CN115397426A - Ibutotinib glucolactone eutectic and preparation method thereof - Google Patents
Ibutotinib glucolactone eutectic and preparation method thereof Download PDFInfo
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- CN115397426A CN115397426A CN202080099799.8A CN202080099799A CN115397426A CN 115397426 A CN115397426 A CN 115397426A CN 202080099799 A CN202080099799 A CN 202080099799A CN 115397426 A CN115397426 A CN 115397426A
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- Prior art keywords
- gluconolactone
- ibutinib
- eutectic
- cocrystal
- butyl ether
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- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 title claims abstract description 83
- 230000005496 eutectics Effects 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 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 claims abstract description 51
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims abstract description 36
- 229960001507 ibrutinib Drugs 0.000 claims abstract description 36
- 239000003513 alkali Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 11
- 235000012209 glucono delta-lactone Nutrition 0.000 claims description 56
- 229960003681 gluconolactone Drugs 0.000 claims description 56
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 239000013078 crystal Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 claims description 11
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 claims description 11
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 9
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 6
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
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- 208000017760 chronic graft versus host disease Diseases 0.000 claims description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
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- -1 methyl isobutyl ketone compound Chemical class 0.000 description 3
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
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- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
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- 239000001530 fumaric acid Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-PZFLKRBQSA-N 4-amino-3,5-ditritiobenzoic acid Chemical compound [3H]c1cc(cc([3H])c1N)C(O)=O ALYNCZNDIQEVRV-PZFLKRBQSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- SBNKFTQSBPKMBZ-UHFFFAOYSA-N ethenzamide Chemical compound CCOC1=CC=CC=C1C(N)=O SBNKFTQSBPKMBZ-UHFFFAOYSA-N 0.000 description 1
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- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- 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
-
- 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
Abstract
The ibutinib glucolactone cocrystal has stability not inferior to that of ibutinib free alkali and is pharmaceutically acceptable. The eutectic powder is more beneficial to sieving, the loss is small, the yield is high, and the static is not obvious. The bulk density and the tap density of the eutectic are not greatly different from those of ibrutinib free alkali, but the angle of repose is obviously different, and the fluidity of the eutectic is obviously better than that of the ibrutinib free alkali. And the eutectic is the main drug, and the prescription has the best mixing uniformity, thereby meeting the production requirements of the preparation.
Description
The invention relates to the field of crystal forms, and particularly relates to an ibutinib glucolactone eutectic and a preparation method thereof.
Ibutinib was first developed by Celera Genomics, usa in 2007, and later was assigned to Pharmacyclics, california, a subsidiary of qiangsheng, yang pharmaceutical (Jassen), 2011. The drug has been approved by the FDA in 11 months of 2013 for the treatment of Mantle Cell Lymphoma (MCL) patients who have previously received at least one treatment with lenalidomide or other drug. Ibrutinib is the first once daily, single formulation, oral Bruton's Tyrosine Kinase (BTK) inhibitor. Currently, the approved indications for ibrutinib include: (1) recurrent Mantle Cell Lymphoma (MCL); (2) recurrent Chronic Lymphoid Leukemia (CLL); (3) 17p deficiency chronic lymphoid leukemia; (4) waldenstrom Macroglobulinemia (WM); (5) recurrent Marginal Zone Lymphoma (MZL) (6) chronic graft versus host disease (cGVHD).
Ibrutinib is a Bruton's Tyrosine Kinase (BTK) small molecule inhibitor that forms a covalent bond with a cysteine residue of the BTK active site, resulting in inhibition of BTK enzyme activity. BTK is a signaling molecule for the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK acts by signaling B-cell surface receptors, activating pathways required for B-cell trafficking, chemotaxis and adhesion. Non-clinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and in vivo survival, while also inhibiting in vitro cell migration and substrate adhesion. Patients with recurrent B-cell lymphoma were administered ibutinib at a dose of 2.5mg/kg/day or more (a daily average human dose of over 175mg/day based on 70 kg of average human body weight), and more than 90% of the BTK active sites were observed to be occupied by peripheral blood mononuclear cells after 24 hours.
The chemical name of ibrutinib is: 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one, having the formula II:
the molecular structure of ibrutinib was first reported in patent document WO2008039218.
Three crystalline forms a, B and C of the free base are reported in patent WO2013184572, together with various solvates: ibutinib methyl isobutyl ketone compound (D), ibutinib toluene compound (E) and ibutinib methanol compound (F). The existing ibrutinib capsules adopt active ingredients with the crystal form A as raw material medicaments, but the crystal form A has the defects of large static electricity and poor liquidity in the preparation process, causes adverse effects on the production process of the preparation and the safety of personnel, and has potential safety hazards.
In patents WO2016160604, WO2016156127, co-crystals of ibrutinib with different organic acids are reported, including: benzoic acid, succinic acid, 3-hydroxybenzoic acid, nicotinamide, 4-aminobenzoic acid, salicylic acid, sorbic acid, fumaric acid, salicylamide, trans-cinnamic acid, 4-hydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, sulfamic acid, 1, 5-dinaphthalenesulfonic acid, 2-ethoxybenzamide, 4-aminosalicylic acid, stearic acid, fumaric acid, and succinic acid.
Patents WO2016050422, WO2016206662 and WO2016207172 report cocrystals of ibrutinib with mineral acids including: hydrochloric acid and sulfuric acid.
The eutectic compound formed by the ibrutinib, the organic acid and the inorganic acid does not overcome the defects of large static electricity and poor fluidity. Therefore, the provision of a new and stable ibutinib organic acid co-crystal has important practical significance.
Disclosure of Invention
In view of the above, the invention provides an ibutinib gluconolactone eutectic and a preparation method thereof. The ibutinib glucolactone eutectic powder is more beneficial to sieving, and has the advantages of small loss, high yield and unobvious static electricity. By adopting the same prescription and the same mixing process, the prescription using the ibutinib glucolactone eutectic as the main drug has the best mixing uniformity, and meets the production requirements of the preparation. Ibutinib free base is difficult to mix uniformly.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an ibrutinib gluconolactone eutectic, which has a structure shown in a formula I and exists in an anhydrous and solvent-free form;
which exhibits at least 3 of the following high intensity peaks as 2 theta values in any combination in an X-ray powder diffraction pattern recorded with Cu-ka radiation at 25 ℃:5.807 ° (± 0.1 °), 16.445 ° (± 0.1 °), 21.459 ° (± 0.1 °), 23.998 ° (± 0.1 °), or 26.769 ° (± 0.1 °).
In some embodiments of the invention, it exhibits at least 3 characteristic peaks in any combination as 2 θ values in an X-ray powder diffraction pattern recorded with Cu-ka radiation at 25 ℃:18.493 ° (± 0.1 °), 19.133 ° (± 0.1 °), 26.769 ° (± 0.1 °), 27.371 ° (± 0.1 °).
It will be appreciated by those skilled in the art that the relative intensity of diffraction may vary depending on a number of factors, such as the method of preparing the sample and the type of instrument used. In addition, in certain cases, a part of the above peaks may not be detectable. Indeed, the peaks listed above are only the significant peaks identified by the applicant. A complete list of peaks (although in many cases small) is given in figure 3.
Again, this is a comprehensive list of peaks identified by the applicant. Based on the relative intensities of many of these peaks, the skilled artisan will appreciate that analysis of the same polymorphic form by different investigators on another instrument may not identify all of the small peaks identified above, and the peaks in the tables are provided merely as a comprehensive list. For identification purposes, the peaks identified in figure 3, particularly the moderately strong peaks, are believed to be more characteristic of the presence of the polymorphic forms of the invention.
It is noted that for the X-ray powder diffraction patterns of the above-described forms, the characteristic peaks of the X-ray powder diffraction patterns may vary slightly between one machine and another and between one sample and another, and their values may differ by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, and thus the values given cannot be considered absolute. Also the numerical values given in the differential scanning calorimetry diagrams of the above described forms cannot be considered absolute.
In some embodiments of the invention, the differential scanning calorimetry curve shows an endothermic peak in the range of 141.7 ℃ to 159.7 ℃; the endothermic melting peak was 148.4 ℃.
In some embodiments of the invention, the IR spectrum has characteristic absorption peaks at 3469.26cm-1, 3436.21cm-1, 3062.46cm-1, 1725.95cm-1, 1653cm-1, and 1520.7 cm-1.
In some embodiments of the invention, the thermogravimetric analysis is shown in figure 2. The weight loss of the thermogravimetric analysis curve is 0.705% when the thermogravimetric analysis curve is heated to 185.92 ℃; weight loss was 10.297% when heated to 212.71 ℃; the weight loss was 20.385% when heated to 240.17 ℃.
In some embodiments of the invention, the nmr spectrum is as shown in figure 5.
On the basis of the research, the invention also provides a method for preparing the ibutinib glucolactone eutectic, which comprises the step of dissolving a crude product of the compound shown as the formula I in a solvent for crystallization.
In some embodiments of the invention, the solvent comprises one or a mixture of two or more of acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether, and dichloromethane/methyl tert-butyl ether. More preferably, the solvent is selected from: acetonitrile, methanol.
In some embodiments of the invention, the crystallizing comprises:
(1) By concentrating the solvent; or
(2) Cooling to ambient temperature or to any temperature between 25 ℃ and 30 ℃; or
(3) By adding a seed crystal of the ibutinib gluconolactone cocrystal; or
(4) By any combination of (1), (2) or (3).
In some embodiments of the invention, the crude compound of formula I is prepared by a process comprising: heating and dissolving ibrutinib free alkali in a solvent, and adding glucolactone under the condition of heat preservation to prepare a crude product of the compound shown in the formula (I);
the solvent comprises one or more mixed solvents of acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether and dichloromethane/methyl tert-butyl ether; more preferably, the solvent is selected from: acetonitrile, methanol.
So the heating temperature is 40-80 ℃.
The invention also provides the use of the ibutinib glucolactone cocrystal or the ibutinib glucolactone cocrystal prepared by the method in preparation of an inhibitor of Bruton's Tyrosine Kinase (BTK) or a medicament for preventing and/or treating recurrent Mantle Cell Lymphoma (MCL), recurrent Chronic Lymphoid Leukemia (CLL), 17 p-deficient chronic lymphoid leukemia, fahrenheit macroglobulinemia (WM), recurrent Marginal Zone Lymphoma (MZL) and/or chronic graft-versus-host disease (cGVHD).
The invention also provides a pharmaceutical composition or a pharmaceutical preparation, which comprises the ibrutinib gluconolactone eutectic or the ibrutinib gluconolactone eutectic prepared by the method and pharmaceutically acceptable auxiliary materials.
The invention provides an ibutinib gluconolactone eutectic crystal form, wherein the ibutinib gluconolactone eutectic crystal is a compound with a structure shown as a formula I. The invention further relates to a process for preparing said crystalline form.
The experimental result shows that the ibutinib glucolactone cocrystal has the stability not inferior to the ibutinib free base and has the druggability according to the data comparison in the tables 2 and 3. According to the sieving yield and the observed phenomenon after sieving in the table 4, the ibutinib gluconolactone eutectic powder state is more beneficial to sieving, the loss is small, the yield is high, and the static electricity is not obvious. The results in tables 5 and 6 show that the bulk density and the tap density of the ibutinib gluconolactone eutectic are not much different from those of the ibutinib free alkali, but the angle of repose is obviously different, and the fluidity of the ibutinib gluconolactone eutectic is obviously better than that of the free alkali. From the results in tables 7 and 8, it can be seen that the prescription using the ibutinib gluconolactone eutectic as the main ingredient has the best mixing uniformity and meets the requirements of the preparation production by using the same prescription and the same mixing process. The ibutinib free base is difficult to mix uniformly.
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows a compound of formula (I): a DSC of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal;
FIG. 2 shows a compound of formula (I): TGA of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal;
FIG. 3 shows a compound of formula (I): an XRPD of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal;
FIG. 4 shows a compound of formula (I): IR of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal;
FIG. 5 shows a compound of formula (I): H-NMR of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal.
The invention discloses an ibutinib gluconolactone eutectic and a preparation method thereof, and a person skilled in the art can use the content for reference and appropriately improve process parameters to realize the ibutinib gluconolactone eutectic. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The invention aims to provide a crystalline ibrutinib glucolactone cocrystal, which is shown as a formula I:
in one aspect of the invention, the compound of formula I exists in a substantially crystalline form. The compound of formula I is generally designated as a 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal.
In one aspect of the invention, the crystalline form of the compound of formula I is in an anhydrous, solvent-free form.
The ibutinib gluconolactone cocrystal crystal form can be identified by a melting starting point and a powder X-ray diffraction pattern.
DSC test results show that the alloy has an endothermic peak in the range of 141.7-159.7 ℃, the peak value is 148.4 ℃, and the melting temperature is obtained.
An Ibutotinib gluconolactone cocrystal form, when it is in a substantially pure and substantially anhydrous, solvent-free form, has an X-ray powder diffraction pattern having specific high intensity peaks at 5.807 ° (+ -0.1 °), 16.445 ° (+ -0.1 °), 21.459 ° (+ -0.1 °), 23.998 ° (+ -0.1 °), 26.769 ° (+ -0.1 °) 2 θ. Still further, the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at 5.807 ° (± 0.1 °), 16.445 ° (± 0.1 °), 18.493 ° (± 0.1 °), 19.133 ° (± 0.1 °), 21.459 ° (± 0.1 °), 23.998 ° (± 0.1 °), 26.769 ° (± 0.1 °), 27.371 ° (± 0.1 °) 2 θ.
It is noted that for the X-ray powder diffraction patterns of the above-described crystalline forms, the characteristic peaks of the X-ray powder diffraction patterns may vary slightly between one machine and another and between one sample and another, and may differ in value by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, and thus the values given are not to be considered absolute. Also the numerical values given in the differential scanning calorimetry diagram of the above-mentioned forms cannot be regarded as absolute.
The infrared spectrum of the ibutinib gluconolactone eutectic crystal form has characteristic absorption peaks at 3469.26cm-1, 3436.21cm-1, 3062.46cm-1, 1725.95cm-1, 1653cm-1 and 1520.7 cm-1.
In another aspect of the invention, there is provided a process for the preparation of a crystalline form of the compound of formula I by crystallisation of a crude compound of formula I in a suitable solvent selected from: acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether, dichloromethane/methyl tert-butyl ether, more preferably the solvent is selected from: acetonitrile, methanol.
According to another aspect of the invention, the preparation method of the crystal form of the compound of the formula I is provided, I-ibrutinib free base is dissolved in acetonitrile or methanol by heating, gluconolactone is added under heat preservation, crystallization is carried out after cooling, then the solid crystal form is separated by using a conventional separation means, and the crystal form of the compound of the formula I is obtained after drying.
The invention will now be described with reference to the following non-limiting examples.
The invention adopts internationally accepted X-ray powder diffraction method (XRPD), DSC, TGA, IR and H-NMR to research and characterize the ibutinib glucolactone cocrystal.
The terms:
XRPD: x-ray powder diffraction;
DSC: differential scanning calorimetry;
TGA: thermogravimetric analysis;
IR: infrared spectrum analysis;
H-NMR: hydrogen nuclear magnetic resonance spectroscopy.
The measurement conditions and methods:
wherein the X-ray powder diffraction pattern of the invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:
x-ray reflectance parameters: cu-Ka;
voltage: 40 kilovolts (kV);
current: 40 milliamperes (mA);
entrance slit: 0.6MM;
receiving a slit: 5.7MM;
scanning range: from 3 to 70 degrees;
sampling step length: 0.02 degree;
measurement time per step: 0.2 sec/step.
The scan parameters are shown in table 1.
TABLE 1 XRPD test parameters
No | 2θ | d | I/I o | I,cps | FWHM |
1 | 5.807 | 15.2071 | 37.6 | 5476 | 0.39 |
2 | 8.072 | 10.9434 | 1.3 | 196 | |
3 | 10.800 | 8.1850 | 12.9 | 1875 | 0.53 |
4 | 11.281 | 7.8368 | 6.6 | 968 | 0.28 |
5 | 12.486 | 7.0834 | 9.9 | 1448 | 0.39 |
6 | 13.387 | 6.6088 | 6.2 | 901 | 0.28 |
7 | 13.798 | 6.4128 | 12.2 | 1782 | 0.42 |
8 | 14.457 | 6.1218 | 13.4 | 1957 | 0.28 |
9 | 15.295 | 5.7883 | 2.8 | 402 | |
10 | 15.801 | 5.6039 | 6.7 | 982 | 0.28 |
11 | 16.445 | 5.3858 | 36.3 | 5290 | |
12 | 16.814 | 5.2686 | 7.8 | 1130 | 0.28 |
13 | 17.412 | 5.0888 | 4.5 | 654 | 0.20 |
14 | 17.983 | 4.9287 | 23.4 | 3400 | 0.39 |
15 | 18.493 | 4.7937 | 26.8 | 3896 | 0.28 |
16 | 19.133 | 4.6349 | 27.6 | 4016 | 0.34 |
17 | 19.991 | 4.4378 | 7.6 | 1111 | 0.42 |
18 | 20.711 | 4.2851 | 6.3 | 915 | 0.25 |
19 | 21.459 | 4.1375 | 44.0 | 6403 | 0.34 |
20 | 21.866 | 4.0613 | 29.9 | 4349 | 0.31 |
21 | 22.729 | 3.9091 | 27.0 | 3926 | 0.25 |
22 | 23.998 | 3.7051 | 100 | 14561 | 0.25 |
23 | 24.754 | 3.5937 | 3.2 | 469 | |
24 | 25.766 | 3.4547 | 3.0 | 430 | |
25 | 26.769 | 3.3276 | 23.0 | 3342 | 0.28 |
26 | 27.371 | 3.2557 | 17.2 | 2511 | 0.25 |
27 | 27.856 | 3.2001 | 9.5 | 1386 | 0.20 |
28 | 29.090 | 3.0671 | 7.2 | 1048 | 0.36 |
29 | 30.713 | 2.9086 | 2.1 | 300 | |
30 | 31.344 | 2.8515 | 10.3 | 1506 | 0.31 |
31 | 32.354 | 2.7648 | 2.5 | 367 | 0.25 |
32 | 33.882 | 2.6435 | 2.3 | 339 | |
33 | 34.348 | 2.6087 | 7.6 | 1110 | 0.28 |
34 | 35.206 | 2.5470 | 1.5 | 220 | |
35 | 36.428 | 2.4644 | 3.6 | 520 | |
36 | 37.749 | 2.3811 | 4.4 | 646 | 0.28 |
37 | 39.279 | 2.2918 | 7.4 | 1078 | 0.25 |
38 | 39.700 | 2.2685 | 3.3 | 478 | 0.28 |
39 | 40.701 | 2.2150 | 1.7 | 242 | 0.34 |
40 | 42.929 | 2.1050 | 7.5 | 1098 | 0.25 |
41 | 43.549 | 2.0765 | 1.9 | 281 | |
42 | 46.835 | 1.9382 | 2.1 | 311 | |
43 | 48.782 | 1.8653 | 3.0 | 432 | 0.28 |
44 | 50.028 | 1.8217 | 3.2 | 467 | 0.34 |
45 | 50.515 | 1.8053 | 1.7 | 241 | |
46 | 51.995 | 1.7573 | 2.5 | 361 | |
47 | 52.866 | 1.7304 | 1.6 | 234 |
The differential scanning thermograms of the present invention were collected on a DSC 204F1 differential scanning calorimeter. The parameters of the differential scanning calorimetry analysis method are as follows:
the temperature range is 30-250 ℃;
scanning rate/° c/min 10 ℃/min;
protective gas: nitrogen, 20 ml/min.
The infrared spectrogram testing method comprises the following steps:
testing an instrument: spectrum 65 Fourier transform infrared spectrometer
And (3) testing conditions are as follows: KBr pellet process
And (3) correcting the instrument: the infrared spectrum absorption peak of the polystyrene film was used to correct the instrument wave number (refer to the 0402 rule in the four parts of pharmacopoeia 2015, china).
Sample preparation conditions are as follows: KBr pellet process
Scanning range: 400-4000cm-1
The parameters of the thermogravimetric analysis method of the invention are as follows:
temperature range: 30-250 ℃;
temperature rise rate: 10 ℃/minute;
atmosphere: nitrogen, 20 ml/min.
The parameters of the method of the nuclear magnetic resonance hydrogen spectrum are as follows:
the instrument model is as follows: bruker-F-400 NMR spectrometer (frequency: 400 HMz);
testing the solvent: according to the solubility and structural characteristics of the product, deuterated DMSO is selected as a test solvent.
The ibutinib glucolactone eutectic and the raw materials and reagents used in the preparation method thereof can be purchased from the market.
The invention is further illustrated by the following examples:
example 1: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal
Adding 5 mL of acetonitrile into a 50mL three-necked bottle, starting stirring, adding 500 mg of ibrutinib free alkali, heating to 70 ℃, preserving heat and stirring for 30 minutes, and dissolving and clearing the system. 222.66 mg of gluconolactone was added to the solution, and stirring was continued for 30 minutes, whereby the system was cleared. Stopping heating, naturally cooling to 25-30 ℃, and keeping the temperature and stirring for 2 hours. Filtering, leaching a filter cake by using 1 ml of acetonitrile, and carrying out forced air drying at the temperature of 40 ℃ for 8-12 hours to obtain 600 mg of the ibrutinib glucolactone eutectic which is white powder with the yield of 83%.
Example 2: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal
Adding 5 mL of isopropanol into a 50mL three-necked bottle, starting stirring, adding 500 mg of ibrutinib free alkali, heating to 80 ℃, preserving heat and stirring for 30 minutes, and dissolving the system to be clear. 222.66 mg of gluconolactone was added to the solution, and stirring was continued for 30 minutes, whereby the system was clear. Stopping heating, naturally cooling to 25-30 ℃, and stirring for 2 hours under the condition of heat preservation. Filtering, leaching the filter cake with 1 ml of isopropanol, and drying by blowing air at 40 ℃ for 8-12 hours to obtain 240 mg of the ibrutinib glucolactone eutectic, which is yellow powder and has the yield of 33%.
Example 3: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal
Adding 5 mL of acetone into a 50mL three-necked bottle, starting stirring, adding 500 mg of ibrutinib free alkali, heating to 56 ℃, keeping the temperature and stirring for 30 minutes, and dissolving the system to be clear. 222.66 mg of gluconolactone was added to the solution, and stirring was continued for 30 minutes, whereby the system was clear. Stopping heating, dropwise adding 2 ml of methyl tert-butyl ether, naturally cooling to 25-30 ℃, and stirring for 2 hours under the condition of heat preservation. Filtering, leaching the filter cake with 1 ml of methyl tert-butyl ether, and drying by blowing at 40 ℃ for 8-12 hours to obtain 480 mg of the ibutinib glucolactone cocrystal which is light yellow powder with the yield of 66%.
Example 4: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal
Adding 5 mL of methanol into a 50mL three-neck flask, starting stirring, adding 500 mg of ibrutinib free alkali, heating to 65 ℃, keeping the temperature and stirring for 30 minutes, and dissolving and clearing the system. 222.66 mg of gluconolactone was added to the solution, and stirring was continued for 30 minutes, whereby the system was cleared. Stopping heating, naturally cooling to 25-30 ℃, and stirring for 2 hours under the condition of heat preservation. Filtering, leaching the filter cake with 1 ml of methanol, and drying by blowing air at 40 ℃ for 8-12 hours to obtain 300 mg of the ibrutinib glucolactone eutectic which is white powder with the yield of 42%.
Example 5: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconate
Adding 5 mL of ethanol into a 50mL three-necked bottle, starting stirring, adding 500 mg of ibrutinib free alkali, heating to 78 ℃, keeping the temperature and stirring for 30 minutes, and dissolving the system to be clear. 222.66 mg of gluconic acid was added to the solution and stirring was continued for 30 minutes, and the system was clear. Stopping heating, naturally cooling to 25-30 ℃, and keeping the temperature and stirring for 2 hours. Filtering, leaching the filter cake with 1 ml of ethanol, and drying by blowing air at 40 ℃ for 8-12 hours to obtain 520 mg of the ibrutinib glucolactone eutectic which is white powder with the yield of 72%.
Example 6: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal
Adding 5 mL of tetrahydrofuran into a 50mL three-necked bottle, starting stirring, adding 500 mg of ibrutinib free alkali, heating to 66 ℃, preserving heat and stirring for 30 minutes, and dissolving and clearing the system. 222.66 mg of gluconolactone was added to the solution, and stirring was continued for 30 minutes, whereby the system was cleared. Stopping heating, dropwise adding 1 ml of methyl tert-butyl ether, naturally cooling to 25-30 ℃, and keeping the temperature and stirring for 2 hours. Filtering, leaching the filter cake with 1 ml of methyl tert-butyl ether, and drying by blowing at 40 ℃ for 8-12 hours to obtain 390 mg of the ibutinib glucolactone eutectic which is light yellow powder with the yield of 54%.
Example 7: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal
Adding 5 mL of dichloromethane into a 50mL three-necked bottle, starting stirring, adding 500 mg of ibrutinib free alkali, heating to 40 ℃, keeping the temperature and stirring for 30 minutes, and dissolving the system to be clear. 222.66 mg of gluconolactone was added to the solution, and stirring was continued for 30 minutes, whereby the system was clear. Stopping heating, dropwise adding 5 ml of methyl tert-butyl ether, naturally cooling to 25-30 ℃, and keeping the temperature and stirring for 2 hours. Filtering, leaching the filter cake with 1 ml of methyl tert-butyl ether, and drying by blowing air at 40 ℃ for 8-12 hours to obtain 580 mg of the ibutinib glucolactone eutectic which is yellow powder with the yield of 80%.
Example 8: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one gluconolactone cocrystal
Adding 1000 ml of acetonitrile into a 2L three-necked bottle, starting stirring, adding 100 g of ibutinib free alkali, heating to 70 ℃, keeping the temperature and stirring for 30 minutes, and dissolving the system to be clear. 44.53 g of gluconolactone was added to the solution, and stirring was continued for 30 minutes, so that the system was clear. Stopping heating, naturally cooling to 25-30 ℃, and keeping the temperature and stirring for 2 hours. Filtering, leaching a filter cake by using 1 ml of acetonitrile, and carrying out forced air drying for 8-12 hours at the temperature of 40 ℃ to obtain 118 g of the ibrutinib glucolactone eutectic which is white powder with the yield of 82%.
Comparative example 1: preparation of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one free base
Dissolving 86g of crude ibrutinib in 516ml of absolute ethyl alcohol, heating to 60 ℃, adding 0.86g of activated carbon into the system until the system is clear, keeping the temperature at 60 ℃, stirring for 20-30 minutes, and filtering while the system is hot. Cooling the filtrate in water bath under stirring, controlling the temperature to be 25-30 ℃, and dripping 774ml of purified water for the following dripping time: 60-90 minutes, stirring for 3-4 hours at 25-30 ℃ after the dropwise addition is completed, filtering, leaching a filter cake once by using a 129mL ethanol and purified water (1.5), controlling the temperature of the obtained solid to be 40 +/-2 ℃, and drying for 12-15 hours under reduced pressure (the vacuum degree is-0.1 MPa) to obtain 66g of a crude product. Adding the crude product into 990mL acetonitrile, stirring, heating, controlling the temperature to be 60-65 ℃, stirring for 20-30 minutes, dissolving the system clearly, cooling in water bath, controlling the temperature to be 20-25 ℃ after 30-40 min at the cooling rate of 1 ℃/min, stirring for crystallization for 3-4 hours, filtering, leaching a filter cake once by using 99mL acetonitrile, and controlling the vacuum degree at 40 +/-2 ℃ to: drying under-0.1 MPa for 8-15 hours to obtain 52g of white powdery solid which is the ibrutinib free base.
Test example 1: comparison of ibutinib gluconolactone cocrystal and ibutinib free base influencing factor experiment
The ibutinib gluconolactone cocrystal and the ibutinib free base are used as influencing factors for experiments, the stability is compared, and the results are as follows:
TABLE 2 Ibritinib gluconolactone cocrystal influencing factor experiment
TABLE 3 Ibutinib free base influence factor experiment
According to the comparison of the data in the table 2 and the table 3, the ibutinib gluconolactone cocrystal has the stability which is not inferior to the stability of the ibutinib free base and has the property of becoming a medicine.
Test example 2: comparison of sieving
A circular sieve with the diameter of 20cm is adopted, the mesh number is 100, an 8411 type electric oscillating screen (a city geotechnical instrument factory in the ruin and the cross country in Shaoxing province) is adopted, the rotating speed is 1400 rpm, 30g of each of 3 materials is sieved for 20 minutes, the materials in a tray below the sieve are collected, the phenomenon after sieving is observed, the phenomenon comprises the residual situation of the materials on the sieve and the situation of large-particle materials, and the adsorption situation of the sieve to the materials is observed, and the results are as follows:
TABLE 4 comparison of screening results
The above yield results were subjected to one-way anova, with the following results:
TABLE 5 results of analysis of sieving yield and variance
Source of difference | SS | df | MS | F | P-value | F crit |
Between groups | 1258.602 | 1 | 1258.602 | 18.26796 | 0.012908 | 7.708647 |
In group | 275.5867 | 4 | 68.89667 | / | / | / |
In total | 1534.188 | 5 | / | / | / | / |
From the data, the sieving yields of the two materials are obviously different.
According to the sieving yield and the observed phenomenon after sieving, the ibutinib gluconolactone eutectic powder is more beneficial to sieving, the loss is small, the yield is high, and the static electricity is not obvious.
Test example 3: comparison of particle size and fluidity of ibrutinib gluconolactone cocrystal and ibrutinib free base
And detecting the particle sizes of the ibutinib gluconolactone eutectic and the ibutinib free alkali by using a laser particle size analyzer and water as a dispersing agent. And respectively measuring the angle of repose, the bulk density and the tap density of the ibutinib gluconolactone eutectic and the ibutinib free alkali by adopting a BT-1000 powder comprehensive characteristic tester. The results are as follows:
table 5 particle size measurement results
Name of article | D10 (micron) | D50 (micron) | D90 (micron) |
Ibutotinib gluconolactone cocrystal | 0.692 | 5.852 | 41.41 |
Ibutinib free base | 0.844 | 7.240 | 52.68 |
According to the results, the particle sizes of the two materials are not greatly different.
TABLE 6 results of fluidity test
Name of a brand | Angle of repose (°) | Bulk Density (g/ml) | Tap density (g/ml) |
|
43 | 0.23 | 0.40 |
Ibutinib |
55 | 0.25 | 0.44 |
According to the results, the bulk density and the tap density of the ibutinib gluconolactone eutectic are not greatly different from those of the ibutinib free alkali, but the repose angle is obviously different, and the fluidity of the ibutinib gluconolactone eutectic is obviously better than that of the free alkali.
Test example 4: comparison of mixing difficulty in preparation production process
Mixing the following prescription materials by using an FH laboratory type mixer (0.5L hopper), rotating at 8rpm for 30min, taking 5 points at different positions in the hopper to detect the content of the main drug, calculating RSD, and evaluating the mixing difficulty degree.
Table 7 recipe composition
Prescription composition | Dosage (g) |
Main drug (batch charge measured in Ebritinib) | 10.0 |
Microcrystalline cellulose | 82.0 |
Croscarmellose sodium | 4.0 |
Sodium dodecyl sulfate | 1.0 |
Magnesium stearate | 1.0 |
TABLE 8 results of fluidity test
Name of a brand | Ibutotinib glucolactone eutectic | Ibutotinib free base |
RSD(%) | 1.34 | 6.87 |
According to the results, the prescription using the same prescription and the same mixing process has the best mixing uniformity by using the ibutinib glucolactone eutectic as the main drug, and meets the production requirements of the preparation. The ibutinib free base is difficult to mix uniformly.
The ibutinib gluconolactone eutectic and the preparation method thereof provided by the invention are described in detail above. The principles and embodiments of the present invention have been described herein using specific examples, which are set forth only to help understand the method and its core ideas of the present invention. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, it is possible to make various improvements and modifications to the present invention, and those improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (10)
- The ibrutinib glucolactone eutectic is characterized by having a structure shown as a formula I and existing in an anhydrous and solvent-free form;which exhibits at least 3 of the following high intensity peaks as 2 theta values in any combination in an X-ray powder diffraction pattern recorded with Cu-ka radiation at 25 ℃:5.807 ° (± 0.1 °), 16.445 ° (± 0.1 °), 21.459 ° (± 0.1 °), 23.998 ° (± 0.1 °) or 26.769 ° (± 0.1 °).
- Ibtinib gluconolactone cocrystal according to claim 1, characterized in that it exhibits at least 3 characteristic peaks in any combination as 2 θ values in an X-ray powder diffraction pattern recorded with Cu-Ka radiation at 25 ℃:18.493 ° (± 0.1 °), 19.133 ° (± 0.1 °), 26.769 ° (± 0.1 °), 27.371 ° (± 0.1 °).
- Ibtinib gluconolactone cocrystal according to claim 1 or 2, characterized by a differential scanning calorimetry curve showing an endothermic peak in the range of 141.7 ℃ to 159.7 ℃; the endothermic melting peak was 148.4 ℃.
- Ibutinib gluconolactone cocrystal according to any one of claims 1 to 3, characterized in that it has an infrared spectrum at 3469.26cm -1 、3436.21cm -1 、3062.46cm -1 、1725.95cm -1 、1653cm -1 、1520.7cm -1 Has a characteristic absorption peak.
- A method for preparing the ibutinib gluconolactone cocrystal as claimed in any one of claims 1 to 4, characterized in that a crude product of the compound represented by the formula I is taken and dissolved in a solvent for crystallization.
- The method according to claim 5, wherein the solvent comprises one or more of acetonitrile, isopropanol, acetone/methyl t-butyl ether, methanol, ethanol, tetrahydrofuran/methyl t-butyl ether, and dichloromethane/methyl t-butyl ether.
- The method according to claim 5 or 6, wherein the crystallizing comprises:(1) By concentrating the solvent; or(2) Cooling to ambient temperature or to any temperature between 25 ℃ and 30 ℃; or(3) By adding a seed crystal of the ibutinib gluconolactone co-crystal; or(4) By any combination of (1), (2) or (3).
- The process of any one of claims 5 to 7, wherein the crude compound of formula I is prepared by a process comprising: heating and dissolving the ibrutinib free alkali in a solvent, and adding glucolactone under the condition of heat preservation to prepare a crude product of the compound shown in the formula I;the solvent comprises one or more mixed solvents of acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether and dichloromethane/methyl tert-butyl ether;so the heating temperature is 40-80 ℃.
- Use of the ibutinib gluconolactone co-crystal according to any one of claims 1 to 4 or prepared by the process according to any one of claims 5 to 7 for the preparation of an inhibitor of Bruton's Tyrosine Kinase (BTK) or for the preparation of a medicament for the prevention and/or treatment of relapsing Mantle Cell Lymphoma (MCL), relapsing Chronic Lymphoid Leukemia (CLL), 17 p-deficient chronic lymphoid leukemia, fahrenheit macroglobulinemia (WM), relapsing Marginal Zone Lymphoma (MZL) and/or chronic graft-versus-host disease (cgd).
- Pharmaceutical composition or pharmaceutical preparation comprising an ibutinib gluconolactone cocrystal according to any one of claims 1 to 4 or prepared by the process according to any one of claims 5 to 7 and a pharmaceutically acceptable excipient.
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CN107530347A (en) * | 2015-03-27 | 2018-01-02 | 药品循环有限责任公司 | The co-crystal thereof of bruton's tyrosine kinase inhibitor |
CN107873029A (en) * | 2015-04-02 | 2018-04-03 | 拉蒂奥法姆有限责任公司 | According to Shandong for Buddhist nun and the eutectic of carboxylic acid |
WO2019138326A1 (en) * | 2018-01-09 | 2019-07-18 | Dr. Reddy's Laboratories Limited | Solid forms of ibrutinib |
CN110283052A (en) * | 2019-07-19 | 2019-09-27 | 黄泳华 | The eutectic compound that is made of resveratrol and kinases inhibitor and containing the composition of the eutectic compound |
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CN110540539A (en) * | 2018-05-29 | 2019-12-06 | 阿普泰克斯公司 | Novel crystal form of ibrutinib |
EP3575300A1 (en) * | 2018-05-31 | 2019-12-04 | Apotex Inc. | Novel crystalline forms of ibrutinib |
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CN107530347A (en) * | 2015-03-27 | 2018-01-02 | 药品循环有限责任公司 | The co-crystal thereof of bruton's tyrosine kinase inhibitor |
CN107873029A (en) * | 2015-04-02 | 2018-04-03 | 拉蒂奥法姆有限责任公司 | According to Shandong for Buddhist nun and the eutectic of carboxylic acid |
WO2019138326A1 (en) * | 2018-01-09 | 2019-07-18 | Dr. Reddy's Laboratories Limited | Solid forms of ibrutinib |
CN110283052A (en) * | 2019-07-19 | 2019-09-27 | 黄泳华 | The eutectic compound that is made of resveratrol and kinases inhibitor and containing the composition of the eutectic compound |
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王义成;冯成亮;杨素勤;吉民;: "药物共晶的最新研究进展" * |
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