WO2016139588A1 - Polymorphs of ibrutinib - Google Patents
Polymorphs of ibrutinib Download PDFInfo
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- WO2016139588A1 WO2016139588A1 PCT/IB2016/051164 IB2016051164W WO2016139588A1 WO 2016139588 A1 WO2016139588 A1 WO 2016139588A1 IB 2016051164 W IB2016051164 W IB 2016051164W WO 2016139588 A1 WO2016139588 A1 WO 2016139588A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ibrutinib
- crystalline
- temperature
- alcohol
- suspension
- Prior art date
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- 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 296
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title claims abstract description 162
- 229960001507 ibrutinib Drugs 0.000 title claims abstract description 162
- 238000000034 method Methods 0.000 claims abstract description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 48
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 22
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 22
- 238000001144 powder X-ray diffraction data Methods 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 239000012296 anti-solvent Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 abstract description 27
- 239000000725 suspension Substances 0.000 description 44
- 239000002904 solvent Substances 0.000 description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 150000001875 compounds Chemical class 0.000 description 34
- 238000001035 drying Methods 0.000 description 33
- 239000000203 mixture Substances 0.000 description 31
- 238000001704 evaporation Methods 0.000 description 30
- 230000008020 evaporation Effects 0.000 description 30
- 238000001914 filtration Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000013078 crystal Substances 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 16
- 238000004821 distillation Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000005119 centrifugation Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 238000013537 high throughput screening Methods 0.000 description 13
- 238000010926 purge Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000012453 solvate Substances 0.000 description 11
- UUIQMZJEGPQKFD-UHFFFAOYSA-N Methyl butyrate Chemical compound CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 8
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 8
- 230000005484 gravity Effects 0.000 description 7
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 5
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 5
- 229940093475 2-ethoxyethanol Drugs 0.000 description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 5
- -1 alicyclic hydrocarbons Chemical class 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 5
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 5
- 229940090181 propyl acetate Drugs 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 2
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000002560 therapeutic procedure 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention provides polymorphs of Ibrutinib and process for their preparation.
- the drug compound having the adopted name "Ibrutinib” has a chemical name I- ((H)-3-(4-amino-3-(4 ⁇ henoxyphenyl)-l - ⁇ yrazolo[3,4- ⁇ pyrimidin-l-yl)piperidin-l-yl)prop- 2-en-l-one, and is structurally represented below.
- Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) and is approved in US for the treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy.
- BTK Bruton's tyrosine kinase
- US patent 7,514,444 discloses process for the preparation of Ibrutinib.
- the US '444 discloses isolation of Ibrutinib by flash chromatography using dichloromethane and methanol as eluents.
- WO 2013/184572A1 application discloses crystalline, solvates and amorphous form of Ibrutinib.
- the application discloses polymorphic Forms A, B, C, D, E and F characterized by PXRD, IR, DSC and TGA.
- the WO '572 application discloses process for the preparation of amorphous form of Ibrutinib by dissolving Form A in dichloromethane. The solvent dichloromethane was removed under rotary evaporation to provide amorphous Ibrutinib.
- CN103694241 A discloses crystal form A of Ibrutinib characterized by PXRD.
- CN103923084A discloses crystal forms II, III, IV, V, VI, VII and VIII of Ibrutinib, characterized by PXRD pattern.
- WO 2015/145415A2 application discloses various solid forms of Ibrutinib designated as Form III, Form IV, Form V, Form VI, Form VII, Form VIII and Form IX.
- WO 2016/022942A1 application discloses solid dispersions of ibrutinib.
- WO 2016/025720A1 application discloses crystalline forms of Ibrutinib designated as Form G, Form J and Form K.
- the present invention provides crystalline forms of Ibrutinib designated as Form D1 , Form D1 a, Form D2, Form D2a, Form D3, Form D4, Form D5, Form D6, Form D7, Form D8, Form D9, Form D10, Form D1 1 , Form D12 and Form D13 and processes for their preparation.
- Figure 1 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D1 as obtained in example 1 .
- Figure 2 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D1 as obtained in example 2.
- Figure 3 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D2 as obtained in example 3.
- Figure 4 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D2 as obtained in example 4.
- Figure 5 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D2a.
- Figure 6 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D3 as obtained in example 8.
- Figure 7 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D4 as obtained in example 9.
- Figure 8 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D5 as obtained in example 10.
- Figure 9 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D6 as obtained in example 1 1 .
- Figure 10 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D7 as obtained in example 12.
- Figure 1 1 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D8 as obtained in example 13.
- Figure 13 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D10 as obtained in example 18.
- Figure 14 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D1 1 as obtained in example 19.
- the present invention provides crystalline Ibrutinib, designated as Form D1 , characterized by an x-ray powder diffraction pattern having peaks at about 10.1 1 , 1 1 .45, 18.47 and 20.89 ⁇ 0.20 degrees 2-theta, and also having peaks at about 5.04, 10.79, 23.10 and 26.60 ⁇ 0.20 degrees 2-theta.
- the present invention encompasses a process for preparing crystalline Form D1 of Ibrutinib, comprising the steps of: a) suspending ibrutinib in an alcohol at 10 °C to -40 °C; b) maintaining the suspension at 10 °C to -40 °C; and c) isolating at -10 °C to 10 °C.
- the alcohol that may be used in step a) is selected from a CMO alcohol; preferably a C1-5 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, iso- butanol, pentanol or the like.
- the alcohol used is ethanol.
- Step b) involves maintaining the suspension at a temperature of 10 °C to -40 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D1 .
- Step c) involves isolating the crystalline ibrutinib Form D1 .
- the crystalline ibrutinib Form D1 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D1 may be isolated by evaporation under vacuum and at a temperature of about -10 °C to 10 °C. In a more preferred embodiment, the evaporation is carried out at -2 °C to 10 °C.
- Step d) involves isolating the crystalline Form D1 a of Ibrutinib.
- the crystalline Form D1 a may be isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline Form D1 a is isolated by filtration under vacuum and at a temperature of about 0 °C to 30 °C.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D1 , comprising the steps of: a) obtaining a solution of ibrutinib in an alcohol; b) combining the solution of step a) with an anti-solvent; and c) isolating crystalline form D1 of Ibrutinib.
- Step b) involves combining the solution of step a) with an anti-solvent.
- step b) may involve adding anti-solvent to the ibrutinib solution or conversely, adding ibrutinib solution to the anti-solvent at a temperature of about 0°C to 15 °C and more specifically at about 2 °C to 10 °C.
- the anti-solvent is pre-cooled to 2 °C to 10 °C before mixing with the Ibrutinib solution.
- the anti-solvent used is water.
- the seed crystals of Ibrutinib Form D1 are optionally added to the mixture of anti-solvent and ibrutinib solution.
- the seed crystals can also be added either to the anti-solvent solution or to the ibrutinib solution.
- the seed crystals are added, they are added in a quantity from about 0.5 % w/w to about 15% w/w over the weight of ibrutinib.
- the seed crystals are added in a quantity from about 1 % to about 12% w/w and more specifically the seed crystals are added in a quantity from about 2 % to about 10% w/w.
- the mixture is stirred for about 30 minutes to about 24 hours or longer at the same temperature or at a temperature of about -5 °C to about 10 °C.
- step c) the isolation of ibrutinib crystalline form D1 may optionally proceed through the intermediacy of crystalline Form D1 a of Ibrutinib.
- Isolating crystalline form D1 a of Ibrutinib may optionally involve one or more methods known in the art including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of isolated solid and the like.
- Suitable temperatures for isolation may be less than about 25 °C, less than about 10 °C, less than about 0 °C or any other suitable temperatures. Filtration can be achieved by any means known in the art.
- the solid obtained may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
- the collected material is dried and drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically less than about 40 °C.
- the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
- the obtained Ibrutinib crystalline form D1 may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions by using techniques known in the art.
- the present invention provides crystalline Ibrutinib, designated as Form D2, characterized by an x-ray powder diffraction pattern having peaks at about 1 1 .44, 12.51 and 26.64 ⁇ 0.20 degrees 2-theta, and also having peaks at about 5.00, 10.20, 20.87 and 23.15 ⁇ 0.20 degrees 2-theta.
- the present invention provides crystalline Ibrutinib, designated as Form D2, characterized by an x-ray powder diffraction pattern having peaks located substantially as illustrated in the pattern of Figure 3 or Figure 4.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D2, comprising the steps of: a) suspending ibrutinib in a mixture of an alcohol and water at 10 °C to -40 °C; b) maintaining the suspension at 10 °C to -40 °C; c) isolating at -15 °C to - 5 °C, and d) drying at -5 °C to 5 °C.
- Suspending ibrutinib in step a) involves adding alcohol and water to ibrutinib at 20 °C to -40 °C.
- the ratio of alcohol and water may vary from about 60:40 to 95:5 by volume. In a preferred embodiment, the ratio is 80:20 by volume.
- Ibrutinib used in step a) may be obtained by process known in the art. In a preferred embodiment, amorphous ibrutinib is used.
- the alcohol that may be used in step a) is selected from C M 0 alcohol; preferably a Ci- 5 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, pentanol or the like.
- the alcohol used is ethanol.
- Suspending ibrutinib in step a) involves combining ibrutinib with ethanol and water at a temperature of 10 °C to -40 °C.
- Step b) involves maintaining the suspension at a temperature of 10 °C to -40 °C.
- Step c) involves isolating the crystalline ibrutinib Form D2a.
- the crystalline ibrutinib Form D2a is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- Step d) involves drying the crystalline Ibrutinib Form D2a at a temperature of about -5 °C to 5 °C to obtain Form D2.
- the crystalline Ibrutinib Form D2a characterized by PXRD pattern substantially as shown in figure 5.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D1 , comprising the steps of: a) suspending ibrutinib in a mixture of an alcohol and water at 10 °C to -40 °C; b) maintaining the suspension at 10 °C to -40 °C; c) isolating at -10 °C to 10 °C; and d) drying at 25 °C to 60 °C.
- Suspending ibrutinib in step a) involves adding alcohol and water to ibrutinib at 10 °C to -40 °C.
- the ratio of alcohol and water may vary from about 60:40 to 95:5 by volume. In a preferred embodiment, the ratio is 80:20 by volume.
- Ibrutinib used in step a) may be obtained by process known in the art. In a preferred embodiment, amorphous ibrutinib is used.
- the alcohol that may be used in step a) is selected from CM 0 alcohol; preferably a C-1-5 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, pentanol or the like.
- the alcohol used is ethanol.
- Suspending ibrutinib in step a) involves combining ibrutinib with ethanol and water at a temperature of 10 °C to -40 °C.
- Step b) involves maintaining the suspension at a temperature of 10 °C to -40 °C.
- Step c) involves isolating the crystalline Form D2 of Ibrutinib.
- the crystalline Form D2 may be isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- compound is isolated by evaporation under vacuum and at a temperature of about -10 °C to 10 °C.
- Step d) involves drying the crystalline ibrutinib Form D2 at 25 °C to 60 °C to obtain crystalline ibrutinib Form D1 .
- Drying in step d) may be suitably carried out using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor ® , air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or under reduced pressure.
- the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C.
- the drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
- the present invention provides crystalline Ibrutinib, designated as Form D3, characterized by an x-ray powder diffraction pattern having peaks at about 8.05, 8.77, 15.44, 21 .80, 24.84, 27.65 and 29.10 ⁇ 0.20 degrees 2-theta, and also having peaks at about 7.56, 13.07, 15.15, 16.59, 18.89 and 21.27 ⁇ 0.20 degrees 2- theta.
- Ibrutinib Form D3 may be further characterized by x-ray powder diffraction pattern having additional peaks at about 10.17, 17.58, 18.36, 19.53, 20.42, 21 .00, 22.54 and 24.31 ⁇ 0.20 degrees 2-theta.
- Ibrutinib Form D3 characterized by x-ray powder diffraction pattern substantially as depicted in figure 6.
- ibrutinib Form D3 is acetophenone solvate.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D3, comprising the steps of: a) suspending ibrutinib in acetophenone at about 0 °C to -25 °C; b) maintaining the suspension at about 0 °C to -25 °C; and c) isolating at 25-30 °C.
- ibrutinib form D4 is formamide solvate.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D4, comprising the steps of: a) suspending ibrutinib in formamide at about 10 °C to about -10 °C; b) maintaining the suspension at about 10 °C to about -10 °C; and c) isolating at 0 °C to -5 °C.
- the present invention provides crystalline Ibrutinib, designated as Form D5, characterized by an x-ray powder diffraction pattern having peaks at about 6.50, 9.63, 10.45, 12.41 , 13.02, 14.28, 19.94, 23.88, 25.93, 27.44 and 28.85 ⁇ 0.20 degrees 2-theta, and also having peaks at about 17.64, 18.37, 21 .00, 23.31 and 25.23 ⁇ 0.20 degrees 2-theta.
- Ibrutinib Form D5 may be further characterized by x-ray powder diffraction pattern having additional peaks at about 10.01 and 19.33 ⁇ 0.20 degrees 2- theta.
- Ibrutinib Form D5 characterized by x-ray powder diffraction pattern substantially as depicted in figure 8.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D5, comprising the steps of: a) suspending ibrutinib in acetone at about 20 °C to 30 °C; b) maintaining the suspension at about 20 °C to 30 °C; and c) isolating at 20 °C to 30 °C.
- Step c) involves isolating the crystalline ibrutinib Form D5.
- the crystalline ibrutinib Form D5 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D5 may be isolated by evaporation followed by nitrogen purging at a temperature of about 20 to 25 °C. In a more preferred embodiment, the evaporation is at 25 °C.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D6, comprising the steps of: a) suspending ibrutinib in chlorobenzene at about 20 °C to about -40 °C; b) maintaining the suspension at about 20 °C to about -40 °C; and c) isolating at about -10 °C to about 20 °C.
- Suspending ibrutinib in step a) involves combining ibrutinib with chlorobenzene at a temperature of about 20 °C to about -25 °C.
- Ibrutinib used in step a) may be obtained by process known in the art.
- Form C of ibrutinib disclosed in WO2013184572 is used.
- Step b) involves maintaining the suspension at a temperature of 20 °C to -25 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D6.
- Step c) involves isolating the crystalline ibrutinib Form D6.
- the crystalline ibrutinib Form D6 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D6 may be isolated by evaporation followed by nitrogen purging at a temperature of about - 10 °C to 20 °C. In a more preferred embodiment, the evaporation is at 0 °C.
- the present invention provides crystalline Ibrutinib, designated as Form D7, characterized by an x-ray powder diffraction pattern having peaks at about 8.83, 9.37, 9.92, 10.87, 1 1 .40, 18.48, 19.92, 21 .83, 23.71 and 25.29 ⁇ 0.20 degrees 2- theta, and also having peaks at about 6.40, 16.60, 17.43, 17.67, 19.17, and 24.26 ⁇ 0.20 degrees 2-theta.
- Ibrutinib Form D7 may be further characterized by x-ray powder diffraction having additional peaks at about 13.37, 13.73, 15.93, 22.51 and 22.99 ⁇ 0.20 degrees 2-theta.
- Ibrutinib Form D7 characterized by x-ray powder diffraction pattern substantially as depicted in figure 10.
- Ibrutinib form D7 is dimethylacetamide solvate.
- Step c) involves isolating the crystalline ibrutinib Form D7.
- the crystalline ibrutinib Form D7 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D7 may be isolated by evaporation followed by nitrogen purging at a temperature of about - 10°C to 20 °C. In a more preferred embodiment, the evaporation is at 0-5 °C.
- the present invention provides crystalline Ibrutinib, designated as Form D8, characterized by an x-ray powder diffraction pattern having peaks at about 9.27, 9.69, 10.97, 14.24, 24.83, 25.83, 28.21 and 28.79 ⁇ 0.20 degrees 2-theta, and also having peaks at about 5.03, 7.13, 13.23, 16.00, 17.26, 17.59 21 .60 and 22.75 ⁇ 0.20 degrees 2-theta.
- Ibrutinib Form D8 may be further characterized by x-ray powder diffraction having additional peaks at about 10.17, 18.51 , 19.56, 20.47 and 22.07 ⁇ 0.20 degrees 2-theta.
- Ibrutinib Form D8 characterized by x-ray powder diffraction pattern substantially as depicted in Figure 1 1.
- Ibrutinib form D8 is acetone solvate.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D8, comprising the steps of: a) suspending ibrutinib in acetone at about 20 °C to about -40 °C; b) maintaining at about 20 °C to about -40 °C; and c) isolating at -10 °C to 10 °C.
- Suspending ibrutinib in step a) involves combining ibrutinib with acetone at a temperature of about 20 °C to about -40 °C.
- Ibrutinib used in step a) may be obtained by process known in the art.
- Form C of ibrutinib disclosed in WO2013184572 is used.
- Step b) involves maintaining the suspension at a temperature of about 20 °C to about -40 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D8.
- Step c) involves isolating the crystalline ibrutinib Form D8.
- the crystalline ibrutinib Form D8 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D8 may be isolated by evaporation followed by nitrogen purging at a temperature of about - 10°C to 10 °C. In a more preferred embodiment, the evaporation is at about 0-5 °C.
- the present invention provides crystalline Ibrutinib, designated as Form D9, characterized by an x-ray powder diffraction pattern having peaks at about 7.71 , 12.61 , 13.14, 22.69 and 23.65 ⁇ 0.20 degrees 2 ⁇ ; with peaks at about 8.04, 19.07, 20.20 and 31 .79 ⁇ 0.20 degrees 2 ⁇ .
- Crystalline Ibrutinib Form D9 is further characterized by peaks at about 18.63, 20.81 and 21 .51 ⁇ 0.20 degrees 2 ⁇ .
- the present invention provides crystalline Ibrutinib, designated as Form D9, characterized by an x-ray powder diffraction pattern having peaks located substantially as illustrated in the pattern of Figure 12.
- the solvent or mixture of solvents that may be used in step a) is selected from a C-1-10 alcohol; preferably a C1-5 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, pentanol or the like; ethers such as diethyl ether, diisopropyl ether, i-butyl methyl ether, di-butyl ether, tetrahydrofuran, 1 , 2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1 , 4-dioxane or the like; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, dimethyl carbonate or the like; alipha
- Step b) involves maintaining the suspension at a temperature of 20 °C to 70 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D9.
- Step c) involves isolating the crystalline ibrutinib Form D9.
- the crystalline ibrutinib Form D9 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D9 may be isolated by filtration under vacuum and at a temperature of about 20 °C to 70 °C.
- the present invention provides crystalline Ibrutinib, designated as Form D10, characterized by an x-ray powder diffraction pattern having peaks at about 6.62, 10.57, 13.30, 17.17, 19.97, 21 .27, 25.07 and 29.59 ⁇ 0.20 degrees 2 ⁇ ; with peaks at about 10.19, 15.32, 18.09, 18.80, 21 .95, 26.35 and 26.85 ⁇ 0.20 degrees 2 ⁇ .
- Crystalline Ibrutinib Form D10 is further characterized by peaks at about 9.68, 19.28 and 28.08 ⁇ 0.20 degrees 2 ⁇ .
- the present invention provides crystalline Ibrutinib, designated as Form D10, characterized by an x-ray powder diffraction pattern having peaks located substantially as illustrated in the pattern of Figure 13.
- Ibrutinib form D10 is a 1 , 2-dimethoxyethane solvate.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D10, comprising the steps of: a) suspending ibrutinib in a solvent or mixture of solvents at 2 °C to 25 °C; b) maintaining the suspension at 2 °C to 25 °C; c) isolating at 2 °C to 25 °C.
- Obtaining the suspension of ibrutinib in step a) involves adding a solvent or mixture of solvents at 2 °C to 25 °C.
- Ibrutinib used in step a) may be obtained by process known in the art.
- the solvent or mixture of solvents that may be used in step a) is selected from a Ci-io alcohol; preferably a C 1 -5 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, pentanol or the like; ethers such as diethyl ether, diisopropyl ether, i-butyl methyl ether, di-butyl ether, tetrahydrofuran, 1 , 2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1 ,4-dioxane or the like; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, dimethyl carbonate or the like;
- Step b) involves maintaining the suspension at a temperature of 2 °C to 25 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D10.
- Step c) involves isolating the crystalline ibrutinib Form D10.
- the crystalline ibrutinib Form D10 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D10 may be isolated by filtration under vacuum and at a temperature of about 2 °C to 25 °C.
- Crystalline Form D10 obtained in step c) may be optionally dried using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor ® , air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or under reduced pressure.
- the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C.
- the drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
- the present invention provides crystalline Ibrutinib, designated as Form D1 1 , characterized by an x-ray powder diffraction pattern having peaks at about 6.49, 9.60, 10.44, 12.99, 14.28, 18.23, 19.94, 23.85, 25.99, 27.39 and 28.85 ⁇ 0.20 degrees 2 ⁇ ; with peaks at about 12.46, 20.97, 23.34 and 25.13 ⁇ 0.20 degrees 2 ⁇ .
- the present invention provides crystalline Ibrutinib, designated as Form D1 1 , characterized by an x-ray powder diffraction pattern having peaks located substantially as illustrated in the pattern of Figure 14.
- Ibrutinib form D1 1 is an anisole solvate.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D1 1 , comprising the steps of: a) suspending ibrutinib in a solvent or mixture of solvents at 2 °C to 25 °C; b) maintaining the suspension at 2 °C to 25 °C; c) isolating at 2 °C to 25 °C.
- Obtaining the suspension of ibrutinib in step a) involves adding a solvent or mixture of solvents at 2 °C to 25 °C.
- Ibrutinib used in step a) may be obtained by process known in the art.
- the solvent or mixture of solvents that may be used in step a) is selected from a C-1-10 alcohol; preferably a C1-5 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, pentanol or the like; ethers such as diethyl ether, diisopropyl ether, i-butyl methyl ether, di-butyl ether, tetrahydrofuran, 1 , 2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1 ,4-dioxane or the like; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, dimethyl carbonate or the like; ali
- Step b) involves maintaining the suspension at a temperature of 2 °C to 20 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D1 1 .
- Crystalline Form D1 1 obtained in step c) may be optionally dried using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor ® , air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or under reduced pressure.
- the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C.
- the drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
- the present invention provides crystalline Ibrutinib, designated as Form D12, characterized by an x-ray powder diffraction pattern having peaks at about 9.79, 12.95, 14.08, 19.84, 21 .82, 22.48, 23.71 , 25.55 and 26.92 ⁇ 0.20 degrees 2 ⁇ ; with peaks at about 6.46, 10.24, 15.97, 17.65 and 24.71 ⁇ 0.20 degrees 2 ⁇ .
- Crystalline Ibrutinib Form D12 is further characterized by peaks at about 18.17 and 20.60 ⁇ 0.20 degrees 2 ⁇ .
- the present invention provides crystalline Ibrutinib, designated as Form D12, characterized by an x-ray powder diffraction pattern having peaks located substantially as illustrated in the pattern of Figure 15.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D12, comprising the steps of: a) suspending ibrutinib in a solvent or mixture of solvents at 2 °C to 25 °C; b) maintaining the suspension at 2 °C to 25 °C; c) isolating at 2 °C to 25 °C.
- Obtaining the suspension of ibrutinib in step a) involves adding a solvent or mixture of solvents at 2 °C to 25 °C.
- Ibrutinib used in step a) may be obtained by process known in the art.
- the solvent or mixture of solvents that may be used in step a) is selected from a C-1-10 alcohol; preferably a C1-5 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, pentanol or the like; ethers such as diethyl ether, diisopropyl ether, i-butyl methyl ether, di-butyl ether, tetrahydrofuran, 1 , 2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1 ,4-dioxane or the like; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, dimethyl carbonate or the like; ali
- Step b) involves maintaining the suspension at a temperature of 2 °C to 25 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D12.
- Step c) involves isolating the crystalline ibrutinib Form D12.
- the crystalline ibrutinib Form D12 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D12 may be isolated by filtration under vacuum and at a temperature of about 2 °C to 25 °C.
- Crystalline Form D12 obtained in step c) may be optionally dried using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor ® , air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or under reduced pressure.
- the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C.
- the drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
- the present invention provides crystalline Ibrutinib, designated as Form D13, characterized by an x-ray powder diffraction pattern having peaks located substantially as illustrated in the pattern of Figure 16.
- the present invention encompasses a process for preparing crystalline ibrutinib Form D13, comprising the steps of: a) suspending ibrutinib in a solvent or mixture of solvents at 2 °C to 25 °C; b) maintaining the suspension at 2 °C to 25 °C; c) isolating at 2 °C to 25 °C.
- Obtaining the suspension of ibrutinib in step a) involves adding a solvent or mixture of solvents at 2 °C to 25 °C.
- Ibrutinib used in step a) may be obtained by process known in the art.
- Step b) involves maintaining the suspension at a temperature of 2 °C to 25 °C. The suspension is maintained for sufficient time to ensure the formation of crystalline ibrutinib Form D13.
- Step c) involves isolating the crystalline ibrutinib Form D13.
- the crystalline ibrutinib Form D13 is isolated by techniques such as filtration, distillation, centrifugation, or slow evaporation or the like.
- crystalline ibrutinib Form D13 may be isolated by filtration under vacuum and at a temperature of about 2 °C to 25 °C.
- Crystalline Form D13 obtained in step c) may be optionally dried using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor ® , air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or under reduced pressure.
- the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C.
- the drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
- the present invention provides pharmaceutical composition comprising crystalline form of ibrutinib designated as Form D1 , Form D1 a, Form D2, Form D2a, Form D3, Form D4, Form D5, Form D6, Form D7, Form D8, Form D9, Form D10, Form D1 1 , Form D12 and Form D13 and at least one pharmaceutically acceptable excipient.
- compositions include, but are not limited to, suitable surface modifiers.
- excipients include various polymers, low molecular weight oligomers, natural products, and surfactants.
- the crystalline forms of ibrutinib designated as Form D1 , Form D1 a, Form D2, Form D2a, Form D3, Form D4, Form D5, Form D6, Form D7, Form D8, Form D9, Form D10, Form D1 1 , Form D12 and Form D13 of the present invention have advantageous properties selected from at least one: chemical purity, stability - such as storage stability, stability to dehydrate, stability to polymorphic conversion, flowability, solubility, morphology or crystal habit, low hygroscopicity and low content of residual solvents.
- X-ray diffraction was measured using PANalytical X-ray diffractometer, Model: X'Pert PRO.
- Scan type Continuous; Detector - X'Celerator; Measurement parameters: Start Position [°2Th.]: 3; End Position [°2Th.]: 40; Step Size [°2Th.]:0.0170; Scan Step Time [s]: 170.1800.
- the crystal Form D1 is characterized by PXRD given in figure 1 .
- Example 2 Preparation of crystalline ibrutinib Form D1
- the crystal Form D1 is characterized by PXRD given in figure 2.
- the crystal Form D2 is characterized by PXRD given in figure 4.
- ibrutinib 80 mg was taken into the well of high throughput screening instrument at 25- 30 °C and cooled to -25 °C. 0.25 mL of ethanol-water mixture (90:10) was added to the above well -25°C. The contents were vortexed at -25 °C for 13 hours. The compound was dried under vacuum followed by nitrogen purging at 0 °C to obtain the title compound.
- ibrutinib 80 mg was taken into the well of high throughput screening instrument at 25- 30 °C and cooled to -25 °C. 0.25 mL of ethanol-water mixture (85:15) was added to the above well at -25 °C. The contents were vortexed at -25 °C for 13 hours. The compound was dried under vacuum followed by nitrogen purging at 0 °C to obtain the title compound.
- the crystal Form D4 is characterized by PXRD given in figure 7.
- ibrutinib 50 mg was taken into the well of high throughput screening instrument at 25- 30 °C and cooled to -25 °C. 0.25 ml_ of chlorobenzene was added to the above well at - 25 °C. The contents were vortexed at -25 °C for 13 hours. The compound was dried under vacuum followed by nitrogen purging at 0 °C to obtain the title compound.
- the crystal Form D6 is characterized by PXRD given in figure 9.
- 30.0 g of ibrutinib was taken in 990 ml_ of methanol in a flask and heated to 50-60°C to form a solution.
- the solution was added to a reactor charged with 1200 ml_ of demineralized water and 3.0 g of seed material of Form D1 , maintained at a temperature of about 2-5°C. After the completion of the addition, the contents of the reactor were maintained at 0-5°C for 15-20 hours.
- the reaction mass was filtered in a pre-cooled ANFD (Jacket temperature: 0°C to 5°C) under mild nitrogen pressure with simultaneous high vacuum. The material was dried in vacuum tray dryer at 25-30° C for 8-9 hours to obtain the title compound.
Abstract
Description
Claims
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RU2017133663A RU2017133663A (en) | 2015-03-03 | 2016-03-02 | POLYMORPHES OF IBRUTINIBE |
US15/553,559 US20180051026A1 (en) | 2015-03-03 | 2016-03-02 | Polymorphs of ibrutinib |
CN201680025850.4A CN107530345A (en) | 2015-03-03 | 2016-03-02 | The polymorph of Buddhist nun is replaced according to Shandong |
JP2017546659A JP2018511580A (en) | 2015-03-03 | 2016-03-02 | Ibrutinib polymorph |
EP16758531.4A EP3265092A4 (en) | 2015-03-03 | 2016-03-02 | Polymorphs of ibrutinib |
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2016
- 2016-03-02 EP EP16758531.4A patent/EP3265092A4/en not_active Withdrawn
- 2016-03-02 CN CN201680025850.4A patent/CN107530345A/en active Pending
- 2016-03-02 US US15/553,559 patent/US20180051026A1/en not_active Abandoned
- 2016-03-02 WO PCT/IB2016/051164 patent/WO2016139588A1/en active Application Filing
- 2016-03-02 JP JP2017546659A patent/JP2018511580A/en active Pending
- 2016-03-02 RU RU2017133663A patent/RU2017133663A/en unknown
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US9828383B1 (en) | 2012-06-04 | 2017-11-28 | Pharmacyclic s LLC | Crystalline forms of a bruton's tyrosine kinase inhibitor |
US10294231B2 (en) | 2012-06-04 | 2019-05-21 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
US10961251B1 (en) | 2012-06-04 | 2021-03-30 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
US10065968B2 (en) | 2012-06-04 | 2018-09-04 | Pharmacyclics Llc | Crystalline forms of a bruton's tyrosine kinase inhibitor |
US10752634B2 (en) | 2012-06-04 | 2020-08-25 | Pharmacyclics Llc | Crystalline forms of a brutons tyrosine kinase inhibitor |
US10125140B1 (en) | 2012-06-04 | 2018-11-13 | Pharmacyclics Llc | Crystalline forms of a bruton's tyrosine kinase inhibitor |
US10294232B2 (en) | 2012-06-04 | 2019-05-21 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
US10106548B2 (en) | 2012-06-04 | 2018-10-23 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
US10266540B2 (en) | 2012-06-04 | 2019-04-23 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
US20180028537A1 (en) | 2014-08-07 | 2018-02-01 | Pharmacyclics Llc | Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor |
US10213386B2 (en) | 2015-03-03 | 2019-02-26 | Pharmacyclics Llc | Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor |
US10010507B1 (en) | 2015-03-03 | 2018-07-03 | Pharmacyclics Llc | Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor |
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EP3337485A4 (en) * | 2015-08-19 | 2019-01-09 | Sun Pharmaceutical Industries Ltd | Crystalline forms of ibrutinib |
US11001585B2 (en) | 2015-08-19 | 2021-05-11 | Sun Pharmaceutical Industries Limited | Crystalline forms of ibrutinib |
US10183024B2 (en) | 2016-12-02 | 2019-01-22 | Apotex Inc. | Crystalline forms of ibrutinib |
EP3501609A1 (en) | 2017-12-08 | 2019-06-26 | Zentiva K.S. | Pharmaceutical compositions comprising ibrutinib |
WO2019138326A1 (en) * | 2018-01-09 | 2019-07-18 | Dr. Reddy's Laboratories Limited | Solid forms of ibrutinib |
WO2019211870A1 (en) * | 2018-05-02 | 2019-11-07 | Cipla Limited | Polymorphic forms of ibrutinib |
EP3575300A1 (en) | 2018-05-31 | 2019-12-04 | Apotex Inc. | Novel crystalline forms of ibrutinib |
RU2711106C2 (en) * | 2018-06-06 | 2020-01-15 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Crystalline μ-modification of 1-[(3r)-3-[4-amino-3-(4-phenoxy-phenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-2-propenyl-1-one, method for production thereof and pharmaceutical composition based thereon |
US10688050B1 (en) | 2018-12-21 | 2020-06-23 | Synthon B.V. | Pharmaceutical composition comprising 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 |
WO2023242384A1 (en) | 2022-06-17 | 2023-12-21 | Krka, D.D., Novo Mesto | Crystalline form of ibrutinib |
Also Published As
Publication number | Publication date |
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US20180051026A1 (en) | 2018-02-22 |
RU2017133663A (en) | 2019-04-03 |
EP3265092A4 (en) | 2018-07-18 |
JP2018511580A (en) | 2018-04-26 |
EP3265092A1 (en) | 2018-01-10 |
CN107530345A (en) | 2018-01-02 |
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