WO2017174044A1 - Solid forms of ibrutinib - Google Patents
Solid forms of ibrutinib Download PDFInfo
- 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
Links
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 title claims abstract description 107
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title claims abstract description 100
- 229960001507 ibrutinib Drugs 0.000 title claims abstract description 100
- 239000007787 solid Substances 0.000 title claims abstract description 19
- 239000012458 free base Substances 0.000 claims abstract description 44
- 239000011164 primary particle Substances 0.000 claims abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 20
- 239000000725 suspension Substances 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 abstract description 26
- 239000002245 particle Substances 0.000 abstract description 20
- 239000000243 solution Substances 0.000 description 20
- 239000000843 powder Substances 0.000 description 10
- 238000005259 measurement Methods 0.000 description 7
- 238000001878 scanning electron micrograph Methods 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 229910016523 CuKa Inorganic materials 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 238000001237 Raman spectrum Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000001069 Raman spectroscopy Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZ2016-196A CZ2016196A3 (cs) | 2016-04-06 | 2016-04-06 | Pevné formy Ibrutinibu |
CZPV2016-196 | 2016-04-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017174044A1 true WO2017174044A1 (en) | 2017-10-12 |
Family
ID=58664410
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CZ2017/000019 WO2017174044A1 (en) | 2016-04-06 | 2017-04-03 | Solid forms of ibrutinib |
Country Status (2)
Country | Link |
---|---|
CZ (1) | CZ2016196A3 (cs) |
WO (1) | WO2017174044A1 (cs) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10183024B2 (en) | 2016-12-02 | 2019-01-22 | Apotex Inc. | Crystalline forms of ibrutinib |
WO2019070698A1 (en) | 2017-10-02 | 2019-04-11 | Johnson Matthey Public Limited Company | NEW FORMS OF IBRUTINIB |
EP3501609A1 (en) | 2017-12-08 | 2019-06-26 | Zentiva K.S. | Pharmaceutical compositions comprising ibrutinib |
WO2019195827A1 (en) | 2018-04-06 | 2019-10-10 | Johnson Matthey Public Limited Company | Novel form of ibrutinib |
WO2019211870A1 (en) * | 2018-05-02 | 2019-11-07 | Cipla Limited | Polymorphic forms of ibrutinib |
EP3669867A1 (en) * | 2018-12-21 | 2020-06-24 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
WO2020170270A1 (en) * | 2019-02-19 | 2020-08-27 | Msn Laboratories Private Limited, R&D Center | Novel crystalline polymorphs of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and process for preparation thereof |
US11433072B1 (en) * | 2021-06-10 | 2022-09-06 | Hikma Pharmaceuticals USA, Inc. | Oral dosage forms of ibrutinib |
WO2023242384A1 (en) * | 2022-06-17 | 2023-12-21 | Krka, D.D., Novo Mesto | Crystalline form of ibrutinib |
MA63498A1 (fr) * | 2021-06-10 | 2024-07-31 | Hikma Pharmaceuticals Usa Inc. | Formes posologiques orales d'ibrutinib |
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WO2008039218A2 (en) | 2006-09-22 | 2008-04-03 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2013113841A1 (en) | 2012-02-01 | 2013-08-08 | Euro-Celtique S.A. | Novel therapeutic agents |
WO2013155347A1 (en) | 2012-04-11 | 2013-10-17 | Izumi Raquel | Bruton's tyrosine kinase inhibitors for hematopoietic mobilization |
WO2013184572A1 (en) | 2012-06-04 | 2013-12-12 | Pharmacyclics, Inc. | Crystalline forms of a bruton's tyrosine kinase inhibitor |
WO2014004707A1 (en) | 2012-06-29 | 2014-01-03 | Principia Biopharma Inc. | Formulations comprising 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 |
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WO2016170545A1 (en) * | 2015-04-22 | 2016-10-27 | Msn Laboratories Private Limited | Process for the preparation of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenvl)-1h- pvrazolo[3,4-d]pyriniidin-1-y1]-1-piperidinvl]-2-propen-1-one and its polymorphs thereof |
-
2016
- 2016-04-06 CZ CZ2016-196A patent/CZ2016196A3/cs unknown
-
2017
- 2017-04-03 WO PCT/CZ2017/000019 patent/WO2017174044A1/en active Application Filing
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2008039218A2 (en) | 2006-09-22 | 2008-04-03 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2013113841A1 (en) | 2012-02-01 | 2013-08-08 | Euro-Celtique S.A. | Novel therapeutic agents |
WO2013155347A1 (en) | 2012-04-11 | 2013-10-17 | Izumi Raquel | Bruton's tyrosine kinase inhibitors for hematopoietic mobilization |
WO2013184572A1 (en) | 2012-06-04 | 2013-12-12 | Pharmacyclics, Inc. | Crystalline forms of a bruton's tyrosine kinase inhibitor |
WO2014004707A1 (en) | 2012-06-29 | 2014-01-03 | Principia Biopharma Inc. | Formulations comprising 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 (en) | 2014-03-27 | 2015-10-01 | Perrigo Api Ltd. | Ibrutinib solid forms and production process therefor |
WO2016170545A1 (en) * | 2015-04-22 | 2016-10-27 | Msn Laboratories Private Limited | Process for the preparation of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenvl)-1h- pvrazolo[3,4-d]pyriniidin-1-y1]-1-piperidinvl]-2-propen-1-one and its polymorphs thereof |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10183024B2 (en) | 2016-12-02 | 2019-01-22 | Apotex Inc. | Crystalline forms of ibrutinib |
WO2019070698A1 (en) | 2017-10-02 | 2019-04-11 | Johnson Matthey Public Limited Company | NEW FORMS OF IBRUTINIB |
EP3501609A1 (en) | 2017-12-08 | 2019-06-26 | Zentiva K.S. | Pharmaceutical compositions comprising ibrutinib |
WO2019195827A1 (en) | 2018-04-06 | 2019-10-10 | Johnson Matthey Public Limited Company | Novel form of ibrutinib |
WO2019211870A1 (en) * | 2018-05-02 | 2019-11-07 | Cipla Limited | Polymorphic forms of ibrutinib |
EP3669867A1 (en) * | 2018-12-21 | 2020-06-24 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
WO2020127912A1 (en) * | 2018-12-21 | 2020-06-25 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
WO2020170270A1 (en) * | 2019-02-19 | 2020-08-27 | Msn Laboratories Private Limited, R&D Center | Novel crystalline polymorphs of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and process for preparation thereof |
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 (en) * | 2022-06-17 | 2023-12-21 | Krka, D.D., Novo Mesto | Crystalline form of ibrutinib |
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