WO2016030439A1 - Procédé de production de palbociclib et compositions pharmaceutiques comprenant celui-ci - Google Patents

Procédé de production de palbociclib et compositions pharmaceutiques comprenant celui-ci Download PDF

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Publication number
WO2016030439A1
WO2016030439A1 PCT/EP2015/069588 EP2015069588W WO2016030439A1 WO 2016030439 A1 WO2016030439 A1 WO 2016030439A1 EP 2015069588 W EP2015069588 W EP 2015069588W WO 2016030439 A1 WO2016030439 A1 WO 2016030439A1
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Prior art keywords
formula
compound
palbociclib
μηι
reacting
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PCT/EP2015/069588
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English (en)
Inventor
Ludovic Coutable
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Ratiopharm Gmbh
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Application filed by Ratiopharm Gmbh filed Critical Ratiopharm Gmbh
Priority to EP15754236.6A priority Critical patent/EP3186252A1/fr
Publication of WO2016030439A1 publication Critical patent/WO2016030439A1/fr
Priority to IL250744A priority patent/IL250744A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method of producing palbociclib and pharmaceutical compositions comprising the same.
  • 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,
  • 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 ' ⁇ 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.
  • 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.
  • 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.
  • organic solvents are for example ethers, e.g. THF and Dioxane, or dichloromethane and toluene. Preferred is toluene.
  • 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.
  • 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 13 formula 14 formula 15, iii) transformin the compound of formula 15 to the compound of 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.
  • an organic or inorganic alkaline compound preferably an organic alkaline compound, such as triethylamine, can be added to the mixture.
  • 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.
  • NMP N-methylpyrrolidone
  • alcohol and ethers e.g. methanol, ethanol, propanol, THF and Dioxane.
  • Preferred are NMP and THF, particularly THF.
  • an organic or inorganic alkaline compound preferably an organic alkaline compound, such as triethylamine or diisopropylethylamine
  • an organic alkaline compound such as triethylamine or diisopropylethylamine
  • 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.
  • NMP N- methylpyrrolidone
  • DMF dimethylformamide
  • alcohol and ethers e.g. methanol, ethanol, propanol, THF and Dioxane.
  • DMF and acetonitrile particularly DMF.
  • the reaction can preferably be carried out in presence of an organic bromination reagent, such as N-bromosuccinimide (NBS).
  • NBS N-bromosuccinimide
  • the method for preparing palbociclib according to formula 10 further comprises the steps
  • 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).
  • a catalyst such as [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) or Pd(OAc) 2
  • a phosphine such as bis-[2-(diphenylphosphino)phenyl]ether (DPEPhos).
  • 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.
  • the method for preparing palbociclib according to formula 10 further comprises the step
  • 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).
  • a catalyst such as [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).
  • 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.
  • 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,
  • 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.
  • 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.
  • Palbociclib particles can have an average particle size (D50) of 0.1 to 50 ⁇ , preferably 0.5 to 30 ⁇ , more preferably 1 to 15 ⁇ , particularly preferably 1 .5 to 4 ⁇ .
  • 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.
  • Palbociclib can have an average particle size (D10) of 0.01 to 30 ⁇ , preferably 0.05 to 9 ⁇ , more preferably 0.1 to 4 ⁇ , particularly preferably 0.3 to 3 ⁇ .
  • 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.
  • Palbociclib can have an average particle size (D90) of 0.5 to 100 ⁇ , preferably 1 to 50 ⁇ , more preferably 1 .5 to 30 ⁇ , particularly preferably 2.5 to 25 ⁇ , most preferably 2.5 to 20 ⁇ .
  • 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.
  • the above mentioned small particles can be dissolved in an organic solvent, such as a mixture of n-butanol and anisole, at 70 to ⁇ ' ⁇ , such as 80 °C.
  • an organic solvent such as a mixture of n-butanol and anisole
  • 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.
  • the so-called "large" Palbociclib particles can have an average particle size (D50) of 10 to 500 ⁇ , preferably 20 to 125 ⁇ , more preferably 30 to 90 ⁇ .
  • Palbociclib can have an average particle size (D10) of 0.1 to 200 ⁇ , preferably 0.5 to 100 ⁇ , more preferably 1 to 50 ⁇ , particularly preferably 3 to 30 ⁇ .
  • Palbociclib can have an average particle size (D90) of 5 to 800 ⁇ , preferably 15 to 300 ⁇ , more preferably 40 to 150 ⁇ .
  • the particle size can be determined by means of laser diffractometry.
  • 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.
  • the BET surface area is 0.5 to 25 m 2 /g, preferably 1 to 20 m 2 /g, more preferably 5 to 18 m 2 /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.
  • 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/cm 3 , preferably 1 .1 to 1 .45 g/cm 3 and more preferably 1 .2 to 1 .4 g/cm 3 .
  • 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.
  • 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.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is cross-linked polyvinylpyrrolidone.
  • the disintegrant is a mixture of croscarmellose sodium and cross-linked polyvinylpyrrolidone.
  • inorganic alkaline disintegrants are used, preferably salts of alkali metals and alkaline metals.
  • Preferred alkali and alkaline metals are sodium, potassium, magnesium and calcium.
  • carbonate, hydrogen carbonate, phosphate, hyd- rogen phosphate and dihydrogen phosphate are preferred.
  • 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.
  • excipient 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.
  • a lubricant may be used.
  • 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.
  • a surfactant (d2) may be used.
  • 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 ® ).
  • 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.
  • silicon dioxide can be used as a glidant (d3).
  • the silicon dioxide has a specific surface area of 50 to 400 m 2 /g, measured by gas adsorption according to Ph. Eur. 6.0, Chapter 2.9.26, multipoint method, volumetric determination.
  • a lubricant (d3) may be used.
  • fumed silica (Carb o Sil) can be used as glidant (d3).
  • 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.
  • plasticizers examples include 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.
  • 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.
  • composition of the present invention is in the form of a tablet.
  • pharmaceutical composition of the present invention is in the form of a capsule.
  • the present pharmaceutical composition preferably comprises
  • lubricant preferably 0.1 to 2.7 wt.% lubricant, more preferably 0.25 to 2.3 wt.% lubricant (d1 ),
  • 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.
  • the composition is can be present in form of a tablet.
  • 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.
  • 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.
  • the dosage form is a capsule, preferably a soft capsule, in particular a soft gelatine capsule.
  • the capsule is a hard capsule, e.g. a hard gelatine capsule.
  • 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.
  • the shell comprises gelatin, optionally a plasticizer and optionally water and optionally colorants and/or flavours.
  • a wet gel formulation is processed as described below.
  • alkali processed (type B) gelatin is used.
  • gelatin is used in an amount of 40 wt.% of the wet gel formulation.
  • plasticizer usually are used in an amount of 20 - 30 wt.% of the wet gel formulation.
  • the shell preferably does not contain any plasticizers.
  • 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.
  • 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.
  • the gel ribbons and the fill matrix are combined to form the softgel capsule by a rotary die encapsulation process.
  • 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.
  • the capsule liquid filling and sealing system CFS 1200 by CAPSUGEL ® can be used.
  • the shell has a residual water content of about 5 to 35 wt.%, more preferably of about 7 to 15 wt.%.
  • 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.
  • 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.
  • the tablet according the present invention is film- coated with a coating (e).
  • Film-coatings that do not affect the release of the active ingredient are preferred.
  • 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).
  • 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.
  • gastric juice resistant coatings can comprise cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) and polyvinyl acetate phthalate (PVAP).
  • 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).
  • 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 %.
  • 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.
  • the components can be sieved before being blended.
  • the sieve has a mesh size of 200 to 1400 ⁇ , preferably of 800 to 1250 ⁇ .
  • 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.
  • 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).
  • 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.
  • the present invention is directed to a method of treating or preventing cancer using a pharmaceutical composition according to the present invention.
  • 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, mye
  • Aluminium crucible 40 ⁇ _
  • the sample was analyzed on a D8 Advance X-ray powder diffractometer (Bruker-AXS, Düsseldorf, 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
  • 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).
  • Carrier gas (flow): He (1 .0 ml/min)
  • 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).
  • Palbociclib, Prosolv SMCC 90 and Kollidon CL were sieved through mesh 500 ⁇ and blended for 10 minutes. The blending of above was then filled into capsules of size 0.
  • Positions 1 to 3 were sieved through mesh 500 ⁇ and blended for 10 minutes.
  • Position 4 was also sieved through mesh 500 ⁇ 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 ⁇ and blended for 10 minutes. Tablets were then prepared by direct compression of the blending.
  • Palbociclib, Prosolv SMCC 90 and Kollidon CL were sieved through mesh 500 ⁇ and blended for 10 minutes. The blending of above was then filled into capsules of size 0.
  • Dissolution is examined by the following method 900ml, 37°, agitation: 75rpm, Paddle (USPII), Dissolution media:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ ⁇ ' ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • Crotonic acid (2.5), PdCI 2 (C 6 H 5 C P(o-tol) 3 , - i-Pr 2 NEt (4.1 ), THF, N) 2 , 0.015 0.015
  • 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
  • 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.

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Abstract

La présente invention concerne un procédé de production de palbociclib et des compositions pharmaceutiques le comprenant.
PCT/EP2015/069588 2014-08-28 2015-08-27 Procédé de production de palbociclib et compositions pharmaceutiques comprenant celui-ci WO2016030439A1 (fr)

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IL250744A IL250744A0 (en) 2014-08-28 2017-02-23 A method for preparing flavociclib and its pharmaceutical preparations

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CN105748435A (zh) * 2016-04-21 2016-07-13 石家庄海瑞药物科技有限公司 一种帕布昔利布药物组合物及其制备方法
CN106018655A (zh) * 2016-08-01 2016-10-12 合肥远志医药科技开发有限公司 一种帕布昔利布原料有关物质的检测方法
CN106220627A (zh) * 2016-07-31 2016-12-14 合肥远志医药科技开发有限公司 一种高纯度帕布昔利布的工业化制备方法
EP3255048A1 (fr) * 2016-06-07 2017-12-13 K.H.S. Pharma Holding GmbH Forme non-cristalline de palbociclib
WO2018007927A1 (fr) * 2016-07-04 2018-01-11 Dr. Reddy's Laboratories Limited Procédé pour la préparation du palbociclib
EP3216450A4 (fr) * 2014-11-07 2018-06-13 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Préparation pharmaceutique comprenant un inhibiteur de la cycline et son procédé de préparation
CN108299422A (zh) * 2018-02-28 2018-07-20 杭州福斯特药业有限公司 一种帕泊昔利布中间体的制备方法
KR101893879B1 (ko) 2017-03-31 2018-09-03 한국화학연구원 신규한 cdk 저해 화합물, 이의 제조방법, 및 이를 유효성분으로 함유하는 cdk 관련 질환의 예방 또는 치료용 약학적 조성물
CN108822026A (zh) * 2018-09-21 2018-11-16 湖北大学 一种抗癌药帕博昔布重要中间体的合成工艺
CN109206373A (zh) * 2017-07-07 2019-01-15 上海医药工业研究院 一种帕博昔布中间体5-溴-2-氯-4-环戊基氨基嘧啶的制备工艺
WO2019020715A1 (fr) * 2017-07-28 2019-01-31 Synthon B.V. Composition pharmaceutique comprenant du palbociclib
WO2019082143A1 (fr) 2017-10-27 2019-05-02 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation de ribociclib et de ses sels
CN109867673A (zh) * 2019-04-16 2019-06-11 淮海工学院 一种合成帕布昔利布的方法
CN110256424A (zh) * 2019-07-03 2019-09-20 武汉工程大学 一种帕博西尼关键中间体v的合成方法
WO2019224194A1 (fr) 2018-05-24 2019-11-28 Synthon B.V. Procédé de production de palbociclib
CN111362939A (zh) * 2020-04-26 2020-07-03 济南磐石医药科技有限公司 一种帕布昔利布母核结构化合物的制备方法
CN112457311A (zh) * 2020-12-04 2021-03-09 江苏豪森药业集团有限公司 一种含有氯溴吡咯嘧啶酮结构化合物的制备方法
CN112552297A (zh) * 2020-12-12 2021-03-26 江西国药有限责任公司 一种哌柏西利的制备方法与流程
CN112898299A (zh) * 2021-01-26 2021-06-04 山东铂源药业有限公司 一种帕布昔利布中间体的制备方法
WO2021139817A1 (fr) * 2020-01-10 2021-07-15 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de kinases
WO2021220295A1 (fr) * 2020-04-29 2021-11-04 Natco Pharma Limited Compositions pharmaceutiques à libération immédiate comprenant du palbociclib
CN113999227A (zh) * 2021-11-26 2022-02-01 常州大学 一种帕博西尼中间体的制备方法
WO2022091001A1 (fr) 2020-10-29 2022-05-05 Pfizer Ireland Pharmaceuticals Procédé de préparation de palbociclib
WO2023035667A1 (fr) * 2021-09-07 2023-03-16 山东铂源药业股份有限公司 Procédé de préparation de palbociclib à faible coût
WO2023194870A1 (fr) * 2022-04-06 2023-10-12 Glenmark Life Sciences Limited Procédé de préparation de palbociclib

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Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3216450A4 (fr) * 2014-11-07 2018-06-13 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Préparation pharmaceutique comprenant un inhibiteur de la cycline et son procédé de préparation
CN105748435B (zh) * 2016-04-21 2019-03-29 石家庄海瑞药物科技有限公司 一种帕布昔利布药物组合物及其制备方法
CN105748435A (zh) * 2016-04-21 2016-07-13 石家庄海瑞药物科技有限公司 一种帕布昔利布药物组合物及其制备方法
EP3255048A1 (fr) * 2016-06-07 2017-12-13 K.H.S. Pharma Holding GmbH Forme non-cristalline de palbociclib
WO2017211788A1 (fr) * 2016-06-07 2017-12-14 K.H.S. Pharma Holding Gmbh Forme non cristalline de palbociclib
WO2018007927A1 (fr) * 2016-07-04 2018-01-11 Dr. Reddy's Laboratories Limited Procédé pour la préparation du palbociclib
US10807978B2 (en) 2016-07-04 2020-10-20 Dr. Reddy's Laboratories Limited Process for preparation of palbociclib
CN106220627A (zh) * 2016-07-31 2016-12-14 合肥远志医药科技开发有限公司 一种高纯度帕布昔利布的工业化制备方法
CN106018655A (zh) * 2016-08-01 2016-10-12 合肥远志医药科技开发有限公司 一种帕布昔利布原料有关物质的检测方法
KR101893879B1 (ko) 2017-03-31 2018-09-03 한국화학연구원 신규한 cdk 저해 화합물, 이의 제조방법, 및 이를 유효성분으로 함유하는 cdk 관련 질환의 예방 또는 치료용 약학적 조성물
CN109206373A (zh) * 2017-07-07 2019-01-15 上海医药工业研究院 一种帕博昔布中间体5-溴-2-氯-4-环戊基氨基嘧啶的制备工艺
CN109206373B (zh) * 2017-07-07 2022-02-15 上海医药工业研究院 一种帕博昔布中间体5-溴-2-氯-4-环戊基氨基嘧啶的制备工艺
WO2019020715A1 (fr) * 2017-07-28 2019-01-31 Synthon B.V. Composition pharmaceutique comprenant du palbociclib
US11529353B2 (en) 2017-07-28 2022-12-20 Synthon B.V. Pharmaceutical composition comprising Palbociclib
AU2018354972B2 (en) * 2017-10-27 2021-07-08 Fresenius Kabi Oncology Ltd. An improved process for the preparation of ribociclib and its salts
WO2019082143A1 (fr) 2017-10-27 2019-05-02 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation de ribociclib et de ses sels
US11440912B2 (en) 2017-10-27 2022-09-13 Fresenius Kabi Oncology Ltd Process for the preparation of ribociclib and its salts
CN108299422A (zh) * 2018-02-28 2018-07-20 杭州福斯特药业有限公司 一种帕泊昔利布中间体的制备方法
US11858928B2 (en) 2018-05-24 2024-01-02 Synthon B.V. Process for making palbociclib
EP4289844A2 (fr) 2018-05-24 2023-12-13 Synthon B.V. Procédé de préparation de palbociclib
WO2019224194A1 (fr) 2018-05-24 2019-11-28 Synthon B.V. Procédé de production de palbociclib
CN108822026A (zh) * 2018-09-21 2018-11-16 湖北大学 一种抗癌药帕博昔布重要中间体的合成工艺
CN109867673A (zh) * 2019-04-16 2019-06-11 淮海工学院 一种合成帕布昔利布的方法
CN109867673B (zh) * 2019-04-16 2021-03-16 淮海工学院 一种合成帕布昔利布的方法
CN110256424A (zh) * 2019-07-03 2019-09-20 武汉工程大学 一种帕博西尼关键中间体v的合成方法
WO2021139817A1 (fr) * 2020-01-10 2021-07-15 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de kinases
CN114174296B (zh) * 2020-01-10 2024-01-23 石药集团中奇制药技术（石家庄）有限公司 作为激酶抑制剂的多环化合物
CN114174296A (zh) * 2020-01-10 2022-03-11 石药集团中奇制药技术（石家庄）有限公司 作为激酶抑制剂的多环化合物
CN111362939A (zh) * 2020-04-26 2020-07-03 济南磐石医药科技有限公司 一种帕布昔利布母核结构化合物的制备方法
WO2021220295A1 (fr) * 2020-04-29 2021-11-04 Natco Pharma Limited Compositions pharmaceutiques à libération immédiate comprenant du palbociclib
WO2022091001A1 (fr) 2020-10-29 2022-05-05 Pfizer Ireland Pharmaceuticals Procédé de préparation de palbociclib
CN112457311B (zh) * 2020-12-04 2022-07-12 江苏豪森药业集团有限公司 一种含有氯溴吡咯嘧啶酮结构化合物的制备方法
CN112457311A (zh) * 2020-12-04 2021-03-09 江苏豪森药业集团有限公司 一种含有氯溴吡咯嘧啶酮结构化合物的制备方法
CN112552297A (zh) * 2020-12-12 2021-03-26 江西国药有限责任公司 一种哌柏西利的制备方法与流程
CN112898299B (zh) * 2021-01-26 2021-11-26 山东铂源药业有限公司 一种帕布昔利布中间体的制备方法
CN112898299A (zh) * 2021-01-26 2021-06-04 山东铂源药业有限公司 一种帕布昔利布中间体的制备方法
WO2023035667A1 (fr) * 2021-09-07 2023-03-16 山东铂源药业股份有限公司 Procédé de préparation de palbociclib à faible coût
CN113999227A (zh) * 2021-11-26 2022-02-01 常州大学 一种帕博西尼中间体的制备方法
WO2023194870A1 (fr) * 2022-04-06 2023-10-12 Glenmark Life Sciences Limited Procédé de préparation de palbociclib

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