WO2016127963A1 - Formes solides de sels de palbociclib - Google Patents

Formes solides de sels de palbociclib Download PDF

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Publication number
WO2016127963A1
WO2016127963A1 PCT/CZ2016/000017 CZ2016000017W WO2016127963A1 WO 2016127963 A1 WO2016127963 A1 WO 2016127963A1 CZ 2016000017 W CZ2016000017 W CZ 2016000017W WO 2016127963 A1 WO2016127963 A1 WO 2016127963A1
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WO
WIPO (PCT)
Prior art keywords
palbociclib
acid
salt
exhibits
crystalline form
Prior art date
Application number
PCT/CZ2016/000017
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English (en)
Inventor
Pavel ZVATORA
Ondrej Dammer
Jiri MIKSATKO
Lukas KREJCIK
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Zentiva, K.S.
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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Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2016127963A1 publication Critical patent/WO2016127963A1/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

Definitions

  • the invention relates to solid forms of 6-acetyl-8-cyciopentyl-5-methyl-2- ⁇ [5-(l-piperazinyl)- 2 ⁇ yridinyl]amino ⁇ pyrido[2, -d pyrimidin-7(8H)-one of formula I,
  • palbociclib known as palbociclib, and to methods of their preparation.
  • d3pyrimidin-7(8H)-one which is known as palbociclib (CAS no. 571190-30-2) belongs to the group of "cyclin-dependent kinase” (CDK4) inhibitors and is suitable for the treatment of inflammatory diseases, cancer and some vascular diseases.
  • CDK4 cyclin-dependent kinase
  • the enzymatic inhibition capability of palbociclib at low concentrations has been published in specialized literature (D.W. Fry et al. J. Biol. Chem. (2001) 16617-16623). Clinical studies with animal models have shown that the free base of palbociclib only exhibits a limited solubility (9 ⁇ g ml of water) and biological availability and for this reason it is not suitable for pharmaceutical use.
  • the palbociclib di-hydrochloride salt exhibits a suitable solubility in water, but its physical-chemical properties, especially hygroscopicity, make its use in preparation and formulation of drugs impossible.
  • Some salts of palbociclib exhibit a variable internal structure (polymorphism) depending on the method and conditions of their preparation.
  • the patent document WO 2005/005426 described the following polymorphic forms of palbociclib isethionate: "Form A”, “Form B” and “Form D"; and of palbociclib mono-mesylate: "Form A”, “Form B", “Form C” and "Form D".
  • the invention provides solid forms of palbociclib with inorganic and organic acids and methods of their preparation. These compounds are prepared by a reaction of palbociclib in the basic form with an acid selected from the group containing hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2,4-dihydroxybenzoic acid, benzoic acid in the molar ratio of 1 : 1 or 1 :2 in a suitable solvent or mixtures of solvents.
  • an acid selected from the group containing hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2,4-dihydroxybenzoic acid, benzoic acid in the molar ratio of 1 : 1 or 1 :2 in a suitable solvent or mixtures of solvents.
  • the prepared solid forms are crystalline and are prepared in a purity corresponding to the demands for their pharmaceutical use in formulation of new dosage forms.
  • Figure 15 X-ray powder pattern of palbociclib salicylate (1 :1)
  • Figure 23 X-ray powder pattern of palbociclib 2,4-dihydroxybenzoate (1:1)
  • Figure 24 DSC record of palbociclib 2,4-dihydroxybenzoate (1:1)
  • Figure 31 X-ray powder pattern of palbociclib mesylate (1:1)
  • Figure 37 Infrared spectrum of palbociclib hydrobromide (1:2)
  • Figure 38 X-ray powder pattern of palbociclib sulphate (1:2)
  • This invention provides a number of salts of palbociclib in the solid phase either or with an admixture of the amorphous form.
  • This invention prefers crystalline forms of palbociclib.
  • the invention provides novel solid forms of palbociclib with hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2.4-dihydroxybenzoic acid and benzoic acid in variable molar ratios. According to the invention, the molar ratios of 1:1 and 1 :2 are preferred.
  • novel solid forms can be both anhydrous and/or non-sol vated and in the form of hydrates/solvates of the respective solvents.
  • the prepared new solid forms of palbociclib may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio.
  • novel solid forms are suitable for preparation of palbociclib with a high chemical purity.
  • the preparation of novel solid forms of palbociclib is achieved by a reaction of the palbociclib base with hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2-4-dihydroxybenzoic acid or benzoic acid.
  • the reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic -C alcohols, esters or their mixtures are preferred.
  • the most commonly used solvents are methanol, ethanol, water or their mixtures.
  • the resulting product is precipitated or crystallized, typically at temperatures in the range of -30 °C to the boiling point of the solvent.
  • the crystalline form of palbociclib hydrobromide (1:1) is characterized by the reflections presented in Table 1.
  • Table 1 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib hydrobromide in accordance with this invention are: 11.5; 14.8; 16.5; 19.1 and 21.9° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 1.
  • the melting point of palbociclib hydrobromide (1:1) ( Figure 2) is 315°C (DSC).
  • the infrared spectrum of palbociclib hydrobromide (1:1) is shown in Figure 3.
  • the crystalline form of palbociclib sulphate (1:1) is characterized by the reflections presented in Table 2.
  • Table 2 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib sulphate in accordance with this invention are: 4.1; 9.3; 11.7; 16.2; 17.2 and 21.2° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 4.
  • the melting point of palbocichb sulphate (1:1) ( Figure 5) is 273°C (DSC).
  • the infrared spectrum of palbocichb sulphate (1:1) is shown in Figure 6.
  • the crystalline form of palbocichb oxalate (1 :1) is characterized by the reflections presented in Table 3.
  • Table 3 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbocichb oxalate in accordance with this invention are: 4.5; 10.0; 13.8; 17.3; 19.6 and 23. ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 7.
  • the melting point of palbociclib oxalate (1:1) ( Figure 8) is 256°C (DSC).
  • Figure 10 shows an example of the 1H NMR spectrum of the prepared palbociclib oxalate (1:1).
  • the crystalline form of palbociclib besyiate (1:1) is characterized by the reflections presented in Table 4.
  • Table 4 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib besyiate in accordance with this invention are: 9.0; 10.7; 11.9; 15.8; 22.1 and 26.2° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 11.
  • the melting point of palbociclib besylate (1:1) ( Figure 12) is 294°C (DSC).
  • Figure 14 shows an example of the 1H NMR spectrum of the prepared palbociclib besylate (1 :1).
  • the crystalline form of palbociclib salicylate (1:1) is characterized by the reflections presented in Table 5.
  • Table 5 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib salicylate in accordance with this invention are: 6.9; 11.7; 13.9; 16.9; 21.8 and 26.2° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 15.
  • the melting point of palbociclib salicylate (1:1) ( Figure 16) is 258°C (DSC).
  • Figure 18 shows an example of the 1H NMR spectrum of the prepared palbociclib salicylate (1:1).
  • the crystalline form of palbociclib fumarate (1 :1) is characterized by the reflections presented in Table 6.
  • Table 6 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib fumarate in accordance with this invention are: 5.1; 7.6; 12.9; 17.8 and 24.9° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 19.
  • Figure 22 shows an example of the 1H NMR spectrum of the prepared palbociclib fumarate (1:1).
  • the crystalline form of palbociclib 2,4-dihydroxybenzoate (1:1) is characterized by the reflections presented in Table 7.
  • Table 7 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib 2,4- dihydroxybenzoate in accordance with this invention are: 6.3; 10.6; 12.7; 16.4; 19.2 and 21.3° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 23.
  • Figure 26 shows an example of the 1H NMR spectrum of the prepared palbociciib 2,4- dihydroxybenzoate (1:1).
  • the crystalline form of palbociciib benzoate (1:1) is characterized by the reflections presented in Table 8.
  • Table 8 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociciib benzoate in accordance with this invention are: 4.1; 8.8; 14.0; 18.9; 21.6 and 23.8° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 27.
  • Figure 30 shows an example of the 1H NMR spectrum of the prepared palbociclib benzoate (1 :1).
  • the crystalline form of palbociclib mesylate (1:1) is characterized by the reflections presented in Table 9.
  • Table 9 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib mesylate in accordance with this invention are: 9.9; 13.4; 19.4 and 21.6° ⁇ 0.2° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 31.
  • meltmg point of palbociclib mesylate (1:1) ( Figure 32) is 312°C (DSC).
  • the crystalline form of palbociclib hydrobromide (1:2) is characterized by the reflections presented in Table 10.
  • Table 10 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib hydrobromide in accordance with this invention are: 9.4; 11.5; 16.3; 19.2; 20.4 and 22.0° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 35.
  • the crystalline form of palbociclib sulphate (1 :2) is characterized by the reflections presented in Table 11.
  • Table 11 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib sulphate in accordance with this invention are: 3.1; 9.1; 12.6; 16.0; 20.1 and 26.6° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 38.
  • the infrared spectrum of palbociclib sulphate (1 :2) is shown in Figure 40.
  • the crystalline form of palbociciib besyiate (1:2) is characterized by the reflections presented in Table 12.
  • Table 12 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociciib besyiate in accordance with this invention are: 6.3; 8.2; 11.4; 14.3; 17.8 and 20.6° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 41.
  • the melting point of palbociciib besyiate (1 :2) ( Figure 42) is 283°C (DSC).
  • Figure 44 shows an example of the ! H NMR spectrum of the prepared palbociciib besyiate (1:2).
  • the crystalline form of palbociclib mesylate (1:2) is characterized by the reflections presented in Table 13, Table 13 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of palbociclib mesylate in accordance with this invention are: 6.9; 9.7; 13.9; 16.6 and 19.6° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 45.
  • Figure 48 shows an example of the 1H NMR spectrum of the prepared palbociclib mesylate (1:2).
  • the invention is clarified in a more detailed way using the working examples below. These examples, which illustrate the preparation of the novel solid forms of palbociclib in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.
  • 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti-dispersion slit were used for the correction of the primary array.
  • the irradiated area of the sample is 10 mm, programmable divergence slits were used.
  • 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used for the correction of the secondary array.
  • ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS KBr detector, in the measurement range of 600-4000 cm “1 and the spectral resolution of 4.0 cm “1 .
  • the data were obtained at 64 spectrum accumulations.
  • the OMNIC 6.2 software was used to process the spectra.
  • the DSC records were measured using a Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 ⁇ ) was 4-5 mg and the heating rate was 10°C/min.
  • 5.0 N 2 at the flow rate of 50 ml/min was used as the carrier gas.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme solide d'un sel de palbociclib de formule I avec un acide HA au rapport molaire de 1/1 ou 1/2, l'acide HA étant sélectionné dans le groupe contenant de l'acide bromhydrique, de l'acide sulfurique, de l'acide oxalique, de l'acide benzènesulfonique, de l'acide salicylique, de l'acide fumarique, de l'acide 2,4-dihydroxybenzoïque, et de l'acide benzoïque. Un autre aspect de la présente invention concerne un procédé de préparation des sels de palbociclib.
PCT/CZ2016/000017 2015-02-11 2016-02-11 Formes solides de sels de palbociclib WO2016127963A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-89A CZ201589A3 (cs) 2015-02-11 2015-02-11 Pevné formy soli Palbociclibu
CZPV2015-89 2015-02-11

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017072543A1 (fr) * 2015-10-28 2017-05-04 Egis Gyógyszergyár Zrt. Sels de palbociclib
CN108017630A (zh) * 2016-10-31 2018-05-11 上海创诺制药有限公司 一种小比表面积帕博西尼游离碱的制备方法
RU2726115C1 (ru) * 2016-08-15 2020-07-09 Пфайзер Инк. Пиридопиримидиновые ингибиторы cdk2/4/6
US10813937B2 (en) 2016-03-29 2020-10-27 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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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
WO2008032157A2 (fr) * 2006-09-08 2008-03-20 Pfizer Products Inc. Synthèse de 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
WO2014128588A1 (fr) 2013-02-21 2014-08-28 Pfizer Inc. Formes solides d'un inhibiteur sélectif de cdk4/6

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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
WO2008032157A2 (fr) * 2006-09-08 2008-03-20 Pfizer Products Inc. Synthèse de 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
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HILFIKER (ED.): "Polymorphism in the Pharmaceutical Industry", 2006, WILEY-VCH, Weinheim, ISBN: 978-3-527-31146-0, article HILFIKER AT AL.: "Relevance of Solid-state Properties for Pharmaceutical products", pages: 1 - 19, XP002525043 *
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH, Weinheim, ISBN: 978-3-906390-26-0, article "Pharmaceutical Salts: Properties, Selections, and Use, passages", pages: 212 - 214,254,305,306, XP002550486 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017072543A1 (fr) * 2015-10-28 2017-05-04 Egis Gyógyszergyár Zrt. Sels de palbociclib
EA035346B1 (ru) * 2015-10-28 2020-05-29 Эгиш Дьёдьсердьяр Зрт. Соль 4-толуолсульфоновой кислоты и палбоциклиба, способ её получения и её применение в медицине
US10813937B2 (en) 2016-03-29 2020-10-27 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
US10894049B2 (en) 2016-03-29 2021-01-19 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
US11464779B2 (en) 2016-03-29 2022-10-11 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
RU2726115C1 (ru) * 2016-08-15 2020-07-09 Пфайзер Инк. Пиридопиримидиновые ингибиторы cdk2/4/6
US10800783B2 (en) 2016-08-15 2020-10-13 Pfizer Inc. CDK2/4/6 inhibitors
US11396512B2 (en) 2016-08-15 2022-07-26 Pfizer Inc. CDK2/4/6 inhibitors
CN108017630A (zh) * 2016-10-31 2018-05-11 上海创诺制药有限公司 一种小比表面积帕博西尼游离碱的制备方法
CN108017630B (zh) * 2016-10-31 2022-10-11 上海创诺制药有限公司 一种小比表面积帕博西尼游离碱的制备方法
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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