[go: up one dir, main page]

WO2017174044A1 - Formes solides d'ibrutinib - Google Patents

Formes solides d'ibrutinib Download PDF

Info

Publication number
WO2017174044A1
WO2017174044A1 PCT/CZ2017/000019 CZ2017000019W WO2017174044A1 WO 2017174044 A1 WO2017174044 A1 WO 2017174044A1 CZ 2017000019 W CZ2017000019 W CZ 2017000019W WO 2017174044 A1 WO2017174044 A1 WO 2017174044A1
Authority
WO
WIPO (PCT)
Prior art keywords
ibrutinib
free base
crystalline form
prepared
solution
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/CZ2017/000019
Other languages
English (en)
Inventor
Pavel ZVATORA
Ondrej Dammer
Vit ZVONICEK
Radka MIKESOVA
Josef Beranek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
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.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of WO2017174044A1 publication Critical patent/WO2017174044A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to a solid form of l-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one of formula I,
  • the patent document WO 2013/184572 deals with the pharmaceutical composition of crystalline and solvated forms of ibrutinib for oral administration and mentions pharmaceutically acceptable salts of this drug without any further description or production example. Further use of ibrutinib for the treatment of cancer, inflammatory and autoimmune diseases, together with a description of pharmaceutical compositions mentioning its pharmaceutically acceptable salts without their further description or production example is mentioned in the patent document WO2014/004707.
  • the dissolution rate of crystalline form C of ibrutinib free base in a solution having pH 2 is 0.052 mg-min ' ⁇ cm "2
  • the dissolution rate of the thermodynamically most stable form A of ibrutinib free base is 0.017 mg-min " -cm " under identical conditions.
  • the object of the invention is preparation of a crystalline solid form of ibrutinib (form C) with a variable size of the primary particles and their clusters. The morphology of particles is governed by the process parameters during crystallization.
  • Crystalline form C of ibrutinib free base can be prepared from a methanolic solution by crystallization when through a change of process parameters (solution saturation, temperature, cooling rate, inoculation temperature), crystalline form C of ibrutinib free base can be prepared in a yield of > 90% with controlled morphology and the size of primary particles from 5 ⁇ to 120 ⁇ .
  • the crystallization yield of ibrutinib form C described in the patent application WO 2008/039218 is 70% with the primary particle size of about 35 ⁇ .
  • the morphology and size of the primary particles of crystalline form C of ibrutinib free base also significantly influences filterability of the suspension during production.
  • the filtration time is approximately three times shorter than in the case of preparation of crystalline form C of ibrutinib free base according to the procedure described in the patent application WO2008/039218, when the size of primary particles was ⁇ 35 ⁇ .
  • a larger size of the primary particles and clusters also enables easier handling after filtration of the product and faster achievement of a constant weight during product drying.
  • the prepared crystalline forms C of ibrutinib free base have suitable physicochemical properties for use in pharmacy and formulation of new drug forms.
  • a crystalline product is often stable, its required purity is easier to achieve and it dissolves more slowly.
  • the problem may be solved by crystalline forms of active pharmaceutical ingredients with a lower melting point than the corresponding thermodynamically most stable crystalline form, when such crystal arrangement guarantees higher solubility of the crystalline form.
  • the size of the primary particles and morphology of clusters can be controlled by the process parameters of crystallization as solution saturation, temperature, cooling rate, inoculation temperature.
  • the size of the primary particles and clusters influences the filtering rate of the suspension during preparation and the time of achievement of a constant weight during product drying.
  • This product provides a preparation method of crystalline form C of ibrutinib free base in high yields, when the obtained crystalline forms exhibit higher solubility than in the case of the thermodynamically most stable crystalline form A of ibrutinib free base.
  • the object of the invention is a preparation method of a crystalline solid form of ibrutinib (form C) with a variable size of the primary particles and their clusters.
  • Crystalline form C of ibrutinib free base can be prepared from a methanolic solution by crystallization or from a suspension.
  • the preparation method of form C of ibrutinib free base comprises dissolution of ibrutinib at a concentration of 10 mg/ml to 260 mg/ml at 60°C or at a concentration of 90 mg/ml to 260 mg/ml at 60°C.
  • the solution is cooled down at a rate of 0.1°C/min to 3°C/min, preferably 0.1°C/min to l°C/min.
  • the solution is inoculated at a temperature from 45°C to 0°C.
  • the preparation method of form C of ibrutinib free base consists in that ibrutinib is obtained by crystallization of a solution produced by dissolution of ibrutinib in methanol at the concentration of 90 mg/ml at 60°C, the solution is cooled down at the rate of 0.3°C/min until the temperature 0°C is achieved, the solution is inoculated by addition of 2% of crystalline form C of ibrutinib free base at 25°C, the solid fraction is obtained by filtering and drying of the filter cake at 40°C and the pressure of 20 kPa; drying being applied until a constant product weight is achieved.
  • the size of the primary particles and morphology of clusters can be controlled by the process parameters of crystallization as solution saturation, temperature, cooling rate, inoculation temperature.
  • the size of the primary particles and clusters influences the filtering rate of the suspension during preparation and the time of achievement of a constant weight during product drying.
  • crystalline form C of ibrutinib free base with the primary particle size of ⁇ 120 ⁇ is preferred, the ratio of the primary particle size to the cluster size being at least 1 :5 and the cluster size being at least 150 ⁇ , and the particles prepared this way were prepared in a high yield, with good filterability and workability in the powder state as well as a short time to achieve a constant weight during product drying.
  • crystalline form C of ibrutinib can be prepared by suspending or recrystallization of forms A, B or their mixtures in methanol (see tab. 1).
  • Table 1 Polymorphic transformation of crystalline forms of ibrutinib in a methanolic suspension (3 weeks at 35°C)
  • the characteristic diffraction peaks of crystalline form C of ibrutinib free base with the use of CuKa radiation are: 7.0; 14.0; 15.7; 18.2; 19.1; 19.5; 20.3; 22.1; 22.9 ⁇ 0.1° 2-theta.
  • the melting point of crystalline form C of ibrutinib free base is 134°C according to DSC.
  • An image of the morphology and size of the primary particles from the SEM is shown in Figure 4.
  • a powder material with the primary particle size (max. Feret) of ⁇ 35 ⁇ without the presence of clusters at 70% crystallization yield was obtained by a reproduction of the procedure disclosed in the patent application (WO2008/039218).
  • An example of the X-ray powder pattern is shown in Figure 5.
  • Figure no. 6 shows an image of the morphology and size of the primary particles and a cluster of crystalline form C of ibrutinib from the SEM.
  • the particles were prepared according to the procedure described in Example 4.
  • Figure no. 7 shows an image of the morphology and size of the primary particles and a cluster of crystalline form C of ibrutinib from the SEM.
  • the particles were prepared according to the procedure described in Example 5.
  • Figure no. 8 shows an image of the morphology and size of the primary particles and a cluster of crystalline form C of ibrutinib from the SEM.
  • the particles were prepared according to the procedure described in Example 6.
  • Figure no. 9 shows an image of the morphology and size of the primary particles and a cluster of crystalline form C of ibrutinib from the SEM.
  • the particles were prepared according to the procedure described in Example 7.
  • the prepared particles of crystalline ibrutinib of form C showed a different resistance during filtration depending on the size of the primary particles or clusters (see Tab. 2).
  • Table 2 Resistance of the prepared particles of crystalline ibrutinib of form C during filtration
  • a 10mm mask and a 1/4° fixed anti-dispersion slit were used.
  • the irradiated area of the sample is 10 mm, programmable divergence slits were used.
  • For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.
  • the melting points of the solid forms of ibrutinib were measured with the Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 ⁇ ,) was in the range of 4-5 mg and the heating rate was 5°C/min.
  • As the carrier gas 5.0 N2 was used at the flow of 50 ml/min.
  • the electron microscope images were obtained using a MIRA II device, Tescan, Czech Republic, 2006.
  • W fiber with the applied voltage of 7 kV was used with a YAG scintillation detector positioned in the optical axis under the pole piece of the objective (BSE).
  • BSE pole piece of the objective
  • the measurement was carried out under high vacuum.
  • the sample was applied onto a carbon tape and plated with Pt in a vacuum sprayer before the measurement.
  • the dissolution rate was measured using an Agilent 708-DS dissolution device. Disks for true dissolution with the surface area available for dissolution of 0.125 cm were prepared using a Specac press. The pressing time was 30 seconds under the pressure of 1 ton. The dissolution was carried out in 500 ml of a solution with pH 2 (10 mM HC1) at the constant speed of 100 rpm. Samples were extracted in 5-minute intervals and the concentration of dissolved ibrutinib was determined with an Agilent Cary 60 UV/Vis spectrophotometer at the wavelength of 274 nm.
  • the Raman spectra were measured using a Bruker RFS 100/S device. Wavelength of the laser radiation source 1064 nm. The measurements were carried with the accumulation of 64 scans with the resolution of 4 cm "1 .
  • the filtration rate was determined by measuring the flow time of the solvent through the prepared filter cake.
  • the filter cake was prepared by weighing of the corresponding quantity of dried particles of crystalline ibrutinib after the preparation of the sample. The weighed particles were washed with 20 ml of water on frit of defined dimensions. The filter cake prepared this way was characterized by measurement of the height and the filtration resistance was determined by measurement of the flow time of 25 ml of water. All the samples were measured under identical conditions. Examples
  • Example 2 At the temperature of 0°C, the solution was inoculated with 5% of the crystalline form C of ibrutinib prepared in Example 1. The obtained suspension was filtered and the solid fraction was dried in a vacuum drier at the temperature of 40°C and pressure of 13 kPa. A solid crystalline product of ibrutinib (Form C) was obtained. An image of the prepared product from the SEM is shown in figure 6. This way, particles were prepared with generally spherical clusters with the size of ⁇ 150 ⁇ and the primary particle size of ⁇ 5 ⁇ . Crystallization yield 3.91 g (93%).

Landscapes

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

Abstract

L'invention concerne une forme solide de la 1-[(3R)-3-[4-amino-3-(4-phénoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]pipéridin-1-yl]prop-2-en-1-one de formule (I) et des procédés de préparation de particules cristallines à morphologie variable. La forme cristalline (C) de la base libre de l'ibrutinib présente une taille de particules primaires inférieure ou égale à 120 µm, le rapport entre la taille des particules primaires et la taille des agrégats étant d'au moins 1:5 et les agrégats présentant la taille minimale de 150 µm.
PCT/CZ2017/000019 2016-04-06 2017-04-03 Formes solides d'ibrutinib Ceased WO2017174044A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2016-196 2016-04-06
CZ2016-196A CZ2016196A3 (cs) 2016-04-06 2016-04-06 Pevné formy Ibrutinibu

Publications (1)

Publication Number Publication Date
WO2017174044A1 true WO2017174044A1 (fr) 2017-10-12

Family

ID=58664410

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2017/000019 Ceased WO2017174044A1 (fr) 2016-04-06 2017-04-03 Formes solides d'ibrutinib

Country Status (2)

Country Link
CZ (1) CZ2016196A3 (fr)
WO (1) WO2017174044A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10183024B2 (en) 2016-12-02 2019-01-22 Apotex Inc. Crystalline forms of ibrutinib
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
EP3501609A1 (fr) 2017-12-08 2019-06-26 Zentiva K.S. Compositions pharmaceutiques comprenant de l'ibrutinib
WO2019195827A1 (fr) 2018-04-06 2019-10-10 Johnson Matthey Public Limited Company Nouvelle forme d'ibrutinib
WO2019211870A1 (fr) * 2018-05-02 2019-11-07 Cipla Limited Formes polymorphes d'ibrutinib
EP3669867A1 (fr) * 2018-12-21 2020-06-24 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib
WO2020170270A1 (fr) * 2019-02-19 2020-08-27 Msn Laboratories Private Limited, R&D Center Nouveaux polymorphes cristallins de 1-[(3r)-3-[4-amino-3-(4-phénoxyphényl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pipéridinyl]-2-propène-1-one et leur procédé de préparation
US11433072B1 (en) * 2021-06-10 2022-09-06 Hikma Pharmaceuticals USA, Inc. Oral dosage forms of ibrutinib
WO2023242384A1 (fr) * 2022-06-17 2023-12-21 Krka, D.D., Novo Mesto Formes cristallines d'ibrutinib
MA63498A1 (fr) * 2021-06-10 2024-07-31 Hikma Pharmaceuticals Usa Inc. Formes posologiques orales d'ibrutinib

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008039218A2 (fr) 2006-09-22 2008-04-03 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton
WO2013113841A1 (fr) 2012-02-01 2013-08-08 Euro-Celtique S.A. Nouveaux agents thérapeutiques
WO2013155347A1 (fr) 2012-04-11 2013-10-17 Izumi Raquel Inhibiteurs de tyrosine kinase de bruton pour la mobilisation hematopoïétique
WO2013184572A1 (fr) 2012-06-04 2013-12-12 Pharmacyclics, Inc. Formes cristallines d'un inhibiteur de tyrosine kinase de bruton
WO2014004707A1 (fr) 2012-06-29 2014-01-03 Principia Biopharma Inc. Formulations comprenant de l'ibrutinib
CN103694241A (zh) 2013-11-27 2014-04-02 苏州晶云药物科技有限公司 Pci-32765的新晶型a及其制备方法
WO2015145415A2 (fr) 2014-03-27 2015-10-01 Perrigo Api Ltd. Formes solides d'ibrutinib et leur procédé de production
WO2016170545A1 (fr) * 2015-04-22 2016-10-27 Msn Laboratories Private Limited Procédé de préparation de 1-[(3r)-3-[4-amino-3-(4-phénoxyphényl)-1h- pyrazolo[3,4-d]pyriniidin-1-y1]-1-pipéridinyl]-2-propèn-1-one et de ses polymorphes

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008039218A2 (fr) 2006-09-22 2008-04-03 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton
WO2013113841A1 (fr) 2012-02-01 2013-08-08 Euro-Celtique S.A. Nouveaux agents thérapeutiques
WO2013155347A1 (fr) 2012-04-11 2013-10-17 Izumi Raquel Inhibiteurs de tyrosine kinase de bruton pour la mobilisation hematopoïétique
WO2013184572A1 (fr) 2012-06-04 2013-12-12 Pharmacyclics, Inc. Formes cristallines d'un inhibiteur de tyrosine kinase de bruton
WO2014004707A1 (fr) 2012-06-29 2014-01-03 Principia Biopharma Inc. Formulations comprenant de l'ibrutinib
CN103694241A (zh) 2013-11-27 2014-04-02 苏州晶云药物科技有限公司 Pci-32765的新晶型a及其制备方法
WO2015145415A2 (fr) 2014-03-27 2015-10-01 Perrigo Api Ltd. Formes solides d'ibrutinib et leur procédé de production
WO2016170545A1 (fr) * 2015-04-22 2016-10-27 Msn Laboratories Private Limited Procédé de préparation de 1-[(3r)-3-[4-amino-3-(4-phénoxyphényl)-1h- pyrazolo[3,4-d]pyriniidin-1-y1]-1-pipéridinyl]-2-propèn-1-one et de ses polymorphes

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10183024B2 (en) 2016-12-02 2019-01-22 Apotex Inc. Crystalline forms of ibrutinib
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
EP3501609A1 (fr) 2017-12-08 2019-06-26 Zentiva K.S. Compositions pharmaceutiques comprenant de l'ibrutinib
WO2019195827A1 (fr) 2018-04-06 2019-10-10 Johnson Matthey Public Limited Company Nouvelle forme d'ibrutinib
WO2019211870A1 (fr) * 2018-05-02 2019-11-07 Cipla Limited Formes polymorphes d'ibrutinib
EP3669867A1 (fr) * 2018-12-21 2020-06-24 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib
WO2020127912A1 (fr) * 2018-12-21 2020-06-25 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib
WO2020170270A1 (fr) * 2019-02-19 2020-08-27 Msn Laboratories Private Limited, R&D Center Nouveaux polymorphes cristallins de 1-[(3r)-3-[4-amino-3-(4-phénoxyphényl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pipéridinyl]-2-propène-1-one et leur procédé de préparation
US11433072B1 (en) * 2021-06-10 2022-09-06 Hikma Pharmaceuticals USA, Inc. Oral dosage forms of ibrutinib
MA63498A1 (fr) * 2021-06-10 2024-07-31 Hikma Pharmaceuticals Usa Inc. Formes posologiques orales d'ibrutinib
WO2023242384A1 (fr) * 2022-06-17 2023-12-21 Krka, D.D., Novo Mesto Formes cristallines d'ibrutinib

Also Published As

Publication number Publication date
CZ2016196A3 (cs) 2017-10-18

Similar Documents

Publication Publication Date Title
WO2017174044A1 (fr) Formes solides d'ibrutinib
EP2411394B1 (fr) Sels pharmaceutiques utiles de 7-[(3r,4r)-3-hydroxy-4-hydroxyméthyl-pyrrolidin-1-ylméthyl]-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one
KR102078077B1 (ko) 타이로신 키나제 억제제 다이말리에이트의 결정형 아이 및 그의 제조 방법
WO2017172811A1 (fr) Nouveaux co-cristaux
US20140031352A1 (en) Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof
WO2017008773A1 (fr) Formes cristallines d'acide obéticholique
EP3256474A1 (fr) Sel de sulfate ibrutinib
WO2016090257A1 (fr) Sels et forme cristallines de 6-acétyl-8-cyclopentyl-5-méthyl-2((5-(pipérazin-1-yl) pyridin-2-yl)amino)pyrido [2,3-d] pyrimidin -7 (8h)-one (palbociclib)
EP3321267A1 (fr) Formes cristallines de sels de 2-[1-éthylsulfonyl-3-[4-(7h-pyrrolo [2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azétidin-3-yl]acétonitrile et leur préparation
WO2018113801A1 (fr) Formes cristallines de 2-[1-éthylsulfonyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azétidin-3-yl]acétonitrile avec de l'acide phosphorique et leur procédé de préparation
WO2017186197A1 (fr) Sels de lenvatinib
EP3063151B1 (fr) Polymorphe stable du sel de (2r)-4-oxo-4-[3-(trifiuorométhyl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)butan-2-amine avec du l-acide tartrique
EP4177257B1 (fr) Succinate de composé octahydrothiénoquinoline et cristaux de celui-ci
WO2016206662A1 (fr) Hémisulfate d'ibrutinib
EP3328848A1 (fr) Formes solides de ceritinib base libre
WO2016169532A1 (fr) Formes cristallines de tramétinib
WO2016157136A1 (fr) Formes cristallines de l'idélalisib
CN108718526B (zh) 尼达尼布盐的结晶变态和其制备方法
US20090137844A1 (en) Crystallization process
TW202340192A (zh) 一種己二酸鹽結晶及其製備方法
TWI592397B (zh) 卡維地洛硫酸鹽的結晶、其製備方法及其在醫藥上的應用
JP2016534047A (ja) テノホビルジソプロキシルの二水素リン酸塩
WO2016198031A1 (fr) Sel de bédaquiline avec acide citrique
CZ27930U1 (cs) Krystalická modifikace 3 L-vínanu (3R)-3-amino-1-[3-(trifluormethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorfenyl)butan-1-onu
CZ27898U1 (cs) Krystalická modifikace 2 L-vínanu (3R)-3-amino-1-[3-(trifluormethyl)-6,8-dihydro-5H-[1,2,4,]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorfenyl)butan-1-onu

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17720657

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17720657

Country of ref document: EP

Kind code of ref document: A1