EP3186252A1

EP3186252A1 - Method of producing palbociclib and pharmaceutical compositions comprising the same

Info

Publication number: EP3186252A1
Application number: EP15754236.6A
Authority: EP
Inventors: Ludovic Coutable
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2014-08-28
Filing date: 2015-08-27
Publication date: 2017-07-05
Also published as: WO2016030439A1; IL250744A0

Abstract

The present invention relates to a method of producing palbociclib and to pharmaceutical compositions comprising the same.

Description

METHOD OF PRODUCING PALBOCICLIB AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME

The present invention relates to a method of producing palbociclib and pharmaceutical compositions comprising the same.

The compound according to formula 10

formula 10 is named 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1 -yl-pyridin-2-ylamino)- 8H-pyrido[2,3-d]pyrimidin-7-one (palbociclib). It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. The compound of formula 10 can be obtained by methods for producing a compound according to formula 10.

The method for producing a compound according to formula 10 comprises the steps: a) reacting the compounds of formula 1 and 2 to obtain a compound of formula 3,

formula 1 formula 2 formula 3 transforming the compound of formula 3 to a compound of formula 4,

formula 4 reacting the compound of formula 4 with a compound of formula 5 to compound of formula 6,

formula 5 formula 6 and converting the compound of formula 6 to palbociclib.

"Reacting" as used herein has the same meaning as transforming. Step a) of reacting the compound of formula 1 with a compound of formula 2 to obtain a compound of formula 3 can be carried out in a solvent, preferably an organic solvent or a mixture of an organic solvent with water, such as DMSO/water. Further, preferably an organic or inorganic alkaline compound, preferably an inorganic alkaline compound, such as potassium carbonate, can be added to the mixture. The reaction can be carried out a temperature in the range of 30 'Ό to 100 °C, preferably in the range of 40 to 90 ^<€.

Step b) of reacting the compound of formula 3 to a compound of formula 4 which is a reduction of a nitro group to an amine can preferably be carried out in an organic solvent or in an organic solvent in mixture with water. Suitable organic solvents are for example alcohol and ethers, e.g. methanol, ethanol, propanol, THF and Dioxane. Preferred are methanol and THF, in particular methanol. Further, the reduction of the nitro group can preferably be carried out in the presence of a catalyst, such as 10% Pd/C and/or hydrogen. Preferably, the reaction is carried out in an autoclave reactor pressurized to 1 to 10, preferably 2 to 6 bar hydrogen. Particularly preferred conditions are 10% Pd/C in methanol.

Step c) of reacting the compound of formula 4 with a compound of formula 5 to obtain a compound of formula 6 can preferably be carried out in an organic solvent. Suitable organic solvents are for example ethers, e.g. THF and Dioxane, or dichloromethane and toluene. Preferred is toluene. Further, preferably an organic or inorganic alkaline compound, preferably an organic alkaline compound, such as lithium hexamethyldisilazide or a Grignard reagent such as isopropylmagnesium chloride, can be added to the mixture. Preferably, the reaction is carried out at a temperature of O'C to 30 ^<€, preferably 5° to 20 °C.

The compound of formula 5 is obtained by a method comprising the steps i) reacting the compound of formula 1 1 with the compound of formula 12 to obtain a compound of formula 13,

formula 1 1 formula 12 formula 13 reacting the compound of formula 13 with the compound of formula 14 to obtain a com ound of formula 15,

formula 13 formula 14 formula 15, iii) transformin the compound of formula 15 to the compound of formula 5,

formula 15 formula 5.

The step i) of reacting the compound of formula 1 1 with the compound of formula 12 to obtain a compound of formula 13 can preferably be carried out in an organic solvent or in an organic solvent in mixture with water. Suitable organic solvents are for example alcohol and ethers, e.g. methanol, ethanol, propanol, THF and Dioxane. Preferred are ethanol and THF, in particular ethanol. Further, preferably an organic or inorganic alkaline compound, preferably an organic alkaline compound, such as triethylamine, can be added to the mixture. Further, the reaction can preferably be carried out a temperature of preferably 5^<€ to 25 °C.

The step ii) of reacting the compound of formula 13 with the compound of formula 14 (crotonic acid) to obtain a compound of formula 15 can preferably be carried out as a one-pot two-steps reaction. The first step can preferably be carried out in an organic solvent or in an organic solvent in mixture with water, preferably in an organic solvent. Suitable organic solvents are for example N-methylpyrrolidone (NMP), alcohol and ethers, e.g. methanol, ethanol, propanol, THF and Dioxane. Preferred are NMP and THF, particularly THF. Further, preferably an organic or inorganic alkaline compound, preferably an organic alkaline compound, such as triethylamine or diisopropylethylamine, can be added to the mixture. Further, the reaction can preferably be carried out in the presence of a catalyst, such as dichlorobis(benzonitrile) palladium(ll) or Pd(OAc)₂, optionally in the presence of a phosphine, such as tri-o- tolylphosphine. The second step can preferably carried out by adding to the resulting mixture of the first step an organic anhydride, such as acetic anhydride.

Step iii) of transforming the compound of formula 15 to the compound of formula 5 can preferably be carried out in an organic solvent or in an organic solvent in mixture with water, preferably in an organic solvent. Suitable organic solvents are for example N- methylpyrrolidone (NMP), acetonitrile, dimethylformamide (DMF), alcohol and ethers, e.g. methanol, ethanol, propanol, THF and Dioxane. Preferred are DMF and acetonitrile, particularly DMF. Further, the reaction can preferably be carried out in presence of an organic bromination reagent, such as N-bromosuccinimide (NBS).

The method for preparing palbociclib according to formula 10 further comprises the steps

d1 ) reacting the compound of formula 6 with a compound of formula 7 to a

mpound of formula 8,

formula 6 formula 7 formula 8. The reaction d1 ) can preferably be carried out in an organic solvent or in an organic solvent in mixture with water. Suitable organic solvents are for example alcohol and ethers, e.g. methanol, ethanol, propanol, n-butanol, THF and Dioxan. Preferred is n- butanol. The reaction can preferably be carried out in the presence of a catalyst, such as [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) or Pd(OAc)₂, optionally in the presence of a phosphine, such as bis-[2-(diphenylphosphino)phenyl]ether (DPEPhos).

The method for preparing palbociclib according to formula 10 further comprising the step

e1 reacting the compound of formula 8 to palbociclib of formula 10,

formula 8 formula 10. The reaction step e1 ) can preferably be carried out in an organic solvent. Suitable organic solvents are for example alcohol and ethers, e.g. methanol, ethanol, propanol, n-butanol, THF and Dioxane. Preferred is ethanol. The reaction can preferably be carried out with organic or inorganic acids, preferably inorganic acids, such as HCI, followed by the addition of a base, preferably an inorganic base, such as NaOH, to a pH > 9.

Alternatively, the method for preparing palbociclib according to formula 10 further comprises the step

d2) reacting the compound of formula 6 with a compound of formula 7 to a

compound of formula 9,

formula 6 formula 7 formula 9.

The reaction step d2) can preferably be carried out in an organic solvent or in an organic solvent in mixture with water. Suitable organic solvents are for example alcohol and ethers, e.g. methanol, ethanol, propanol, n-butanol, THF and Dioxan. Preferred is n-butanol. The reaction can preferably be carried out in the presence of a catalyst, such as [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll). After formation of the ether (according formula 8 of step d1 )), the ether is cleaved by adding an organic or inorganic acid, preferably an inorganic acid, such as HCI. HCI is preferred for large scale synthesis.

Additionally, the method for preparing palbociclib according to formula 10 further comprises the step e2) reactin the compound of formula 9 to palbociclib of formula 10,

formula 9 formula 10. The reaction step e2) can preferably be carried out in an organic solvent. Suitable organic solvents are for example alcohol and ethers, e.g. methanol, ethanol, propanol, n-butanol, THF and Dioxane. Preferred is ethanol. The reaction can preferably be carried out with organic or inorganic acids, preferably inorganic acids, such as HCI, followed by the addition of a base, preferably an inorganic base, such as NaOH, to a pH > 9.

The pharmaceutical composition of the present invention can comprise Palbociclib and suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as "pharmaceutical excipients"). The pharmaceutical composition can be in a form suitable for oral administration, preferably in the form of a tablet or capsule, liposome, or as an agglomerated powder.

The Palbociclib comprised in the composition of the present invention can be used in different particle sizes.

The method of the present invention preferably leads to relatively small palbociclib particles. In a preferred embodiment the particles obtained by the method of the present invention can be subsequently milled in order to reduce the particle size even more. The milling can be carried out by using e.g. a spiral jet mill (such as AS50 spiral jet mill, Alpine). It has been unexpectedly found that these "small" palbociclib particles have superior properties in the pharmaceutical compositions. It was further found that these particles can be unexpectedly advantageously processed, e.g. advantageously blended with excipients and processed into final dosage forms.

In such a preferred embodiment Palbociclib particles can have an average particle size (D50) of 0.1 to 50 μηι, preferably 0.5 to 30 μηι, more preferably 1 to 15 μηι, particularly preferably 1 .5 to 4 μηι. The average particle size (D50), which is also denoted as D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter, at which 50 per cent by volume of the particles have a smaller diameter than the diameter which corresponds to the D50 value. Likewise, 50 per cent by volume of the particles have a larger diameter than the D50 value. In a preferred embodiment Palbociclib can have an average particle size (D10) of 0.01 to 30 μηι, preferably 0.05 to 9 μηι, more preferably 0.1 to 4 μηι, particularly preferably 0.3 to 3 μπι. The particle size (D10), which is also denoted as D10 value of the integral volume distribution, is defined in the context of this invention as the particle diameter, at which 10 per cent by volume of the particles have a smaller diameter than the diameter which corresponds to the D10 value. Likewise, 90 per cent by volume of the particles have a larger diameter than the D10 value.

In preferred embodiment Palbociclib can have an average particle size (D90) of 0.5 to 100 μηι, preferably 1 to 50 μηι, more preferably 1 .5 to 30 μηι, particularly preferably 2.5 to 25 μηι, most preferably 2.5 to 20 μηι. The particle size (D90), which is also denoted as D90 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 90 per cent by volume of the particles have a smaller diameter than the diameter which corresponds to the D90 value. Likewise, 10 per cent by volume of the particles have a larger diameter than the D90 value.

However, it is also possible that the above described small particles are transferred into larger particles.

Preferably, the above mentioned small particles can be dissolved in an organic solvent, such as a mixture of n-butanol and anisole, at 70 to ΘΟ 'Ό, such as 80 °C. To this solution, a slurry containing free base palbociclib seed crystals suspended in an organic solvent, such as n-butanol can be added to induce crystallization and the mixture is kept at 70 to 90 °C for 1 to 4 hours, such as 3 hours, and is then cooled to about 10°C over a time of 200 to 400 min, such as 350 min, followed by filtration and washing.

In such a preferred embodiment the so-called "large" Palbociclib particles can have an average particle size (D50) of 10 to 500 μηι, preferably 20 to 125 μηι, more preferably 30 to 90 μπι. In preferred embodiment Palbociclib can have an average particle size (D10) of 0.1 to 200 μηι, preferably 0.5 to 100 μηι, more preferably 1 to 50 μηι, particularly preferably 3 to 30 μπι. In preferred embodiment Palbociclib can have an average particle size (D90) of 5 to 800 μηι, preferably 15 to 300 μηι, more preferably 40 to 150 μηι.

The particle size can be determined by means of laser diffractometry. In particular, a Malvern Instruments Mastersizer 2000 can be used to determine the size (preferably wet measurement with ultrasound 60 sec, 2,000 rpm, preferably dispersed in silicone oil, the evaluation being performed according to the Mie model, further details below in the experimental part below).

The Palbociclib comprised in the composition of the present invention can have different BET surface areas.

In preferred embodiments, the BET surface area is 0.5 to 25 m²/g, preferably 1 to 20 m²/g, more preferably 5 to 18 m²/g. The BET surface area can be measured by using an ASAP (Accelerated Surface Area and Porosity) analyzer 2020 (Micromeritics, Instruments Corp.). Samples can be incubated for 16 hours at RT under vacuum degasation, followed by BET- Measurement at -196^ (liquid nitrogen), using nitrogen as absorbtion gas (more details in the experimental part below).

The present pharmaceutical composition may further comprise filler (b). Fillers can be used to increase the bulk volume and weight of a low-dose drug to a limit at which a pharmaceutical dosage can be formed. Fillers may fulfil several requirements, such as being chemically inert, non-hygroscopic and biocompatible.

Preferred fillers are for example lactose, sucrose, glucose, mannitol, maltodextrin, dextrin, dextrose, hydrogenated vegetable oil and/or cellulose derivatives, such as microcrystalline cellulose and silicified microcrystalline cellulose, and mixtures thereof. More preferred are lactose, mannitol, microcrystalline cellulose and silicified microcrystalline cellulose, particularly lactose, microcrystalline cellulose and silicified microcrystalline cellulose, especially silicified microcrystalline cellulose.

In an alternatively preferred embodiment of the invention the filler can be a high-density filler. A high-density filler is a filler whose bulk density is from 0.9 to 1 .5 g/cm³, preferably 1 .1 to 1 .45 g/cm³ and more preferably 1 .2 to 1 .4 g/cm³. Examples of high- density fillers are calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium carbonate and magnesium carbonate, and mixtures thereof. Especially preferred are calcium phosphate and calcium hydrogen phosphate, in particular calcium hydrogen phosphate.

In the present invention, filler (b) can be present in amounts of 0 to 80 wt.%, preferably of 20 to 70 wt.%, in particular of 30 to 60 wt.% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition of the present invention further comprises disintegrant (c). Disintegrants are reported to be compounds which can enhance the ability of the intermediate to break into smaller fragments when in contact with a liquid, preferably water.

Preferred disintegrants are cross-linked carboxymethyl cellulose sodium (croscarmellose sodium) cross-linked polyvinylpyrrolidone (for example Kollidon^® CL), sodium carboxymethyl glycolate (for example Explotab^®), swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof, protein, for example formaldehyde-casein, sodium bicarbonate or mixtures thereof. In a more preferred embodiment the disintegrant is croscarmellose sodium. In an alternatively more preferred embodiment the disintegrant is cross-linked polyvinylpyrrolidone. In a further, alternatively more preferred embodiment the disintegrant is a mixture of croscarmellose sodium and cross-linked polyvinylpyrrolidone.

Alternatively, inorganic alkaline disintegrants are used, preferably salts of alkali metals and alkaline metals. Preferred alkali and alkaline metals are sodium, potassium, magnesium and calcium. As anions, carbonate, hydrogen carbonate, phosphate, hyd- rogen phosphate and dihydrogen phosphate are preferred. The term "alkaline disintegrants" means disintegrants which produce a pH level of more than 7.0 when dissolved in water. Examples for inorganic alkaline disintegrants are sodium hydrogen carbonate, sodium hydrogen phosphate and calcium hydrogen carbonate. Disintegrant (c) can be present in amounts of 0 to 30 wt.%. In a preferred embodiment, the disintegrant can be present from 3 to 15 wt.%, more preferably from 5 to 12 wt.%, based on the total weight of the pharmaceutical composition of the present invention.

The pharmaceutical composition of the present invention can further comprise at least one excipient (d), selected from lubricants (d1 ), surfactants (d2), glidants (d3), anti- sticking agents (d4), plasticizers (d5), binders (d6) and mixtures thereof.

The function of lubricants (d1 ) is reported to ensure that tablet formation and ejection can occur with low friction between the solid and the wall. The lubricant is preferably a stearate or fatty acid, more preferably an earth alkali metal stearate, such as magnesium stearate. The lubricant can be present in an amount of 0 to 3 wt.%, preferably of 0.1 to 2.7 wt.%, more preferably of 0.25 to 2.3 wt.%, based on the total weight of the pharmaceutical composition. Lubricants generally can increase the powder flowability.

In a preferred embodiment of this invention, a lubricant (d1 ) may be used. In a preferred embodiment of the present invention magnesium stearate can be used as lubricant (d1 ). Surfactants (d2) can be regarded as substances lowering the interfacial tension between two phases, thus enabling or supporting the formation of dispersions or working as solubilizer. Common surfactants are alkylsulfates (for example sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates and the like. Surfactants can be used in an amount of 0 to 5wt.%, preferably of 0.25 to 4.25 wt.%, more preferred 0.5 to 3.5wt.%, based on the total weight of the pharmaceutical composition.

In a preferred embodiment of this invention, a surfactant (d2) may be used. In a preferred embodiment of the present invention sodium lauryl sulfate can be used as surfactant (d2). Glidants (d3) are reported to be substances used to improve the flowability. Examples of glidants are talc and fumed or colloidal silica (for example Aerosil^®). Preferably, the glidant (d3) can be present in an amount of 0 to 2.5 wt.%, preferably 0.1 to 2.25 wt.%, more preferably 0.25 to 2.05 wt.%, based on the total weight of the pharmaceutical composition. In a preferred embodiment of the present invention silicon dioxide can be used as a glidant (d3). Preferably, the silicon dioxide has a specific surface area of 50 to 400 m²/g, measured by gas adsorption according to Ph. Eur. 6.0, Chapter 2.9.26, multipoint method, volumetric determination. In a preferred embodiment of this invention, a lubricant (d3) may be used. In a preferred embodiment of the present invention fumed silica (Carb o Sil) can be used as glidant (d3).

Generally, anti-sticking agents (d4) are reported to be substances to prevent the adhesion of the tableting mass to the compression mould. Further anti-sticking agents may increase the brightness of a tablet. The anti-sticking agent can be for example talcum, magnesium stearate, paraffin and the like. Further, the anti sticking agent (d5) may be present in amounts of 0 to 5wt.%, based on the total weight of the pharmaceutical composition.

Plasticizers (d5) usually are reported to be compounds capable of lowering the glass transition temperature (T_g) of a non-erodible material, preferably of lowering T_g from 1 to 50 'C. Plasticizers (d5) can be low molecular weight compounds (having a molecular weight of 50 to 500 g/mol) and can comprise at least one hydrophilic group. Examples of suitable plasticizers are dibutyl sebacetate (DBS), Myvacet^® (acetylated monoglycerides), triacetin (GTA), citric acid esters, like acetyltriethyl citrate (ATEC) or triethyl citrate (TEC), propylene glycol, dibutyl phthalate, diethyl phthalate, or mixtures thereof. Binders (d6) are reported to be substances that ensure that granulates or tablets can be formed with the required mechanical strength. Binders can be, for example, starch, sucrose, gelatine, polyvinylpyrrolidone, cellulose derivatives, such as hydroxypropyl methylcellulose, or mixtures thereof. Polyvinylpyrrolidone, or hydroxypropyl methylcellulose is preferred. Binders can for example be used in an amount of up to 15 wt%, preferably 2 to 12 wt%, more preferably 3 to 9 wt%, based on the total weight of the present composition.

Regarding the above-mentioned pharmaceutically acceptable excipients, the application generally refers to "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", edited by H. P. Fiedler, 5^th Edition, Editio Cantor Verlag, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", third edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.

In this regard it is generally noted that due to the nature of pharmaceutical excipients, it cannot be excluded that a certain compound meets the requirements of more than one of the components (d1 ) to (d6). However, to enable an unambiguous distinction, it is preferred in the present application that one and the same pharmaceutical compound be only used as one of the compounds (d1 ) to (d6). For example, if magnesium stearate is used as lubricant (d1 ) it is not additionally used as anti-sticking agent (d4), even though magnesium stearate also exhibits a certain anti-sticking effect.

Another preferred embodiment the pharmaceutical composition of the present invention is in the form of a tablet. Another preferred embodiment the pharmaceutical composition of the present invention is in the form of a capsule.

The present pharmaceutical composition preferably comprises

- 5 to 80 wt.% Palbociclib, preferably 20 to 70 wt.% Palbociclib, more preferably 30 to 55 wt.% Palbociclib (a1 ),

- 10 to 90 wt.% filler, preferably 20 to 80 wt.% filler, more preferably 30 to 60 wt.% filler (b),

- 0 to 20 wt.% disintegrant, preferably 1 to 20 wt.% disintegrant, more preferably 2 to 12 wt.% disintegrant (c),

- 0 to 3 wt.% lubricant, preferably 0.1 to 2.7 wt.% lubricant, more preferably 0.25 to 2.3 wt.% lubricant (d1 ),

- 0 to 5 wt.% surfactant, preferably 0.25 to 4.25 wt.% surfactant, more preferably 0.5 to 3.5 wt.% surfactant (d2),

- 0 to 2.5 wt.% glidant, preferably 0.1 to 2.25 wt.% glidant, more preferably 0.25 to 2.05 wt.% glidant (d3), wherein all weight percent are based on the total weight of the composition.

In a preferred the composition is can be present in form of a tablet. In a further preferred embodiment of the present invention the hardness of the tablet is from 40 to 350 N, more preferred from 50 to 325 N, still more preferred from 75 to 300 N, in particular from 85 to 275 N, wherein the hardness is measured according to Ph. Eur. 6.0, Chapter 2.9.8. In addition, the tablets preferably can have a friability of less than 5%, particularly preferably less than 2%, especially less than 1 %, in particular 0.5 to 0.9. The friability is determined in accordance with Ph. Eur., 7.7, chapter 2.9.7.

In an alternative preferred embodiment the dosage form is a capsule, preferably a soft capsule, in particular a soft gelatine capsule. Alternatively preferred the capsule is a hard capsule, e.g. a hard gelatine capsule.

In a preferred embodiment the soft capsule comprises

a shell and

a fill matrix.

Preferably, the fill matrix contains or consists of the above-described dissolved Palbociclib (i.e. Palbociclib together with the above described excipients). The shell preferably has a thickness of 0.2 to 1 .8 mm.

In a preferred embodiment the shell comprises gelatin, optionally a plasticizer and optionally water and optionally colorants and/or flavours. For producing such a shell, a wet gel formulation is processed as described below. Preferably, alkali processed (type B) gelatin is used. Preferably, gelatin is used in an amount of 40 wt.% of the wet gel formulation.

Preferably glycerol, sorbitol or propylene glycol is used as plasticizer. Plasticizers usually are used in an amount of 20 - 30 wt.% of the wet gel formulation. In an alternative embodiment the shell preferably does not contain any plasticizers. In particular, the shell preferably does not contain any plasticizers selected from citric acid esters, phthalates, triacetin and mixtures thereof. Water usually is used in an amount of 30-40 wt.% of the wet gel formulation.

Usually, the wet gel formulation is prepared by dissolving the gelatine in water (e.g. at 70 to 85 °C), followed by the addition of plasticizer and optionally colorant/flavours. The wet gel formulation is then supplied to an encapsulation machine, preferably through transfer pipes by a casting method that forms two separate gelatine ribbons. Each gel ribbon may be suitable for providing half of the soft capsule.

The fill matrix containing the Palbociclib containing pharmaceutical composition can be manufactured separately.

Preferably, the gel ribbons and the fill matrix are combined to form the softgel capsule by a rotary die encapsulation process. Usually, metered volumes of the liquid fill matrix are injected, e.g. from a wedge device, into the space between the gelatine ribbons. The two softgel capsule halves can be sealed together, e.g. by the application of heat and pressure. The sealed body of the capsule can preferably not be opened without visible damage and it is preferably tamper-evident. Further, the capsule can preferably be highly impermeable.

For example, the capsule liquid filling and sealing system CFS 1200 by CAPSUGEL^® can be used.

After the encapsulation process water can be removed. Preferably, the shell has a residual water content of about 5 to 35 wt.%, more preferably of about 7 to 15 wt.%. It is alternatively preferred that the solid oral dosage form is a hard capsule. Hard capsules known also as two-pieces capsules can be formed by two precast cylinders each being hemispherically sealed at one end, respectively.

The hard gelatine capsules can preferably have a volume from 0.02 to 1 .37 ml, more preferably from 0.1 to 0.95 ml. Hard capsules can preferably be produced using gelatine or other pharmaceutically acceptable materials, preferably polymers such as hydroxypropyl methylcellulose. The capsules may be dyed by adding dyes during the production process. The preparation of hard capsules can preferably be carried out according to the Colton process in which pins are dipped into an aqueous gelatine or polymer solution such that the pins are covered with a thin film of gelatine or polymer wherein the film is further solidified and dried. Hard gelatine capsules preferably comprise gelatine, water and optionally dye. It is preferred that hard gelatine capsules do not comprise further components, in particular no plasticizers.

The hard capsules can be preferably filled with liquid, semi-solid or solid pharmaceutical compositions.

Further, the tablets or capsules of the invention preferably have a content uniformity, i.e. a content of active agent(s), which lies within the concentration of 90 to 1 10%, preferably of 95 to 105%, especially preferred of 98 to 102% of the average content of the active agents(s). The "content uniformity" is determined with a test in accordance with Ph. Eur., 6.0, Chapter 2.9.6. According to that test, the content of the active agents of each individual tablet out of 20 tablets must lie between 90 and 1 10%, preferably between 95 and 105%, especially between 98 and 102% of the average content of the active agents(s). Therefore, the content of the active drugs in each tablet of the invention differs from the average content of the active agent by at most 10%, preferably by at most 5% and especially by at most 2%.

Hardness, friability and content uniformity are determined preferably from an uncoated tablet.

In another preferred embodiment the tablet according the present invention is film- coated with a coating (e).

In the present invention, the following three types of film-coatings are possible

- film-coating without effecting the release of the active ingredient (preferred), - gastric juice resistant film-coatings,

- retard coatings.

Film-coatings that do not affect the release of the active ingredient are preferred. In gastric juice resistant coatings the solubility depends on the pH of the surrounding. Retard coatings are usually non-soluble (preferably having a water-solubility at 25 °C of less than 10 mg/ml).

Generally, film-coatings can be prepared by using cellulose derivatives, poly(meth)- acrylate, polyvinylpyrrolidone, polyvinyl acetate phthalate, and/or shellac or natural rubbers such as carrageenan.

Preferred examples of coatings (e), which do not affect the release of the active ingredient can be those including poly(meth)acrylate, methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP) and mixtures thereof. These polymers can have a median molecular weight of 10,000 to 150,000 g/mol.

Examples of gastric juice resistant coatings can comprise cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) and polyvinyl acetate phthalate (PVAP). Examples of retard coatings can comprise ethyl cellulose (EC, commercially available e.g. as Surelease^®) and poly(meth)acrylate (commercially available e.g. as Eudragit^® RL or RS and IJS). In a preferred embodiment the pharmaceutical composition according to the invention provides an immediate release ("IR") of Palbociclib. This means that the release profile of the dosage forms of the invention according to USP app. II (paddle, 900 ml, pH 1 .2, 4.5 and 6.8, 75 rpm, 37 °C) after 10 minutes usually indicates a content release of at least 75 %, preferably at least 85 %, especially at least 90 %.

In a preferred embodiment the pharmaceutical composition of the present invention is prepared by blending the palbociclib with excipients. The blending of above components can preferably be carried out in a mixer, preferably in a tumble blender. In a preferred embodiment the components can be sieved before being blended. In a preferred embodiment the sieve has a mesh size of 200 to 1400 μηι, preferably of 800 to 1250 μπι. Further, the mixture resulting from the blending step preferably possesses a Hausner ratio in the range of 1 .02 to 1 .6, preferably of 1 .08 to 1 .4, more preferably of 1 .10 to 1 .20. The Hausner ratio is the ratio of tapped density to bulk density. Bulk density and tapped density can be determined according to USP 24, Test 616 "Bulk Density and Tapped Density". A Hausner ratio within the above limits improved processability unexpectedly.

In a preferred embodiment the blended composition is filled into capsules or compressed into tablets. Compressing the mixture from step (ii) into tablets can be carried out by compressing said mixture on a press, for example on a rotary press, e.g. on a Fette^® (Fette GmbH, Germany) or a Riva^® Piccola (Riva, Argentina) or on an eccentric press, for example (Korsch EK0). In a preferred embodiment step (iii) comprises direct compression of the mixture from step (ii). The direct compression of the mixture from step (ii) avoids a granulation step and ensures a direct and easy procedure. The compression force can preferably range from 1 to 50 kN, preferably 3 to 40 kN.

Further, the present invention is directed to a method of treating or preventing cancer using a pharmaceutical composition according to the present invention.

The term "cancer" includes both solid tumors and hematological malignancies. Cancers include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, NSCLC and SCLC), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma), bladder cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., AML, CML, myelodysplastic syndrome and promyelocytic leukemia), and lymphoid disorders (e.g., leukemia, multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma). EXAMPLES

(A) ANALYTICAL METHODS

NMR Spectroscopy

Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS, 400 MHz

HPLC/UV methods

Method 1

Instrument: Agilent 1200

Column: Discovery C18, 150 ^* 4.6 mm; dp = 5 μηι

Flow: 1 .5 ml/min

Temperature: Not controlled

Eluent

B: 10 mM KH₂P0₄, pH 2.3

C: acetonitrile

Gradient: Time [min] eluent B [%] eluent C [%]

0.0 75 25

8.0 40 60

13.0 40 60

14.0 75 25

Stop time 17.0

Injection volu 5 μΙ

Detection: DAD (λ = 230 and 254 nm) Method 2:

Instrument: Agilent 1200

Column: Kinetex C18, 150^*4.6 mm; dp = 2.

Flow: 0.7 ml/min

Temperature: 25.00 ^<C

Eluent

A: acetonitrile

B: 0.1 % NH₄HCO₃ (20 mM), pH 9

Gradient: Time [min] eluent A [%] eluent B [%]

0.0 30 70

10.0 85 15

12.0 85 15

12.5 30 70

Stop time 18.0

Injection volume: 3 μΙ

Detection: DAD (λ = 246 and 300 nm)

Method 3:

Instrument: Agilent 1 100

Column: Agilent Eclipse XDB-C18, 150^*4.6 mm; dp = 5 μηι

Flow: 1 .0 ml/min

Temperature: 40.00 ^<C

Eluent

A: acetonitrile

B: H₂0 + 0.1 % HCOOH + 0.05% HFBA

Gradient: Time [min] eluent A [%] eluent B [%]

0.0 5 95

10.0 95 5

12.0 95 5

12.5 5 95

Stop time 15.0

Injection volu 3 μΙ

Detection: DAD (λ = 254 and 292 nm) Differential Scanning Calorimetry (DSC)

Instrument: Mettler Toledo DSC 822E coupled with a Mettler Toledo Gas-Flow- Controller TS0800GC1 (Mettler-Toledo GmbH, GieBen, Germany)

Aluminium crucible: 40 μΙ_

Lid: perforated

Temperature range: 30°C to 350 °C

Heating rate: 10°C/ min

Nitrogen flush: 50 ml_ / min

Software: STARe Version. 8.10

Interpretation: Endothermic modus

X-Ray Powder Diffraction (PXRD)

The sample was analyzed on a D8 Advance X-ray powder diffractometer (Bruker-AXS, Karlsruhe, Germany). The sample holder was rotated in a plane parallel to its surface at 20 rpm during the measurement. Further conditions for the measurements are summarized in the table below. The raw data were analyzed with the program EVA (Bruker-AXS, Germany). standard measurement

radiation Cu Κ_α (Ι = 1 .5406A)

source 38 kV / 40 mA

detector Vantec

detector slit variable

divergence slit v6

antiscattering slit v6

2Θ range / ⁰ 2 < 2Θ < 55

step size / ⁰ 0.017 Headspace Gaschromatography

Sample Preparation Sample was dissolved in 1 ml of dimethylsulfoxide (the concentration was approx. 5 mg/ml for acetone determination). Calibration was realized with standards containing the solvent of interest in the concentration recommended by ICH guidelines (5000 ppm for acetone).

Instrument settings

Instrument: G1888 Network Headspace Sampler coupled with a 7890A GC- System from Agilent Technologies

Method: HS EP 35 2.M

Column settings:

Column: HP-624

Column length (i.d.): 30 m ( 0.25 mm)

Film thickness 1 .4 μηι

Carrier gas (flow): He (1 .0 ml/min)

Injector settings:

Injector temp.: 220 °C

Split: 10:1

Detector settings:

transfer line 280 °C

MS source: 230 °C

MS Quadrupole: 150 °C

Ionization: EI+

Detection mode: Scan (m/z 20 - 300)

Temperature program

Initial: 35^ (5 min isotherm)

Rate: 5°C/min

Final: 190°C (9.4 min isotherm)

Total run time: 45.4 min

Headspace settings:

Oven temp.: 70 °C

Loop temp.: 100°C

Transfer temp.: 120°C Injection loop: 1 ml

vial pressure: 13.5 ps

vial equilibration time: 15 min

pressurize time: 0.2 min

loop fill time: 0.2 min

loop equilibration time: 0.1 min

injection time: 0.5 min

sequence purge time: 20 min

BET Method (Determination of Specific Surface Area)

In the examples, specific surface area is measured by ASAP Analyzer 2020 (Micromeritics, Instruments Corp.).

Accelerated Surface Area and Porosity analyzer ASAP (Reference: (1 ) "Application of surface area measurement for identifying the source of batch-to-batch variation in processability", Radha R. Vippagunta, Changkang Pan, Ronak Vakil, Vindhya Meda, Richard Vivilecchia, and Michael Motto; Pharmaceutical Development and Technology, 1097-9867, first published on 25 February 2009).

A standardized method was used: Samples were incubated for 16 hours at RT under vacuum degasation, followed by BET-Measurement at -196^ (liquid nitrogen), using nitrogen as absorbtion gas.

(B) Particle Size Example

The following particle size distribution is preferably used (as determined in silicone oil, (Rl: 1 .403), 2000 rpm, 2min ultrasonic 50%, MIE-Modell (Rl 1 .6, Absorption: 1 )) Particle Sizes

Micronisation was carried out by using an AS50 spiral jet mill (Alpine).

Capsule formulation examples of Palbociclib according to formula 10 with small particles, large-particles and micronized palbociclib were carried out as shown below.

(C) Formulation Examples Formulation Example 1 :

Formulation for hard gelatin capsule, capsule of size 0

Positions 1 to 3 were sieved through mesh 500 μηι and blended for 10 minutes. The blending of above was then filled into capsules of size 0. Formulation Example 2:

Batch size

[Number DF]

Palbociclib, Prosolv SMCC 90 and Kollidon CL were sieved through mesh 500 μηι and blended for 10 minutes. The blending of above was then filled into capsules of size 0.

Formulation Example 3:

Containing 1 % lubricant Batch size

[Number DF]: 20

Positions 1 to 3 were sieved through mesh 500 μηι and blended for 10 minutes. Position 4 was also sieved through mesh 500 μηι and blended for 5 minutes with the blend of positions 1 -3. The blending of above was then filled into capsules of size 0. Formulation Example 4:

A tablet is prepared of the following composition:

Positions 1 to 5 were sieved through mesh 500 μηι and blended for 10 minutes. Tablets were then prepared by direct compression of the blending.

Formulation Example 5:

Batch size

[Number DF]

(D) Dissolution Example:

Dissolution is examined by the following method 900ml, 37°, agitation: 75rpm, Paddle (USPII), Dissolution media:

- 900ml 0.1 N Hydrochloric acid, pH 1 .2

- 900ml_Buffer Sodium phosphate, pH 6.8 (50 mM)

- 900ml Buffer Sodium acetate trihydrate, pH 4.5 (50 mM)

- Buffer change:

- 750ml 0.1 N Hydrochloric acid, pH 1 .2 + 250ml 0.2m Buffer Sodium phosphate Na₃P0₄ x 12H₂0.→ pH 6.8

The dissolution profiles are as shown in the Figures 1 to 8. Further, the influence of the particle size on the dissolution was examined. Therefore, the dissolution profiles of 75 mg Palbociclib capsules of Formulation Examples 1 , 2 and 5 were under the same conditions as described at the beginning of chapter (D) (0.1 N HCI). Accordingly, tablets formed by direct compression of the blended components of Formulation Examples 1 , 2 and 5 were dissolved under the same conditions as the capsules. The normalized curves to capsule/tablet weight are disclosed in Figure 9.

These data demonstrate that there is no significant influence on dissolution properties among small-particles, large-particles and micronized palbociclib. Additionally, as shown in Figure 10, exemplary for small nonmicronised particles of Formulation Example 1 , the difference in the dissolution of the capsules and tablets is minimal. (E) Synthesis Example of Palbociclib

1. Materials Standard reagents and solvents were purchased from TCI, Sigma-Aldrich and Merck.

2. Synthesis of Palbociclib (formula 10)

Step a): synthesis of 1-Boc-4-(6-nitro-3-pyridyl)piperazine (formula 3)

Step b): A 1 -L RBF, was charged with 50 g of 5-Bromo-2-nitro-pyridine (0.246 mol, 1 .00 eq.), 175 ml DMSO and 35 ml water. To the resulting mixture was added 37.45 g potassium carbonate (0.271 mol, 1 .1 eq.) followed by 59.64 g boc-piperazine (0.320 mol, 1 .3 eq.). The mixture was heated to 70^ and stirred under argon until completion (approx. 28 h). The reaction was diluted with 315 ml of water and allowed to cool down to RT. After 2 h stirring, the solid was collected by filtration, washed with water (2 x 250 ml) and left in air at RT overnight to give crude wet 1 -Boc-4-(6-nitro-3- pyridyl)piperazine as yellow solid. HPLC (Method 1 ): 6.49 min (96.4%) (230 nm)

Crude product was suspended in 250 ml toluene, followed by concentrated under reduced pressure. The residue was dissolved in 200 ml toluene, under reflux. Resulting orange solution was allowed to cool down slowly to RT without stirring. After 3 h, precipitated solid was filtered, washed with toluene (50 ml), TBME (2 x 100 ml) and dried at 50 ^<C/20 mbar for 7 h to yield 63.88 g of 1 -Boc-4-(6-nitro-3-pyridyl)piperazine as yellow solid (84.1 % yield). HPLC (Method 1 ): 6.49 min (99.1 %) (230 nm). Step b): synthesis of 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert- butyl ester formula 4)

Step b): A 10 L autoclave was charged with 328.2 g of nitro 1 -Boc-4-(6-nitro-3- pyridyl)piperazine (formula 3) (1 .064 mol, 1 .00 eq.) and 3.5 L MeOH. The system was purged with N₂ then 22.7 g of 10% Pd/C (50% wet, 21 .3 mmol, 0.02 eq.) were added in one portion. While stirring (300 r.p.m), the reactor was again purged with N₂ (2 x 2 bar) then pressurized to 3 bar hydrogen. The temperature of the reaction mixture was set to 25°C. IPC of the mixture after 4 h revealed full consumption of starting material. Hydrogen was carefully evacuated from the autoclave and the mixture filtrated. Solids were rinsed with 200 ml MeOH and the filtrate concentrated under reduced pressure. The residue was taken up with 250 ml toluene, concentrated again under reduced pressure and dried at 50°C/15 mbar for 8 h to give 293.5 g of 4-(6-Amino-pyridin-3-yl)- piperazine-1 -carboxylic acid tert-butyl ester (formula 4) as pale violet solid (99.1 % yield).

HPLC (Method 2): 6.65 min (99.6%) (246 nm). Step i): synthesis of (5-Bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine (formula 13)

Step i: A 4 L 3-necked RBF, equipped with a 500 ml addition funnel, was charged with 250.0 g of 5-Bromo-2,4-dichloro-pyrimidine (1 .097 mol, 1 .00 eq.) and 880 ml absolute EtOH. The mixture was cooled to 10°C with an ice-bath A solution of 250 ml cyclopentylamine (130 mmol, 1 .18 eq.) in 250 ml absolute EtOH was added dropwise over 60 min while maintaining the temperature between 10-15°C After stirring for 1 h, the mixture was allowed to warm up to RT and further stirred for 1 h. The reaction was quenched with 1 .1 L water then seeding material was added. After stirring at RT for 2 h, the precipitated solid was collected by filtration, washed with 1 L water/EtOH (8/2) acetonitrile and left in air at RT to give crude wet (5-Bromo-2-chloro-pyrimidin-4-yl)- cyclopentyl-amine as white solid.

HPLC (Method 1 ): 9.67 min (89.3%) (254 nm).

Crude product was suspended in 1 .5 L hexane and heated to reflux for 45 min. Resulting slurry was allowed to cool down slowly to RT with stirring. After 3 h, stirring was stopped and the mixture left at RT. Solid was collected by filtration, washed with hexane (350 ml), dried in air for 10 min then at 50^/35 mbar for 2 h to give 264.51 g of purified (5-Bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine (87.2% yield) as white solid.

HPLC (Method 1 ): 10.02 min (99.7%) (254 nm).

Step ii): synthesis of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin- 7-one formula 15)

Step ii): A 1 L 3-necked RBF was charged with 50.0 g of (5-Bromo-2-chloro-pyrimidin- 4-yl)-cyclopentyl-amine (0.181 mol, 1 .00 eq.), 39.0 g crotonic acid (0.452 mol, 2.5 eq.), 125 ml diisopropylethylamine (0.741 mol, 4.1 eq.) and 125 ml THF. The mixture was degassed by applying 3 vacuum/argon cycles then 1 .10 g of tri-o-tolyl-phosphine (3.62 mmol, 0.02 eq.) and 1 .39 g dichlorobis(benzonitrile)palladium(ll) (3.62 mmol, 0.02 eq.) were added. The mixture was degassed again by applying 3 vacuum/argon cycles then heated to 75°C and stirred under argon for 20 h. Then, 43.0 ml of acetic anhydride (0.452 mol, 2.5 eq.) were added and the mixture further stirred at 75^ for 2 h. The reaction was quenched with 250 ml water and the mixture allowed to cool down to RT. After 1 h stirring, 125 ml water was added while cooling to Ι δ'Ό. The precipitated solid was collected by filtration, washed with water (125 ml), cold isopropanol (3 x 125 ml), dried in air for 10 min then at 50 ^<€/25 mbar for 20 h to give 38.13 g of 2-Chloro-8- cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (formula 15) (80.0% yield) as yellowish solid. HPLC (Method 1 ): 8.67 min (99.6%) (254 nm).

¹H NMR (400 MHz, CDCI₃, δ ppm): 1 .68 (br. s, 2 H), 1 .84 - 1 .98 (m, 2 H), 2.12 (br. s, 2 H), 2.22 (br. s, 2 H), 2.44 (s, 3 H), 5.84 (m, 1 H), 6.53 (br. s, 1 H), 8.74 (s, 1 H).

Step iii): synthesis of 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3- d]pyrimidin-7-one (formula 5)

Step iii). A 10 L reactor was charged with 191 .0 g of 2-chloro-8-cyclopentyl-5-methyl- 8H-pyrido[2,3-d]pyrimidin-7-one (0.724 mol, 1 .00 eq.) and 1 .24 L DMF. The resulting slurry was cooled to Ι δ'Ό under argon then a solution of 322.3 g of N- bromosuccinimide (1 .81 mol, 2.5 eq.) in 0.70 L DMF was added over 30 min. The mixture was heated to 50 °C and stirred under argon for 6.5 h. After cooling to 15°C, 6.0 L water was added to the reactor. The mixture was further cooled to 5°C and 290 ml of sodium hydrogen sulfite solution (39%, 1 .45 mol, 2.0 eq.) was added carefully. After stirring at RT for 20 h, the precipitated solid was collected by filtration, washed with water (2 x 1 .7 L), isopropanol (1 x 1 .1 L), dried at δΟ 'Ό under vacuum for 24 h to give 219.0 g of 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (formula 5) (88.3% yield) as off-white cotton-like solid. HPLC (Method 1 ): 1 1 .14 min (97.2%) (230

Step c): synthesis of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert- butyl ester (formula 6)

Step c): A 2 L 3-necked RBF was charged with 54.60 g of 4-(6-Amino-pyridin-3-yl)- piperazine-1 -carboxylic acid tert-butyl ester (0.196 mol, 2.1 eq.) and 360 ml toluene. The mixture was cooled to 10°C then 196 ml of LiHMDS solution (1 M in THF, 0.196 mol, 2.1 eq.) was added dropwise, under argon, within 10 min. After stirring for 10 min at Ι Ο 'Ό, a slurry of 32.00 g aryl chloride 6-bromo-2-chloro-8-cyclopentyl-5- methyl-8H-pyrido[2,3-d]pyrimidin-7-one in 250 ml toluene was added dropwise within 10 min. After 15 min, the cooling bath was removed, the mixture stirred at RT for 1 .5 h then quenched with 375 ml of sodium hydrogen carbonate saturated aqueous solution. After 1 h, the precipitated solid was collected by filtration, washed with toluene (240 ml), acetone/water 1 /1 (240 ml), acetone (320 ml) then dried at RT/20 mbar for 6 h to give 50.10 g of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3- d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 -carboxylic acid tert-butyl ester (formula 6) (91 .8% yield) as yellow solid.

HPLC (Method 1 ): 9.06 min (97.2%) (254 Step d1): synthesis of 4-{6-[6-(1-Butoxy-vinyl)-8-cyclopentyl-5-m dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-but l ester (formula 8)

Step d1 ): A 3 L RBF was charged with 109.8 g of 4-[6-(6-bromo-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 - carboxylic acid tert-butyl ester (formula 6) (187.9 mmol, 1 .00 eq.) and 1 .1 L n-butanol. To the resulting slurry were added successively, at RT under argon, 39.5 ml diisopropylethylamine (231 .1 mmol, 1 .23 eq.) and 97.2 ml of butyl vinyl ether (751 .4 mmol, 4.0 eq.). The mixture was degassed by applying 3 vacuum/argon cycles then 3.15 g of [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (3.9 mmol, 0.02 eq.) was added. The mixture was degassed again by applying 1 vacuum/argon cycle then heated to 95 'Ό and stirred under argon for 20 h. Due to incomplete conversion, 12.2 ml of butyl vinyl ether (93.9 mmol, 0.5 eq.) was added and the mixture further stirred at 95 'Ό for 8 h. After cooling to RT, the mixture was stirred overnight at RT then cooled to 5°C and quenched by the addition of 143 ml potassium carbonate saturated solution, within 15 min. After 30 min, the precipitated solid was collected by filtration. The residue was taken up with 1 L water / ethanol (1 /1 v/v), filtrated and washed with heptane (500 ml): Drying at 50 ^<€ / 35 mbar for 18 h gave 86.70 g of 4-{6-[6-(1 -Butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1 -carboxylic acid tert-butyl ester (77.0% yield)as yellow solid. HPLC (Method 1 ): 1 1 .61 min (94.6%) (254 nm). Step d2): synthesis of 4-[6-(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert- but l ester hydrochloride (formula 9)

Step d2):_A 10 L reactor was charged with 500.0 g of 4-[6-(6-bromo-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 - carboxylic acid tert-butyl ester (0.855 mol, 1 .00 eq.) and 5 L n-butanol. To the resulting slurry were added successively, at RT under argon, 180 ml diisopropylethylamine (1 .052 mol, 1 .23 eq.) and 443 ml of butyl vinyl ether (3.422 mmol, 4.0 eq.). The mixture was degassed by applying 2 vacuum/argon cycles then 14.40 g of [1 ,1 - Bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (17.5 mmol, 0.02 eq.) was added. The mixture was degassed again by applying 1 vacuum/argon cycle then heated to 90 'Ό and stirred under argon for 24 h. After cooling to RT, the mixture was diluted with 1 .5 L n-butanol, and quenched by the addition of 1 .3 L HCI 2 M solution (2.566 mol, 3.0 eq.). After 3 h stirring at RT, the precipitated solid was collected by filtration, washed with acetone (2 x 2 L), dried at 50°C under vacuum to give 479.0 g of 4-[6-(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro- pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 -carboxylic acid tert-butyl ester hydrochloride (95.9% yield) as yellow solid.

HPLC (Method 3): 8.80 min (95.7%) (254 nm).

¹H NMR (400 MHz, DMSO-d6) δ ppm: 1 .41 (s, 9 H), 1 .5 - 1 .7 (m, 2 H), 1 .7 - 1 .9 (m, 2 H), 1 .9 -2.0 (m, 2 H), 2.1 - 2.3 (m, 2 H), 2.33 (s, 3 H), 2.42 (s, 3 H), 3.1 - 3.2 (m, 4 H), 3.4 - 3.5 (m, 4 H), 5.83 (t, J=8.60 Hz, 1 H), 7.76 (d, J=8.99 Hz, 1 H), 7.88 (d, J=8.60 Hz, 1 H), 7.99 (d, J=2.74 Hz, 1 H), 8.99 (s, 1 H), 10.9 - 1 1 .1 (m, 1 H). A H NMR spectrum is shown in Figure 1 1 . XRPD: An XRPD spectrum is shown in Figure 12.

Ste e1 ): synthesis of palbociclib free-base (formula 10)

Step e1 ): A 3 L 3-necked RBF was charged with 85.70 g of 4-{6-[6-(1 -butoxy-vinyl)-8- cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}- piperazine-1 -carboxylic acid tert-butyl ester (formula 8) (141 .9 mmol, 1 .00 eq.) and 1 .6 L absolute EtOH. The resulting slurry was heated to 50 ^<€ then 288 ml of HCI 32% solution (2.98 mol, 21 .0 eq.) was added dropwise over 15 min. The mixture was stirred at 50°C under argon overnight. After cooling to RT, a solution of 141 .9 g NaOH (3.55 mol, 25 eq.) in 889 ml water was slowly added. The mixture was further stirred at RT for 20 h then filtrated. The solid was successively washed with acetonitrile / water (1/1 v/v, 400 ml), acetonitrile (400 ml), TBME (400 ml) and n-hexane (600 ml) then dried at 40 ^qC/15 mbar for 20 h to give compound palbociclib free base of formula 10 (48.50 g, 76.3% yield) as yellow solid.

HPLC (Method 3): 6.15 min (96.6%) (254 nm)

H NMR (400 MHz, DMSO-d6) δ ppm: 1 .5 - 1 .6 (m, 2 H), 1 .7 - 1 .8 (m, 2 H), 1 .8 - 1 .9 (m, 2 H), 2.1 - 2.3 (m, 2 H), 2.29 (s, 3 H), 2.40 (s, 3 H), 2.8 - 2.9 (m, 4 H), 3.0 - 3.1 (m, 4 H), 3.30 (s, 3 H), 5.7 - 5.9 (m, 1 H), 7.42 (dd, J=8.99, 3.13 Hz, 1 H), 7.82 (d, J=8.99 Hz, 1 H), 8.01 (d, J=3.13 Hz, 1 H), 8.93 (s, 1 H), 10.06 (s, 1 H).

XRPD: An XRPD spectrum of polymorph form A is shown in Figure 13. tep e2): alternative synthesis of palbociclib free-base (formula 10)

Step e2): A 10 L reactor was charged with 227.0 g of 4-[6-(6-acetyl-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 - carboxylic acid tert-butyl ester hydrochloride (formula 9) (0.389 mmol, 1 .00 eq.) and 2.25 L absolute EtOH. At RT, 190 ml of concentrated HCI solution (32%, 1 .94 mmol,

5.0 eq.) was added dropwise over 15 min. The mixture was stirred at 70°C until completion of the reaction (about 4 hours). After cooling to 50 °C, the mixture was filtered and transferred back into the reactor. At 35 °C, 1 .2 L of 2 N NaOH solution (2.33 mol, 6.0 eq.) was added dropwise over 25 min. Then, the mixture was cooled to RT, stirred for 20 h then filtrated. The solid was successively washed with water (2 x 1 L), acetone (2 x 0.8 L), and n-heptane (1 .5 L) then dried at 50°C/15 mbar for 24 h to give 152.6 g of palbociclib free base (87.7% yield) as yellow solid.

HPLC (Method 3): 6.16 min (97.4%) (254 nm).

¹H NMR (400 MHz, CDCI₃) δ ppm: 1 .6 - 1 .8 (m, 2 H), 1 .7 - 1 .9 (m, 2 H), 1 .8 - 2.0 (m, 2 H), 2.0 - 2.2 (m, 2 H), 2.3 - 2.4 (m, 2 H), 2.38 (s, 3 H), 2.55 (s, 3 H), 3.0 - 3.1 (m, 4 H),

3.1 - 3.2 (m, 4 H), 5.8 - 6.0 (m, 1 H), 7.33 (dd, J=9.19, 2.93 Hz, 1 H), 8.06 (d, J=2.74 Hz, 1 H), 8.16 (d, J=8.99 Hz, 1 H), 8.2 - 8.4 (m, 1 H), 8.83 (s, 1 H).

XRPD: The XRPD spectrum corresponds to that shown in Figure 13

BET (surface area): 15 m²/g.

PSD: D90 = 22 μηι, D50 = 6.6 μηι, D10 = 0.7 μηι. 3. Preparation of large particle size palbociclib free base

A 10 L reactor was charged with 172.3 g of small particles palbociclib free base (0.385 mmol), 2.75 L n-butanol and 4.15 L anisole. The stirred mixture was heated to 95 °C until dissolution of solids then cooled to 80°C. Seeding material was added (0.57 g palbociclib free base suspended in 28 ml n-butanol) afterwards the mixture was cooled to 10 °C within 4 h, stirred at this temperature for 16 h and filtered. The solid was successively washed with anisole (1 x 0.5 L), n-heptane (2 x 1 L) then dried at 50°C/15 mbar for 72 h to give 130.0 g of large particles palbociclib free base (75.4% yield) as yellow solid.

HPLC (Method 3): 6.17 min (99.1 %) (254 nm).

XRPD: The XRPD spectrum corresponds to that shown in Figure 13.

BET (surface area): < 1 m²/g.

PSD: D90 = 48 μπι, D50 = 20 μπι, D10 = 5.6 μπι.

4. Optimization of the synthesis

Step a)

Optimization of the reaction conditions for the preparation of the compound of formula 3.

Apart from DMSO, other reaction solvents were tested, such as acetonitrile and ethanol. The first one led to a product with lower amount of A-1 but same amount of B- 1 (batch LC486). The second one strongly decreased the reaction rate (batch LC494). Finally, slightly different reaction conditions, described in Org. Process Res. Dev. 2014, 18, 122-134 for an analogous transformation, were tested, leading to the formation of product with moderate amount of by-products and a purity of 99.1 % was reached after crystallization from toluene (batch LC500).

Impurity observed during the formation of the compound of formula 3. Step b): Reduction of the nitro group was done using 10% Pd/C and methanol. Quantitative reduction took place within few hours at RT and 3 bar H₂ giving the expected product of formula 4 in high yield and excellent purity.

Step i): Reaction of 5-bromo-2,4-dichloro-pyrimidine with cyclopentylamine was unproblematic and led to product of formula 13 with good yields (82-87%) and high chemical purity (-100%). The use of seeding material is highly recommended to initiate the crystallization.

Step ii): Intermediate of formula 15 was prepared in a one-pot 2-steps process from compound of formula 14. Initially, the effect of the stoichiometry of some reactant/reagents as well as the nature of the catalyst for the Heck coupling was studied. Batch no. Conditions (eq.)^a Pre-catalyst, Ligand, Conversion"

(eq.) (eq.) / time

WO 2008/032157 Crotonic acid (2.5), PdCI₂(C₆H₅C P(o-tol)₃, - i-Pr₂NEt (4.1 ), THF, N)₂, 0.015 0.015

70 °C

LC491 Crotonic acid (2.0), PdCI₂(C₆H₅C P(o-tol)₃, 86% / 16 h i-Pr₂NEt (2.0), THF, N)₂, 0.015 0.015

70 °C

LC492 Crotonic acid (1 .5), Pd/C, 0.01 12% / 16 h i-Pr₂NEt (1 .5),

DMSO, 70 ^<€

LC499 Crotonic acid (2.0), Pd(OAc)₂, P(o-tol)₃, 61 % / 16 h i-Pr₂NEt (2.0), THF, 0.015 0.03

70 °C

LC502 Crotonic acid (2.5), PdCI₂(C₆H₅C P(o-tol)₃, 96% / 16 h i-Pr₂NEt (4.1 ), THF, N)₂, 0.015 0.015

75 °C

LC503 Crotonic acid (2.5), PdCI₂(C₆H₅C P(o-tol)₃, 98% / 16 h i-Pr₂NEt (4.1 ), THF, N)₂, 0.02 0.02

75 °C

a Temperatures refer to the heating bath and not reaction mixture. ^b Determined by

HPLC analysis at 230 nm.

Optimization trials of the Heck coupling between the compound of formula 13 and crotonic acid. As depicted in the Table above, lower amounts of crotonic acid and base led to moderate reaction conversion (batch LC491 ). The use of other palladium sources such as Pd/C or Pd(OAc)₂ had a negative effect on the conversion (batches LC492 and LC499). The reaction conditions of batch LC502 led to 96% conversion after 16 hours. Optimal conditions were obtained by using slightly more catalyst and ligand.

The lactam formation step was done by addition acetic anhydride to the Heck reaction mixture and led quantitatively to the cyclic amide of formula 15. The overall yield of this one-pot 2-steps process was about 80% and purity of the product above 99%. Step iii): Electrophilic bromination of compound of formula 15 was done with N- bromosuccinimide in DMF. Indeed, these conditions appeared to be more effective compare to the one of WO 2008/032157 and also avoided the use of toxic bromine. Halogenation of the compound of formula 15 took place within few hours at 50 'C but showed moderate selectivity. Several by-products were observed in crude material and some of them remained after crystallization from isopropanol. Yields for this reaction were about 85% and purities between 95-97%.

Step c): Coupling of the compounds of formula 4 and 5 was carried out using of 2.1 equivalents of both aryl amine of formula 4 and base leading to the formation of compound of formula 6 with high yield and purity (Table below, batch LC517). Test reactions were also performed with reduced amounts of aryl amine of formula 4 and/or base, or by varying their relative stoichiometry. Lower yields were observed (Table below, batches LC505-LC51 1 ).

a Yield of isolated product. ^b Determined by HPLC analysis at 230 nm. Reaction conditions screening for the synthesis of the compound of formula 6.

Step d1 ): The formation of compound of formula 8 from aryl bromide of formula 6 via Heck coupling was done using conditions depicted in WO 2008/032157. Conversion above 99% was reached. However, work-up of the reaction was unsatisfactory leading to a grey-solid product containing inorganic residues. Optimization of the reaction workup was implemented and the results are summarized in the Table below. Batch no. Work-up conditions Observation

WO 2008/03 Quenching with aq. saturated K₂C0₃,

Grey-solid product

2157 filtration, washing with branched octanes

LC506 Quenching with aq. saturated K₂C0₃, Yellow-grey solid (formula 8), filtration, washing with heptane probably containing rest of K₂C0₃

Then further washings with H₂0 and IPA yellow solid (formula 8), turned orange on surface after 30 min in air

LC518 Quenching with aq. saturated K₂C0₃, Yellow-grey solid (formula 8), filtration, washings with heptane, probably containing rest of K₂C0₃ heptane/EtOH (1/1 ), EtOH/H₂0 (3/1 )

Then further washings with H₂0/EtOH Yellow solid (formula 8)

(9/1 ) and H₂0 73% yield, 96.9% purity (254 nm)

LC547 Quenching with aq. saturated K₂C0₃,

Yellow solid (formula 8) filtration, washings with EtOH/H₂0 (1/1 )

77% yield, 94.6% purity (254 nm) then with heptane

E5739 Quenching with HCI 2 N, filtration, Yellow solid, HCI salt of n-butyl washing with acetone deprotected product (formula 9)

96% yield, 97.0% purity (254 nm)

Work-up conditions for the Heck coupling reaction of the compound of formula 6 with n- butyl vinyl ether. Under basic conditions (with potassium carbonate saturated aqueous solution) led to the formation of expected compound of formula 8. Washing of isolated solid with hydrocarbons (for example octanes, heptane) was not efficient to remove inorganic residues. Additional washings with polar solvents (alcohols, water) were necessary to get rid of inorganic residues. Moreover, traces of n-butyl deprotected compound (corresponding to the free base of compound of formula 9) were always observed in the final product (between 1 to 5%). Work-up under acidic conditions (with hydrochloric acid solution) avoid the problems mentioned above and led to the clean formation of n-butyl deprotected compound of formula 9. Higher yield was observed using this work-up (compare to the one under basic conditions) along with the absence of grey solid.

Steps e1 ) and e2): The formation of palbociclib free base was carried out by acidic treatment followed by neutralization, starting from compound of formula 8 or compound of formula 9. No reactivity differences were observed starting from compound of formula 8 or compound of formula 9 and in both cases palbociclib free base was isolated as small particles size crystals.

Incorporation by Reference

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

Equivalents

The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

Claims Process for producing albociclib accordin to formula 10

formula 10 comprising the steps:

a) reacting the compounds of formulae 1 and 2 to obtain the compound of formula 3,

formula 1 formula 2 formula 3 transforming the compound of formula 3 to the compound of formula 4,

formula 5 formula 6 and converting the compound of formula 6 to palbociclib.

2. Process according to claim 1 , wherein the compound of formula 5 is obtained by the steps

i) reacting the compound of formula 1 1 with the compound of formula 12 to obtain a compound of formula 13,

formula 1 1 formula 12 formula 13 ϋ) reacting the compound of formula 13 with the compound of formula 14 to obtain a compound of formula 15,

formula 13 formula 14 formula 15, i) transformin the compound of formula 15 to the com ound of formula 5,

formula 15 formula 5.

3. Process according to claim 1 or 2, further comprising the steps

d1 ) reacting the compound of formula 6 with a compound of formula 7 to a compound of formula 8,

formula 6 formula 7 formula 8.

4. Process according to claim 3, further comprising the steps

e1 ) reacting the compound of formula 8 to palbociclib of formula 10,

formula 8 formula 10.

5. Process according to claim 1 or 2, further comprising the steps

d2) reacting the compound of formula 6 with a compound of formula 7 to a compound of formula 9,

formula 6 formula 7 formula 9.

6. Process according to claim 5, further comprising the steps

e2) reacting the compound of formula 9 to palbociclib of formula 10,

formula 9 formula 10.

7. Compound according to formula 9

Formula 9.

8. Compound according to claim 7 having the following X-ray powder diffractogram

2-Theta - Scale

9. Pharmaceutical composition comprising

- 10 to 80 wt.% Palbociclib (a), preferably 20 to 70 wt.% Palbociclib, more preferably 30 to 60 wt.% Palbociclib (a1 ), - 10 to 90 wt.% filler, preferably 20 to 70 wt.% filler, more preferably 30 to 60 wt.% filler (b),

- 0 to 30 wt.% disintegrant, preferably 2 to 25 wt.% disintegrant, more preferably 5 to 10 wt.% disintegrant (c),

- 0 to 3 wt.% lubricant, preferably 0.1 to 2.7 wt.% lubricant, more preferably 0.25 to 2.3 wt.% lubricant (d1 )

- 0 to 5 wt.% surfactant, preferably 0.25 to 4.25 wt.% surfactant, more preferably 0.5 to 3.5 wt.% surfactant (d2)

- 0 to 2.5 wt.% glidant, preferably 0.1 to 2.25 wt.% glidant, more preferably 0.25 to 2.05 wt.% glidant (d3),

wherein all weight percent are based on the total weight of the composition.

10. Pharmaceutical composition according to claim 9, wherein the composition is in form of a capsule or tablet, preferably capsule.

1 1 . Pharmaceutical composition according to claim 9 or 10, wherein the particle size of Palbociclib (a) (D50) is 0.1 to 50 μηι, preferably 0.5 to 30 μηι, more preferably 1 to 10 μηι, particularly preferably 1 .5 to 5 μηι.

12. Pharmaceutical composition according to any one of claims 9 to 1 1 , wherein the particle size of Palbociclib (a) (D10) is 0.01 to 30 μηι, preferably 0.05 to 15 μηι, more preferably 0.1 to 5 μηι, particularly preferably 0.3 to 3 μηι.

13. Pharmaceutical composition according to any one of claims 9 to 12, wherein the particle size of Palbociclib (a) (D90) is 0.5 to 100 μηι, preferably 1 to 50 μηι, more preferably 1 .5 to 30μηι, particularly preferably 2.5 to 20 μηι.

14. Pharmaceutical composition according to any one of claims 9 to 13, wherein the release profile according to USP app. II (paddle, 900 ml, pH 1 .2, 4.5 and 6.8, 75 rpm, 37 ^<Ό) after 10 minutes usually indicates a content release of at least 75 %, preferably at least 85 %, especially at least 90 %.

15. Method of treating or preventing cancer using pharmaceutical composition

according to claims 9 to 14.