The present invention relates to polymorphic forms of palbociclib and processes for preparation thereof. The present invention also provides a pharmaceutical composition comprising polymorphic forms of palbociclib and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of cancer. BACKGROUND OF INVENTION

Palbociclib of Formula I is chemically described as 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-( 1 -piperazin l)-2-pyridinyl]amino]pyrido [2,3-d]pyrimidin-7(8H)-one.

Formula I

Palbociclib is commercially available in Europe under the trade name IBRANCE® and is indicated for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.

US6936612 relates to substituted 2-amino pyridines that are potent inhibitors of cyclin- dependent kinase 4. The compounds of the invention are useful for the treatment of inflammation, and cell proliferative diseases such as cancer and restenosis. US6936612 discloses a process for the preparation of palbociclib hydrochloride.

US7781583 relates to novel synthetic routes for the preparation of substituted 2-(pyridin-2- ylamino)-pirido[2,3-d]pyrimidin-7-ones and their intermediates. It further discloses a process for the preparation of palbociclib.

US7863278 relates to salt forms of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl- pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, which is a selective cyclin-dependent kinase 4 (CDK4) inhibitor that is useful for treating inflammation and cell proliferative diseases such as cancer and restenosis. US7863278 discloses polymorphs of mono- isoethionate, mono- mesylate, di-mesylate, mono-hydrochloride, and di-hydrochloride salts of palbociclib.

PCT Publication No. WO 2014/128588 relates to a crystalline free base of 6-acetyl-8- cyclopentyl-5-memyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7- one, having a specific surface area of < 2m²/g. WO 20140/128588 further discloses crystalline Forms A and B of palbociclib free base.

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing. Therefore, it is desirable to have a stable amorphous form of drug with high purity to meet the needs of regulatory agencies and highly reproducible processes for its preparation.

In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of polymorphic forms of palbociclib.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide polymorphic forms of palbociclib. Another object of the present invention is to provide a crystalline free base of palbociclib having a specific surface area of > 2m²/g.

Another object of the present invention is to provide a crystalline free base Form A of palbociclib having a specific surface area of > 2m²/g.

Another object of the present invention is to provide a crystalline free base Form B of palbociclib having a specific surface area of > 2m²/g.

Another object of the present invention is to provide a process of preparation of a crystalline free base Form A of palbociclib having a specific surface area of > 2m²/g.

Another object of the present invention is to provide a process of preparation of a crystalline free base Form B of palbociclib having a specific surface area of > 2m²/g. Another object of the present invention is to provide an amorphous form of palbociclib.

Another object of the present invention is to provide an amorphous form of palbociclib having a specific surface area of < 2 m²/g.

Another object of the present invention is to provide a stable amorphous form of palbociclib free from any crystalline form of palbociclib.

Another object of the present invention is to provide a process for the preparation of an amorphous form of palbociclib.

Another object of the present invention is to provide a premix of palbociclib and copovidone.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a palbociclib - copovidone premix.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of palbociclib having a specific surface area of < 2m²/g.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of crystalline free base of palbociclib, such as Form A or Form B, having a specific surface area of > 2m²/g. SUMMARY OF THE INVENTION

In line with the above objectives, the present invention provides polymorphic forms of palbociclib. In a first aspect of the present invention, there is provided a crystalline free base of palbociclib having a specific surface area of > 2m²/g.

The present invention provides a crystalline free base Form A of palbociclib having a specific surface area of > 2m²/g, such as > 2m²/g, for example from about 5 to about 8m²/g.

The present invention provides a crystalline free base Form B of palbociclib having a specific surface area of > 2m²/g, such as > 2m²/g, for example from about 10 to 15m²/g. The present invention provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m²/g.

The present invention provides a process for preparing crystalline free base Form A of palbociclib having a specific surface area of > 2m²/g, such as > 2m²/g, for example from about 5 to about 8m²/g.

The present invention provides a process for preparing crystalline free base Form B of palbociclib having a specific surface area of > 2m²/g, such as > 2m²/g, for example from about 10-15m²/g.

The present invention provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m²/g, comprising the steps of: i. coupling 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)- one, compound (VII):

(VII)

with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l-carboxylate, compound (VI):

(VI) using a suitable coupling agent in a suitable solvent to form compound (V):

in presence of a transition metal catalyst, a base and optionally a phosphine agent, in a suitable solvent, to form a compound to form a compound (III):

(III)

iii. reacting the compound (ΙΠ) in presence of acid and suitable solvent to form compound (II):

iv. converting compound (Π) to palbociclib crystalline free base having a specific surface area of > 2m²/g; and optionally purifying the product so formed.

The present invention further provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m²/g without isolation of compound (III).

The present invention provides crystalline free base Form A of palbociclib prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in one or more suitable solvents;

i. optionally filtering the solution so formed, for example over hyflow;

ii. adjusting the pH of the solution obtained using a suitable base;

iii. isolating crystalline free base Form A; and

iv. optionally purifying the compound so formed. The present invention provides crystalline free base Form B of palbociclib prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in a suitable solvent under an inert atmosphere;

ii. optionally filtering the solution so obtained, for example over hyflow;

iii. adding the solution to an aqueous ammonia solution under an inert atmosphere;

iv. isolating crystalline free base Form B; and

v. optionally purifying the compound so formed.

The present invention provides an amorphous form of palbociclib. The amorphous form of palbociclib is characterised by having a specific surface area of < 2 m²/g. The amorphous form of palbociclib is further characterised by an X-Ray Powder Diffraction (XRD) pattern as depicted in Figure 2.

The present invention further provides a process for the preparation of an amorphous form of palbociclib.

The present invention provides a premix of palbociclib and copovidone. The premix of palbociclib and copovidone is characterised by an XRD pattern as depicted in Figure 3. The advantages of the above-noted processes include simplicity of manufacturing, eco- friendliness and suitability for commercial use.

References herein to the crystalline forms of palbociclib free base designated as "Form A" and "Form B" shall mean those crystalline forms of the same designation as disclosed and characterised in WO 2014/128588, the contents of which are incorporated herein by reference.

Palbociclib crystalline free base Form A is characterised by an XRD pattern comprising a peaks at: (l) 10.1 ±0.2 ° 2Θ; (n) 8.0 and 10.1 ±0.2 ° 2Θ; and/or (hi) 8.0, 10.1, 10.3 and 1 1.5 ±0.2 ° 2Θ.

Palbociclib crystalline free base Form B is characterised by an XRD pattem comprising a peaks at: (l) 6.0 ±0.2 ° 2Θ; (n) 6.0, 19.8 and 26.7 ±0.2 ° 2Θ; (in) 6.0, 16.4, 19.8 and 26.7 ±0.2 ° 2Θ; (iv) 6.0, 12.8, 16.4, 19.8 and 26.7 ±0.2 ° 2Θ; (v) 6.0, 12.8, 16.4, 19.8, 22.6 and 26.7 ±0.2 ° 2Θ; (vi) 6.0, 12.8, 16.4, 19.8, 22.6 and 26.7 ±0.2 ° 2Θ; and/or (vi) 6.0, 10.9, 12.8, 16.4, 19.8, 22.6 and 26.7 ±0.2 ° 2Θ.

As used herein, the term "premix" means a composition formed by the admixture of palbociclib and one or more pharmaceutically acceptable polymers, such as copovidone.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : Depicts an X-ray powder diffractogram crystalline palbociclib free base Form A having a specific surface area > 2m²/g.

Figure 2: Depicts an X-ray powder diffractogram of crystalline palbociclib free base Form B having a specific surface area > 2m²/g. Figure 3: Depicts an X-ray powder diffractogram of an amorphous form of palbociclib having a specific surface area < 2m²/g.

Figure 4: Depicts an X-ray powder diffractogram of a palbociclib-copovidone premix. DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

According to a first aspect of the present invention, there is provided a crystalline free base of palbociclib, preferably selected from Form A and Form B, having a specific surface area of greater than or equal to (>) 2m²/g. In one aspect of the invention there is provided crystalline free base of palbociclib Form A having a specific surface area of greater than (>) 2m²/g. In another aspect of the invention there is provided crystalline free base of palbociclib Form A having a specific surface area in the range from about 5 to about 8m²/g, including about 5m²/g, about 6 m²/g, about 7 m²/g and about 8 m²/g.

In one aspect of the invention there is provided crystalline free base of palbociclib Form B having a specific surface area of greater than (>) 2m²/g. In another aspect of the invention there is provided crystalline free base of palbociclib Form B having a specific surface area in the ranges from about 10 to about 15m²/g, from about 11 to about 15m²/g, from about 12 to about 15m²/g, and from 13 to about 15m²/g; including about 10m²/g, about 11 m²/g, about 12 m²/g, about 13m²/g, about 14 m²/g and about 15 m²/g.

The present invention further provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m²/g as depicted in Scheme I.

Scheme I

Coupling of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one compound (VII) with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l -carboxylate - compound (VI) as depicted in step 1 of Scheme I is preferably undertaken using a suitable coupling agent in a suitable solvent to form compound (V).

Suitable coupling agents for use in step (1) of Scheme I include, but are not limited to, suitable organic or inorganic compounds such as lithium hexamethyldisilazide or a Grignard reagent such as isopropylmagnesium chloride, cyclohexylmagnesium chloride and the like. Suitable organic solvents for use in step (1) of Scheme I include, but are not limited to, halogenated solvents such as dichloroethane, dichloromethane, chloroform and the like; non- polar solvents such as toluene, xylene, cyclohexane, heptane, xylene and the like; polar aprotic solvents such as THF, ethylacetate, acetone, dimethylformamide and the like; and mixtures thereof in various proportion without limitation.

Optionally, prior to step 2 of Scheme I, compound (V) may be subjected to purification using one or more suitable solvents selected from polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like, or mixtures thereof in various proportion without limitation.

In one aspect, as depicted in step (1) of Scheme I, the present invention comprises coupling compound (VII) with compound (VI) at a temperature in the range of from about 0°C to about 30°C, preferably from about 5°C to about 20°C.

In one aspect of the present invention, as depicted in step (2) of Scheme I, the present invention comprises reacting compound (V) with vinyl n-butyl ether (IV) in the presence of a transition metal catalyst, a base and optionally a phosphine agent, in a suitable solvent to form a compound to form a compound (III).

Suitable transition metal catalysts for use as depicted in step (2) in Scheme I include, but are not limited to, a palladium compound selected from the group consisting of tetrakis(triphenylphosphine)palladium [(Ph3PPd], tris(dibenzylideneacetone)dipalladium [Pd₂(dba)3], bis(dibenzylideneacetone) palladium(O) [{dba)₂Pd],palladium acetate [Pd(OAc)₂], palladium chloride (PdCI₂), bis(benzonitrile)dichloropalladium[(C6H5CN)₂PdCI₂]and(Bis-(diphenylphosphine ferrocene) palladium dichloride dichloromethane complex (Pd(dppf)₂CI₂), and the phospine compound is selected from 2,2'-bis(diphenylphosphino)-l ,Γ- binaphthalene (BINAP), 1 ,3 bis(diphenylphosphino)propane, triphenylphosphine (Ph3P), triorthotolylphosphine [(0- CI¾Ph)3P] and tri-f-butylphosphine, bis(2-diphenylphosphenophenyl)ether [DPEPhos]. Suitable bases for use as depicted in step (2) of Scheme I include, but are not limited to, diisopropyl ethylamine, lithium carbonate, dicyclohexyl methylamine and trimethylamine and the like. In one aspect, as depicted in step (3) of Scheme I, the present invention comprises reacting the compound (ΙΠ) in the presence of a suitable solvent under acidic conditions to obtain compound (II). Suitable solvents include, but are not limited to, water, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like, or mixtures thereof in various proportions without limitation.

In one aspect, as depicted in step (4) of Scheme I, the present invention comprises isolating compound (I) from compound (II) using a suitable solvent under basic conditions. Suitable solvents include, but are not limited to, water, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like, or mixture thereof in various proportion without limitation.

Basic conditions may be acquired by adjusting the pH of the reaction mixture slowly to 8-8.5 using 5% aqueous sodium hydroxide solution.

Upon formation, compound (I) is preferably isolated and further dried at temperature in the range from about 55°C to about 65°C, preferably for about 8 to about 10 hours. Alternatively, any salt of palbociclib can be used for the preparation of crystalline free base of palbociclib having a specific surface area of > 2m²/g. Suitable salts include acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di- mesylate, mono-hydrochloride and di-hydrochloride salts of palbociclib. The present invention further provides a ("one-pot") process for preparing crystalline free base of palbociclib having a specific surface area of > 2m²/g without the isolation of intermediate compounds, preferably intermediate of formula (ΙΠ), as depicted Scheme II.

Scheme II

As used herein, "[ ]" / bracket in Scheme II indicates the intermediate (preferably compound of formula (III)) is not isolated in the synthesis of palbociclib of formula I.

The reagents, solvents and reaction conditions employed in the one-pot process depicted in Scheme Π may be similar or identical to those employed in the reactions as depicted in Scheme I and as discussed herein. Suitably, the one-pot process for preparing crystalline free base of palbociclib having a specific surface area of > 2m²/g according to the present invention comprises:

A. preparing a compound teri-butyl4-(6-((6-(l-butoxyvinyl)-8-cyclopentyl-5-methyl-7- oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l- carboxylate (III) by carrying out Heck coupling of vinyl n-butyl ether (IV) and 4-[6- (6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i ]pyrimidin-2- ylamino)-pyridin-3-yl]-piperazine-l -carboxylic Acid tert- utyl Ester (V) in presence of a transition metal catalyst, a base and optionally a phosphine agent, in a suitable solvent;

B. without isolating the compound/intermediate (ΠΙ), reacting the compound (ΙΠ) in presence of acid and a suitable solvent to obtain compound (II); and

C. converting compound (II) to palbociclib crystalline free base having a specific surface area of > 2m²/g.

As used herein, the term "without isolating" refers to a process step in which the organic layer (comprising the compound of formula III and solvent) is reacted with concentrated HC1 and suitable solvent as depicted in Scheme I.

The one-pot synthesis (i.e. without isolation of the compound III) of the present invention advantageously avoids the need for lengthy separation processes such as filtration, washing and purification of the intermediates and also saves time and resources. This increases the chemical yield and makes the process economical and suitable for industrial scale up.

The present invention further comprises processes for preparing crystalline free base Form A and Form B of palbociclib having a specific surface area of > 2m²/g, for example, crystalline free base Form A of palbociclib having a specific surface area in the range from about 5 to about 8m²/g and crystalline free base Form B of palbociclib having a specific surface area in the range from about 10 to about 15m²/g.

In one aspect, the present invention provides crystalline palbociclib free base Form A prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in one or more suitable solvents;

ii. optionally filtering the solution so formed, for example over hyflow;

iii. adjusting the pH of the solution obtained using a suitable base;

iv. isolating crystalline free base Form A; and v. optionally thereafter purifying the compound so formed.

Preferably, the crystalline palbociclib free base Form A has a specific surface area of > 2m²/g, such as >2 m²/g, and more preferably from about 5 to about 8m²/g.

In this aspect of the present invention, palbociclib is dissolved in one or more suitable solvents. Suitable solvents include, but are not limited to, water, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like or mixture thereof in various proportion without limitation.

Palbociclib may be in free base form or in salt form such as an acid addition salt. Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono- mesylate, di-mesylate, mono-hydrochloride and di-hydrochloride salts of palbociclib.

The dissolution temperature may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.

Suitable bases include, but are not limited to, organic bases such as methylamine, dimethylamine, triethylamine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide and the like.

The process comprises isolating and drying the crystalline Form A of palbociclib free base in a solid form. Any suitable techniques known in the art may be used, for example filtering and then drying under vacuum.

In one aspect, the present invention provides crystalline palbociclib free base Form A having a specific surface area of > 2m²/g, preferably in the range from about 5 to about 8m²/g, and a particle size distribution (PSD) having at least one of:

(i) a Dio value in the range of from about 1 μπι to about 5 μπι, preferably, in the range of from about 1 μπι to about 3 μπι; and/or

(ii) a D50 value in the range of from about 2 μπι to about 7 μπι, preferably, in the range of from about 3 μπι to about 5 μπι; and/or (iii) a D90 value in the range of from about 7 μηι to about 15 μπι, preferably, in the range of from about 8 μηι to about 13 μηι.

The present invention further provides crystalline free base Form B of palbociclib prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in a suitable solvent under an inert atmosphere;

ii. optionally filtering the solution so obtained, for example over hyflow;

iv. isolating crystalline free base Form B; and

v. optionally thereafter purifying the compound so formed.

Preferably, the crystalline palbociclib free base Form B has a specific surface area of > 2m²/g, such as >2 m²/g, and more preferably in the range from about 10 to about 15m²/g.

In this aspect of the invention, palbociclib can be prepared by any known method, or may be prepared according to the process of the present invention. Further, palbociclib may be used be in any suitable form, such as a crystalline, semi-crystalline, solvate, or salt form, for example an acid addition salt. Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di-mesylate, mono-hydrochloride and di- hydrochloride salts.

In a preferred aspect, the solvent used in the preparation of crystalline free base Form B of palbociclib is water. The dissolution temperature may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.

The reaction is typically performed in an inert atmosphere. An inert atmosphere may be maintained by purging with nitrogen, argon or like, followed by degassing under vacuum in order to remove any traces of impurity.

The (clear) solution so obtained is added to aqueous ammonia solution under inert atmosphere. The addition is preferably carried out maintaining the temperature in the range from about 25°C to 35°C.

The process comprises isolating and drying the crystalline Form B of palbociclib free base in a solid form. Any suitable techniques known in the art may be used, for example filtering and then drying under vacuum. In one aspect, the present invention provides crystalline palbociclib free base Form B having a specific surface area of > 2m²/g, preferably in the range from about 10 to about 15m²/g, and a particle size distribution (PSD) having at least one of:

(i) a Dio value in the range of from about 0.1 μηι to about 2 μτη, preferably, in the range of from about 0.1 μηι to about 1 μιη; and/or

(ii) a D50 value in the range of from about 1 μιη to about 5 μτη, preferably, in the range of from about 1 μιη to about 3 μηι; and/or

(iii) a D90 value in the range of from about 5 μηι to about 10 μτη, preferably, in the range of from about 6 μηι to about 9 μηι.

US 2016/0002223 provides BET-N2 SSA analysis of four batches of palbociclib free base, one comprising crystalline free base of palbociclib having a specific surface area of > 2m²/g (Batch 5 as shown in the Table below) prepared by the traditional salt break method and three batches comprising the API having surface area < 2m²/g. It further also states that the Batch 5 contained palbociclib free base having small primary particles and large agglomerates, which was very static-prone, sticky, difficult to disperse by sieving and were unsuitable for further development.

Advantageously, the crystalline free base Form A and Form B of palbociclib of the present invention having a specific surface area of > 2m²/g do not form large agglomerates and are easy to disperse by sieving.

The present invention further provides an amorphous form of palbociclib free base. In one aspect, the amorphous form of palbociclib free base is characterised by having a specific surface area of < 2m²/g. In a further aspect, the amorphous form of palbociclib free base according to the present invention is characterised by having an XRD pattern as depicted in Figure 2.

The present invention provides a process for the preparation of an amorphous form of free base of palbociclib having a specific surface area of < 2m²/g, the process comprising:

(A) providing a solution of palbociclib in one or more suitable solvents; and

(B) isolating an amorphous form of palbociclib from the solution so formed. Suitable solvents for use in step (A) include, but are not limited to, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like, or mixtures thereof in various proportions without limitation.

Palbociclib used in step (A) can be prepared by any known method or may be prepared according to the process of the present invention. Further, palbociclib may be used be in any suitable form, such as a crystalline, semi-crystalline, solvate, or salt form, for example an acid addition salt. Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di-mesylate, mono-hydrochloride and di-hydrochloride salts.

The dissolution temperatures employed in step (A) may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.

Step (B) involves isolation of an amorphous form of palbociclib from the solution of step (A). The isolation may be affected by removing the solvent. The techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), flash evaporation, and vacuum distillation.

In one aspect of the present invention, there is provided an amorphous form of palbociclib characterized by a glass transition temperature of about 165 °C ±3°C, preferably about 165°C, such as 165.78°C.

In one aspect of the present invention there is provided amorphous palbociclib having a specific surface area of < 2m²/g and a D90 particle size in the range of from about 1 μιη to about 10 μτη, such as from about 5 μηι to about 10 μηι. In one aspect of the present invention there is provided amorphous palbociclib having a specific surface area in the range of from about 1 to about 2m²/g. Amorphous palbociclib obtained by the process of the present invention is chemically and thermodynamically stable. Amorphous forms are generally more readily soluble than their crystalline counter parts and therefore, the amorphous form of palbociclib provided according to the invention is expected to have higher dissolution, solubility and hence bioavailability.

According to a further aspect of the present invention, there is provided a premix comprising palbociclib and copovidone. The formation of such a premix is intended to improve the bioavailability of palbociclib free base.

Copovidone is an analog of povidone, is used as a tablet binder, a film-former, and as part of the matrix material used in controlled-release formulations. In tableting, copovidone can be used as a binder for direct compression and as a binder in wet granulation. In accordance with the above, in a preferred aspect, the present invention provides a novel premix of palbociclib and copovidone. The palbociclib-copovidone premix according to the present invention is stable and amorphous in nature.

In one aspect of the present invention there is provided a process for preparing a palbociclib - copovidone premix comprising the steps of:

(I) providing a solution of palbociclib and copovidone in one or more suitable solvents; and

(II) (II) isolating the premix so formed from the solution.

Palbociclib used in step (I) can be prepared by any known method or may be prepared according to the process of the present invention. Further, palbociclib may be used be in any suitable form, such as an amorphous, crystalline, semi-crystalline, solvate, or salt form, for example an acid addition salt. Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di-mesylate, mono-hydrochloride and di- hydrochloride salts.

Suitable solvents for use in step (I) include, but are not limited to, alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like or mixture thereof, in various proportions without limitation.

The dissolution temperature in step (I) may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.

Copovidone may be used in different grades concerning the particle size. The weight ratio of palbociclib and copovidone employed in the premix of the present invention is typically from about 1 : 10 to about 10: 1 , and is preferably about 1 :1.

Step (Π) involves isolation of a premix of palbociclib-copovidone from the solution of step (I). The isolation may be affected by removing the solvent. The techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), flash evaporation, and vacuum distillation.

The palbociclib-copovidone premix of the present invention may be characterized by DSC glass transition. The palbociclib-copovidone premix of the present invention may be further characterized by having an XRD pattern as depicted in Figure 3.

In one aspect, the palbociclib-copovidone premix of the present invention is amorphous in nature and stable. Amorphous forms are generally more readily soluble than their crystalline counterparts and therefore, the amorphous palbociclib-copovidone premix of the present invention is expected to have higher dissolution, solubility and hence bioavailability.

In accordance with the present invention, palbociclib premixes can also be prepared using other suitable premixing agents that can facilitate the bioavailability of the palbociclib. Suitable premixing agents include, but are not limited to, pharmaceutically acceptable polymers, such as microcrystalline cellulose (MCC), Silicified MCC, lactose, co-processed MCC, co-processed lactose and the like. The weight ratio of palbociclib to premixing agents is typically from about 1 : 10 to about 10: 1 , and is preferably about 1 :1.

The solid state forms and premixes of palbociclib of the present invention may be formulated with one or more pharmaceutically acceptable excipients as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. Suitable pharmaceutically acceptable excipients are commercially available. Such compositions may be useful for the treatment of cancer, particularly breast cancer. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. X-ray powder diffraction was carried out using a Rigaku D-Max 2200 X-Ray diffractometer. The D-Max 2200 system was equipped with a 1.2kW Cu anode X-ray tube and a scintillation detector. Cu K alpha radiation (λ=1.5405Α) was used to obtain all patterns. Nickel filter was placed in the receiving path of the X-ray to remove Cu Κβ radiation. Samples were ground using mortar and pestle to reduce the crystal size and orientation effects. Material was then tightly packed in a glass holder using glass slides to match the surface level of the sample holder and analyzed using the following parameters.

I. Source Cu Ka

II. Wavelength : -1.5405 A°

III. Voltage : 40 KV

IV. Current : 30 mA

V. Scan axis : theta/2 theta

VI. Measurement method : Continuous

vn. Scanning range : 3°-40° 2Θ

VIII. Goniometer speed : 2° 20/min

IX. Sampling width : 0.02° 2Θ

X. Divergence slit : 1 °

XI. Receiving slit : 0.3 mm

ΧΠ. Counting unit : cps

XIII. Detector type : Scintillation counter

NMR data were collected using a Varian spectrometer at 300 MHz under standard operating conditions.

Particle size data were collected using a Malvern Mastersizer 2000 with Hydro 2000S (A) under standard operating conditions.

Specific surface area was measured under the following experimental conditions:

Sample Mass Approximately ¾ full cell

Sample Preparation Smart Prep (Flow degassing using Nitrogen)

Out gassing condition 16Hrs at 25°C Under gas flow (10°C/min)

Isothermal Jacket Used

Isothermal Collection points 11 point BET in range 0.05-0.03 P/Po

Isothermal data analysis range 7 Point BET in the range 0.05-0.20 P/Po

Leak Test 120s

Free space Measured

Evacuation Time lhr

Out gas test duration 180s

Equilibration interval 10s

Equilibration Timeout 600s

EXAMPLES Example 1: teri-butyl4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido

[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (V)

105gm 6-Bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (ΙΠ) was added in 13 volume of THF, cooled at 10-16°C, followed by addition of 225.0 ml of cyclohexyl magnesium chloride slowly under nitrogen over a period of 60 to 90 minutes, maintaining the temperature of reaction material to 10-15°C. The mixture was stirred for 30minutes at 10-15°C. Further, lOOgm of 4-(6-aminopyridin-3-yl)piperazine-l-carboxylic acid tert-butyl ester (VI) was added lot wise at 10-16°C followed by addition of 225 ml cyclohexyl magnesium chloride at 10-16°C under nitrogen in time interval of 60-90 minutes. The material was stirred for 120 to 180 minutes at 10-16°C and checked for completion of reaction. On completion of reaction, a mixture of 300 ml of THF and 24 ml of acetic acid was added at 5-15°C. The product thus obtained was stirred for 240 minutes at 25-35°C, cooled to 10±5°C, stirred for 120 minutes at 5-10°C, followed by filtration and washed with 5 volume of acetone, 5 volume of hot water (50-55°C) and 5 volume of acetone. The crude material was dried at 50±5°C under vacuum for 8 hours to get 88 gm of 4-[6-(6-Bromo-8- cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-<i]pyrimidin-2-ylamino)-pyridin-3-yl]- piperazine-l-carboxylic acid tert-butyl ester (V). ¾ NMR (300 MHz, CDCh): δ 8.79 (s, 1H), 8.16-8.19 (d, 1H), 8.03-8.04 (m, 2H), 7.31 -7.35 (dd, 1H), 5.92-6.04 (q, 1H), 3.60-3.63 (m, 4H), 3.10-3.14 (m, 4H), 2.61 (s,3H), 1.62-1.76 & 2.03-2.18 (m, 4H), 1.81-1.97 &2.24-2.41 (m, 4H), 1.49 (s, 9H). Example la: Purification of ferf-buryl4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (V)

88gm of 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i ]pyrimidin-2- ylamino)-pyridin-3-yl]-piperazine-l -carboxylic Acid tert-Butyl Ester was added to a mixture of methanol (10 volumes) and MDC (30 volume) at 25-35°C, heated to reflux and stirred for 15 minutes to get clear yellow coloured solution. The solution was filtered through Hyflo bed and washed with 2 volume of 1 :1 MDC and Methanol. The clear solution was heated followed by distillation of MDC at 40 to 45°C. The solid thus obtained was cooled to 25 - 30°C, stirred for one hour, filtered and washed with 2 volumes of methanol. The solid was further subjected to drying at 50±5°C under vacuum for 8 hours to get 75.0 gm of pure 4-[6- (6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i ]pyrimidin-2-ylamino)- pyridin-3-yl]-piperazine-l-carboxylic acid tert-butyl ester.

¾ NMR (300 MHz, CDCh): δ 8.79 (s, 1H), 8.16-8.19 (d, 1H), 8.03-8.04 (m, 2H), 7.31 -7.35 (dd, 1H), 5.92-6.04 (q, 1H), 3.60-3.63 (m, 4H), 3.10-3.14 (m, 4H), 2.61 (s,3H), 1.62-1.76 & 2.03-2.18 (m, 4H), 1.81-1.97 &2.24-2.41 (m, 4H), 1.49 (s, 9H).

Example 2: teri-butyl4-(6-((6-(l-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (III)

To a dry nitrogen purged reactor was added lOO.Ogm 4-[6-(6-Bromo-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydropyrido[2,3-<i]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-l- carboxylic acid tert-butyl ester (V) followed by 6 volumes of n-Butanol at 25-35°C. Nitrogen gas was purged for 1 hour, degased for 20 minutes. Further, 53gms of DIPEA, 90gms of Butyl vinyl ether, 6.2gms of Palladium complex [Pd(dppf)C12.MDC] and 4.2gms of bis-[2-Diphenylphosphenophenyl] ether [DPEPhos] was charged. The material temperature was raised to 94-100°C and stirred till to completion of reaction. On completion of reaction, the material was cooled to 75-85°C and filtered through Hyflow bed. The clear black organic layer was collected and washed with 4 volumes of hot water. The aqueous layer was separated at 75-85°C. The reaction material was further cooled to 50-55°C and added with 4 volume MTBE. The contents were cooled to 5±3°C over a period of about 60 minutes, stirred for another 60 minutes and filtered. The solid obtained was washed with a mixture of chilled (n-Butanol : MTBE, 1 :1) 2 volumes and dried at 55-65°C under vacuum for 8 hours to get 85 gm of tert-butyl 4-(6-((6-(l-butoxyvinyl)-8-cyclopentyl-5-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l -carboxylate. ¾ NMR (300 MHz, CDCh): δ 8.75 (s, 1H), 8.19-8.22 (d, 1H), 8.03-8.04 (m, 2H), 7.31 -7.35 (dd, 1H), 5.84-5.96 (q, 1H), 4.17-4.18 & 4.52-5.53 (m, 2H), 3.84-3.88 (t, 2H), 3.59-3.63 (m, 4H), 3.10-3.13 (m, 4H), 2.41 (s, 3H), 1.63-1.72 & 2.00-2.14 (m, 4H), 1.79-1.93 & 2.30-2.44 (m, 4H), 1.67-1.77 (m, 2H), 1.49 (s, 9H), 1.38-1.49 (m, 2H), 0.92-0.97 (t, 3H).

Example 3: 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one dihydrochloride (II).

The content of tert-butyl 4-(6-((6-(l-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (III) lOOgm, 10 volume of acetone and 1 volume of water was heated to 55±3°C. To this, was added 3 volumes of HC1 solution dropwise maintaining the temperature 55±3°C. The material was stirred for 2 hours at 55±3°C. On completion of reaction, the material was cooled to 25-30°C and stirred for 1 hour at 25-30°C. The product thus obtained was filtered, washed with 2 volumes of acetone and dried at 50-60°C under vacuum for 8 hours to get 80 gm of 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l -yl-pyridin-2-ylamino)-8H- pyrido [2,3 -<fjpyrimidin-7-one.2HC1 (Π) .

¾ NMR (300 MHz, CD3OD): 9.14 (s, 1H), 8.23-8.27 (dd, 1H), 8.00-8.02 (d, 1H), 7.56-7.59 (d, 1H), 5.95-6.07 (q, 1H), 3.55-3.59 (m, 4H), 3.44-3.47 (m, 4H), 2.50 (s, 3H), 2.44 (s, 3H), 1.60-2.40 (m, 8H). Due to CD3OD solvent, exchangeable NH proton and hydrochloride proton signals are not observed in ¾ NMR spectrum.

Example 3a: 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one dihydrochloride (Π) (without isolation of compound III).

5gms of 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-i ]pyrimidin-2- ylamino)-pyridin-3-yl]-piperazine-l -carboxylic acid tert-butyl ester (V) was added to 30 ml of n-Butanol at 25±3°C. Nitrogen gas was purged for 1.0 hour and degased for 20 minutes. 2.65gms of DIPEA was charge, degased for 5 minutes, followed by addition of 4.5gms of Butyl vinyl ether, 0.31 gm of Palladium complex [Pd(dppf)Cl₂.MDC] and 0.21 gm of bis-[2- Diphenylphosphenophenyl] ether [DPEPhos]. Temperature was raised to 94-100°C and stirred till to completion of reaction. On completion of reaction, the material was cooled to 70 to 75 °C, followed by filtration through hyflo bed and washing with 5 ml of volume of water. The organic layer was separated and further heated to 55±3°C. To the organic layer was added with 10 ml of acetone at 55±3°C. 20 ml of concentrated HC1 and 20 ml of acetone was added slowly at 55±3°C. Contents were stirred for 120 minutes at 55±3°C. On completion of reaction, the reaction mass was cooled to 30±5°C, stirred for 60 minutes at 30±5°C, filtered the product obtained, washed the product with 20 ml of chilled acetone and dried at 60±3°C under vacuum for 8 hours to get 6-Acetyl-8-cyclopentyl-5-methyl-2-(5- piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3-i ]pyrimidin-7-one.2HCl (II). ¾ NMR (300 MHz, CD₃OD): 9.14 (s, 1H), 8.23-8.27 (dd, 1H), 8.00-8.02 (d, 1H), 7.56-7.59 (d, 1H), 5.95-6.07 (q, 1H), 3.55-3.59 (m, 4H), 3.44-3.47 (m, 4H), 2.50 (s, 3H), 2.44 (s, 3H), 1.60-2.40 (m, 8H). Due to CD3OD solvent, exchangeable NH proton and hydrochloride proton signals are not observed in ¾ NMR spectrum.

Example 4: Preparation of crystalline free base Form A of palbociclib having a specific surface area of > 2m²/g (I).

6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3- <fjpyrimidin-7-one.2HCl (Π) 100 gm was added to 10 volumes of water and 10 volumes of methanol. The material was heated to 35-45°C and stirred for 20 minutes. The pH of the solution was adjusted slowly to 8 to 8.5 with 5% aqueous NaOH solution at 35-45°C, stirred for 180 minutes at 35-45°C. The product obtained was filtered and washed with 3 volumes of hot water. The solid was further dried at 50-60°C under vacuum for 8 hours to get 74 gm of 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3- i ]pyrimidin-7-one (I).

Specific surface area m²/g by BET: 5.575 m²/g

Particle size distribution (PSD): D 10 (μπι): 0.81 Ιμ,ηι; DsoOim): 2.26μιη ; D90(um): 7.69μηι.

Example 5: Preparation of crystalline free base Form A of palbociclib having a specific surface area of > 2m²/g (I).

6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3- <fjpyrimidin-7-one.2HCl (Π) 100 gm was added to 18 volumes of water and 4 volumes of methanol. The material was heated to 35-45°C and stirred for 20 minutes, further filtered through hyflow bed and washed with methanol. The pH of the solution was adjusted slowly to 8 to 8.5 with 5% aqueous NaOH solution at 35-45°C, stirred for 180 minutes at 35-45°C. The product obtained was filtered and washed with 3 volumes of hot water. The solid was further dried at 50-60°C under vacuum for 8 hours to get 74 gm of 6-Acetyl-8-cyclopentyl-5- methyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3-i ]pyrimidin-7-one (I).

Specific surface area m²/g by BET: 6.5358 m²/g

Example 6: Preparation of crystalline free base Form B of palbociclib having a specific surface area of > 2m²/g (I).

-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l -yl-pyridin-2-ylamino)-8H-pyrido[2,3- <fjpyrimidin-7-one.2HCl (Π) lOOgm was added to 20 volume of water taken in reactor at 25 to 35°C and stirred for 30 minutes. Nitrogen was applied for 30 minutes and degassed with vacuum with 400 mm/hg for 15 minutes. The material was filtered through hyflo bed and washed with 2 volume of water. 8 volume of water was taken in another reactor, Nitrogen was purged for 30 minutes, degassed with vacuum 400 mm/hg for 10 to 15 minutes and added with 2 volume of aqueous ammonia. The filtered solution was added to the ammonia solution at 25 to 35°C in 30 minutes, further the material was stirred for 2 hours at 25 to 35°C. The solid obtained was further filtered and washed with 15 volume of water. Suck dried under vacuum for 2 hours, and dried under vacuum at 30 to 35°C for 24 hours to get 74 gm palbociclib Form B.

Specific surface area m²/g by BET: 10.0250 m²/g.

Example 7: Preparation of crystalline free base Form B of palbociclib having a specific surface area of > 2m²/g (I).

Specific surface area m²/g by BET: 13.2464 m²/g

Example 8: Preparation of amorphous Palbociclib.

Palbociclib lOgm, was dissolved in 100ml of methanol and 200 ml of MDC at 25-30°C. The solution was further subjected to spray drying to yield lOgm of amorphous palbociclib.

Specific surface area m²/g by BET: 1.6577 m²/g

Particle size: Dio (μηι): 1.85μηι; Β5ο(μιη): 5.54μιτι ; Β9θ(μπι): 12.63μπι

Glass transition temperature having the range 165.78°C ±3°C.

Example 9: Preparation of palbociclib-copovidone.

Palbociclib lOgm and copovidone lOgm was dissolved in 100ml of methanol and 200 ml of MDC at 25-30°C. The solution was further subjected to spray drying to yield lOgm of palbociclib-copovidone.

Claims

1. A solid state form of palbociclib free base, selected from the group consisting of:

(a) Palbociclib crystalline free base Form B having a specific surface area of > 2m²/g, and a particle size distribution (PSD) comprising (i) a Dio value in the range of from about 0.1 μηι to about 2 μηι; (ii) a D50 value in the range of from about 1 μιη to about 5 μηι; and (iii) a D90 value in the range of from about 5 μπι to about 10 μηι;

(b) Palbociclib crystalline free base Form B having a specific surface area of >2 m²/g prepared or obtainable by a process comprising the steps of:

i. dissolving palbociclib in a suitable solvent under an inert atmosphere;

ii. optionally filtering the solution so obtained;

iv. isolating crystalline free base Form B; and

v. optionally thereafter purifying the compound so formed;

(c) Palbociclib crystalline free base Form A having a specific surface area in the range from about 5 to about 8m²/g;

(d) Amorphous palbociclib free base having a specific surface area of <2 m²/g; and

(e) A palbociclib free base-copovidone premix.

2. Palbociclib crystalline free base Form B having a specific surface area of > 2m²/g, and a particle size distribution (PSD) comprising (i) a Dio value in the range of from about 0.1 μπι to about 2 μπι; (ii) a D50 value in the range of from about 1 μπι to about 5 μπι; and (iii) a D90 value in the range of from about 5 μπι to about 10 μπι;

3. Palbociclib crystalline free base Form B according to claim 2 having a specific surface area in the range from about 10 to about 15 m²/g.

4. Palbociclib crystalline free base Form B according to claim 2 or claim 3, having an XRD as depicted in Figure 2.

5. Palbociclib crystalline free base Form B having a specific surface area of >2 m²/g prepared or obtainable by a process comprising the steps of:

(a) dissolving palbociclib in a suitable solvent under an inert atmosphere;

(b) optionally filtering the solution so obtained; (c) adding the solution to an aqueous ammonia solution under an inert atmosphere;

(d) isolating crystalline free base Form B; and

(e) optionally thereafter purifying the compound so formed.

6. Palbociclib crystalline free base Form B according to claim 5, having a specific surface area of from about 10 to about 15m²/g.

7. Palbociclib crystalline free base Form B according to claim 5 or claim 6 having a particle size distribution (PSD) comprising (i) a Dio value in the range of from about 0.1 μηι to about 2 μηι; (ii) a D50 value in the range of from about 1 μιη to about 5 μηι; and (iii) a D90 value in the range of from about 5 μηι to about 10 μηι;

8. Palbociclib crystalline free base Form B according to any one of claims 5 to 7, having an XRD as depicted in Figure 2.

9. Palbociclib crystalline free base Form A having a specific surface area in the range from about 5 to about 8m²/g.

10. Palbociclib crystalline free base Form A according to claim 9, having a particle size distribution (PSD) comprising: (i) a Dio value in the range of from about 1 μιη to about 5 μηι; (ii) a D50 value in the range of from about 2 μηι to about 7 μηι; and (iii) a D90 value in the range of from about 7 μηι to about 15 μιτι, preferably, in the range of from about 8 μηι to about 13 μηι.

11. Palbociclib crystalline free base Form A according to claim 9 or claim 10, having an XRD pattern as depicted in Figure 1.

12. Palbociclib crystalline free base Form A prepared or obtainable by a process comprising the steps of:

(a) dissolving palbociclib in one or more suitable solvents;

(b) optionally filtering the solution so formed;

(c) adjusting the pH of the solution obtained using a suitable base;

(d) isolating crystalline free base Form A; and

(e) optionally thereafter purifying the compound so formed.

13. Palbociclib crystalline free base Form A according to claim 12, having a specific surface area in the range from about 5 to about 8m²/g.

14. Amorphous palbociclib free base having a specific surface area of <2 m²/g.

15. Amorphous palbociclib free base according to claim 14, having an XRD pattern as depicted in Figure 3.

16. A process for preparing amorphous palbociclib free base according to claim 14 or claim 15, comprising the steps of:

(A) providing a solution of palbociclib in one or more suitable solvents; and

(B) isolating an amorphous form of palbociclib from the solution so formed.

17. A palbociclib free base-copovidone premix.

18. A palbociclib free base-copovidone premix according to claim 17, comprising a weight ratio of palbociclib to copovidone in the range from about 1 : 10 to about 10:1.

19. A palbociclib free base-copovidone premix according to claim 18, comprising a weight ratio of palbociclib to copovidone of about 1 : 1.

20. A palbociclib free base-copovidone premix according to any one of claims 17 to 19, having an XRD pattern as depicted in Figure 4.

21. A process for preparing a palbociclib-copovidone premix according to any one of claims 17 to 20 comprising the steps of:

(I) providing a solution of palbociclib and copovidone in one or more solvents; and

(II) isolating the premix so formed from the solution.

22. A process according to claim 21, wherein the one or more solvents is selected from the group consisting of alcohols, esters, polar aprotic solvents, nitriles, chlorinated organic solvents and/or hydrocarbons.

23. A pharmaceutical composition comprising a solid state form of palbociclib free base according to claim 1 and one or more pharmaceutically acceptable excipients.

24. A pharmaceutical composition according to claim 23 for use in the treatment of cancer.

25. A method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 23.

26. A solid state form of palbociclib free base according to claim 1 for use in the treatment of cancer.

27. Use of a comprising a solid state form of palbociclib free base according to claim 1 in the manufacture of a medicament for the treatment of cancer.

28. A solid state form of palbociclib free base substantially as hereinbefore described with reference to any one of the Examples.

29. A process for preparing palbociclib comprising the steps of:

i. preparing a compound ieri-butyl4-(6-((6-(l -butoxyvinyl)-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate (ΙΠ) by carrying out Heck coupling of vinyl n- butyl ether (IV) and 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-<fJpyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-l - carboxylic Acid tert- utyl Ester (V) in presence of a transition metal catalyst, a base and optionally a phosphine agent, in a suitable solvent;

ii. without isolating the compound/intermediate (III), reacting the compound (III) in presence of acid and a solvent to obtain compound (II); and

iii. converting compound (II) to palbociclib.

30. A process according to claim 29, wherein the transition metal catalyst is selected from the group consisting of tetrakis(triphenylphosphine)palladium [(Ph3PPd], tris(dibenzylideneacetone)dipalladium [Pd₂(dba)3], bis(dibenzylideneacetone) palladium(O) [{dba)₂Pd], palladium acetate [Pd(OAc)₂], palladium chloride (PdCI₂), bis(benzonitrile)dichloropalladium[(C6H5CN)₂PdCI₂]and(Bis-(diphenylphosphine ferrocene) palladium dichloride dichloromethane complex (Pd(dppf)₂CI₂), and the phospine compound is selected from 2,2'-bis(diphenylphosphino)-l , - binaphthalene (BINAP), 1 ,3 bis(diphenylphosphino)propane, triphenylphosphine (Ph3P), triorthotolylphosphine [(0-Ο¼Ρη)3Ρ] and tri-f-butylphosphine, bis(2- diphenylphosphenophenyl)ether [DPEPhos] .

31. A process according to claim 29 or claim 30, wherein the base is selected from the group consisting of diisopropyl ethylamine, lithium carbonate, dicyclohexyl methylamine and trimethylamine.

32. A process according to any one of claims 29 to 31 , wherein the solvent is selected from the group consisting of water, alcohols, esters, polar aprotic solvents, nitriles, chlorinated organic solvents and hydrocarbons a or mixture thereof.

33. A process according to any one of claims 29 to 32, for preparing palbociclib crystalline free base Form A having a -specific surface area in the range from about 5 to about 8m²/g and/or palbociclib crystalline free base Form B having a -specific surface area in the range from about 10 to about 15m²/g.

34. A process according to any one of claims 29 to 32, for preparing amorphous palbociclib free base having a specific surface area of <2 m²/g.