WO2017130219A1 - Dispersion solide amorphe de palbociclib - Google Patents

Dispersion solide amorphe de palbociclib Download PDF

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Publication number
WO2017130219A1
WO2017130219A1 PCT/IN2017/050033 IN2017050033W WO2017130219A1 WO 2017130219 A1 WO2017130219 A1 WO 2017130219A1 IN 2017050033 W IN2017050033 W IN 2017050033W WO 2017130219 A1 WO2017130219 A1 WO 2017130219A1
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WO
WIPO (PCT)
Prior art keywords
palbociclib
solid dispersion
amorphous solid
solvent
process according
Prior art date
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PCT/IN2017/050033
Other languages
English (en)
Inventor
Ramakoteswara Rao Jetti
Anjaneyaraju Indukuri
Original Assignee
Mylan Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Publication of WO2017130219A1 publication Critical patent/WO2017130219A1/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 disclosure relates generally to active pharmaceutical ingredients and more specifically to anamorphous solid dispersion of palbociclib with pharmaceutically acceptable excipients.
  • the present disclosure also provides processes for the preparation thereof.
  • Palbociclib (PD-0332991)is a potent and selective inhibitor of CDK4 and CDK6. Palbociclib is marketed in the United States as IBRANCE® by Pfizer. Chemically, palbociclib is known as 6-acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(piperazin-l-yl)pyridin-2yl]amino ⁇ pyrido[2,3- d]pyrimidin-7(8H)-one and has a chemical structure represented by formula- 1 below.
  • Palbociclib and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2003/062236 and U.S. Patent Nos. 6,936,612; 7,208,489; and 7,456, 168, which describe the preparation of formula-1 as its hydrochloride salt.
  • International Publication No. WO 2005/005426 and U.S. Patent Nos. 7,345, 171 and 7,863,278 describe the preparation of the free base and various mono- and di-acid addition salts of formula- 1, including polymorphic forms of the isethionate salt of palbociclib.
  • the present disclosure provides an amorphous solid dispersion of palbociclib that is stable and easy to prepare on a commercial scale.
  • the present invention provides an amorphous solid dispersion of palbociclib.
  • the present invention provides a process for the preparation of amorphous solid dispersion of palbociclib.
  • anamorphous solid dispersion of palbociclib may be prepared by a process that includes the steps of: a) dissolving palbociclib in an organic solvent; b) adding a pharmaceutically acceptable excipient; and c) isolating amorphous solid dispersion of palbociclib.
  • the solvent may be, for example, an alcohol solvent, dichloromethane, or mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, isopropanol, n-butanol, 2- methyl- 1-propanol, 3 -methyl- 1-butanol, 1-pentanol, and mixtures thereof.
  • suitable pharmaceutically acceptable excipients include polymeric excipients, for example, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate, povidone, 2- hydroxypropyl-P-cyclodextrin (HPpCD), hydroxypropyl methylcellulose, and mixtures thereof.
  • a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40N-vinyl-2-pyrrolidone:vinyl acetate or a povidone with a K value of 30 is used.
  • the amorphous solid dispersion of palbociclib may be isolated by removal of the solvent.
  • Suitable methods for removing the solvent include for example distillation, spray drying, lyophilization, or combinations thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous solid dispersion of palbociclib together with one or more additional pharmaceutically acceptable excipients.
  • Figure 1 shows a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of palbociclib.
  • the present disclosure provides an amorphous solid dispersion of palbociclib.
  • the amorphous solid dispersion of palbociclib may contain palbociclib and one or more pharmaceutically acceptable excipient.
  • polymeric excipients are particularly useful.
  • the solid dispersions disclosed herein may be characterized as amorphous by powder x-ray diffraction (PXRD). Therefore, samples of the amorphous solid dispersion of palbociclib, prepared by methods disclosed herein, were analyzed by PXRD on a Bruker D8 Discover powder diffractometer equipped with goniometer of ⁇ /2 ⁇ configuration and LYNX EYE detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2 ⁇ range of 2.0 0 - 50.0 °, 0.030 0 step size, and 0.4 seconds step time.
  • PXRD powder x-ray diffraction
  • the amorphous solid dispersion of palbociclib may be characterized as amorphous by PXRD, for example, by the PXRD pattern shown in Figure 1.
  • anamorphous solid dispersion of palbociclib may be prepared by a process that includes the steps of:
  • palbociclib may be dissolved an organic solvent.
  • the solvent may be an alcohol solvent, dichloromethane, or mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, isopropanol, n-butanol, 2-methyl-l-propanol, 3-methyl-l-butanol, and 1-pentanol.
  • a pharmaceutically acceptable excipient may be added to the solution.
  • the pharmaceutically acceptable excipient may be, for example, polysaccharides, polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC ® trade name), and mixtures thereof.
  • PVAC polyvinyl acetate
  • PVA polyvinyl alcohol
  • Ci-C 6 polyalkylene glycols e.g., polypropylene glycol, polyethylene glycol
  • copolymers of polyethylene glycol and polypropylene glycol e.g., the families of
  • Suitable polysaccharides include, for example, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), optionally substituted a-cyclodextrins, optionally substituted ⁇ -cyclodextrins (e.g., hydroxypropyl ⁇ -cyclodextrin), optionally substituted ⁇ - cyclodextrins (e.g., hydroxypropyl y-cyclodextrin)and mixtures thereof.
  • substituted with respect to cyclodextrin means the addition of side chain groups such as hydroxyl, hydroxypropyl, and other Ci-C 6 alkyl and Ci-C 6 hydroxyalkyl.
  • copolymers of N-vinyl-2-pyrrolidone and vinyl acetate for examples, those with a mass ratio of 60:40 (e.g., Plasdone S-630), povidones, for example, those with a K-value of about 30 (e.g., PVP K30), optionally substituted ⁇ - cyclodextrins (e.g., 2-hydroxypropyl-P-cyclodextrin (HPpCD)), hydroxypropyl methylcellulose (HPMC), or combinations thereof are used.
  • ⁇ - cyclodextrins e.g., 2-hydroxypropyl-P-cyclodextrin (HPpCD)
  • HPMC hydroxypropyl methylcellulose
  • the pharmaceutically acceptable excipient may be combined with the solution of palbociclib from about 5 % w/w (pharmaceutically acceptable excipient/total composition mass) to about 90 % w/w, which may be about 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, 80% w/w, 85% w/w, 90% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%- 20%, 5%-10%, 10%-90%, 10%-
  • an amorphous solid dispersion of palbociclib may be isolated. This may be carried out by methods well known in the art, for example, by removing the solvent to isolate an amorphous solid dispersion of palbociclib. Solvent removal may be carried out, for example, by distillation, spray drying, lyophilization, or other similar processes.
  • the solution may be filtered to remove any undissolved materials from the solution.
  • isolation of amorphous solid dispersion of palbociclib is carried out by spray drying using a solution feed rate of about 5 mL/min and an inlet temperature of about 70 °C to 85°C.
  • the amorphous solid dispersions of palbociclib disclosed herein may be combined with one or more pharmaceutically acceptable excipients to create a pharmaceutical composition.
  • the amorphous solid dispersion of palbociclib may be combined with a lubricant, a glidant, a filler, a bulking agent, a binder, an anti-adherant, a disintegrants, a sweetener, a sorbent, artificial colorings or flavorings, or any mixtures thereof.
  • a lubricant for example, a lubricant, a glidant, a filler, a bulking agent, a binder, an anti-adherant, a disintegrants, a sweetener, a sorbent, artificial colorings or flavorings, or any mixtures thereof.
  • the amorphous solid dispersions of palbociclib prepared by methods disclosed herein may be useful in formulating a dosage form, for example, a tablet or a capsule.
  • the tablet or capsule may contain any of the aforementioned pharmaceutically acceptable excipients, for example, microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, gelatin, and mixtures thereof.
  • the tablets or capsules may be coated with a shell or film that may contain gelatin, titanium dioxide, and artificial colorings such as, for example, red iron oxide, yellow iron oxide, and inks that may contain shellac, titanium dioxide, ammonium hydroxide, propylene glycol, and simethicone.
  • Dosage forms containing the amorphous solid dispersion of palbociclib prepared by methods disclosed herein may be useful in the treatment of metastatic breast cancer alone or when used in combination with other active ingredients, such as letrozole or fulvestrant.
  • the amorphous solid dispersion of palbociclib prepared by methods disclosed herein may exhibit long term stability.
  • the stability of several samples of amorphous solid dispersions of palbociclib containing palbociclib and povidone with a Revalue of 30 (PVP K30) were determined by storing the samples at 40°C/75% relative humidity (RH), at 25 °C/60% relative humidity (RH), and at 5+3°C for 6 months.
  • Table 1 shows data collected on amorphous solid dispersions palbociclib with 50% w/w PVP- 30 prepared according to the processes disclosed herein.
  • the amorphous solid dispersion of palbociclib and PVP-30 displayed no change in PXRD pattern over six months under those storage conditions.
  • Example 1 Preparation of solid dispersion of Palbociclib with Plasdone S-630 (50% w/w)
  • Palbociclib (2.0g) was dissolved in a mixture of methanol (50mL) and dichloromethane (50mL) at 40-45°C. Plasdone S-630 (2.0g) was added to this clear solution which was stirred at the same temperature for 15-30minutes to get a clear solution. The clear solution was filtered through a Hyflo bed to remove any undissolved particulate and the filtrate was washed with a 1: 1 mixture of methanol and dichloromethane (20mL).
  • the clear filtrate was then cooled to 25-30°C and subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate of 5mL/min and an inlet temperature of 75°C with 100% aspiration to yield an amorphous solid dispersion of palbociclib with Plasdone S-630.
  • Palbociclib (5.0g) was dissolved in a mixture of methanol (125mL) and dichloromethane (125 mL) at 40-45°C.
  • PVP K30 (5.0g) was added to this clear solution which was then stirred at the same temperature for 15-30minutes to get a clear solution.
  • the clear solution was filtered through a Hyflo bed to remove any undissolved particulate and the filtrate was washed with a 1: 1 mixture of methanol and dichloromethane (50mL).
  • the clear filtrate was then cooled to 25-30°C and subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate of 5mL/min and an inlet temperature at 75°C with 100% aspiration to yield an amorphous solid dispersion of palbociclib with PVP K30.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une dispersion solide amorphe de palbociclib et un procédé de préparation de ladite dispersion. Les dispersions solides selon l'invention peuvent être utiles pour des compositions pharmaceutiques ou des formes posologiques.
PCT/IN2017/050033 2016-01-25 2017-01-21 Dispersion solide amorphe de palbociclib WO2017130219A1 (fr)

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IN201641002806 2016-01-25
IN201641002806 2016-01-25

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11464779B2 (en) 2016-03-29 2022-10-11 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
US11471418B2 (en) * 2020-09-29 2022-10-18 Shenzhen Pharmacin Co., Ltd. Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof

Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2003062236A1 (fr) 2002-01-22 2003-07-31 Warner-Lambert Company Llc 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
WO2005005426A1 (fr) 2003-07-11 2005-01-20 Warner-Lambert Company Llc Sel d'iséthionate d'un inhibiteur sélectif de la cdk4
US20140179719A1 (en) * 2012-12-26 2014-06-26 Sreedhar Cheekoori Novel amorphous solid dispersions of valganciclovir hydrochloride
WO2014128588A1 (fr) 2013-02-21 2014-08-28 Pfizer Inc. Formes solides d'un inhibiteur sélectif de cdk4/6
CN105085517A (zh) * 2015-08-06 2015-11-25 天津华洛康生物科技有限公司 一种结晶型帕博西尼游离碱水合物及其制备方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003062236A1 (fr) 2002-01-22 2003-07-31 Warner-Lambert Company Llc 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
US6936612B2 (en) 2002-01-22 2005-08-30 Warner-Lambert Company 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
US7208489B2 (en) 2002-01-22 2007-04-24 Warner-Lambert Company 2-(pyridin-2-ylamino)-pyrido [2,3-d]pyrimidin-7-ones
US7456168B2 (en) 2002-01-22 2008-11-25 Warner-Lambert Company 2-(pyridin-2-ylamino)-pyrido[2,3, d]pyrimidin-7-ones
WO2005005426A1 (fr) 2003-07-11 2005-01-20 Warner-Lambert Company Llc Sel d'iséthionate d'un inhibiteur sélectif de la cdk4
US7345171B2 (en) 2003-07-11 2008-03-18 Warner-Lambert Company Llc Isethionate salt of a selective CKD4 inhibitor
US7863278B2 (en) 2003-07-11 2011-01-04 Warner-Lambert CompanyLLC Isethionate salt of a selective CDK4 inhibitor
US20140179719A1 (en) * 2012-12-26 2014-06-26 Sreedhar Cheekoori Novel amorphous solid dispersions of valganciclovir hydrochloride
WO2014128588A1 (fr) 2013-02-21 2014-08-28 Pfizer Inc. Formes solides d'un inhibiteur sélectif de cdk4/6
CN105085517A (zh) * 2015-08-06 2015-11-25 天津华洛康生物科技有限公司 一种结晶型帕博西尼游离碱水合物及其制备方法

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Title
ECONNO T., CHEM. PHARM. BULL., vol. 38, 1990, pages 2003 - 2007

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11464779B2 (en) 2016-03-29 2022-10-11 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
US11471418B2 (en) * 2020-09-29 2022-10-18 Shenzhen Pharmacin Co., Ltd. Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof

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