WO2018073574A1 - Formes polymorphes de palbociclib - Google Patents

Formes polymorphes de palbociclib Download PDF

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Publication number
WO2018073574A1
WO2018073574A1 PCT/GB2017/053133 GB2017053133W WO2018073574A1 WO 2018073574 A1 WO2018073574 A1 WO 2018073574A1 GB 2017053133 W GB2017053133 W GB 2017053133W WO 2018073574 A1 WO2018073574 A1 WO 2018073574A1
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WIPO (PCT)
Prior art keywords
palbociclib
free base
range
surface area
specific surface
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PCT/GB2017/053133
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English (en)
Inventor
Dharmaraj Ramachandra Rao
Geena Malhotra
Srinivas Laxminarayan Pathi
Chandrasekaran Ramasubbu
Rajesh RADHAMANALAN
Manish Gopaldas Gangrade
Jennet JAYACHANDRAN
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Cipla Limited
King, Lawrence
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Publication of WO2018073574A1 publication Critical patent/WO2018073574A1/fr

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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 polymorphic forms of palbociclib and processes for preparation thereof.
  • the present invention also provides a pharmaceutical composition comprising polymorphic forms of palbociclib and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of cancer. BACKGROUND OF INVENTION
  • Palbociclib of Formula I is chemically described as 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-( 1 -piperazin l)-2-pyridinyl]amino]pyrido [2,3-d]pyrimidin-7(8H)-one.
  • Palbociclib is commercially available in Europe under the trade name IBRANCE® and is indicated for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.
  • IBRANCE® hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.
  • US6936612 relates to substituted 2-amino pyridines that are potent inhibitors of cyclin- dependent kinase 4.
  • the compounds of the invention are useful for the treatment of inflammation, and cell proliferative diseases such as cancer and restenosis.
  • US6936612 discloses a process for the preparation of palbociclib hydrochloride.
  • US7781583 relates to novel synthetic routes for the preparation of substituted 2-(pyridin-2- ylamino)-pirido[2,3-d]pyrimidin-7-ones and their intermediates. It further discloses a process for the preparation of palbociclib.
  • US7863278 relates to salt forms of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl- pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, which is a selective cyclin-dependent kinase 4 (CDK4) inhibitor that is useful for treating inflammation and cell proliferative diseases such as cancer and restenosis.
  • CDK4 selective cyclin-dependent kinase 4
  • US7863278 discloses polymorphs of mono- isoethionate, mono- mesylate, di-mesylate, mono-hydrochloride, and di-hydrochloride salts of palbociclib.
  • PCT Publication No. WO 2014/128588 relates to a crystalline free base of 6-acetyl-8- cyclopentyl-5-memyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7- one, having a specific surface area of ⁇ 2m 2 /g.
  • WO 20140/128588 further discloses crystalline Forms A and B of palbociclib free base.
  • polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability).
  • An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing. Therefore, it is desirable to have a stable amorphous form of drug with high purity to meet the needs of regulatory agencies and highly reproducible processes for its preparation.
  • Another object of the present invention is to provide a crystalline free base Form A of palbociclib having a specific surface area of > 2m 2 /g.
  • Another object of the present invention is to provide a crystalline free base Form B of palbociclib having a specific surface area of > 2m 2 /g.
  • Another object of the present invention is to provide a process of preparation of a crystalline free base Form A of palbociclib having a specific surface area of > 2m 2 /g.
  • Another object of the present invention is to provide an amorphous form of palbociclib having a specific surface area of ⁇ 2 m 2 /g.
  • Another object of the present invention is to provide a stable amorphous form of palbociclib free from any crystalline form of palbociclib.
  • Another object of the present invention is to provide a process for the preparation of an amorphous form of palbociclib.
  • Another object of the present invention is to provide a premix of palbociclib and copovidone.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a palbociclib - copovidone premix.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of palbociclib having a specific surface area of ⁇ 2m 2 /g.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of crystalline free base of palbociclib, such as Form A or Form B, having a specific surface area of > 2m 2 /g.
  • the present invention provides polymorphic forms of palbociclib.
  • a crystalline free base of palbociclib having a specific surface area of > 2m 2 /g.
  • the present invention provides a crystalline free base Form A of palbociclib having a specific surface area of > 2m 2 /g, such as > 2m 2 /g, for example from about 5 to about 8m 2 /g.
  • the present invention provides a crystalline free base Form B of palbociclib having a specific surface area of > 2m 2 /g, such as > 2m 2 /g, for example from about 10 to 15m 2 /g.
  • the present invention provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m 2 /g.
  • the present invention provides a process for preparing crystalline free base Form A of palbociclib having a specific surface area of > 2m 2 /g, such as > 2m 2 /g, for example from about 5 to about 8m 2 /g.
  • the present invention provides a process for preparing crystalline free base Form B of palbociclib having a specific surface area of > 2m 2 /g, such as > 2m 2 /g, for example from about 10-15m 2 /g.
  • the present invention provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m 2 /g, comprising the steps of: i. coupling 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)- one, compound (VII):
  • the present invention further provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m 2 /g without isolation of compound (III).
  • the present invention provides crystalline free base Form A of palbociclib prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in one or more suitable solvents;
  • the present invention provides crystalline free base Form B of palbociclib prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in a suitable solvent under an inert atmosphere;
  • the present invention provides an amorphous form of palbociclib.
  • the amorphous form of palbociclib is characterised by having a specific surface area of ⁇ 2 m 2 /g.
  • the amorphous form of palbociclib is further characterised by an X-Ray Powder Diffraction (XRD) pattern as depicted in Figure 2.
  • XRD X-Ray Powder Diffraction
  • the present invention further provides a process for the preparation of an amorphous form of palbociclib.
  • the present invention provides a premix of palbociclib and copovidone.
  • the premix of palbociclib and copovidone is characterised by an XRD pattern as depicted in Figure 3.
  • the advantages of the above-noted processes include simplicity of manufacturing, eco- friendliness and suitability for commercial use.
  • Palbociclib crystalline free base Form A is characterised by an XRD pattern comprising a peaks at: (l) 10.1 ⁇ 0.2 ° 2 ⁇ ; (n) 8.0 and 10.1 ⁇ 0.2 ° 2 ⁇ ; and/or (hi) 8.0, 10.1, 10.3 and 1 1.5 ⁇ 0.2 ° 2 ⁇ .
  • Palbociclib crystalline free base Form B is characterised by an XRD pattem comprising a peaks at: (l) 6.0 ⁇ 0.2 ° 2 ⁇ ; (n) 6.0, 19.8 and 26.7 ⁇ 0.2 ° 2 ⁇ ; (in) 6.0, 16.4, 19.8 and 26.7 ⁇ 0.2 ° 2 ⁇ ; (iv) 6.0, 12.8, 16.4, 19.8 and 26.7 ⁇ 0.2 ° 2 ⁇ ; (v) 6.0, 12.8, 16.4, 19.8, 22.6 and 26.7 ⁇ 0.2 ° 2 ⁇ ; (vi) 6.0, 12.8, 16.4, 19.8, 22.6 and 26.7 ⁇ 0.2 ° 2 ⁇ ; and/or (vi) 6.0, 10.9, 12.8, 16.4, 19.8, 22.6 and 26.7 ⁇ 0.2 ° 2 ⁇ .
  • premix means a composition formed by the admixture of palbociclib and one or more pharmaceutically acceptable polymers, such as copovidone.
  • Figure 1 Depicts an X-ray powder diffractogram crystalline palbociclib free base Form A having a specific surface area > 2m 2 /g.
  • Figure 2 Depicts an X-ray powder diffractogram of crystalline palbociclib free base Form B having a specific surface area > 2m 2 /g.
  • Figure 3 Depicts an X-ray powder diffractogram of an amorphous form of palbociclib having a specific surface area ⁇ 2m 2 /g.
  • Figure 4 Depicts an X-ray powder diffractogram of a palbociclib-copovidone premix. DETAILED DESCRIPTION OF THE INVENTION
  • a crystalline free base of palbociclib preferably selected from Form A and Form B, having a specific surface area of greater than or equal to (>) 2m 2 /g.
  • crystalline free base of palbociclib Form A having a specific surface area of greater than (>) 2m 2 /g.
  • crystalline free base of palbociclib Form A having a specific surface area in the range from about 5 to about 8m 2 /g, including about 5m 2 /g, about 6 m 2 /g, about 7 m 2 /g and about 8 m 2 /g.
  • crystalline free base of palbociclib Form B having a specific surface area of greater than (>) 2m 2 /g.
  • crystalline free base of palbociclib Form B having a specific surface area in the ranges from about 10 to about 15m 2 /g, from about 11 to about 15m 2 /g, from about 12 to about 15m 2 /g, and from 13 to about 15m 2 /g; including about 10m 2 /g, about 11 m 2 /g, about 12 m 2 /g, about 13m 2 /g, about 14 m 2 /g and about 15 m 2 /g.
  • the present invention further provides a process for preparing crystalline free base of palbociclib having a specific surface area of > 2m 2 /g as depicted in Scheme I.
  • Suitable coupling agents for use in step (1) of Scheme I include, but are not limited to, suitable organic or inorganic compounds such as lithium hexamethyldisilazide or a Grignard reagent such as isopropylmagnesium chloride, cyclohexylmagnesium chloride and the like.
  • Suitable organic solvents for use in step (1) of Scheme I include, but are not limited to, halogenated solvents such as dichloroethane, dichloromethane, chloroform and the like; non- polar solvents such as toluene, xylene, cyclohexane, heptane, xylene and the like; polar aprotic solvents such as THF, ethylacetate, acetone, dimethylformamide and the like; and mixtures thereof in various proportion without limitation.
  • halogenated solvents such as dichloroethane, dichloromethane, chloroform and the like
  • non- polar solvents such as toluene, xylene, cyclohexane, heptane, xylene and the like
  • polar aprotic solvents such as THF, ethylacetate, acetone, dimethylformamide and the like
  • compound (V) may be subjected to purification using one or more suitable solvents selected from polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloro
  • the present invention comprises coupling compound (VII) with compound (VI) at a temperature in the range of from about 0°C to about 30°C, preferably from about 5°C to about 20°C.
  • the present invention comprises reacting compound (V) with vinyl n-butyl ether (IV) in the presence of a transition metal catalyst, a base and optionally a phosphine agent, in a suitable solvent to form a compound to form a compound (III).
  • Suitable transition metal catalysts for use as depicted in step (2) in Scheme I include, but are not limited to, a palladium compound selected from the group consisting of tetrakis(triphenylphosphine)palladium [(Ph3PPd], tris(dibenzylideneacetone)dipalladium [Pd 2 (dba)3], bis(dibenzylideneacetone) palladium(O) [ ⁇ dba) 2 Pd],palladium acetate [Pd(OAc) 2 ], palladium chloride (PdCI 2 ), bis(benzonitrile)dichloropalladium[(C6H5CN) 2 PdCI 2 ]and(Bis-(diphenylphosphine ferrocene) palladium dichloride dichloromethane complex (Pd(dppf) 2 CI 2 ), and the phospine compound is selected from 2,2'-bis(diphenylphosphino)-l
  • Suitable bases for use as depicted in step (2) of Scheme I include, but are not limited to, diisopropyl ethylamine, lithium carbonate, dicyclohexyl methylamine and trimethylamine and the like.
  • the present invention comprises reacting the compound ( ⁇ ) in the presence of a suitable solvent under acidic conditions to obtain compound (II).
  • Suitable solvents include, but are not limited to, water, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such as tol
  • the present invention comprises isolating compound (I) from compound (II) using a suitable solvent under basic conditions.
  • suitable solvents include, but are not limited to, water, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitrile
  • Basic conditions may be acquired by adjusting the pH of the reaction mixture slowly to 8-8.5 using 5% aqueous sodium hydroxide solution.
  • compound (I) is preferably isolated and further dried at temperature in the range from about 55°C to about 65°C, preferably for about 8 to about 10 hours.
  • any salt of palbociclib can be used for the preparation of crystalline free base of palbociclib having a specific surface area of > 2m 2 /g.
  • Suitable salts include acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di- mesylate, mono-hydrochloride and di-hydrochloride salts of palbociclib.
  • the present invention further provides a ("one-pot") process for preparing crystalline free base of palbociclib having a specific surface area of > 2m 2 /g without the isolation of intermediate compounds, preferably intermediate of formula ( ⁇ ), as depicted Scheme II.
  • the one-pot process for preparing crystalline free base of palbociclib having a specific surface area of > 2m 2 /g comprises:
  • without isolating refers to a process step in which the organic layer (comprising the compound of formula III and solvent) is reacted with concentrated HC1 and suitable solvent as depicted in Scheme I.
  • the one-pot synthesis (i.e. without isolation of the compound III) of the present invention advantageously avoids the need for lengthy separation processes such as filtration, washing and purification of the intermediates and also saves time and resources. This increases the chemical yield and makes the process economical and suitable for industrial scale up.
  • the present invention further comprises processes for preparing crystalline free base Form A and Form B of palbociclib having a specific surface area of > 2m 2 /g, for example, crystalline free base Form A of palbociclib having a specific surface area in the range from about 5 to about 8m 2 /g and crystalline free base Form B of palbociclib having a specific surface area in the range from about 10 to about 15m 2 /g.
  • the present invention provides crystalline palbociclib free base Form A prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in one or more suitable solvents;
  • the crystalline palbociclib free base Form A has a specific surface area of > 2m 2 /g, such as >2 m 2 /g, and more preferably from about 5 to about 8m 2 /g.
  • Suitable solvents include, but are not limited to, water, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloride, polar solvents such as alcohols selected from methanol, ethanol, isoprop
  • Palbociclib may be in free base form or in salt form such as an acid addition salt.
  • Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono- mesylate, di-mesylate, mono-hydrochloride and di-hydrochloride salts of palbociclib.
  • the dissolution temperature may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.
  • Suitable bases include, but are not limited to, organic bases such as methylamine, dimethylamine, triethylamine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide and the like.
  • the process comprises isolating and drying the crystalline Form A of palbociclib free base in a solid form. Any suitable techniques known in the art may be used, for example filtering and then drying under vacuum.
  • the present invention provides crystalline palbociclib free base Form A having a specific surface area of > 2m 2 /g, preferably in the range from about 5 to about 8m 2 /g, and a particle size distribution (PSD) having at least one of:
  • a Dio value in the range of from about 1 ⁇ to about 5 ⁇ , preferably, in the range of from about 1 ⁇ to about 3 ⁇ ;
  • a D50 value in the range of from about 2 ⁇ to about 7 ⁇ , preferably, in the range of from about 3 ⁇ to about 5 ⁇ ; and/or (iii) a D90 value in the range of from about 7 ⁇ to about 15 ⁇ , preferably, in the range of from about 8 ⁇ to about 13 ⁇ .
  • the present invention further provides crystalline free base Form B of palbociclib prepared or obtainable by a process comprising the steps of: i. dissolving palbociclib in a suitable solvent under an inert atmosphere;
  • the crystalline palbociclib free base Form B has a specific surface area of > 2m 2 /g, such as >2 m 2 /g, and more preferably in the range from about 10 to about 15m 2 /g.
  • palbociclib can be prepared by any known method, or may be prepared according to the process of the present invention. Further, palbociclib may be used be in any suitable form, such as a crystalline, semi-crystalline, solvate, or salt form, for example an acid addition salt. Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di-mesylate, mono-hydrochloride and di- hydrochloride salts.
  • the solvent used in the preparation of crystalline free base Form B of palbociclib is water.
  • the dissolution temperature may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.
  • the reaction is typically performed in an inert atmosphere.
  • An inert atmosphere may be maintained by purging with nitrogen, argon or like, followed by degassing under vacuum in order to remove any traces of impurity.
  • the (clear) solution so obtained is added to aqueous ammonia solution under inert atmosphere.
  • the addition is preferably carried out maintaining the temperature in the range from about 25°C to 35°C.
  • the process comprises isolating and drying the crystalline Form B of palbociclib free base in a solid form. Any suitable techniques known in the art may be used, for example filtering and then drying under vacuum.
  • the present invention provides crystalline palbociclib free base Form B having a specific surface area of > 2m 2 /g, preferably in the range from about 10 to about 15m 2 /g, and a particle size distribution (PSD) having at least one of:
  • a Dio value in the range of from about 0.1 ⁇ to about 2 ⁇ , preferably, in the range of from about 0.1 ⁇ to about 1 ⁇ ;
  • a D50 value in the range of from about 1 ⁇ to about 5 ⁇ , preferably, in the range of from about 1 ⁇ to about 3 ⁇ ;
  • US 2016/0002223 provides BET-N2 SSA analysis of four batches of palbociclib free base, one comprising crystalline free base of palbociclib having a specific surface area of > 2m 2 /g (Batch 5 as shown in the Table below) prepared by the traditional salt break method and three batches comprising the API having surface area ⁇ 2m 2 /g. It further also states that the Batch 5 contained palbociclib free base having small primary particles and large agglomerates, which was very static-prone, sticky, difficult to disperse by sieving and were unsuitable for further development.
  • the crystalline free base Form A and Form B of palbociclib of the present invention having a specific surface area of > 2m 2 /g do not form large agglomerates and are easy to disperse by sieving.
  • the present invention further provides an amorphous form of palbociclib free base.
  • the amorphous form of palbociclib free base is characterised by having a specific surface area of ⁇ 2m 2 /g.
  • the amorphous form of palbociclib free base according to the present invention is characterised by having an XRD pattern as depicted in Figure 2.
  • the present invention provides a process for the preparation of an amorphous form of free base of palbociclib having a specific surface area of ⁇ 2m 2 /g, the process comprising:
  • Suitable solvents for use in step (A) include, but are not limited to, polar solvents such as alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated
  • polar solvents such as alcohols selected from methanol, ethanol, isopropan
  • Palbociclib used in step (A) can be prepared by any known method or may be prepared according to the process of the present invention. Further, palbociclib may be used be in any suitable form, such as a crystalline, semi-crystalline, solvate, or salt form, for example an acid addition salt. Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di-mesylate, mono-hydrochloride and di-hydrochloride salts.
  • the dissolution temperatures employed in step (A) may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.
  • Step (B) involves isolation of an amorphous form of palbociclib from the solution of step (A).
  • the isolation may be affected by removing the solvent.
  • the techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD”), freeze drying (lyophilization), flash evaporation, and vacuum distillation.
  • an amorphous form of palbociclib characterized by a glass transition temperature of about 165 °C ⁇ 3°C, preferably about 165°C, such as 165.78°C.
  • amorphous palbociclib having a specific surface area of ⁇ 2m 2 /g and a D90 particle size in the range of from about 1 ⁇ to about 10 ⁇ , such as from about 5 ⁇ to about 10 ⁇ .
  • amorphous palbociclib having a specific surface area in the range of from about 1 to about 2m 2 /g.
  • Amorphous palbociclib obtained by the process of the present invention is chemically and thermodynamically stable. Amorphous forms are generally more readily soluble than their crystalline counter parts and therefore, the amorphous form of palbociclib provided according to the invention is expected to have higher dissolution, solubility and hence bioavailability.
  • a premix comprising palbociclib and copovidone.
  • the formation of such a premix is intended to improve the bioavailability of palbociclib free base.
  • Copovidone is an analog of povidone, is used as a tablet binder, a film-former, and as part of the matrix material used in controlled-release formulations. In tableting, copovidone can be used as a binder for direct compression and as a binder in wet granulation.
  • the present invention provides a novel premix of palbociclib and copovidone.
  • the palbociclib-copovidone premix according to the present invention is stable and amorphous in nature.
  • Palbociclib used in step (I) can be prepared by any known method or may be prepared according to the process of the present invention. Further, palbociclib may be used be in any suitable form, such as an amorphous, crystalline, semi-crystalline, solvate, or salt form, for example an acid addition salt. Suitable acid addition salts of palbociclib include, but are not limited to mono-isoethionate, mono-mesylate, di-mesylate, mono-hydrochloride and di- hydrochloride salts.
  • Suitable solvents for use in step (I) include, but are not limited to, alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrolidone, dimethyl acetamide; selected from acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride; hydrocarbons such
  • the dissolution temperature in step (I) may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution, typically up to about 100 °C.
  • Copovidone may be used in different grades concerning the particle size.
  • the weight ratio of palbociclib and copovidone employed in the premix of the present invention is typically from about 1 : 10 to about 10: 1 , and is preferably about 1 :1.
  • Step ( ⁇ ) involves isolation of a premix of palbociclib-copovidone from the solution of step (I).
  • the isolation may be affected by removing the solvent.
  • the techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD”), freeze drying (lyophilization), flash evaporation, and vacuum distillation.
  • the palbociclib-copovidone premix of the present invention may be characterized by DSC glass transition.
  • the palbociclib-copovidone premix of the present invention may be further characterized by having an XRD pattern as depicted in Figure 3.
  • the palbociclib-copovidone premix of the present invention is amorphous in nature and stable. Amorphous forms are generally more readily soluble than their crystalline counterparts and therefore, the amorphous palbociclib-copovidone premix of the present invention is expected to have higher dissolution, solubility and hence bioavailability.
  • palbociclib premixes can also be prepared using other suitable premixing agents that can facilitate the bioavailability of the palbociclib.
  • suitable premixing agents include, but are not limited to, pharmaceutically acceptable polymers, such as microcrystalline cellulose (MCC), Silicified MCC, lactose, co-processed MCC, co-processed lactose and the like.
  • MCC microcrystalline cellulose
  • the weight ratio of palbociclib to premixing agents is typically from about 1 : 10 to about 10: 1 , and is preferably about 1 :1.
  • the solid state forms and premixes of palbociclib of the present invention may be formulated with one or more pharmaceutically acceptable excipients as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. Suitable pharmaceutically acceptable excipients are commercially available. Such compositions may be useful for the treatment of cancer, particularly breast cancer.
  • the following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
  • X-ray powder diffraction was carried out using a Rigaku D-Max 2200 X-Ray diffractometer.
  • the D-Max 2200 system was equipped with a 1.2kW Cu anode X-ray tube and a scintillation detector.
  • Nickel filter was placed in the receiving path of the X-ray to remove Cu ⁇ radiation.
  • Samples were ground using mortar and pestle to reduce the crystal size and orientation effects. Material was then tightly packed in a glass holder using glass slides to match the surface level of the sample holder and analyzed using the following parameters.
  • NMR data were collected using a Varian spectrometer at 300 MHz under standard operating conditions.
  • Particle size data were collected using a Malvern Mastersizer 2000 with Hydro 2000S (A) under standard operating conditions.
  • Example la Purification of ferf-buryl4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (V)
  • Example 3a 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one dihydrochloride ( ⁇ ) (without isolation of compound III).
  • Example 4 Preparation of crystalline free base Form A of palbociclib having a specific surface area of > 2m 2 /g (I).
  • Particle size distribution D 10 ( ⁇ ): 0.81 ⁇ , ⁇ ; DsoOim): 2.26 ⁇ ; D90(um): 7.69 ⁇ .
  • Example 5 Preparation of crystalline free base Form A of palbociclib having a specific surface area of > 2m 2 /g (I).
  • Example 6 Preparation of crystalline free base Form B of palbociclib having a specific surface area of > 2m 2 /g (I).
  • Example 7 Preparation of crystalline free base Form B of palbociclib having a specific surface area of > 2m 2 /g (I).
  • Palbociclib lOgm was dissolved in 100ml of methanol and 200 ml of MDC at 25-30°C. The solution was further subjected to spray drying to yield lOgm of amorphous palbociclib.
  • Palbociclib lOgm and copovidone lOgm was dissolved in 100ml of methanol and 200 ml of MDC at 25-30°C. The solution was further subjected to spray drying to yield lOgm of palbociclib-copovidone.

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Abstract

La présente invention concerne des formes polymorphes de palbociclib et des procédés de préparation de celles-ci, des compositions pharmaceutiques comprenant de la palbociclib, et l'utilisation de telles compositions pour le traitement du cancer.
PCT/GB2017/053133 2016-10-20 2017-10-17 Formes polymorphes de palbociclib WO2018073574A1 (fr)

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US10526326B2 (en) 2015-08-05 2020-01-07 Ratiopharm Gmbh Crystalline form and acetic acid adducts of palbociclib
US10597393B2 (en) 2016-07-07 2020-03-24 Plantex Ltd. Solid state forms of Palbociclib dimesylate
EP3612230A4 (fr) * 2017-04-21 2020-12-16 Alnova Pharmaceuticals, Ltd. Compositions de palbociclib et méthodes associées
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WO2022072336A1 (fr) * 2020-10-01 2022-04-07 University Of Washington Molécules de type médicament et méthodes pour le ciblage thérapeutique de micro-arn-21

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