CN104211693B - Rivaroxaban crystalline form, preparation method and application - Google Patents
Rivaroxaban crystalline form, preparation method and application Download PDFInfo
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- CN104211693B CN104211693B CN201410384619.7A CN201410384619A CN104211693B CN 104211693 B CN104211693 B CN 104211693B CN 201410384619 A CN201410384619 A CN 201410384619A CN 104211693 B CN104211693 B CN 104211693B
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- C07—ORGANIC CHEMISTRY
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- 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
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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 to a kind of novel crystalline forms of anticoagulant active razaxaban
And preparation method thereof and the purposes in preparing anticoagulation medicine.
Background technology
Razaxaban (Rivaroxaban), its chemical name is the chloro- N- of 5- (((5S) -2- oxo -3- (4- (3- oxo
Quinoline -4- base) phenyl) -1,3-oxazoles quinoline -5- base) methyl) thiophene-2-carboxamide derivatives, its molecular formula is C19H18ClN3O5S, molecular weight
435.88.Structure is as shown in Equation 1：
Razaxaban (Rivaroxaban) is the new anticoagulant after research and development in 10 years for the Beyer Co., Ltd, is a kind of Gao Xuan
Selecting property, the oral drugs of direct inhibitive factor Xa.Endogenouss of blood coagulation waterfall and exogenous can be interrupted by inhibitive factor Xa
Approach, anticoagulant enzyme generation and thrombosiss.There is bioavailability high, treatment spectrum of disease is wide, and dose-effect relationship is stable, mouth
Clothes are convenient, the low feature of bleeding risk.From in September, 2008 first after Canada's listing, razaxaban is in the whole world more than 120
Country is granted.
In recent years, relevant razaxaban crystal formation and preparation method are rarely reported, and such as WO2007/039132 illustrates razaxaban
Polycrystalline state existence form, and disclose I crystal formation, II crystal formation, III crystal formation, amorphous, hydrate, NMP and THF solvated compoundses
Crystal formation characterize data and their preparation method；CN102292332A reports the APO-A novel crystal forms of razaxaban；
WO2011/012321 discloses multiple new methods preparing razaxaban I crystal formation；EP2404920A1 then discloses razaxaban
The preparation method of formic acid solvent compound and two hydrates and crystal formation data；Recently, EP2573084A1 reports razaxaban
The preparation method of B1, B2 and crystal form E and mutually conversion each other moreover it is possible to B1, B2 and E crystalline substance is 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 chemical combination of polycrystalline state
Thing, develops good water solubility, and the raw material of excellent in stability the razaxaban advantage medicinal crystal-form enabling industrialized great production is appointed
Weight road is remote, and the present invention can provide broader crystal formation to select space for the medicinal application of razaxaban.
Content of the invention
Inventor is through substantial amounts of experimentation it was surprisingly found that razaxaban new crystal form, the present invention
Found based on this and invent.
The present invention provides a kind of crystal form of razaxaban novel crystal forms IV, the X-ray powder diffraction figure bag of this novel crystal forms
It is contained 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 novel crystal forms IV be also included in 19.9 ± 0.2,21.9 ±
0.2nd, the peak of 29.3 ± 0.2 degree of 2 θ position.
Further, the X-ray powder diffraction figure of this razaxaban novel crystal forms IV be also included in 32.0 ± 0.2,33.6 ±
0.2nd, the peak of 35.6 ± 0.2,40.9 ± 0.2 degree of 2 θ position.
Further, above-mentioned razaxaban novel crystal forms IV, its X- powder diffraction feature with Prague 2 θ angle, interplanar distance d,
Relative intensity (being represented with the percent with respect to the strongest ray) and peak height (points/second) are expressed as follows：
| 2 θ angle (°) measured values | D interplanar distance measured value | Relative intensity (%) measured value | Peak height (points/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, is radiated using Cu-Ka in a specific embodiment, its with Prague 2 θ angle, interplanar distance d,
The x- powder diffraction that relative intensity (being represented with the percent with respect to the strongest ray) and peak height are represented has following data：
| 2 θ angle (°) measured values | D interplanar distance measured value | Relative intensity (%) measured value | Peak height (points/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 novel crystal forms IV of the present invention have X- powder diffraction spectrum and detection as shown in Figures 1 and 2
Data and.
Razaxaban novel crystal forms IV of the present invention detect at 47.75 DEG C through differential scanning calorimetric analysis (DSC) and
There is faint endothermic peak at 118.86 DEG C, and have strong endothermic peak at 231～233 DEG C, have and the collection of illustrative plates shown in Fig. 3.
Razaxaban novel crystal forms IV of the present invention have absorption molten through thermogravimetric heat analysis (TGA) detection at 47.75 DEG C
Agent loses, and has micro water of crystallization to lose at 118.86 DEG C, starts to decompose at 230 DEG C about, has and the figure shown in Fig. 4
Spectrum.
Present invention also offers a kind of preparation method preparing razaxaban novel crystal forms IV, the method comprises the following steps：
(1) razaxaban crude product is added in anhydrous formic acid, heating is molten clear；
(2) filter, obtain formic acid clear liquor；
(3) to Deca ethyl acetate, stirring and crystallizing in filtrate；
(4) mixture is cooled to after room temperature and is placed in stirring and crystallizing in ice-water bath；
(5) filter, ethyl acetate drip washing obtains white solid；
(6) it is dried, obtain the razaxaban of IV crystalline forms.
Heat molten clear temperature at 30～100 DEG C in step (1)；Preferably 50～80 DEG C.
In step (1), the inventory (ml) of anhydrous formic acid and razaxaban crude product quality (g) ratio are 2ml/g～20ml/g,
Preferably 3ml/g～7ml/g.
In step (3), the ratio of ethyl acetate and anhydrous formic acid is 1:1～5:1；Preferably 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 purposes in preparing anticoagulation medicine for the razaxaban novel crystal forms IV, described anticoagulation further
Medicine is mainly used in select a time hip joint or replacement knee in arthroplasty adult patients, to prevent venous thrombosis (VTE)；Also can use
In prevention non-valve artrial fibrillation patient's apoplexy and non-central nervous system's property thromboembolism, reduce coronary syndrome recurrence
Risk etc..
The above-mentioned preparation method that the present invention provides, obtained sample yield is good, purity high (HPLC purity >=99.5%).
This preparation method process is simple, easy to operate, mild condition, without special installation, it is more suitable for industrialized production.
Brief description
The accompanying drawing that the application includes is a composition part of description, and accompanying drawing is together with specification and claims
For the flesh and blood of the present invention, it is used for more fully understanding the present invention.
The x- powder diffraction spectrum of Fig. 1 razaxaban crystal formation IV
The x- powder diffraction gathered data of Fig. 2 razaxaban crystal formation IV
The DSC collection of illustrative plates of Fig. 3 razaxaban crystal formation IV
The TGA collection of illustrative plates of Fig. 4 razaxaban crystal formation IV
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but embodiments of the present invention not limited to this.
Embodiment 1
Prepare razaxaban crude product by patent documentation " CN1906191A ".
Razaxaban crude product 10g is added in 20ml anhydrous formic acid, is heated with stirring to 75 DEG C, completely molten filter afterwards clearly,
Obtain settled solution.Deca 150ml ethyl acetate, stirring and crystallizing in filtrate；Mixture is placed in ice-water bath after being cooled to room temperature
Stirring and crystallizing 1h；Filter, filter cake obtains 9.5g white solid in 45～55 DEG C of drying under reduced pressure to constant weight；Yield：95%, purity
99.91%.Sample detects consistent with Fig. 1, Fig. 2 through x- powder diffraction；DSC testing result is consistent with Fig. 3；TGA testing result with
Fig. 4 is consistent.
Embodiment 2
Razaxaban crude product 10g is added in 50ml anhydrous formic acid, is heated with stirring to 30 DEG C, completely molten filter afterwards clearly,
Obtain settled solution.Deca 150ml ethyl acetate, stirring and crystallizing in filtrate；Mixture is placed in ice-water bath after being cooled to room temperature
Stirring and crystallizing 2h；Filter, filter cake obtains 9.2g white solid in 45～55 DEG C of drying under reduced pressure to constant weight；Yield：92%, purity
99.93%.Sample detects consistent with Fig. 1, Fig. 2 through x- powder diffraction；DSC testing result is consistent with Fig. 3；TGA testing result with
Fig. 4 is consistent.
Embodiment 3
Razaxaban crude product 10g is added in 100ml anhydrous formic acid, is heated with stirring to 100 DEG C, completely molten rear clearly mistake
Filter, obtains settled solution.Deca 300ml ethyl acetate, stirring and crystallizing in filtrate；Mixture is placed in frozen water after being cooled to room temperature
Stirring and crystallizing 0.5h in bath；Filter, filter cake obtains 9.3g white solid in 45～55 DEG C of drying under reduced pressure to constant weight；Yield：93%,
Purity 99.91%.Sample detects consistent with Fig. 1, Fig. 2 through x- powder diffraction；DSC testing result is consistent with Fig. 3；TGA detection knot
Fruit is consistent with Fig. 4.
Embodiment 4
Razaxaban crude product 10g is added in 200ml anhydrous formic acid, is heated with stirring to 65 DEG C, completely molten filter afterwards clearly,
Obtain settled solution.Deca 200ml ethyl acetate, stirring and crystallizing in filtrate；Mixture is placed in ice-water bath after being cooled to room temperature
Stirring and crystallizing 1h；Filter, filter cake obtains 9.1g white solid in 45～55 DEG C of drying under reduced pressure to constant weight；Yield：91%, purity
99.92%.Sample detects consistent with Fig. 1, Fig. 2 through x- powder diffraction；DSC testing result is consistent with Fig. 3；TGA testing result with
Fig. 4 is consistent.
The razaxaban novel crystal forms IV of the present invention have blood coagulation resisting function, can apply to select a time hip joint or knee joint is put
Hand-off art adult patients, to prevent venous thrombosis (VTE)；Can also be used for preventing non-valve artrial fibrillation patient's apoplexy
With non-central nervous system's property thromboembolism, reduce risk of coronary syndrome recurrence etc..
Razaxaban IV type crystal formation of the present invention compared with published razaxaban I, II type and polymorph, IV type crystal formation
Dissolubility and heat stability be improved significantly, there is when oral more preferable bioavailability.
Razaxaban IV type crystal formation of the present invention can add any one acceptable pharmaceutic adjuvant to be prepared into pharmaceutically may be used
Accept any one dosage form, for example and unrestricted, the preparation of liquid form, the preparation of solid form, granule, tablet,
Capsule, ointment, gel, hydrogel adhesive and other known preparation.
Claims (3)
1. a kind of preparation method of razaxaban crystal formation IV, the X-ray powder diffraction figure of this crystal formation is included in 3.7 ± 0.2,7.3
The peak of ± 0.2,14.5 ± 0.2,18.2 ± 0.2 degree of 2 θ position it is characterised in that：
Razaxaban crude product is added in anhydrous formic acid, heating is molten to filter clearly to obtain formic acid clear liquor, Deca acetic acid thereto afterwards
Ethyl ester, stirring and crystallizing, then mixture is cooled to room temperature, is placed in stirring and crystallizing in ice-water bath；Filtration, drip washing obtain white solid
Body, is dried, obtains final product razaxaban IV crystalline forms.
2. preparation method as claimed in claim 1 it is characterised in that：Heating-up temperature at 30～100 DEG C, the feeding intake of anhydrous formic acid
Amount（ml）With razaxaban crude product quality（g）Than for 2ml/g～20ml/g.
3. the preparation method described in claim 1 it is characterised in that：The ratio of ethyl acetate and anhydrous formic acid is 1:1～5:1,
In ice-water bath, stirring and crystallizing temperature is 0～10 DEG C, keeps this temperature 0.5h～2h.
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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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| CN201410384619.7A CN104211693B (en) | 2014-08-07 | 2014-08-07 | Rivaroxaban crystalline form, preparation method and application |
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| CN104211693B true CN104211693B (en) | 2017-02-22 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105440028B (en) * | 2015-12-07 | 2018-03-13 | 石家庄康贺威药业有限公司 | A kind of razaxaban compound 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 |
| CN115536651A (en) * | 2021-12-15 | 2022-12-30 | 陕西汉江药业集团股份有限公司 | Preparation method of rivaroxaban |
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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 |
| 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 |
| 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 |
-
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 |
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