CN104211693A - Rivaroxaban new crystalline form, preparation method and application - Google Patents
Rivaroxaban new crystalline form, preparation method and application Download PDFInfo
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- CN104211693A CN104211693A CN201410384619.7A CN201410384619A CN104211693A CN 104211693 A CN104211693 A CN 104211693A CN 201410384619 A CN201410384619 A CN 201410384619A CN 104211693 A CN104211693 A CN 104211693A
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- razaxaban
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses an anticoagulant rivaroxaban new crystalline form IV which is low in molecular weight and is used in a manner of oral administration. The new crystalline is represented by an x-powder diffraction diagram thereof. The invention also discloses a method for preparing the rivaroxaban new crystalline form IV in a mixed solvent including anhydrous formic acid and ethyl acetate. The method is simple in processes, is convenient to carry out, is mild in condition and is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly a kind of anticoagulant active razaxaban novel crystalline forms and preparation method thereof and preparing the purposes in anticoagulation medicine.
Background technology
Razaxaban (Rivaroxaban), its chemical name is the chloro-N-of 5-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl)-1,3-oxazoline-5-base) methyl) thiophene-2-carboxamide derivatives, its molecular formula is C
19h
18clN
3o
5s, molecular weight 435.88.Structure is as shown in Equation 1:
Razaxaban (Rivaroxaban) is the novel anticoagulant that Beyer Co., Ltd goes through research and development in 10 years, is the oral pharmaceutical of a kind of highly selective, direct supressor Xa.Endogenous and the extrinsic pathway of blood coagulation waterfall can be interrupted, the generation of Trombin inhibiting and thrombosis by supressor Xa.Have bioavailability high, disease therapy spectrum is wide, and dose-effect relationship is stablized, convenient oral, the feature that bleeding risk is low.From in September, 2008 first after Canada's listing, razaxaban is granted more than 120 countries in the whole world.
In recent years, relevant razaxaban crystal formation and preparation method rarely have report, as WO2007/039132 illustrates the polycrystalline state existence form of razaxaban, and disclose I crystal formation, II crystal formation, III crystal formation, the crystal formation characterization data of amorphous, hydrate, NMP and THF solvated compounds and their preparation method; CN102292332A reports the APO-A new crystal of razaxaban; WO2011/012321 discloses the multiple novel method preparing razaxaban I crystal formation; EP2404920A1 then discloses preparation method and the crystal formation data of razaxaban formic acid solvent compound and two hydrates; Recently, EP2573084A1 reports B1, B2 of razaxaban and the preparation method of crystal form E and conversion mutually each other, B1, B2 and E crystalline substance can also be converted into II crystal formation, III crystal formation, obviously also provide a kind of a kind of method preparing II crystal formation, III crystal formation.In sum, razaxaban belongs to the compound of polycrystalline state, exploitation good water solubility, the raw material that excellent in stability also can realize the razaxaban advantage medicinal crystal-form of industrialized production is shouldered heavy responsibilities, and the medicinal application that the present invention can be razaxaban provides more wide crystal formation to select space.
Summary of the invention
Contriver, through a large amount of experimental studies, have surprisingly been discovered that the crystalline form that razaxaban is new, the present invention is based on this and finds and invent.
The invention provides a kind of crystalline form of razaxaban new crystal IV, the X-ray powder diffraction figure of this new crystal is included in the peak of 3.7 ± 0.2,7.3 ± 0.2,14.5 ± 0.2,18.2 ± 0.2 degree of 2 θ position.
Further, the X-ray powder diffraction figure of this razaxaban new crystal IV is also included in the peak of 19.9 ± 0.2,21.9 ± 0.2,29.3 ± 0.2 degree of 2 θ position.
Further, the X-ray powder diffraction figure of this razaxaban new crystal IV is also included in the peak of 32.0 ± 0.2,33.6 ± 0.2,35.6 ± 0.2,40.9 ± 0.2 degree of 2 θ position.
Further, above-mentioned razaxaban new crystal IV, its X-powdery diffractometry feature is expressed as follows with θ angle, Prague 2, spacing d, relative intensity (to represent relative to the percentage ratio of the strongest ray) and peak height (counting/second):
| 2 θ angle (°) measured values | D spacing measured value | Relative intensity (%) measured value | Peak height (counting/second) |
| 3.775 | 23.3884 | 100 | 2476 |
| 7.377 | 11.9740 | 12.7 | 314 |
| 14.599 | 6.0626 | 40.8 | 1010 |
| 18.249 | 4.8574 | 29.8 | 738 |
| 19.951 | 4.4466 | 15.8 | 391 |
| 21.936 | 4.0486 | 91.9 | 2275 |
| 29.345 | 3.0411 | 85.9 | 2127 |
| 32.004 | 2.7942 | 54.9 | 1360 |
| 33.604 | 2.6647 | 55.4 | 1372 |
| 35.609 | 2.5191 | 20.3 | 503 |
| 40.946 | 2.2023 | 41.2 | 1019 |
Described IV crystal formation in a specific embodiment, use Cu-Ka radiation, its x-powdery diffractometry represented with θ angle, Prague 2, spacing d, relative intensity (to represent relative to the percentage ratio of the strongest ray) and peak height has following data:
| 2 θ angle (°) measured values | D spacing measured value | Relative intensity (%) measured value | Peak height (counting/second) |
| 3.775 | 23.3884 | 100 | 2476 |
| 7.377 | 11.9740 | 12.7 | 314 |
| 14.599 | 6.0626 | 40.8 | 1010 |
| 18.249 | 4.8574 | 29.8 | 738 |
| 19.951 | 4.4466 | 15.8 | 391 |
| 21.936 | 4.0486 | 91.9 | 2275 |
| 25.135 | 3.5401 | 9.2 | 228 |
| 29.345 | 3.0411 | 85.9 | 2127 |
| 32.004 | 2.7942 | 54.9 | 1360 |
| 33.604 | 2.6647 | 55.4 | 1372 |
| 34.290 | 2.6129 | 12.4 | 306 |
| 35.609 | 2.5191 | 20.3 | 503 |
| 36.905 | 2.4336 | 11.8 | 291 |
| 40.946 | 2.2023 | 41.2 | 1019 |
| 43.039 | 2.0999 | 10.8 | 268 |
| 44.595 | 2.0302 | 13.7 | 338 |
| 46.849 | 1.9376 | 16.7 | 413 |
| 48.552 | 1.8735 | 10.9 | 269 |
Razaxaban new crystal IV of the present invention there is X-powder diffraction spectrum as shown in Figures 1 and 2 and detect data and.
Razaxaban new crystal IV of the present invention detects through differential scanning calorimetric analysis (DSC) has faint endotherm(ic)peak at 47.75 DEG C and 118.86 DEG C of places, and has strong endotherm(ic)peak at 231 ~ 233 DEG C of places, has and the collection of illustrative plates shown in Fig. 3.
Razaxaban new crystal IV of the present invention detects through thermogravimetric thermal analyses (TGA) has adsorption solvent to lose at 47.75 DEG C of places, has the crystal water of trace to lose at 118.86 DEG C of places, starts to decompose, have and the collection of illustrative plates shown in Fig. 4 at about 230 DEG C.
Present invention also offers a kind of preparation method preparing razaxaban new crystal IV, the method comprises the following steps:
(1) razaxaban crude product is joined in anhydrous formic acid, add thermosol clear;
(2) filter, obtain formic acid clear liquor;
(3) in filtrate, ethyl acetate is dripped, stirring and crystallizing;
(4) mixture is cooled to room temperature and is placed on stirring and crystallizing in ice-water bath;
(5) filtration, ethyl acetate drip washing obtain white solid;
(6) dry, obtain the razaxaban of IV crystalline forms.
The clear temperature of thermosol is added at 30 ~ 100 DEG C in step (1); Preferably 50 ~ 80 DEG C.
In step (1), the charging capacity (ml) of anhydrous formic acid is 2ml/g ~ 20ml/g, preferred 3ml/g ~ 7ml/g with razaxaban crude product quality (g) ratio.
In step (3), the ratio of ethyl acetate and anhydrous formic acid is 1:1 ~ 5:1; Preferred 2:1 ~ 3:1.
In step (4), in ice-water bath, stirring and crystallizing temperature is 0 ~ 10 DEG C, keeps this temperature 0.5h ~ 2h.
The present invention protects razaxaban new crystal IV further and is preparing the purposes in anticoagulation medicine, and described anticoagulation medicine is mainly used in select a time hip joint or replacement knee in arthroplasty adult patients, to prevent venous thrombosis (VTE); Also can be used for prevention non-valve artrial fibrillation patient's cerebral apoplexy and non-central nervous system embolism, reduce the risk etc. of coronary syndrome recurrence.
Above-mentioned preparation method provided by the invention, the sample yield obtained is good, purity is high (HPLC purity >=99.5%).This preparation method's technique is simple, and easy to operate, mild condition, without specific installation, is more suitable for suitability for industrialized production.
Accompanying drawing explanation
The accompanying drawing that the application comprises is a component part of specification sheets, and accompanying drawing and specification sheets and claims one are used from flesh and blood of the present invention, for understanding the present invention better.
The x-powder diffraction spectrum of Fig. 1 razaxaban crystalline form IV
The x-powdery diffractometry image data of Fig. 2 razaxaban crystalline form IV
The DSC collection of illustrative plates of Fig. 3 razaxaban crystalline form IV
The TGA collection of illustrative plates of Fig. 4 razaxaban crystalline form IV
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1
Razaxaban crude product is prepared by patent documentation " CN1906191A ".
Joined in 20ml anhydrous formic acid by razaxaban crude product 10g, be heated with stirring to 75 DEG C, complete molten clear rear filtration, obtains settled solution.150ml ethyl acetate is dripped, stirring and crystallizing in filtrate; Mixture is cooled to room temperature and is placed on stirring and crystallizing 1h in ice-water bath; Filter, filter cake, in 45 ~ 55 DEG C of drying under reduced pressure to constant weight, obtains 9.5g white solid; Yield: 95%, purity 99.91%.Sample detects consistent with Fig. 1, Fig. 2 through x-powdery diffractometry; DSC detected result is consistent with Fig. 3; TGA detected result is consistent with Fig. 4.
Embodiment 2
Joined in 50ml anhydrous formic acid by razaxaban crude product 10g, be heated with stirring to 30 DEG C, complete molten clear rear filtration, obtains settled solution.150ml ethyl acetate is dripped, stirring and crystallizing in filtrate; Mixture is cooled to room temperature and is placed on stirring and crystallizing 2h in ice-water bath; Filter, filter cake, in 45 ~ 55 DEG C of drying under reduced pressure to constant weight, obtains 9.2g white solid; Yield: 92%, purity 99.93%.Sample detects consistent with Fig. 1, Fig. 2 through x-powdery diffractometry; DSC detected result is consistent with Fig. 3; TGA detected result is consistent with Fig. 4.
Embodiment 3
Joined in 100ml anhydrous formic acid by razaxaban crude product 10g, be heated with stirring to 100 DEG C, complete molten clear rear filtration, obtains settled solution.300ml ethyl acetate is dripped, stirring and crystallizing in filtrate; Mixture is cooled to room temperature and is placed on stirring and crystallizing 0.5h in ice-water bath; Filter, filter cake, in 45 ~ 55 DEG C of drying under reduced pressure to constant weight, obtains 9.3g white solid; Yield: 93%, purity 99.91%.Sample detects consistent with Fig. 1, Fig. 2 through x-powdery diffractometry; DSC detected result is consistent with Fig. 3; TGA detected result is consistent with Fig. 4.
Embodiment 4
Joined in 200ml anhydrous formic acid by razaxaban crude product 10g, be heated with stirring to 65 DEG C, complete molten clear rear filtration, obtains settled solution.200ml ethyl acetate is dripped, stirring and crystallizing in filtrate; Mixture is cooled to room temperature and is placed on stirring and crystallizing 1h in ice-water bath; Filter, filter cake, in 45 ~ 55 DEG C of drying under reduced pressure to constant weight, obtains 9.1g white solid; Yield: 91%, purity 99.92%.Sample detects consistent with Fig. 1, Fig. 2 through x-powdery diffractometry; DSC detected result is consistent with Fig. 3; TGA detected result is consistent with Fig. 4.
Razaxaban new crystal IV of the present invention has blood coagulation resisting function, can be applied to select a time hip joint or replacement knee in arthroplasty adult patients, to prevent venous thrombosis (VTE); Also can be used for prevention non-valve artrial fibrillation patient's cerebral apoplexy and non-central nervous system embolism, reduce the risk etc. of coronary syndrome recurrence.
Razaxaban IV type crystal formation of the present invention is compared with published razaxaban I, II type and polymorphic form, and solubleness and the thermostability of IV type crystal formation are improved significantly, and have better bioavailability when oral.
Razaxaban IV type crystal formation of the present invention can add any one acceptable pharmaceutical excipient and be prepared into any one formulation pharmaceutically acceptable, such as and unrestricted, the preparation of liquid form, the preparation of solid form, granule, tablet, capsule, ointment, gelifying agent, hydrogel adhesive and other known preparation.
Claims (10)
1. a razaxaban new crystal IV, is characterized in that, its X-ray powder diffraction figure is included in the peak of 3.7 ± 0.2,7.3 ± 0.2,14.5 ± 0.2,18.2 ± 0.2 degree of 2 θ position.
2. razaxaban new crystal IV as claimed in claim 1, it is characterized in that, its X-ray powder diffraction figure is included in the peak of 19.9 ± 0.2,21.9 ± 0.2,29.3 ± 0.2 degree of 2 θ position.
3. razaxaban new crystal IV as claimed in claim 1, it is characterized in that, its X-ray powder diffraction figure is included in the peak of 32.0 ± 0.2,33.6 ± 0.2,35.6 ± 0.2,40.9 ± 0.2 degree of 2 θ position.
4. razaxaban new crystal IV as claimed in claim 1, it is characterized in that, its X-ray powder diffraction figure has following diffraction peak:
5. razaxaban new crystal IV as shown in claim 1, is characterized in that, its X-ray powder diffraction figure has following diffraction peak:
6. the arbitrary described razaxaban new crystal IV of claim 1-5, it is characterized in that, its DSC Thermogram is presented at 47.75 DEG C and there is endotherm(ic)peak at 118.86 DEG C of places, and has endotherm(ic)peak at 231 ~ 233 DEG C of places.
7. the preparation method of the arbitrary described razaxaban new crystal IV of claim 1-6, it is characterized in that, razaxaban crude product is joined in anhydrous formic acid, add thermosol and filter to obtain formic acid clear liquor clearly afterwards, drip ethyl acetate wherein, stirring and crystallizing, is then cooled to room temperature by mixture, is placed in ice-water bath stirring and crystallizing; Filtration, drip washing obtain white solid, dry, obtain razaxaban IV crystalline forms.
8. preparation method as claimed in claim 7, is characterized in that, Heating temperature is at 30 ~ 100 DEG C, and the charging capacity (ml) of anhydrous formic acid is 2ml/g ~ 20ml/g with razaxaban crude product quality (g) ratio.
9. preparation method according to claim 7, is characterized in that, the ratio of ethyl acetate and anhydrous formic acid is 1:1 ~ 5:1, and in ice-water bath, stirring and crystallizing temperature is 0 ~ 10 DEG C, keeps this temperature 0.5h ~ 2h.
10. the razaxaban new crystal IV as described in as arbitrary in claim 1-9 is preparing the purposes in anticoagulation medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410384619.7A CN104211693B (en) | 2014-08-07 | 2014-08-07 | Rivaroxaban crystalline form, preparation method and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440028A (en) * | 2015-12-07 | 2016-03-30 | 石家庄康贺威药业有限公司 | Rivaroxaban compound and preparing method thereof |
| CN106008490A (en) * | 2016-01-11 | 2016-10-12 | 南京生命能科技开发有限公司 | New crystal of rivaroxaban and preparation method thereof |
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| CN1906191A (en) * | 2004-01-15 | 2007-01-31 | 拜耳医药保健股份公司 | Preparation method |
| CN101282968A (en) * | 2005-10-04 | 2008-10-08 | 拜耳医药保健股份公司 | Novel polymorphous form and the amorphous form of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide |
| WO2011012321A1 (en) * | 2009-07-31 | 2011-02-03 | Krka, D.D., Novo Mesto | Processes for crystallization of rivaroxaban |
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| WO2012004245A1 (en) * | 2010-07-06 | 2012-01-12 | Sandoz Ag | Crystalline form of rivaroxaban dihydrate |
| EP2573084A1 (en) * | 2011-09-22 | 2013-03-27 | Enantia, S.L. | Novel crystalline forms of rivaroxaban and processes for their preparation |
| WO2013053739A1 (en) * | 2011-10-10 | 2013-04-18 | Laboratorios Lesvi, S. L. | Process for preparing factor xa inhibitors |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
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2014
- 2014-08-07 CN CN201410384619.7A patent/CN104211693B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1906191A (en) * | 2004-01-15 | 2007-01-31 | 拜耳医药保健股份公司 | Preparation method |
| CN101282968A (en) * | 2005-10-04 | 2008-10-08 | 拜耳医药保健股份公司 | Novel polymorphous form and the amorphous form of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide |
| CN102292332A (en) * | 2008-12-31 | 2011-12-21 | 阿普泰克斯药物化学公司 | Polymorphic form of 5-chloro-n-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide |
| WO2011012321A1 (en) * | 2009-07-31 | 2011-02-03 | Krka, D.D., Novo Mesto | Processes for crystallization of rivaroxaban |
| WO2012004245A1 (en) * | 2010-07-06 | 2012-01-12 | Sandoz Ag | Crystalline form of rivaroxaban dihydrate |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| EP2573084A1 (en) * | 2011-09-22 | 2013-03-27 | Enantia, S.L. | Novel crystalline forms of rivaroxaban and processes for their preparation |
| WO2013053739A1 (en) * | 2011-10-10 | 2013-04-18 | Laboratorios Lesvi, S. L. | Process for preparing factor xa inhibitors |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440028A (en) * | 2015-12-07 | 2016-03-30 | 石家庄康贺威药业有限公司 | Rivaroxaban compound and preparing method thereof |
| CN106008490A (en) * | 2016-01-11 | 2016-10-12 | 南京生命能科技开发有限公司 | New crystal of rivaroxaban and preparation method thereof |
| CN106008490B (en) * | 2016-01-11 | 2019-01-04 | 南京生命能科技开发有限公司 | A kind of new crystal of razaxaban and preparation method thereof |
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