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WO2017145054A1 - Particules modifiées d'une base libre de palbociclib cristallin et son procédé de préparation - Google Patents

Particules modifiées d'une base libre de palbociclib cristallin et son procédé de préparation Download PDF

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Publication number
WO2017145054A1
WO2017145054A1 PCT/IB2017/050988 IB2017050988W WO2017145054A1 WO 2017145054 A1 WO2017145054 A1 WO 2017145054A1 IB 2017050988 W IB2017050988 W IB 2017050988W WO 2017145054 A1 WO2017145054 A1 WO 2017145054A1
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WO
WIPO (PCT)
Prior art keywords
free base
palbociclib
crystalline
surface area
palbociclib free
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2017/050988
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English (en)
Inventor
Narendra Dattatraya Mane
Sagar Purushottam Nehate
Himanshu Madhav Godbole
Girij Pal Singh
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Lupin Ltd
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Lupin Ltd
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Publication of WO2017145054A1 publication Critical patent/WO2017145054A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 modified particles of crystalline palbociclib free base and its process for the preparation thereof.
  • Palbociclib is a selective inhibitor of cyclin-dependent kinases and is used for the treatment of ER-positive and HER2-negative breast cancer. It is chemically known as 6- acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(piperazin-l-yl) pyridin-2-yl] amino ⁇ pyrido[2,3- d]pyrimidin-7(8H)-one having chemical structure of formula I.
  • the U.S. Patent No. 7863278 describes Isethionate salts of palbociclib.
  • the U.S. Patent application No. 20160002223 describes crystalline Forms A and B of palbociclib free base and palbociclib free base having a specific surface area of ⁇ 2 m 2 /g.
  • the PCT Publication no. WO 2016/156070 describes a crystalline palbociclib free base is having a specific surface area in the range of from 2.1 to 6.0 m /g as determined by BET- nitrogen analysis.
  • the present invention relates to a crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m /g.
  • the present invention further relates to a process for the preparation of crystalline
  • the present invention also provides a process for the preparation of crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m /g comprising:
  • Figure 1 depicts an X-Ray powder diffraction (XRPD) pattern of palbociclib free base form B.
  • Figure 2 depicts an X-Ray powder diffraction (XRPD) pattern of palbociclib free base form A.
  • One aspect of the present invention provides a crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m Ig.
  • Another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m 2 /g.
  • Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base having a specific surface area in the range from 7 to 15 m Ig comprising:
  • Palbociclib or salt thereof can be obtained by the process known in the art such as US 6936612, US 7345171 , US 7863278 or US 20160002223 and salt's includes any acid addition salt but not limited to hydrochloride, hydrobromide, sulfuric acid, and isethionate.
  • solvent is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile and water or a mixture thereof.
  • alcohols such as methanol, ethanol, isopropanol, n-
  • optionally adding base is selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate.
  • inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate.
  • the quantity of base is 1 to 5 times per mole of palbociclib or its salt thereof.
  • Another aspect of the present invention provides a crystalline palbociclib free base form B having a specific surface area in the range of from 3 to 15 m /g.
  • Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from 3 to 15 m 2 /g.
  • a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from 3 to 15 m /g comprising:
  • Another aspect of the present invention provides a crystalline palbociclib free base form
  • Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from 7 to 15 m 2 /g.
  • Yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from 7 to 15 m 2 /g.
  • In yet another aspect of the present invention provides a process for the preparation of crystalline palbociclib free base form B having a specific surface area in the range of from
  • Yet another aspect of the present invention provides a process for the preparation of crystalline form B of palbociclib comprising suspending palbociclib or its acid addition salt thereof in water, adding a base and isolating the crystalline form B of palbociclib.
  • salt includes any acid addition salt such as hydrochloride, hydrobromide salt.
  • base is inorganic or organic base .
  • the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate.
  • palbociclib free base form B is characterized by having PXRD pattern substantially as depicted in Figure 1.
  • palbociclib free base form B is characterized by having PXRD pattern comprising peaks at diffraction angles (2 ⁇ ) of 5.9 ⁇ 0.2, 10.9 ⁇ 0.2, 12.7 ⁇ 0.2, 16.3 ⁇ 0.2,19.6 ⁇ 0.2, 22.4 ⁇ 0.2, and 26.6 ⁇ 0.2.
  • Table- 1 provides the d- spacing values (A°), the corresponding 2 ⁇ values, and the relative intensity of crystalline palbociclib free base form B.
  • a base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate.
  • isolating crystalline palbociclib free base form B by filtration or centrifugation and palbociclib free base form B having a specific surface area in the range of from 3 to 15 m /g is determined by using BET-adsorption analysis.
  • palbociclib free base form B has particle size distribution characterized by a) D10 value from about 0.4 ⁇ to 3 ⁇
  • palbociclib free base form A is characterized by having PXRD pattern substantially as depicted in Figure 2.
  • palbociclib free base form A is characterized by having PXRD pattern comprising peaks at diffraction angles (2 ⁇ ) of 4.9 ⁇ 0.2, 7.9 ⁇ 0.2, 10+ 0.2, 10.1 ⁇ 0.2, 11.4 ⁇ 0.2, 17+ 0.2,22.2 + 0.2 and 22.4+ 0.2.
  • Table-2 provides the d-spacing values (A°), the corresponding 2 ⁇ values, and the relative intensity of crystalline palbociclib free base form A.
  • dissolving palbociclib hydrochloride salt in a solvent is selected from ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone, water or its mixture thereof.
  • ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone, water or its mixture thereof.
  • a base selected from sodium hydroxide, potassium hydroxide, sodium carbonate.
  • isolating crystalline palbociclib free base form A by removal of the solvent by using suitable techniques such as distillation, distillation by using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, filtration, filtration under vacuum, decantation and centrifugation, or any other technique known in the art. various techniques like filtration or centrifugation.
  • palbociclib free base form A has particle size distribution characterized by a) D10 value from about 0.4 ⁇ to 1.5 ⁇
  • crystalline palbociclib free base (form B or Form A) is characterized by obtained by the process of the present invention is having a purity of greater than about 95%, or greater than about 98%, or greater than about 99%, when measured by using high performance liquid chromatography (HPLC) and the details are given below;
  • crystalline palbociclib free base (form B or Form A) is characterized by having specific surface area in the range of from about 3 to 15 m /g, preferably from about 3.5 to 13 m 2 /g, more preferably from about 4 to 12 m 2 /g, as determined by the specific surface area measurements (BET nitrogen) were performed by using BET specific surface area analyzer.
  • Adsorbate gas Nitrogen (5%, 7%, 10%, 12% and 15%)
  • Equilibration time 90 sec (point to point).
  • the particle size was analyzed using the laser diffraction (or small angle light scattering) technique by dispersing the dry sample powder with compressed air. Specifically, the particle size distribution was analyzed using the Sympatec HELOS RODOS system equipped with a Vibri dry powder feeder. The powder sample was dispersed with a dispersion pressure of 0.5 bar. In some instances, an Aspiros micro-dosing device was used, and the powder sample was dispersed with a dispersion pressure of 0.2 bar. A suitable lens was selected to cover the particle size range of each sample.
  • Palbociclib dihydrochloride trihydrate 35 g was dissolved in water (840 ml) at room temperature.
  • Aqueous sodium hydroxide solution (5.25 g sodium hydroxide in 53 ml of water) was added to the above slurry at 25-30 °C and stirred for 1 hr.
  • the solid was filtered, washed with water (70 ml) and dried under vacuum. Obtained material was passed through 40 and 20 mesh, thus obtained crystalline palbociclib free base form B. Yield: 27.1 g
  • Palbociclib hydrochloride (3.0 g, 5.22 mmol) was suspended in water (45 ml) and the resulting slurry was cooled to 0-5 °C.
  • Aqueous sodium hydroxide solution (0.417 g sodium hydroxide in 15 ml water) was added to the above slurry at 5 °C and stirred for 2 hours at the same temperature. The solid was filtered, washed with chilled water (15 ml) and dried under vacuum. Yield: 1.45 g.
  • Palbociclib dihydrochloride trihydrate (100 g) was dissolved in a mixture of acetone (300 ml) and water (650 ml) at room temperature 25-30°C. To the above reaction mass water (50 ml), aqueous sodium hydroxide solution (75 ml) was added and stirred the mass for 2 hours at the same temperature. The solid was filtered, washed with chilled acetone and water mixture (150 ml), and dried the material under vacuum. Obtained material was passed the through 20 mesh, thus obtained crystalline palbociclib free base form A.
  • Palbociclib hydrochloride 50 g was dissolved in a mixture of acetone (350 ml) and water (650 ml) at room temperature 25-30°C. To the above reaction mass water (50 ml), aqueous sodium hydroxide solution (75 ml) was added and stirred the mass for 2 hours at the same temperature. The solid was filtered, washed with chilled acetone and water mixture (150 ml), and dried the material under vacuum.

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

Abstract

La présente invention concerne des particules modifiées de base libre de palbociclib cristallin ayant une surface spécifique située dans la plage de 7 à 15 m2jg. L'invention concerne en outre la forme base libre de palbociclib B ayant une surface spécifique située dans la plage de 3 à 15 m/g et la forme base libre de palbociclib A ayant une surface spécifique située dans la plage de 7 à 15 m2jg, et son procédé de préparation.
PCT/IB2017/050988 2016-02-24 2017-02-22 Particules modifiées d'une base libre de palbociclib cristallin et son procédé de préparation Ceased WO2017145054A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN201621006482 2016-02-24
IN201621006482 2016-02-24
IN201621041371 2016-12-02
IN201621041371 2016-12-02

Publications (1)

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WO2017145054A1 true WO2017145054A1 (fr) 2017-08-31

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018073574A1 (fr) * 2016-10-20 2018-04-26 Cipla Limited Formes polymorphes de palbociclib
WO2019020715A1 (fr) * 2017-07-28 2019-01-31 Synthon B.V. Composition pharmaceutique comprenant du palbociclib
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
WO2024133726A1 (fr) * 2022-12-22 2024-06-27 Synthon B.V. Composition pharmaceutique contenant du palbociclib
WO2024132652A1 (fr) * 2022-12-22 2024-06-27 Synthon B.V. Composition pharmaceutique comprenant du palbociclib

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6936612B2 (en) 2002-01-22 2005-08-30 Warner-Lambert Company 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
US7345171B2 (en) 2003-07-11 2008-03-18 Warner-Lambert Company Llc Isethionate salt of a selective CKD4 inhibitor
WO2014128588A1 (fr) * 2013-02-21 2014-08-28 Pfizer Inc. Formes solides d'un inhibiteur sélectif de cdk4/6
WO2016024249A1 (fr) 2014-08-14 2016-02-18 Sun Pharmaceutical Industries Limited Formes cristallines de palbociclib
WO2016156070A1 (fr) 2015-04-02 2016-10-06 Sandoz Ag Particules modifiées de palbociclib
WO2017021111A1 (fr) 2015-08-05 2017-02-09 Ratiopharm Gmbh Nouvelle forme cristalline du palbociclib et adduits d'acide acétique et de palbociclib

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6936612B2 (en) 2002-01-22 2005-08-30 Warner-Lambert Company 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
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
WO2014128588A1 (fr) * 2013-02-21 2014-08-28 Pfizer Inc. Formes solides d'un inhibiteur sélectif de cdk4/6
US20160002223A1 (en) 2013-02-21 2016-01-07 Pfizer Inc. Solid forms of a selective cdk4/6 inhibitor
WO2016024249A1 (fr) 2014-08-14 2016-02-18 Sun Pharmaceutical Industries Limited Formes cristallines de palbociclib
WO2016156070A1 (fr) 2015-04-02 2016-10-06 Sandoz Ag Particules modifiées de palbociclib
WO2017021111A1 (fr) 2015-08-05 2017-02-09 Ratiopharm Gmbh Nouvelle forme cristalline du palbociclib et adduits d'acide acétique et de palbociclib

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US11332467B2 (en) 2016-07-07 2022-05-17 Plantex Ltd. Solid state forms of palbociclib dimesylate
WO2018073574A1 (fr) * 2016-10-20 2018-04-26 Cipla Limited Formes polymorphes de palbociclib
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
WO2024133726A1 (fr) * 2022-12-22 2024-06-27 Synthon B.V. Composition pharmaceutique contenant du palbociclib
WO2024132652A1 (fr) * 2022-12-22 2024-06-27 Synthon B.V. Composition pharmaceutique comprenant du palbociclib

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