CN105622614A - Ibrutinib amorpphis and preparation method thereof - Google Patents
Ibrutinib amorpphis and preparation method thereof Download PDFInfo
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- CN105622614A CN105622614A CN201510952168.7A CN201510952168A CN105622614A CN 105622614 A CN105622614 A CN 105622614A CN 201510952168 A CN201510952168 A CN 201510952168A CN 105622614 A CN105622614 A CN 105622614A
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- 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
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- 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
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Abstract
The invention discloses a method for preparing ibrutinib amorpphis. The method comprises the following steps: (1) adding ibrutinib into a high-quality organic solvent, and heating to completely dissolve the ibrutinib; (2) adding the solution into an anti-solvent, and performing stirring and curing, wherein in the adding process, the temperature of the anti-solvent system is maintained below 5 DEG C; (3) filtering, decompressing and drying solids to obtain the ibrutinib amorpphis. The ibrutinib amorpphis prepared by the method is stable and suitable for preparation production.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to one according to Shandong for Buddhist nun's amorphous article and preparation method thereof.
Background technology
According to Shandong for Buddhist nun (Ibrutinib) chemistry 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone by name, its structural formula is as follows.
Replace Buddhist nun to be bruton's tyrosine kinase (BTK) inhibitor according to Shandong, be used for treating chronic lymphocytic leukemia (CLL) and lymphoma mantle cell (MCL). MCL and CLL belongs to B cell non-Hodgkin lymphoma, has healing property of refractory and easy recurrent, and conventional chemoimmunotherapy does not possess targeting, and 3 or 4 grades of untoward reaction often occur. According to Shandong for Buddhist nun by with target protein BTK active site cysteine residue (Cys-481) optionally covalent bond, irreversibility ground suppresses BTK, thus effectively stoping tumor to move to the lymphoid tissue being adapted to tumor growth environment from B cell, become the newly selected for the treatment of CLL and MCL.
Replace the preparation method of Buddhist nun and therapeutic use open at PCT application patent WO2008039218 and WO2013003629 respectively according to Shandong. PCT application patent WO2013184572 discloses the multiple crystal formation such as A, B, C, D and unformed, and described unformed employing dichloromethane dissolves and obtains according to Shandong for Buddhist nun's amorphous article for rotary evaporation removal solvent after Buddhist nun's compound according to Shandong. But the technical matters operating condition of the method is indefinite, poor reproducibility, the amorphous article stability prepared are weak, it is easy to change into other crystal formations or form mixed crystal, being not suitable for industrialized production.
Summary of the invention
It is an object of the invention to provide a kind of stable according to Shandong for Buddhist nun's amorphous article (i.e. amorphous article) and preparation method thereof, the problem the method overcoming prior art repeatability and poor stability, the method favorable reproducibility of the present invention, the good stability replacing Buddhist nun's amorphous article according to Shandong prepared, production suitable for industrialized.
The present invention provides a kind of and replaces Buddhist nun's amorphous article according to Shandong, and its X powder diffraction figure has the characteristic peak such as Fig. 1.
The present invention replaces Buddhist nun's amorphous article according to Shandong, and its IR collection of illustrative plates has the characteristic absorption peak of Fig. 2.
The method that the preparation of the present invention replaces Buddhist nun's amorphous article according to Shandong, comprises the following steps:
1) joining in optimum organic solvent for Buddhist nun according to Shandong, heating makes it be completely dissolved;
2) joining in anti-solvent by above-mentioned solution, stirring solidifies, and wherein, in adition process, the temperature of anti-solvent system maintains less than 5 DEG C;
3) filtering, drying under reduced pressure obtains according to Shandong for Buddhist nun's amorphous article.
The method of the invention described above, in step 1), heating-up temperature be 30 DEG C to solvent reflux temperature, it is preferred to 50 DEG C��reflux temperature, described optimum organic solvent is selected from: methanol, ethanol, isopropanol, butanol; Acetone, butanone; Ethyl acetate, methyl acetate, oxolane, 2-methyltetrahydrofuran, acetonitrile, toluene, N, dinethylformamide, N, N-dimethyl acetylamide, dimethyl sulfoxide and glycol dimethyl ether; Step 2) in anti-solvent system temperature step be preferably-20 DEG C��5 DEG C; It is more preferably-20 DEG C��0 DEG C; Described anti-solvent is water or the mixed solution for water with the arbitrary proportion selected from organic solvents such as methanol, ethanol, isopropanol, acetone, oxolane, 2-methyltetrahydrofuran, heptane, hexane, ethyl acetate, methyl acetates. In step 3), described drying as drying under reduced pressure, baking temperature is 30 DEG C��70 DEG C, it is preferred to 50��70 DEG C.
In a preferred embodiment, the method that the preparation of the present invention replaces Buddhist nun's amorphous article according to Shandong, comprise the following steps:
1) will join in optimum organic solvent for Buddhist nun according to Shandong, heat to 50 DEG C-reflux temperature so that it is be completely dissolved, obtain solution;
2) joining in anti-solvent by above-mentioned solution, stirring solidifies, and wherein, in adition process, the temperature of anti-solvent system maintains-20 DEG C��5 DEG C;
3) filtering, drying under reduced pressure obtains according to Shandong for Buddhist nun's amorphous article, and baking temperature is 50��70 DEG C,
Wherein, optimum organic solvent in step 1) is selected from: methanol, ethanol, isopropanol, acetonitrile, butanone and oxolane, step 2) in anti-solvent selected from the mixed solvent of water or water and methanol, ethanol, isopropanol, acetone or heptane, it is preferred that described water is frozen water.
In another embodiment, the present invention prepares the method replacing Buddhist nun's amorphous article according to Shandong, including being dissolved in organic solvent for Buddhist nun with high molecular polymer according to Shandong, obtains amorphous article then through spray drying or evaporation solvent and (replaces Buddhist nun's solid dispersion also referred to as according to Shandong.
Preferably, the method for the invention described above, described high molecular polymer is vinylpyrrolidone and/or poloxamer, described organic solvent is for being selected from: methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl acetate, oxolane, dichloromethane, it is preferable that ethanol or dichloromethane.
Concrete, the a kind of of the present invention prepares the method replacing Buddhist nun's amorphous article according to Shandong, including being dissolved in organic solvent for Buddhist nun with macromolecular material according to Shandong, spray-dried or solvent evaporated obtains according to Shandong for Buddhist nun's solid dispersion and amorphous article, and described organic solvent is ethanol or dichloromethane.
The method of above-mentioned all present invention, the prepared feature replacing the powder diagram of Buddhist nun's amorphous article to have Fig. 1 according to Shandong, it may have the IR characteristic absorption peak of Fig. 2.
It is yet another object of the invention to provide a kind of pharmaceutical composition, comprise according to Shandong for Buddhist nun's solid dispersion and pharmaceutically acceptable adjuvant.
Described pharmaceutically acceptable adjuvant includes diluent, disintegrating agent, fluidizer, lubricant or stabilizer. These adjuvants are all the adjuvants that this area has been commonly used.
It is more more stable than the product that prior art obtains and easy and simple to handle for the stability of Buddhist nun's amorphous article according to Shandong that this preparation method provides, it is easy to industrial amplification production.
Accompanying drawing explanation.
Fig. 1 is the XRPD collection of illustrative plates replacing Buddhist nun's amorphous article according to Shandong prepared by the present invention.
Fig. 2 is the IR collection of illustrative plates replacing Buddhist nun's amorphous article according to Shandong prepared by the present invention.
Detailed description of the invention.
Below in conjunction with embodiment, the invention will be further described, it is possible to makes those skilled in the art be more completely understood by the essence of the present invention, but the scope not limited the present invention in any way.
X-ray powder diffraction figure of the present invention gathers on Japan's Shimadzu XRD-6000 type x-ray diffractometer. The parameter that X-ray powder diffraction of the present invention analyzes method is specific as follows:
X ray reflection parameter: CuKa
CuKa source (a=1.54063A)
Voltage: 40 kilovolts (Kv)
Electric current: 30 milliamperes (mA)
Divergent slit: automatically
Scan pattern: continuously
Sweep limits: 3��40 degree
Sampling step length: 0.02 degree
Scanning speed: 2 degrees/min.
Embodiment 1
To join in methanol 6.0ml for Buddhist nun 1.0g according to Shandong, heating to 50 DEG C, stir molten clearly. Being joined by above-mentioned solution in 18g frozen water mixed liquor, temperature control is below 5 DEG C, and stirring solidifies 30 minutes, filters, and filter cake to constant weight, obtains white solid 0.96g, HPLC:99.57% at 50 DEG C of drying under reduced pressure. Test its X-ray powder diffraction, its XRPD such as Fig. 1; Test infrared spectrum such as Fig. 2.
Embodiment 2
To join in ethanol 25.0ml for Buddhist nun 5.0g according to Shandong, heating to 65 DEG C, stir molten clearly. Being joined by above-mentioned solution in 100g ice and ethanol 30g mixed liquor, temperature control is between-20 DEG C��0 DEG C, and stirring solidifies 2 hours, filters, and filter cake to constant weight, obtains white solid 4.8g, HPLC:99.77% at 70 DEG C of drying under reduced pressure. Identical with the XRPD of embodiment 1 through the test of X-ray powder diffraction, test infrared spectrum is basically identical with embodiment 1, is according to Shandong for Buddhist nun's amorphous article.
Embodiment 3
To join in acetonitrile 10.0ml for Buddhist nun 1.0g according to Shandong, heating to backflow, stir molten clearly. Being joined by above-mentioned solution in ice 18g and acetone 3.0g mixed liquor, temperature control is below 0 DEG C, and stirring solidifies 4 hours, filters, and filter cake to constant weight, obtains white solid 0.87g, HPLC:99.37% at 60 DEG C of drying under reduced pressure. Identical with the XRPD of embodiment 1 through the test of X-ray powder diffraction, test infrared spectrum is basically identical with embodiment 1, is according to Shandong for Buddhist nun's amorphous article.
Embodiment 4
To join in butanone 10.0ml for Buddhist nun 1.0g according to Shandong, heating to 60 DEG C, stir molten clearly. Being joined by above-mentioned solution in ice 30g and heptane 10.0g mixed liquor, temperature control is below-5 DEG C, and stirring solidifies 15 minutes, filters, and filter cake to constant weight, obtains white solid 0.9g, HPLC:99.52% at 30 DEG C of drying under reduced pressure. Identical with the XRPD of embodiment 1 through the test of X-ray powder diffraction, test infrared spectrum is basically identical with embodiment 1, is according to Shandong for Buddhist nun's amorphous article.
Embodiment 5
To join in oxolane 8.0ml for Buddhist nun 1.0g according to Shandong, heating to backflow, stir molten clearly. Being joined by above-mentioned solution in ice 30g, temperature control is at 0-5 DEG C, and stirring solidifies 15 minutes, filters, and filter cake to constant weight, obtains white solid 0.80g, HPLC:99.41% at 70 DEG C of drying under reduced pressure. Identical with the XRPD of embodiment 1 through the test of X-ray powder diffraction, test infrared spectrum is basically identical with embodiment 1, is according to Shandong for Buddhist nun's amorphous article.
Embodiment 6
To join in 20ml dichloromethane for Buddhist nun amorphous article 1.0g and polyvinylpyrrolidone 2.5g according to Shandong, under room temperature, stirring obtains molten clear solution, and gained solution is carried out spray drying, obtain pulverous according to Shandong for Buddhist nun's solid dispersion. Identical with the XRPD of embodiment 1 through the test of X-ray powder diffraction, test infrared spectrum is basically identical with embodiment 1, is according to Shandong for Buddhist nun's amorphous article.
According to Shandong for Buddhist nun solid dispersion 1.0g, PEARLITOL 25C 1.0g, sodium carboxymethyl cellulose 0.3g, Pulvis Talci 0.05g, magnesium stearate 0.02g, calcium gluconate 0.01g, sodium alginate 0.01g mix and blend, will prepare according to Shandong for Buddhist nun's pharmaceutical composition.
Stability test
What the method for the present invention prepared carries out influence factor's study on the stability according to Shandong for Buddhist nun's amorphous article, and with prior art WO2013184572 disclosed in method namely adopt dichloromethane to dissolve to remove dichloromethane solvent according to Shandong for rotary evaporation after Buddhist nun's compound and obtain comparing for Buddhist nun's amorphous article (comparative example) according to Shandong, investigate its stability.
The above results shows, what adopt that preparation method of the present invention obtains is substantially more stable than the product that prior art obtains for the stability of Buddhist nun's amorphous substance according to Shandong.
The above; it is only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope that disclosed herein; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention. Therefore, protection scope of the present invention should be as the criterion with claims protection defined.
Claims (10)
1. prepare the method replacing Buddhist nun's amorphous article according to Shandong, comprise the following steps:
1) joining in optimum organic solvent for Buddhist nun according to Shandong, heating makes it be completely dissolved;
2) joining in anti-solvent by above-mentioned solution, stirring solidifies, and wherein, in adition process, the temperature of anti-solvent system maintains less than 5 DEG C;
3) filtering, solid obtains according to Shandong for Buddhist nun's amorphous article through drying under reduced pressure.
2. the method for claim 1, in step 1), heating-up temperature be 30 DEG C to solvent reflux temperature, it is preferred to 50 DEG C��reflux temperature.
3. the method for claim 1, described in step 1), optimum organic solvent is selected from: methanol, ethanol, isopropanol, butanol; Acetone, butanone; Ethyl acetate, methyl acetate, oxolane, 2-methyltetrahydrofuran, acetonitrile, toluene, N, dinethylformamide, N, N-dimethyl acetylamide, dimethyl sulfoxide and glycol dimethyl ether.
4. method as claimed in claim 3, described optimum organic solvent is selected from: methanol, ethanol, isopropanol, butanone, acetonitrile and oxolane.
5. the method for claim 1, step 2) in the temperature of anti-solvent system control at-20 DEG C��5 DEG C.
6. the method for claim 1, described anti-solvent is water or water and the mixed solvent of arbitrary proportion of the organic solvent selected from methanol, ethanol, isopropanol, acetone, oxolane, 2-methyltetrahydrofuran, heptane, hexane, ethyl acetate and methyl acetate.
7. the method for claim 1, described anti-solvent is water or the mixed solvent of water and methanol, ethanol, isopropanol, acetone, oxolane or heptane.
8. the method for claim 1, in step 3), baking temperature is 30 DEG C��70 DEG C, it is preferred to 50 DEG C��70 DEG C.
9. preparing the method replacing Buddhist nun's amorphous article according to Shandong, including being dissolved in organic solvent for Buddhist nun with macromolecular material according to Shandong, spray-dried or solvent evaporated obtains according to Shandong for Buddhist nun's solid dispersion and amorphous article.
10., according to Shandong for Buddhist nun's amorphous article, its X powder diffraction figure has the characteristic peak such as Fig. 1.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107722016A (en) * | 2017-10-20 | 2018-02-23 | 尚科生物医药（上海）有限公司 | A kind of unformed preparation method that Buddhist nun is replaced according to Shandong |
| CN108976234A (en) * | 2018-08-29 | 2018-12-11 | 浙江工业大学 | It is a kind of to replace Buddhist nun and the total amorphous article of saccharin and preparation method thereof according to Shandong |
| WO2019070698A1 (en) * | 2017-10-02 | 2019-04-11 | Johnson Matthey Public Limited Company | Novel forms of ibrutinib |
| CN112121014A (en) * | 2020-08-19 | 2020-12-25 | 汕尾市前瞻高等理工研究院 | Method for preparing stable amorphous drug solid preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104736178A (en) * | 2012-06-04 | 2015-06-24 | 药品循环公司 | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| WO2015145415A2 (en) * | 2014-03-27 | 2015-10-01 | Perrigo Api Ltd. | Ibrutinib solid forms and production process therefor |
-
2015
- 2015-12-18 CN CN201510952168.7A patent/CN105622614B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104736178A (en) * | 2012-06-04 | 2015-06-24 | 药品循环公司 | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| WO2015145415A2 (en) * | 2014-03-27 | 2015-10-01 | Perrigo Api Ltd. | Ibrutinib solid forms and production process therefor |
Non-Patent Citations (2)
| Title |
|---|
| ANON.: "Preparation of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, its salt and intermediates thereof", 《IP.COM JOURNAL》 * |
| 欧育湘 主译: "《含能材料》", 28 February 2009 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019070698A1 (en) * | 2017-10-02 | 2019-04-11 | Johnson Matthey Public Limited Company | Novel forms of ibrutinib |
| CN107722016A (en) * | 2017-10-20 | 2018-02-23 | 尚科生物医药（上海）有限公司 | A kind of unformed preparation method that Buddhist nun is replaced according to Shandong |
| CN108976234A (en) * | 2018-08-29 | 2018-12-11 | 浙江工业大学 | It is a kind of to replace Buddhist nun and the total amorphous article of saccharin and preparation method thereof according to Shandong |
| CN108976234B (en) * | 2018-08-29 | 2020-03-17 | 浙江工业大学 | Co-amorphous substance of ibrutinib and saccharin and preparation method thereof |
| CN112121014A (en) * | 2020-08-19 | 2020-12-25 | 汕尾市前瞻高等理工研究院 | Method for preparing stable amorphous drug solid preparation |
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