CN103833755A - Crystal form B of Apixaban and preparation method thereof - Google Patents
Crystal form B of Apixaban and preparation method thereof Download PDFInfo
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- 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
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Abstract
The invention relates to a crystal form B of 4, 5, 6, 7-tetrahydro-1-(4-methoyxl phenyl)-7-oxo-6-[4-(2-oxo-1-piperidyl) phenyl]-1H-pyrazolo[3,4] pyridine-3-formamide (apixaban). The X-powder diffraction pattern of the crystal form is shown in the figure. The crystal form is good in solubleness and can be prepared into a formulation which is qualified to dissolve out without controlling the granularity in a micronizing manner. Meanwhile, the invention further provides two methods for preparing the crystal form. One method comprises the following step: carrying out ammonolysis on ester groups of a compound A under the effect of formamide and sodium alkoxide under a proper organic solvent condition to obtain crystal form B of Apixaban. The preparation method is simple and convenient and easy to amplify for industrialized production. The other method comprises the step of obtaining the crystal form B of apixaban by a non-crystal form B apixaban product by way of dissolution and crystallization, so that the crystal form is convenient to convert.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl] new crystal B and two kinds of different preparation methods thereof of-1H-pyrazolo [3,4-C] pyridine-3-carboxamide.
Background technology
Eliquis (Apixaban, BMS-562247), chemistry by name 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-1H-pyrazolo [3,4-C] pyridine-3-carboxamide, structural formula is as follows:
Eliquis is a kind of Xa factor avtive spot inhibitor of potent, orally active reversible, direct, highly selective, and its antithrombotic acitivity does not rely on Antithrombin III.Eliquis can suppress Xa factor free and that be combined with thrombus, and Trombin inhibiting original enzyme activity.Eliquis on platelet aggregation without direct impact, but the indirect platelet aggregation of anticoagulant enzyme induction.By the inhibition to Xa factor, the generation of Eliquis Trombin inhibiting, and suppress thrombosis.
Medicine polymorphism is one of important factor affecting drug quality and clinical efficacy, and therefore Eliquis polymorphic and technology of preparing thereof have very important significance as medicinal application for Eliquis.Patent documentation CN 101065379 B disclose the Eliquis of N-1 and two kinds of crystal habits of H2-2, and have provided the X-powdery diffractometry characteristic of two kinds of crystalline forms, as following table (2 θ):
| N-1 type | 10.0 | 10.6 | 12.3 | 12.9 | 18.5 | 27.1 |
| H2-2 type | 5.8 | 7.4 | 16.0 | 20.2 | 23.5 | 25.2 |
In two kinds of crystal habits, H2-2 type is not suitable for pharmaceutical preparation, need to transform into N-1 type by shear agitation and could be used for pharmaceutical preparation.Eliquis is a strong medicine of hydrophobicity, in water, solubleness is low, patent documentation CN102770126 A report need to carry out N-1 type just making pharmaceutical preparation after micronization, have enough strippings by granularity guarantee pharmaceutical preparation in certain scope of controlling bulk drug, preferred D90 is less than 25 μ m.As can be seen here, the Eliquis pharmaceutical preparation complexity of above-mentioned crystal formation, high to equipment requirements, particularly micronized granularity control is large to the quality influence of preparation.
Therefore all need a kind of solubleness high from the angle of producing and use, can be used for preparation without micronization, and the Eliquis new crystal that stripping is good, stability is high.
Summary of the invention
The invention provides one has than existing crystal formation H2-2 and the better Eliquis crystal form B of N-1; The present invention also provides the method for preparing Eliquis crystal form B.Eliquis crystal form B of the present invention is 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl] polymorphic of-1H-pyrazolo [3,4-C] pyridine-3-carboxamide.
For realizing above-mentioned technical purpose, the technical solution used in the present invention is as follows:
A kind of Eliquis crystal form B, the X-powder diagram of described Eliquis crystal form B is as shown in Figure of description 1.
Preferably, described Eliquis crystal form B uses Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 5.926 ± 0.2 °, 6.997 ± 0.2 °, 10.958 ± 0.2 °, 11.903 ± 0.2 °, 12.743 ± 0.2 °, 13.499 ± 0.2 °, 15.026 ± 0.2 °, 15.600 ± 0.2 °, 16.127 ± 0.2 °, 17.458 ± 0.2 °, 19.029 ± 0.2 °, 21.412 ± 0.2 °, 22.639 ± 0.2 °, 24.351 ± 0.2 °, 25.900 ± 0.2 °, 26.590 ± 0.2 °, 27.111 ± 0.2 °, 28.708 ± 0.2 °, 30.024 ± 0.2 °, 30.991 ± 0.2 °, 36.615 ± 0.2 °, 38.807 ± 0.2 °, 41.633 ± 0.2 °, locate diffraction peak for 42.705 ± 0.2 °.
The present invention also provides a kind of preparation method of Eliquis crystal form B, and the reaction formula of preparing Eliquis is as follows:
Concrete steps are:
(1) compd A, methane amide are joined in organic solvent, stirring heating, obtains the organic solvent solution containing compd A;
(2) in the compd A organic solvent solution of step (1), add trimethyl orthoformate and trifluoroacetic acid, mix and stir, lower the temperature;
(3) add again alcohol sodium solution, continue stir, through HPLC determine reacted after, stirring separatory adds water;
(4) concentrating under reduced pressure organic layer, remove portion solvent, cooling and crystallization, suction filtration, oven dry obtain product.
Here organic solvent is selected the solvent of middle polarity or lower polarity, preferred aromatic hydrocarbons, substituted arene, ether, ester, the non-protonic solvents such as halohydrocarbon, concrete solvent is selected from benzene, toluene, dimethylbenzene, chlorobenzene, dichlorobenzene, oil of mirbane, methyl-phenoxide, phenyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl malonate, diethyl malonate, methylene dichloride, trichloromethane, ethylene dichloride, one or more in Ethylene Dichloride and zellon.
Range of reaction temperature is preferably 0 ~ 100 DEG C, more preferably 0 ~ 50 DEG C; Crystalline range is preferably-20 ~ 50 DEG C, more preferably-10 ~ 30 DEG C.
The present invention also provides the preparation method of another Eliquis crystal form B, and by non-B crystal formation Eliquis product is obtained by dissolving crystallized mode, concrete steps are:
(1) in non-B crystal formation Eliquis, add in organic solvent, be heated with stirring to solid and all dissolve, obtain the organic solvent solution of Eliquis;
(2), by the Eliquis organic solvent solution in step (1), crystallisation by cooling, obtains Eliquis crystal form B product;
In step (2), preferably add Eliquis crystal form B as crystal seed, contribute to stably to obtain Eliquis crystal form B product.
The preferred alcohols of described organic solvent, aromatic hydrocarbons, substituted arene, ether, ester, halohydrocarbon, amides equal solvent, concrete organic solvent is selected from methyl alcohol, ethanol, ethylene glycol, propyl alcohol, Virahol, propylene glycol, glycerol, butanols, amylalcohol, hexanol, hexalin, benzene, toluene, dimethylbenzene, chlorobenzene, dichlorobenzene, oil of mirbane, methyl-phenoxide, phenyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl malonate, diethyl malonate, methylene dichloride, trichloromethane, ethylene dichloride, Ethylene Dichloride and zellon, methane amide, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, one or more in N-Methyl pyrrolidone.
In the time having the solvent miscible with water in the solvent using, in crystallizing system, can add water, to reduce the solubleness of Eliquis in solution, improve crystallization yield.
Technical solution of the present invention has following advantage: the Eliquis crystal form B 1, providing, and its solubleness is significantly improved compared with N-1 crystalline form; 2, its stripping of the pharmaceutical preparation of being prepared by Eliquis crystal form B is significantly improved compared with N-1 type, bulk drug need not be carried out to micronization and control granularity; 3, provide a kind of preparation method from compd A Eliquis crystal form B, its preparation method is easy, is easy to amplify carry out suitability for industrialized production; 4, provide a kind of Eliquis from non-B crystal formation by the dissolving crystallized method of preparing Eliquis crystal form B, be convenient to carry out the conversion of crystal formation.
Brief description of the drawings
The X-powder diagram that Figure 1 shows that Eliquis Type B crystal of the present invention, the longitudinal axis represents peak intensity, transverse axis represents diffraction angle (2 θ);
Fig. 2 is the stripping curve schematic diagram containing the pharmaceutical preparation of Eliquis crystal form B.
Embodiment
In order to make those skilled in the art, the present invention may be better understood, below in conjunction with drawings and Examples, technical solution of the present invention further illustrated.
Be illustrated in figure 1 the X-powder diagram of Eliquis crystal form B, wherein this Eliquis crystal form B uses Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 5.926 ± 0.2 °, 6.997 ± 0.2 °, 10.958 ± 0.2 °, 11.903 ± 0.2 °, 12.743 ± 0.2 °, 13.499 ± 0.2 °, 15.026 ± 0.2 °, 15.600 ± 0.2 °, 16.127 ± 0.2 °, 17.458 ± 0.2 °, 19.029 ± 0.2 °, 21.412 ± 0.2 °, 22.639 ± 0.2 °, 24.351 ± 0.2 °, 25.900 ± 0.2 °, 26.590 ± 0.2 °, 27.111 ± 0.2 °, 28.708 ± 0.2 °, 30.024 ± 0.2 °, 30.991 ± 0.2 °, 36.615 ± 0.2 °, 38.807 ± 0.2 °, 41.633 ± 0.2 °, locate diffraction peak (characteristic peak) for 42.705 ± 0.2 °.The reasonable measuring error scope that " ± 0.2 ° " representation feature peak position allows
Embodiment 1 ~ 5 is for being prepared the specific embodiment of Eliquis crystal form B by compd A.
embodiment 1:
In 1L reaction flask, drop into compd A (10g), add trichloromethane (600ml) and methane amide (100g), be heated with stirring to backflow, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5g), this mixture is continued to stir 30 minutes, be down to below 50 DEG C.Add the methanol solution (9g) of sodium methylate, determine and reacted through HPLC, add water 200ml, stir separatory.Concentrating under reduced pressure organic layer, removes 70% solvent, is cooled to 0 DEG C of crystallization, and suction filtration is dried and obtained 7.3g Eliquis B crystal formation product, yield 77.6%.
embodiment 2:
In 1L reaction flask, drop into compd A (5g), add toluene (600ml) and methane amide (100g), be heated with stirring to backflow, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5g), this mixture is continued to stir 30 minutes, be down to below 50 DEG C.Add the methanol solution (5g) of sodium methylate, determine and reacted through HPLC, add water 200ml, stir separatory.Concentrating under reduced pressure organic layer, removes 70% solvent, is cooled to 0 DEG C of crystallization, and suction filtration is dried and obtained 3.5g Eliquis B crystal formation product, yield 74.4%.
embodiment 3:
In 1L reaction flask, drop into compd A (10g), add tetrahydrofuran (THF) (300ml), ethyl acetate (300ml) and methane amide (100g), be heated with stirring to backflow, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5g), this mixture is continued to stir 30 minutes, be down to below 50 DEG C.Add the methanol solution (10g) of sodium methylate, determine and reacted through HPLC, add water 200ml, stir separatory.Concentrating under reduced pressure organic layer, removes 70% solvent, is cooled to 0 DEG C of crystallization, and suction filtration is dried and obtained 6.3g Eliquis B crystal formation product, yield 67%.
embodiment 4:
In 1L reaction flask, drop into compd A (10g), add tetrahydrofuran (THF) (300ml), methylene dichloride (300ml) and methane amide (100g), be heated with stirring to backflow, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5g), this mixture is continued to stir 30 minutes, be down to below 50 DEG C.Add the methanol solution (10g) of sodium methylate, determine and reacted through HPLC, add water 200ml, stir separatory.Concentrating under reduced pressure organic layer, removes 70% solvent, is cooled to 0 DEG C of crystallization, and suction filtration is dried and obtained 5.9g Eliquis B crystal formation product, yield 62.7%.
embodiment 5:
In 1L reaction flask, drop into compd A (5g), add glycol dimethyl ether (300ml), butylacetate (300ml) and methane amide (100g), be heated with stirring to backflow, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5g), this mixture is continued to stir 30 minutes, be down to below 50 DEG C.Add the methanol solution (5g) of sodium methylate, determine and reacted through HPLC, add water 200ml, stir separatory.Concentrating under reduced pressure organic layer, removes 70% solvent, is cooled to 0 DEG C of crystallization, and suction filtration is dried and obtained 3.2g Eliquis B crystal formation product, yield 68%.
Embodiment 6 ~ 13rd, is prepared the specific embodiment of Eliquis crystal form B by non-B crystal formation Eliquis.
embodiment 6:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (2g), add tetrahydrofuran (THF) (350ml), be heated with stirring to solid and all dissolve, be cooled to below 40 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, add 100ml water, continue to be cooled to 0 DEG C of crystallization, suction filtration, oven dry obtains 1.7g Eliquis B crystal formation product, yield 85%.
embodiment 7:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (2g), add methylene dichloride (350ml), being heated with stirring to solid all dissolves, be cooled to below 30 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, continue to be cooled to 0 DEG C of crystallization, suction filtration, dries and obtains 1.1g Eliquis B crystal formation product, yield 55%.
embodiment 8:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (3g), add toluene (350ml), being heated with stirring to solid all dissolves, be cooled to below 80 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, continue to be cooled to 0 DEG C of crystallization, suction filtration, dries and obtains 1.9g Eliquis B crystal formation product, yield 63%.
embodiment 9:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (3g), add ethylene glycol (350ml), be heated with stirring to solid and all dissolve, be cooled to below 60 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, add 150ml water, continue to be cooled to 0 DEG C of crystallization, suction filtration, oven dry obtains 2.2g Eliquis B crystal formation product, yield 73%.
embodiment 10:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (5g), add trichloromethane (150ml) and methane amide (50ml), be heated with stirring to solid and all dissolve, be cooled to below 50 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, add 150ml water, continue to be cooled to 0 DEG C of crystallization, suction filtration, oven dry obtains 4.3g Eliquis B crystal formation product, yield 86%.
embodiment 11:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (5g), add ethyl acetate (150ml) and DMF (50ml), be heated with stirring to solid and all dissolve, be cooled to below 60 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, add 150ml water, continue to be cooled to 0 DEG C of crystallization, suction filtration, dries and obtains 4.1g Eliquis B crystal formation product, yield 82%.
embodiment 12:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (5g), add ethanol (100ml) and N,N-dimethylacetamide (100ml), be heated with stirring to solid and all dissolve, be cooled to below 50 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, add 200ml water, continue to be cooled to 0 DEG C of crystallization, suction filtration, dries and obtains 3.7g Eliquis B crystal formation product, yield 74%.
embodiment 13:
In 500ml reaction flask, drop into non-B crystal formation Eliquis (5g), add methyl alcohol (150ml) and N-Methyl pyrrolidone (50ml), be heated with stirring to solid and all dissolve, be cooled to below 50 DEG C, add Eliquis B crystal formation crystal seed, slowly cool to room temperature, add 150ml water, continue to be cooled to 0 DEG C of crystallization, suction filtration, oven dry obtains 2.6g Eliquis B crystal formation product, yield 52%.
Following embodiment provide preparation 10000 (specification is: 2.5mg/ sheet) containing Eliquis crystal form B preparation proportioning and preparation method:
Table 1 is containing Eliquis crystal form B pharmaceutical preparation proportioning
Table 2 is containing Eliquis crystal form B pharmaceutical preparation proportioning
test case one:
Prepare N-1 crystal formation Eliquis with reference to the method in CN 101065379 B.
Gained N-1 crystal formation and B crystal formation Eliquis are put respectively in the medium (pH=1.2,4.5,6.8) of constant temperature at 37 DEG C and stirred, make its supersaturation, get saturated solution and filter, get subsequent filtrate and measure, by the concentration of external standard method calculating saturated solution, the results are shown in following table.
Test-results shows, N-1 and B crystal formation Eliquis are all with the increase of pH value, and solvability reduces; Wherein the dissolving of N-1 type in pH=1.2 ~ 6.8 is the highest only has 2.74mg/250ml; And the solvability of crystal form B between pH=1.2～6.8 is far above the solvability of N-1 type.
test case two:
With reference to dissolution rate testing method and the sample time of FDA, use USP device 2 (oar) method, with the 0.05M sodium phosphate (pH 6.8) that contains 0.05%SDS solution, as dissolution medium, (SDS (tensio-active agent) is acting as wetting aid to promote hydrophobicity Eliquis to be completed by the stripping of tablet in the dissolution medium of method in the back, instead of the solubleness of increase Eliquis), in 900mL dissolution medium, carry out stripping test at 37 ° of C in the speed of rotation of 75rpm.Test starts to remove sample and analyze Eliquis by HPLC at 280nm after 10,20,30,45,60 minutes.Stripping (external) test is using as quality control tools, and is more preferably used in biology (in the body) performance of the described tablet of prediction, wherein established in body-external relation (IVIVR).
Test stripping data are included in the present invention's record and unless otherwise mentioned, the result of report is the mean value from six tablets.
The dissolution data recording compares with import drugs and Comparative formulation (CN102770126A) respectively, and result is as following table:
Table 3 import drugs information
| Trade(brand)name | Specification | Lot number | Date manufactured | Validity period | Manufacturer |
| Ai Le appropriate (eliquis) | 2.5mg | 2M52276 | 201301 | 2015.12 | Bristol Myers Squibb |
The contrast of table 4 stripping curve
remarks:comparative formulation is to manufacture experimently with reference to patent of invention CN102770126A table 3 embodiment.
related substance test:
Known from the preparation process of above-described embodiment, the product yield of preparing according to the preparation method of the Eliquis described in the application is high, and preparation time is short, favorable reproducibility, the pharmaceutical preparation that adopts Eliquis crystal form B of the present invention to make has good stripping and stability, can be used for suitability for industrialized production.
Above Eliquis crystal form B provided by the invention and preparation method thereof is described in detail.The explanation of specific embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (6)
1. an Eliquis crystal form B, is characterized in that, the X-powder diagram of described Eliquis crystal form B is as shown in Figure of description 1.
2. Eliquis crystal form B according to claim 1, it is characterized in that, described Eliquis crystal form B uses Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 5.926 ± 0.2 °, 6.997 ± 0.2 °, 10.958 ± 0.2 °, 11.903 ± 0.2 °, 12.743 ± 0.2 °, 13.499 ± 0.2 °, 15.026 ± 0.2 °, 15.600 ± 0.2 °, 16.127 ± 0.2 °, 17.458 ± 0.2 °, 19.029 ± 0.2 °, 21.412 ± 0.2 °, 22.639 ± 0.2 °, 24.351 ± 0.2 °, 25.900 ± 0.2 °, 26.590 ± 0.2 °, 27.111 ± 0.2 °, 28.708 ± 0.2 °, 30.024 ± 0.2 °, 30.991 ± 0.2 °, 36.615 ± 0.2 °, 38.807 ± 0.2 °, 41.633 ± 0.2 °, locate diffraction peak for 42.705 ± 0.2 °.
3. a kind of preparation method of Eliquis crystal form B as claimed in claim 1, is characterized in that, is prepared by following reaction formula:
Concrete steps are:
(1) compd A, methane amide are joined in organic solvent, stirring heating, obtains the organic solvent solution containing compd A;
(2) in the compd A organic solvent solution of step (1), add trimethyl orthoformate and trifluoroacetic acid, mix and stir, lower the temperature;
(3) add again alcohol sodium solution, continue stir, through HPLC determine reacted after, stirring separatory adds water;
(4) concentrating under reduced pressure organic layer, remove portion solvent, cooling and crystallization, suction filtration, oven dry obtain product.
4. preparation method according to claim 3, it is characterized in that, described organic solvent is selected from benzene, toluene, dimethylbenzene, chlorobenzene, dichlorobenzene, oil of mirbane, methyl-phenoxide, phenyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl malonate, diethyl malonate, methylene dichloride, trichloromethane, ethylene dichloride, one or more in Ethylene Dichloride and zellon.
5. the another kind of preparation method of Eliquis crystal form B as claimed in claim 1, is characterized in that, obtains Eliquis crystal form B by dissolving crystallized mode, and concrete steps are:
(1) in non-B crystal formation Eliquis, add organic solvent, be heated with stirring to solid and all dissolve, obtain the organic solvent solution of Eliquis;
(2) in the Eliquis organic solvent solution of step (1), add Eliquis crystal form B as crystal seed, then crystallisation by cooling, obtains Eliquis crystal form B product.
6. preparation method according to claim 4, it is characterized in that, described solvent is selected from methyl alcohol, ethanol, ethylene glycol, propyl alcohol, Virahol, propylene glycol, glycerol, butanols, amylalcohol, hexanol, hexalin, benzene, toluene, dimethylbenzene, chlorobenzene, dichlorobenzene, oil of mirbane, methyl-phenoxide, phenyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl malonate, diethyl malonate, methylene dichloride, trichloromethane, ethylene dichloride, Ethylene Dichloride, zellon, methane amide, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, one or more in N-Methyl pyrrolidone.
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| CN104316637A (en) * | 2014-10-30 | 2015-01-28 | 江苏宝众宝达药业有限公司 | Method for determining apixaban cleaning residues by high performance liquid chromatography |
| CN104672233A (en) * | 2015-02-13 | 2015-06-03 | 河北科技大学 | Apixaban crystal form gamma and preparation method thereof |
| CN105037349A (en) * | 2015-05-04 | 2015-11-11 | 西安泰科迈医药科技有限公司 | Apixaban in [gamma]-crystal form and preparation method thereof |
| CN106986868A (en) * | 2016-01-21 | 2017-07-28 | 广东东阳光药业有限公司 | Eutectic comprising Eliquis and preparation method thereof |
| CN111377915A (en) * | 2018-12-30 | 2020-07-07 | 山东新时代药业有限公司 | Pyrazolo-pyridone compound crystal form D |
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