WO2014173377A2 - New crystalline forms of apixaban and a method of their preparation - Google Patents
New crystalline forms of apixaban and a method of their preparation Download PDFInfo
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- WO2014173377A2 WO2014173377A2 PCT/CZ2014/000041 CZ2014000041W WO2014173377A2 WO 2014173377 A2 WO2014173377 A2 WO 2014173377A2 CZ 2014000041 W CZ2014000041 W CZ 2014000041W WO 2014173377 A2 WO2014173377 A2 WO 2014173377A2
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- apixaban
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- 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
Definitions
- the invention relates to new crystalline forms of Apixaban of formula (I), chemically l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin- 1 -yl)phenyl]-4,5,6,7-tetrahydro- lH-pyrazolo[3,4- c]pyridine-3-carboxamide of formula I and a method of its preparation.
- Apixaban a substance having anticoagulant activity, which is indicated for treatment of both venous and arterial thromboembolism, was first described in EP 1 427 415, which describes the basic synthetic approaches to preparation of apixaban and similar molecules, and it also briefly describes pharmaceutical formulations.
- WO2006078331 describes two different forms of apixaban, apixaban dihydrate H2-2 and an anhydrous form identified as N-1 there.
- the examples included in this document indicate that the dihydrate is formed by crystallization from a water : polyethylene glycol mixture as needle-like crystals, which, after heating of the crystallizing matter in the presence of a crystallizing solvent and under treatment by an elevated temperature and/or intensive stirring, are transformed to the anhydrous form N-1. Crystals of the anhydrous form can be obtained in the desired particle size by controlling the crystallization conditions.
- Document WO2007001385 describes the same transformation of the dihydrate to the anhydrous form.
- Document US 20070203178 describes dimethyl formamide and formamide solvates of apixaban.
- Apixaban is very poorly soluble in water;
- document WO2011106478 indicates a solubility of only 40 nanog/ml and discusses dependence of the apixaban particle size during the preparation of a formulation by wet and dry granulation and their influence on the dissolution rate and bioavailability of the formulation.
- Form AP3 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 1.
- the diffractogram is shown in Fig. 2.
- Form AP4 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 2.
- the diffractogram is shown in Fig. 5.
- Form AP5 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 3.
- the diffractogram is shown in Fig. 8.
- Table 2 Characteristic diffraction peaks corresponding to form AP4 of apixaban.
- crystalline forms AP3, AP4 and AP5 of apixaban in accordance with this invention have been further characterized by differential scanning calorimetry DSC and thermogravknetry TGA.
- the results are summarized in Table 4.
- Figs. 3, 4, 6, 7, 9 and 10 present the respective DSC and TGA records of these forms.
- the TGA analysis of forms AP3, AP4 and AP5 indicates that all the forms contain 5 to 7% of water.
- the form AP4 contains ca. 13% of a solvent. This means that they are solvates.
- Table 4 DSC and TGA analysis of the crystalline forms of apixaban
- thermodynamic solubility of the known crystalline forms Nl and H2-2 and the new forms AP3, AP4 and AP5 were conducted.
- An Eppendorf Thermomixer Comfort shaker was used to carry out the experiments. The samples were dosed into Eppendorf tubes and stirred up with water. The experiments were performed at 37°C and the stirring speed of 900 rpm for 24 h. The results are summarized in Table 5.
- Table 5 Thermodynamic solubility values of crystalline forms of apixaban
- thermodynamic solubility results show that the thermodynamic solubility of crystalline form AP3 is more than double as compared to the anhydrous form Nl and nearly 80% higher than that of the dihydrate H2-2. So the assumption can be m ade that the bioavailability of the new crystalline forms AP3 and AP5 will be better, compared to the known forms Nl and H2-2.
- Fig. 1 Stability of individual crystalline forms
- Fig. 2 Diffractogram of apixaban form AP3
- Fig. 3 DSC record of apixaban form AP3
- Fig. 4 TGA record of apixaban form AP3
- Fig. 5 Diffractogram of apixaban form AP4
- Fig. 6 DSC record of apixaban form AP4
- Fig. 7 TGA record of apixaban form AP4
- Fig. 8 Diffractogram of apixaban form AP5
- Fig. 9 DSC record of apixaban form AP5
- Fig. 10 TGA record of apixaban form AP5
- the measurement was carried out using a flat powder sample that was placed on a Si plate.
- a 10 mm mask and a 1/4° fixed anti-dispersion diaphragm were used.
- the irradiated area of the sample was 10 mm, programmable divergence diaphn s were used.
- programmable divergence diaphn s were used for the correction of the secondary beam 0.02 rad Soller diaphragms and 5.0 mm anti- dispersion diaphragm were used.
- DSC measurements were conducted using a Perkin Elmer Pyris 1 DSC device. The samples were weighed and dosed into Al pots and measured in a nitrogen stream (4N 2 20 ml/min). The temperature program was set in the range of 50°C to 280°C at the heating rate op 10°C/min. The weight of the samples varied in the range of 3.2 to 3.4 mg.
- TGA was measured using a Perkin Elmer TGA 6 device. The samples were ⁇ eighed and dosed into ceramic pots and measured in a nitrogen stream (4N 2 20 ml/min). The TGA measurements were conducted in the temperature range of 25°C to 300°C at the heating rate of 10°C/min. The weight of the samples varied in the range of 18.5 to 21.2 mg.
- apixaban prepared in accordance with the method described in patent WO 2003/026652, in an amount of 200 mg (0.435 mmol) was dissolved apixaban in a hot state.
- the hot solution was abruptly cooled down to 0 to 5°C and maintained at this temperature for 18 to 24 h.
- the resulting suspension was filtered and) the product, crystalline form AP3, was dried in vacuo at the room temperature.
- apixaban prepared in accordance with the method described in patent WO 2003/026652, in an amount of 150 mg (0.326 mmol) was dissolved in 3 ml of chloroform under reflux. The clear solution was abruptly cooled down to 0 to 5°C and maintained at this temperature for 24 to 48 h. The resulting suspension was filtered and the product, crystalline form A5, was dried in vacuo at the room temperature.
- the individual crystalline forms H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg into an HPLC vial and suspended in 1 ml of a solvent, ethyl acetate or 2-propanol.
- the vials were placed in an HLC shaker and shaken at 900 rpm at the room temperature for 11 days.
- the solid residue was isolated by filtration and further characterized.
- the individual crystalline forms H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg onto Petri dishes and placed in a Memmert vacuum drier. The samples were heated up to 80°C at the ambient humidity and at the atmospheric pressure for 24 hours.
- the individual crystalline forms Nl, H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg into Eppendorf tubes and placed in the shaker.
- the samples were stirred at 900 rpm at 37°C for 24 h.
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The present invention relates to new crystalline forms of apixaban of formula (I), chemically 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 of formula I, and a method of their preparation. The concerned forms are AP3, AP4 and AP5.
Description
New crystalline forms of apixaban and a method of their preparation Technical Field The invention relates to new crystalline forms of Apixaban of formula (I), chemically l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin- 1 -yl)phenyl]-4,5,6,7-tetrahydro- lH-pyrazolo[3,4- c]pyridine-3-carboxamide of formula I and a method of its preparation.
Apixaban, a substance having anticoagulant activity, which is indicated for treatment of both venous and arterial thromboembolism, was first described in EP 1 427 415, which describes the basic synthetic approaches to preparation of apixaban and similar molecules, and it also briefly describes pharmaceutical formulations.
Synthesis of apixaban is also described in the later WO03049681.
WO2006078331 describes two different forms of apixaban, apixaban dihydrate H2-2 and an anhydrous form identified as N-1 there. The examples included in this document indicate that the dihydrate is formed by crystallization from a water : polyethylene glycol mixture as needle-like crystals, which, after heating of the crystallizing matter in the presence of a crystallizing solvent and under treatment by an elevated temperature and/or intensive stirring, are transformed to the anhydrous form N-1. Crystals of the anhydrous form can be obtained in the desired particle size by controlling the crystallization conditions.
Document WO2007001385 describes the same transformation of the dihydrate to the anhydrous form. Document US 20070203178 describes dimethyl formamide and formamide solvates of apixaban.
Apixaban is very poorly soluble in water; document WO2011106478 indicates a solubility of only 40 nanog/ml and discusses dependence of the apixaban particle size during the preparation of a formulation by wet and dry granulation and their influence on the dissolution rate and bioavailability of the formulation.
Disclosure of Invention
The invention provides three new crystalline forms of apixaban, identified as AP3, AP4, AP5. These forms have been characterized by means of X-ray powder diffraction with the use of CuKot radiation λ=0.1542 nm, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Thermodynamical properties (solubility, physical stability) of these new forms have also been studied.
Form AP3 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 1. The diffractogram is shown in Fig. 2. Form AP4 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 2. The diffractogram is shown in Fig. 5. Form AP5 in accordance with this invention is characterized by the reflections in the X-ray powder pattern presented in Table 3. The diffractogram is shown in Fig. 8. Table 1: Characteristic diffraction peaks corresponding to form AP3 of apixaban.
Relative
Position d-distance intensity
[°2Th.] [nm] [%]
5.85 1.4997 100.0
6.97 1.2673 14.8
11.84 0.7469 12.4
13.47 0.6570 35.5
15.01 0.5896 12.8
16.06 0.5514 32.3
17.45 0.5079 64.5
18.99 0.4669 21.2
20.44 0.4342 10.2
21.52 0.4126 38.7
22.64 0.3924 29.2
24.37 0.3650 16.2
25.92 0.3435 11.3
26.59 0.3349 5.4
27.15 0.3282 4.3
28.73 0.3105 4.2
30.02 0.2974 11.8
Table 2: Characteristic diffraction peaks corresponding to form AP4 of apixaban.
Relative
Position d-distance intensity
[°2Th.] [nm] [%}
5.44 1.6232 65.0
7.10 1.2437 67.9
10.49 0.8426 10.3
10.92 0.8096 17.8
12.75 0.6940 11.7
13.15 0.6726 12.4
15.16 0.5838 20.4
16.00 0.5536 39.9
17.69 0.5008 22.9
19.05 0.4656 29.3
20.28 0.4376 74.9
21.50 0.4130 79.8
22.72 0.3911 100.0
24.56 0.3621 43.5
25.17 0.3536 26.3
26.94 0.3307 16.6
31.09 0.2875 26.5
36.30 0.2473 12.2
Table 3: Characteristic diffraction peaks corresponding to form AP5 of apixaban.
The crystalline forms AP3, AP4 and AP5 of apixaban in accordance with this invention have been further characterized by differential scanning calorimetry DSC and thermogravknetry TGA. The results are summarized in Table 4. Figs. 3, 4, 6, 7, 9 and 10 present the respective DSC and TGA records of these forms. The TGA analysis of forms AP3, AP4 and AP5 indicates that all the forms contain 5 to 7% of water. In addition, the form AP4 contains ca. 13% of a solvent. This means that they are solvates.
Table 4: DSC and TGA analysis of the crystalline forms of apixaban
Properties of the newly prepared crystalline forms and their mutual thermodynamic relationships were studied, which were further compared to the described forms H2-2 and Nl. First, solvent and temperature influenced stability tests of the crystalline forms were conducted. The tests were carried out in an HLC shaker. The samples were dosed into HPLC vials and stirred up in ethyl acetate or 2-propanol. The experiments were carried out at 25°C and the stirring speed of 900 rpm for 11 days. The temperature influenced stability tests were performed in a Memmert vacuum drier without the presence of a solvent. The samples were dosed onto Petri dishes and placed in the drier for 24 hours. The test was conducted at 80°C and normal humidity at the atmospheric pressure.
Occurrence of the transformations shown in Fig. 1 has been observed.
Further on, tests of thermodynamic solubility of the known crystalline forms Nl and H2-2 and the new forms AP3, AP4 and AP5 were conducted. An Eppendorf Thermomixer Comfort shaker was used to carry out the experiments. The samples were dosed into Eppendorf tubes and stirred up with water. The experiments were performed at 37°C and the stirring speed of 900 rpm for 24 h. The results are summarized in Table 5. Table 5: Thermodynamic solubility values of crystalline forms of apixaban
List of drawings:
Fig. 1 : Stability of individual crystalline forms
Fig. 2: Diffractogram of apixaban form AP3
Fig. 3: DSC record of apixaban form AP3
Fig. 4: TGA record of apixaban form AP3
Fig. 5: Diffractogram of apixaban form AP4
Fig. 6: DSC record of apixaban form AP4
Fig. 7: TGA record of apixaban form AP4
Fig. 8: Diffractogram of apixaban form AP5
Fig. 9: DSC record of apixaban form AP5
Fig. 10: TGA record of apixaban form AP5
Experimental part:
Analytic methods:
X-ray powder diffraction
The diffractograms were obtained using an X'PERT PRO MPD PANahjtical powder diffractometer with a graphite monochromator, used radiation CuKa λ=0.1542 nm, excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 to 40° 20, increment: 0.01° 20 with the reflection dwell time of 50 s. The measurement was carried out using a flat powder sample that was placed on a Si plate. For the correction of the primary beam 0.02 rad Soller diaphragms, a 10 mm mask and a 1/4° fixed anti-dispersion diaphragm were used. The irradiated area of the sample was 10 mm, programmable divergence diaphn s were used. For the correction of the secondary beam 0.02 rad Soller diaphragms and 5.0 mm anti- dispersion diaphragm were used.
DSC:
DSC measurements were conducted using a Perkin Elmer Pyris 1 DSC device. The samples were weighed and dosed into Al pots and measured in a nitrogen stream (4N2 20 ml/min). The temperature program was set in the range of 50°C to 280°C at the heating rate op 10°C/min. The weight of the samples varied in the range of 3.2 to 3.4 mg.
TGA:
TGA was measured using a Perkin Elmer TGA 6 device. The samples were ^eighed and dosed into ceramic pots and measured in a nitrogen stream (4N2 20 ml/min). The TGA measurements were conducted in the temperature range of 25°C to 300°C at the heating rate of 10°C/min. The weight of the samples varied in the range of 18.5 to 21.2 mg.
Example 1
Preparation of crystalline l-(4-Memoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydrd-lH- pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban), prepared in accordance with the method described in patent WO 2003/026652, in an amount of 200 mg (0.435 mmol) was dissolved apixaban in a hot state. The hot solution was abruptly cooled down to 0 to 5°C and maintained at this temperature for 18 to 24 h. The resulting suspension was filtered and) the product, crystalline form AP3, was dried in vacuo at the room temperature.
Yield: 150 mg (75.0%)
Example 2
Preparation of crystalline form AP3 l-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide (apixaban), prepared in accordance with the method described in patent WO 2003/026652, in an amount of 200 mg (0.435 mmol) was dissolved in 0.4 ml of chloroform under reflux. The clear solution was left to spontaneously cool down to the room temperature. During slow evaporation of the solvent the crystalline form AP3 separated.
Yield: 182 mg (92.0%)
Example 3
Preparation of crystalline form AP4 l-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo|3,4- c]pyridine-3-carboxamide (apixaban), prepared in accordance with the method described in patent WO 2003/026652, in an amount of 150 mg (0.326 mmol) was dissolved in 3 ml of chloroform under reflux. The clear solution was abruptly cooled down to 5°C and maintained at this temperature for 1 week. The resulting suspension was filtered and ihe product, crystalline form AP4, was dried in vacuo at the room temperature.
Yield: 99 mg (66.0%)
Example 4
Preparation of crystalline form AP5
l-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4 c]pyridine-3-carboxamide (apixaban), prepared in accordance with the method described in patent WO 2003/026652, in an amount of 150 mg (0.326 mmol) was dissolved in 3 ml of chloroform under reflux. The clear solution was abruptly cooled down to 0 to 5°C and maintained at this temperature for 24 to 48 h. The resulting suspension was filtered and the product, crystalline form A5, was dried in vacuo at the room temperature.
Yield: 104 mg (69.0%)
Example 5
Solvent controlled change of the crystalline form
The individual crystalline forms H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg into an HPLC vial and suspended in 1 ml of a solvent, ethyl acetate or 2-propanol. The vials were placed in an HLC shaker and shaken at 900 rpm at the room temperature for 11 days. The solid residue was isolated by filtration and further characterized.
Example 6
Temperature controlled change of the crystalline form
The individual crystalline forms H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg onto Petri dishes and placed in a Memmert vacuum drier. The samples were heated up to 80°C at the ambient humidity and at the atmospheric pressure for 24 hours.
Example 7
Determination of thermodynamic solubility
The determination was conducted using an Eppendorf Thermomixer Comfort shaker. The individual crystalline forms Nl, H2-2, AP3, AP4 and AP5 were each dosed in an amount of 20 mg into Eppendorf tubes and placed in the shaker. The samples were stirred at 900 rpm at 37°C for 24 h.
Claims
1. Crystalline form AP3 of apixaban, which is characterized by the following reflections in the X-ray powder pattern: 5.9; 7.0; 13.5; 16.1; 17.5; 21.5 and 22.6 ± 0.2° 2Θ, measured using CuKa radiation λ=0.1542 nm.
2. Crystalline form AP3 of apixaban according to claim 1, which exhibits the main temperature onsets of 157.9 °C - exotherm and 232.9 - endotherm in differential scanning calorimetry DSC.
3. Crystalline form AP3 of apixaban according to claim 1, which exhibits the water content of 5% according to TGA.
4. Crystalline form AP4 of apixaban, which is characterized by the following reflections in the X-ray powder pattern: 5.4; 7.1; 16.0; 20.3; 21.5; 22.7 and 24.6 ± 0.2° 2Θ, measured using
CuKa radiation λ=0.1542 nm.
5. Crystalline form AP4 of apixaban according to claim 4, which exhibits the main temperature onsets of 154.8 °C - exotherm and 236.5 °C - endotherm in differential scanning calorimetry DSC.
6. Crystalline form AP4 of apixaban according to claim 4, which exhibits the water content of 6.7% and the solvent content of 12.9 % according to TGA.
7. Crystalline form AP5 of apixaban, which is characterized by the following reflections in the X-ray powder pattern: 5.1; 13.6; 16.1; 17.6; 21.5; 22.8 and 24.5 ± 0.2° 2Θ, measured using CuKa radiation λ=0.1542 nm.
8. Crystalline form AP5 of apixaban according to claim 7, which exhibits the main temperature onsets of 160.2 °C - exotherm and 235.2 °C - endotherm in differential scanning calorimetry.
9. Crystalline form AP5 of apixaban according to claim 7, which exhibits the water content of 5.5% and the solvent content of 1.3% according to TGA.
10. A process for the preparation of crystalline form AP3 as defined in claims 1 to 3, characterized in that apixaban is dissolved in acetonitrile in a hot state and then the clear solution is abruptly cooled down to 0 to 5°C.
11. The process according to claim 10, characterized in that 1 g of apixaban is dissolved in 30 to 40 ml of acetonitrile.
12. A process for the preparation of crystalline form AP3 defined in claim 1, characterized in that apixaban is dissolved in chloroform under reflux conditions and the clear solution is left to spontaneously cool down to the room temperature.
13. The process according to claim 12, characterized in that 1 g of apixaban is dissolved in 1 to 3 ml of chloroform.
14. A process for the preparation of crystalline form AP4 according to claims 4-6, comprising the steps of dissolution of apixaban in chloroform under reflux and abrupt cooling of the clear solution to 5°C and maintaining it at this temperature for 1 week.
15. The process according to claim 14, wherein 1 g of apixaban is dissolved in 18 to 22 ml of chloroform.
16. A process for the preparation of crystalline form AP5 according to claims 7-9, comprising the steps of dissolution of apixaban in chloroform under reflux and abrupt cooling of the clear solution to 0°C and maintaining it at this temperature for 1 to 2 days.
17. The process according to claim 16, wherein 1 g of apixaban is dissolved in 15 to 25 ml of chloroform.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZPV2013-305 | 2013-04-23 | ||
| CZ2013-305A CZ2013305A3 (en) | 2013-04-23 | 2013-04-23 | Novel crystalline forms of APIXABAN and process of their preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2014173377A2 true WO2014173377A2 (en) | 2014-10-30 |
| WO2014173377A3 WO2014173377A3 (en) | 2014-12-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CZ2014/000041 Ceased WO2014173377A2 (en) | 2013-04-23 | 2014-04-23 | New crystalline forms of apixaban and a method of their preparation |
Country Status (2)
| Country | Link |
|---|---|
| CZ (1) | CZ2013305A3 (en) |
| WO (1) | WO2014173377A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017088841A1 (en) | 2015-11-26 | 2017-06-01 | Zentiva, K.S. | Preparation of a drug form containing amorphous apixaban |
| 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 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003026652A1 (en) | 2001-09-21 | 2003-04-03 | Bristol-Myers Squibb Company | Lactam-containing compounds and derivatives thereof as factor xa inhibitors |
| WO2003049681A2 (en) | 2001-12-10 | 2003-06-19 | Bristol-Myers Squibb Company | Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2006078331A2 (en) | 2005-01-19 | 2006-07-27 | Bristol-Myers Squibb Company | Crystallization via high-shear transformation |
| WO2007001385A2 (en) | 2004-09-28 | 2007-01-04 | Bristol-Myers Squibb Company | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| US20070203178A1 (en) | 2004-09-28 | 2007-08-30 | Malley Mary F | Crystalline solvates of apixaban |
| WO2011106478A2 (en) | 2010-02-25 | 2011-09-01 | Bristol-Myers Squibb Company | Apixaban formulations |
-
2013
- 2013-04-23 CZ CZ2013-305A patent/CZ2013305A3/en unknown
-
2014
- 2014-04-23 WO PCT/CZ2014/000041 patent/WO2014173377A2/en not_active Ceased
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003026652A1 (en) | 2001-09-21 | 2003-04-03 | Bristol-Myers Squibb Company | Lactam-containing compounds and derivatives thereof as factor xa inhibitors |
| EP1427415A1 (en) | 2001-09-21 | 2004-06-16 | Bristol-Myers Squibb Company | Lactam-containing compounds and derivatives thereof as factor xa inhibitors |
| WO2003049681A2 (en) | 2001-12-10 | 2003-06-19 | Bristol-Myers Squibb Company | Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2007001385A2 (en) | 2004-09-28 | 2007-01-04 | Bristol-Myers Squibb Company | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| US20070203178A1 (en) | 2004-09-28 | 2007-08-30 | Malley Mary F | Crystalline solvates of apixaban |
| WO2006078331A2 (en) | 2005-01-19 | 2006-07-27 | Bristol-Myers Squibb Company | Crystallization via high-shear transformation |
| WO2011106478A2 (en) | 2010-02-25 | 2011-09-01 | Bristol-Myers Squibb Company | Apixaban formulations |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017088841A1 (en) | 2015-11-26 | 2017-06-01 | Zentiva, K.S. | Preparation of a drug form containing amorphous apixaban |
| 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 |
| CN111377915B (en) * | 2018-12-30 | 2023-10-24 | 鲁南制药集团股份有限公司 | Pyrazolo-pyridone compound crystal form D |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ2013305A3 (en) | 2014-11-05 |
| WO2014173377A3 (en) | 2014-12-24 |
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