CN104370902A - Apixaban novel crystal form and preparation method thereof - Google Patents
Apixaban novel crystal form and preparation method thereof Download PDFInfo
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- CN104370902A CN104370902A CN201310349409.XA CN201310349409A CN104370902A CN 104370902 A CN104370902 A CN 104370902A CN 201310349409 A CN201310349409 A CN 201310349409A CN 104370902 A CN104370902 A CN 104370902A
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- 239000013078 crystal Substances 0.000 title claims abstract description 160
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 111
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 229960003886 apixaban Drugs 0.000 title abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- 229940047562 eliquis Drugs 0.000 claims description 102
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 238000009835 boiling Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010013786 Dry skin Diseases 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 238000001228 spectrum Methods 0.000 abstract 2
- 230000015572 biosynthetic process Effects 0.000 description 65
- 238000005755 formation reaction Methods 0.000 description 65
- 230000000052 comparative effect Effects 0.000 description 19
- 239000012046 mixed solvent Substances 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000010008 shearing Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- -1 methane amide Chemical class 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 206010014522 Embolism venous Diseases 0.000 description 2
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- NUKZAGXMHTUAFE-UHFFFAOYSA-N hexanoic acid methyl ester Natural products CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical class [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel apixaban crystal form named as A-type, and a preparation method thereof. The disclosed apixaban crystal form A has a characteristic absorption peak in an X-ray powder diffraction spectrum and a characteristic absorption peak in a differential scanning calorimeter (DSC) spectrum. The crystal form is stable and does not absorb water. The preparation method is simple and has a good repeatability.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology.Be specifically related to be commonly called Eliquis (Apixaban), i.e. 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6, new crystal of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide and preparation method thereof.
Background technology
The Chinese of Eliquis (Apixaban) is called: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide, English by name:
1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide。Trade(brand)name: ELIQUIS.Structural formula is as follows:
Eliquis (Apixaban) is by Bristol-MyersSquibb(Bristol Myers Squibb) company's discovery, Hou You Pfizer (Pfizer) and Bristol-Myers Squibb Co.'s joint development.2011, European Union ratified it and uses in 27 member statess of European Union, occurs venous thromboembolism (VTE) event for preventing the adult patients accepting to select a time hip joint or knee replacements.FDA have approved this medicine and went on the market in the U.S. in December, 2012.
Eliquis (Apixaban) has multiple crystal formation, and WO03026652 first time discloses Eliquis and preparation method thereof.In US20060069258, first time openly reports polymorphic formH2-2(hydrate) and N-1(neat) two kinds of crystal formations.By react directly obtain for crystal formation H2-2, give also the method for transformation from crystal formation H2-2 to crystal formation N-1.At US20060069258(WO2007001385) report method polymorphic H2-2 being converted into N-1 crystal formation in patent families CN200580040778.4 embodiment 9, need first small quantities of H2-2 reaction solution to be put in transition tank shearing device to carry out shearing and stirring, H2-2 is changed into short grained N-1 stable crystal form, then large quantities of reaction solution is added shear-induced crystallization together.Therefore need special shearing device is installed.
US20070203178 patent protection crystal formation DMF-5 and FA-2, this two kinds of crystal formations can be used for preparing hydrate (H2-2) and N-1(neat) crystal formation.Crystal formation α is disclosed in WO2012168364.Crystal formation DMF-5, FA-2 and α can be converted into crystal formation N-1 under certain condition, but do not provide its method for transformation.
Now reporting in crystal formation, comparatively ambassador's used time need be converted into crystal formation N-1 to crystal formation H2-2 particle; Crystal formation DMF-5 and crystal formation FA-2 is respectively the crystal formation of DMF and FA solvation, and containing DMF and FA, high temperature is unstable; Crystal formation α is with electrostatic, and Yi Zhuanjing, is not suitable for preparation; Crystal formation N-1 stablizes, but its preparation technology needs special shearing device according to bibliographical information, just can obtain this crystal formation, and this shearing device does not also widely use at pharmacy field at present.
Wherein, the gimmick that crystallization art is conventional is induction crystallization.Induction crystallization generally needs crystal seed induction crystallization to refer to complete for a kind of solute clearly molten, obtains a whole clear soln.Then add required crystal seed in suitable temperature, slow cooling crystallization, obtain required crystal formation.Can therefore the preparation of crystal seed be most important, be the key that obtain the crystal formation wanted.Before the crystal seed not obtaining certain new crystal, certain solvent system often may separate out another crystal formation, and when add another crystal formation carry out inducing when, the crystal formation wanted can be changed into.
Summary of the invention
Technical problem to be solved by this invention is, by great many of experiments, work out a kind of stable novel Eliquis crystal formation, described crystal formation preparation method can supply industrialization.
The invention provides new crystal of a kind of Eliquis and preparation method thereof, this crystal formation called after A type.
Technical problem of the present invention is achieved by the following technical solution:
A kind of Eliquis crystal form A, its X-ray powder diffraction pattern is that 12.84 ± 0.2 °, 13.90 ± 0.2 °, 16.96 ± 0.2 °, 18.44 ± 0.2 °, 19.56 ± 0.2 ° and 32.74 ± 0.2 ° of places have characteristic peak at 2 θ.
Described Eliquis crystal form A has X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 1 substantially.
Described Eliquis crystal form A has substantially differential scanning calorimeter (DSC) collection of illustrative plates as shown in Figure 2.
DSC collection of illustrative plates shows: described Eliquis crystal form A has 235 ~ 242 DEG C of fusing endotherm(ic)peaks, and maximum heat absorption melt temperature is about 238 DEG C.
The test condition of DSC is: 30-300 DEG C, 10.0K/min, uncaps, nitrogen environment.
Described Eliquis crystal form A has substantially infrared (IR) collection of illustrative plates as shown in Figure 3.
Present invention also offers the preparation method of described Eliquis crystal form A, it comprises the steps:
(1) in room temperature under solvent boiling point temperature condition, dissolve in the organic solvent (namely 1g Eliquis is dissolved in 5 ~ 200mL organic solvent) Eliquis solid being joined 5 ~ 200 times of volume/weight ratio;
(2) at 0 ~ 150 DEG C, be preferably 40 ~ 150 DEG C, in step (1) gained solution, add the crystal seed of Eliquis crystal form A, be cooled to 0 ~ 30 DEG C, stir 0 ~ 48h, preferably 0.5 ~ 48h, obtain suspension liquid;
(3) solid is separated from suspension liquid;
(4) solid drying will be separated, obtains Eliquis crystal form A;
Wherein, the crystal seed of step (2) described Eliquis crystal form A is prepared by following method:
(2.1) in room temperature under solvent boiling point temperature condition, dissolve in the organic solvent (namely 1g Eliquis is dissolved in 5 ~ 400mL organic solvent) Eliquis solid being joined 5 ~ 400 times of volume/weight ratio;
(2.2) after solvent boiling point is incubated 0.5 hour ~ 10 hours, solution is slowly cooled to 0 ~ 30 DEG C, obtain a kind of suspension liquid;
(2.3) solid is separated from suspension liquid;
(2.4) by be separated solid 30 ~ 60 DEG C of dryings, obtain the crystal seed of Eliquis crystal form A.
Preferably,
Step (1) and step (2.1) described organic solvent independently be selected from ether, ester, ketone, alcoholic solvent or its combination; Ether solvent is wherein selected from methyl tertiary butyl ether (MTBE), ether, isopropyl ether or its combination; Esters solvent is selected from methyl-formiate, butyl formate, ethyl acetate, methyl acetate, butylacetate or its combination; Ketones solvent is selected from acetone, butanone or its combination; Alcoholic solvent is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols or its combination, and this alcohol also comprises moisture alcohol.
One or several the mixture of described organic solvent more preferably in methyl tertiary butyl ether, ether, acetone, ethyl acetate, methyl alcohol, ethanol, Virahol.
Organic solvent in step (1) and step (2.1) can disposablely add when being mixed solvent, adds another kind of organic solvent again after also first can adding a kind of organic solvent and Eliquis solids mixing.
Add the weight of the crystal seed of Eliquis crystal form A in step (2) for 1 ~ 50% of the Eliquis weight described in step (1), ensure that the crystal seed of Eliquis crystal form A is not completely dissolved.
Add the opportunity of the crystal seed of Eliquis crystal form A, need to add when basic saturation concentration, in order to avoid crystal seed dissolves, do not have inducing action.Substantially the saturated saturated solution referring to clarification, or have the undissolved Eliquis solid of a small amount of part.
The method be separated described in step (3) can comprise filtration, and washs with step (1) described organic solvent.
The method be separated described in step (2.3) can comprise filtration, and washs with step (2.1) described organic solvent.
Drying described in step (4), can use conventional drying, such as loft drier etc., temperature range is not limit, and is preferably 30-80 DEG C.
Room temperature of the present invention is about 25 DEG C.The boiling temperature that described solvent boiling point temperature is added organic solvent.
Of the present inventionly prepare that Eliquis polymorphic A is reproducible, easy and simple to handle, product utilization rate is high, purity is high, be applicable to suitability for industrialized production.
Eliquis crystal form A of the present invention is not containing crystal water and solvent, not static electrification, and have good stability, nonhygroscopic, its character is obviously better than the crystal formations such as crystal formation H2-2 of the prior art, crystal formation DMF-5, crystal formation FA-2, crystal formation α.According to existing bibliographical information, crystal formation DMF-5, crystal formation FA-2 can remain corresponding DMF(N, dinethylformamide) and methane amide; And crystal formation H2-2 is hydrate, grain size number is large, is not suitable for preparation; Crystal formation α static electrifications etc., are not suitable for preparation process requirement.
And the Eliquis crystal form A that the present invention relates to, its preparation method is simple, by crystallization and crystal seed induced crystallization, technique does not need specific installation.And in CN200580040778.4 embodiment 9, disclose the preparation method of Eliquis crystal formation N-1, it needs the slurry of Eliquis H2-2 to transfer in transition tank, change into short grained N-1 crystal after shearing after being heated to 55-60 DEG C, need through special shearing technique and and relevant device.Compared with crystal formation N-1, the preparation method of Eliquis crystal form A of the present invention is obviously simple, does not need specific installation, does not need, via other transformation of crystals, to reduce costs, workable.
Accompanying drawing explanation
The XRPD collection of illustrative plates of Fig. 1 embodiment 3 Eliquis A crystal formation;
The DSC collection of illustrative plates of Fig. 2 embodiment 3 Eliquis A crystal formation;
The IR collection of illustrative plates of Fig. 3 embodiment 3 Eliquis A crystal formation;
The DSC collection of illustrative plates of 6 days is placed in the illumination of Fig. 4 embodiment 3 Eliquis crystal form A;
Fig. 5 embodiment 3 Eliquis crystal form A high temperature places the DSC collection of illustrative plates of 6 days;
Fig. 6 embodiment 3 Eliquis crystal form A high humidity places the DSC collection of illustrative plates of 6 days;
The DSC collection of illustrative plates of Fig. 7 comparative example 4 Eliquis crystal formation α;
The DSC collection of illustrative plates of Fig. 8 comparative example 3 Eliquis crystal formation H2-2;
The DSC collection of illustrative plates of Fig. 9 comparative example 1 Eliquis crystal formation DMF-5;
The DSC collection of illustrative plates of Figure 10 comparative example 2 Eliquis crystal formation FA-2.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited thereto.
Analyzing and testing condition of the present invention is as follows:
1, X-ray powder diffraction is recorded by RigakuD/max2550VB-pc diffractometer, adopts Cu/K-alphal (λ=1.540598
) radiation, power: 40kV × 100mA gathers associated diffraction data in 2 θ 3 °-40 ° (or 2 °-40 °) scope, walks wide 0.02 °, sweep velocity 6 °/min.
2, DSC is detected by the resistance to DSC200F3 that speeds of Germany, and temperature range 30-300 DEG C, heat-up rate 10.0K/min, hole is pricked in sealing, nitrogen environment.
3, infrared spectra (IR) is detected by PEspectrumRXI, and temperature is 23 DEG C, and humidity is 54%.
In the Eliquis referenced patent CN1639147 used in the embodiment of the present invention prepared by embodiment 56.
The preparation of the crystal seed of embodiment 1 Eliquis crystal form A
0.5g Eliquis is joined in 150mL ethyl acetate, temperature is risen to 78 DEG C, be stirred to and obtain settled solution, insulated and stirred 1 hour, is cooled to 25 DEG C, stirs 48h, filter, with the washing of 1mL ethyl acetate, dry to obtain the crystal seed of Eliquis crystal form A 30 DEG C of air blast.
The preparation of the crystal seed of embodiment 2 Eliquis crystal form A
0.5g Eliquis is joined in the mixed solvent (volume ratio of ethanol and ethyl acetate is 4:1) of 13mL ethanol and ethyl acetate, temperature is risen to 78 DEG C, be stirred to and obtain settled solution, insulated and stirred 1 hour, be cooled to 25 DEG C, stir 3h, filter, wash with the mixed solvent (volume ratio of ethanol and ethyl acetate is 4:1) of 0.5mL ethanol and ethyl acetate, dry to obtain the crystal seed of Eliquis crystal form A 30 DEG C of air blast.
The preparation of the crystal seed of embodiment 3 Eliquis crystal form A
0.5g Eliquis is joined in the mixed solvent (volume ratio of methyl alcohol and MTBE is 1:2) of 22.5mL methyl alcohol and methyl tertiary butyl ether, temperature is risen to 60 DEG C, insulated and stirred 1 hour, be cooled to 25 DEG C, stir 3h, filter, wash with the mixed solvent (methyl alcohol and MTBE volume ratio are 1:2) of 1mL methyl alcohol and MTBE, dry to obtain the crystal seed of Eliquis crystal form A 30 DEG C of air blast.
The preparation of the crystal seed of embodiment 4 Eliquis crystal form A
0.5g Eliquis is joined in 7.5mL methyl alcohol, temperature is risen to 60 DEG C, insulated and stirred 1 hour, add 15mL methyl tertiary butyl ether, insulated and stirred 1.5 hours, is cooled to 25 DEG C, stir 3h, filter, wash with the mixed solvent (methyl alcohol and MTBE volume ratio are 1:2) of 1mL methyl alcohol and MTBE, dry to obtain the crystal seed of Eliquis crystal form A 30 DEG C of air blast.
The preparation of the crystal seed of embodiment 5 Eliquis crystal form A
0.5g Eliquis is joined in the mixed solvent (volume ratio of methyl alcohol and MTBE is 1:2) of 7.5mL methyl alcohol and methyl tertiary butyl ether, temperature is risen to 60 DEG C, insulated and stirred 1 hour, be cooled to 25 DEG C, stir 3h, filter, wash with the mixed solvent (methyl alcohol and MTBE volume ratio are 1:2) of 1mL methyl alcohol and MTBE, dry to obtain the crystal seed of Eliquis crystal form A 30 DEG C of air blast.
The preparation of embodiment 6 Eliquis crystal form A
0.2g Eliquis is joined in the mixed solvent (volume ratio of acetone and ethanol is 1:2) of 12mL acetone and ethanol, temperature is risen to 70 DEG C, stir, and add the crystal seed of the Eliquis crystal form A of embodiment 3 gained, naturally cooling, be cooled to 25 DEG C, stir 3h, filter, wash with the mixed solvent (volume ratio of acetone and ethanol is 1:2) of 1mL acetone and ethanol, dry to obtain Eliquis crystal form A 30 DEG C of air blast.
The preparation of embodiment 7 Eliquis crystal form A
0.2g Eliquis is joined in 20mL Virahol, temperature is risen to 82 DEG C, stir, and add the crystal seed of the Eliquis crystal form A of embodiment 3 gained, naturally cooling, is cooled to 25 DEG C, stirs 3h, filter, use 0.5mL washed with isopropyl alcohol, dry to obtain Eliquis crystal form A 30 DEG C of air blast.
The preparation of embodiment 8 Eliquis crystal form A
0.4g Eliquis is joined in the ethanol of 8mL95%, temperature is risen to 78 DEG C, stir, and add the crystal seed of the Eliquis crystal form A of embodiment 3 gained, naturally cooling, is cooled to 25 DEG C, stirs 16h, filter, by the washing with alcohol of 0.5mL95%, dry to obtain Eliquis crystal form A 30 DEG C of air blast.
The preparation of comparative example 1 crystal formation DMF-5
In the Eliquis crystal formation DMF-5 referenced patent US2007/0203178 used in the present invention prepared by embodiment 1.
The preparation of comparative example 2 crystal formation FA-2
In the Eliquis crystal formation FA-2 referenced patent US2007/0203178 used in the present invention prepared by embodiment 1.
The preparation of comparative example 3 crystal formation H2-2
In the Eliquis crystal formation H2-2 referenced patent CN200580040778.4 used in the present invention prepared by embodiment 9.
The preparation of comparative example 4 crystal formation α
In the Eliquis crystal formation α referenced patent WO2012168364 used in the present invention prepared by embodiment 7.
Test case 1 electrostatic detection
Contact with the glass stick after friction the Eliquis crystal formation that various embodiment 3 and comparative example 1-4 obtain respectively, observe whether static electrification, the results are shown in Table 1.
The electrostatic detection result of each crystal formation of table 1 Eliquis
| Crystal formation type | Embodiment 3 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 |
| Electrostatic | Nothing | Nothing | Nothing | Nothing | Have |
Test case 2DSC collection of illustrative plates
Measure the DSC collection of illustrative plates of the Eliquis crystal formation of embodiment 3 and comparative example 1-4 acquisition respectively, the results are shown in Figure 2 and Fig. 9,10,8,7.
The DSC collection of illustrative plates display of the Eliquis crystal formation FA-2 of comparative example 1 Eliquis crystal formation DMF-5 and comparative example 2, the Eliquis crystal formation DMF-5 of the comparative example 1 and Eliquis crystal formation FA-2 of comparative example 2 is respectively at DMF(N, dinethylformamide) and FA(methane amide) there is a broad peak near boiling point, see Fig. 9-10, prove that it contains solvent DMF and FA, and DMF(boiling point 153 DEG C) and methane amide (boiling point 210 DEG C) boiling point high, be not easy to be removed by drying.
The DSC collection of illustrative plates display of comparative example 3 Eliquis crystal formation H2-2, except having except endotherm(ic)peak at 235 ~ 242 DEG C, having different heat absorption and release peaks respectively, seeing Fig. 8, prove that it is stable not before 200 DEG C.
And the DSC collection of illustrative plates display of the Eliquis crystal form A of the embodiment of the present invention 3 gained, it only has 235 ~ 242 DEG C of fusing endotherm(ic)peaks, and maximum heat absorption melt temperature is about 238 DEG C, other positions do not find any heat absorption and release peak, prove that it is stablized, not sticky solvent and water, do not occur to turn brilliant, see Fig. 2.
Test case 3 Detection of Stability
The Eliquis crystal formation of embodiment 3 gained is placed in illumination, high temperature or high humidity environment respectively, within 6 days, is DSC respectively after placement and detects.
Test condition is:
Illumination condition: exposure intensity 5000Lux;
Hot conditions: temperature 60 C;
The saturated potassium nitrate solution of super-humid conditions: humidity 95%(), temperature 25 DEG C.
Result shows:
The Eliquis crystal form A of embodiment 3 place 0 day consistent with the DSC spectrogram placing 6 days, as Fig. 4-6, there is no the moisture absorption, any change do not occur, prove at its stable crystal form of this condition.
The above; be 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 disclosed technical scope; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.
Claims (10)
1. an Eliquis crystal form A, is characterized in that: its X-ray powder diffraction pattern is that 12.84 ± 0.2 °, 13.90 ± 0.2 °, 16.96 ± 0.2 °, 18.44 ± 0.2 °, 19.56 ± 0.2 ° and 32.74 ± 0.2 ° of places have characteristic peak at 2 θ.
2. Eliquis crystal form A as claimed in claim 1, is characterized in that: have XRPD collection of illustrative plates as shown in Figure 1 substantially.
3. Eliquis crystal form A as claimed in claim 1, is characterized in that: its DSC collection of illustrative plates has 235 ~ 242 DEG C of fusing endotherm(ic)peaks.
4. Eliquis crystal form A as claimed in claim 3, is characterized in that: have DSC collection of illustrative plates as shown in Figure 2 substantially.
5. Eliquis crystal form A as claimed in claim 1, is characterized in that: have IR collection of illustrative plates as shown in Figure 3 substantially.
6. the preparation method of Eliquis crystal form A according to any one of claim 1-5, it comprises the steps:
(1) in room temperature under solvent boiling point temperature condition, Eliquis solid is joined in the organic solvent of 5 ~ 200 times of volume/weight ratio and dissolves;
(2) at 0 ~ 150 DEG C, in step (1) gained solution, add the crystal seed of Eliquis crystal form A, be cooled to 0 ~ 30 DEG C, stir 0 ~ 48h, obtain suspension liquid;
(3) solid is separated from suspension liquid;
(4) solid drying will be separated, obtains Eliquis crystal form A;
Wherein, the crystal seed of step (2) described Eliquis crystal form A is prepared by following method:
(2.1) in room temperature under solvent boiling point temperature condition, Eliquis solid is joined in the organic solvent of 5 ~ 400 times of volume/weight ratio and dissolves;
(2.2) after solvent boiling point is incubated 0.5 hour ~ 10 hours, solution is slowly cooled to 0 ~ 30 DEG C, obtain a kind of suspension liquid;
(2.3) solid is separated from suspension liquid;
(2.4) by be separated solid 30 ~ 60 DEG C of dryings, obtain the crystal seed of Eliquis crystal form A.
7. preparation method as claimed in claim 6, it is characterized in that: described step (1) and the organic solvent described in step (2.1) independently be selected from one in methyl tertiary butyl ether, ether, isopropyl ether, methyl-formiate, butyl formate, ethyl acetate, methyl acetate, butylacetate, acetone, butanone, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols or its mixture, be preferably one or several the mixture in methyl tertiary butyl ether, ether, acetone, ethyl acetate, methyl alcohol, ethanol, Virahol.
8. preparation method as claimed in claim 6, is characterized in that: 1 ~ 50% of the weight that the weight adding the crystal seed of Eliquis crystal form A in described step (2) is the Eliquis described in step (1), the crystal seed of Eliquis crystal form A is not completely dissolved.
9. preparation method as claimed in claim 6, is characterized in that: the method for the separation described in described step (3) comprises filtration, and washs with step (1) described organic solvent.
10. preparation method as claimed in claim 6, is characterized in that: the method for the separation described in described step (2.3) comprises filtration, and washs with step (2.1) described organic solvent.
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| CN201310349409.XA CN104370902A (en) | 2013-08-12 | 2013-08-12 | Apixaban novel crystal form and preparation method thereof |
| PCT/CN2014/084155 WO2015021902A1 (en) | 2013-08-12 | 2014-08-12 | Novel apixaban crystal form and preparation method thereof |
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| CN201310349409.XA CN104370902A (en) | 2013-08-12 | 2013-08-12 | Apixaban novel crystal form and preparation method thereof |
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| WO2021056850A1 (en) * | 2019-09-26 | 2021-04-01 | 浙江天宇药业股份有限公司 | Eutectic crystal formed by apixaban and carboxylic acid, and preparation method therefor |
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| AR122679A1 (en) | 2020-06-23 | 2022-09-28 | Guilherme Savoi | COCRYSTALS DERIVED FROM APIXABÁN |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060160841A1 (en) * | 2005-01-19 | 2006-07-20 | Chenkou Wei | Crystallization via high-shear transformation |
| US20070203178A1 (en) * | 2004-09-28 | 2007-08-30 | Malley Mary F | Crystalline solvates of apixaban |
| CN101065379A (en) * | 2004-09-28 | 2007-10-31 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2012168364A1 (en) * | 2011-06-10 | 2012-12-13 | Dipharma Francis S.R.L. | Apixaban preparation process |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744461A (en) * | 2001-09-21 | 2015-07-01 | 百时美施贵宝公司 | Lactam-containing compounds and derivatives thereof as factor Xa inhibitors |
| US7396932B2 (en) * | 2004-09-28 | 2008-07-08 | Bristol-Myers Squibb Company | Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones |
| WO2013119328A1 (en) * | 2012-02-07 | 2013-08-15 | Assia Chemical Industries Ltd. | Solid state forms of apixaban |
| CN104797580A (en) * | 2012-10-10 | 2015-07-22 | 广东东阳光药业有限公司 | Crystal form or amorphous form of apixaban and preparation process thereof |
| EP2752414A1 (en) * | 2013-01-04 | 2014-07-09 | Sandoz AG | Crystalline form of apixaban |
| CN103539795A (en) * | 2013-03-18 | 2014-01-29 | 齐鲁制药有限公司 | Apixaban polymorph and preparation method thereof |
| CN103360391B (en) * | 2013-08-06 | 2015-03-25 | 齐鲁制药有限公司 | Novel apixaban crystal form and preparation method thereof |
-
2013
- 2013-08-12 CN CN201310349409.XA patent/CN104370902A/en active Pending
-
2014
- 2014-08-12 WO PCT/CN2014/084155 patent/WO2015021902A1/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070203178A1 (en) * | 2004-09-28 | 2007-08-30 | Malley Mary F | Crystalline solvates of apixaban |
| CN101065379A (en) * | 2004-09-28 | 2007-10-31 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| US20060160841A1 (en) * | 2005-01-19 | 2006-07-20 | Chenkou Wei | Crystallization via high-shear transformation |
| WO2012168364A1 (en) * | 2011-06-10 | 2012-12-13 | Dipharma Francis S.R.L. | Apixaban preparation process |
Non-Patent Citations (3)
| Title |
|---|
| ANONYMOUSLY: "Solid state forms of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide", 《IP.COM JOURNAL》, vol. 12, no. 4, 25 March 2012 (2012-03-25), pages 1 - 5 * |
| ANONYMOUSLY: "Solid state forms of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide", 《IP.COM JOURNAL》, vol. 12, no. 5, 23 April 2012 (2012-04-23), pages 1 - 5 * |
| ANONYMOUSLY: "Solid state forms of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide", 《IP.COM JOURNAL》, vol. 13, no. 5, 9 May 2013 (2013-05-09), pages 1 - 5 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021056850A1 (en) * | 2019-09-26 | 2021-04-01 | 浙江天宇药业股份有限公司 | Eutectic crystal formed by apixaban and carboxylic acid, and preparation method therefor |
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