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Apixaban crystal form and preparation method thereof

A technology of apixaban and crystal form, applied in the field of anticoagulant drugs, co-crystals and their preparation, can solve the problems of chemical stability and hygroscopicity and other physical and chemical druggability characteristics without further relevant reports, and achieve shortening The production cycle, the reduction of production energy consumption, and the effect of facilitating the processing and production of preparations

Active Publication Date: 2021-10-26
GUANGZHOU BAIYUSN TIANXIN PHARMA
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  • Description
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Problems solved by technology

[0008] Guangdong East Sunshine Pharmaceutical Co., Ltd. announced the apixaban-oxalic acid co-crystal, apixaban-isonicotine co-crystal, apixaban-3-aminopyridine co-crystal in the Chinese patent application number CN201710025644.X, There are four co-crystals of apixaban-urea co-crystal, but there is no further report on the physical and chemical properties of these four co-crystals such as saturation solubility, chemical stability and hygroscopicity

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  • Apixaban crystal form and preparation method thereof
  • Apixaban crystal form and preparation method thereof
  • Apixaban crystal form and preparation method thereof

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Effect test

Embodiment 1

[0040] Preparation of Apixaban Nicotinic Acid Monohydrate Cocrystal

[0041] Apixaban N-1 crystal form is prepared by the method disclosed in the patent US2006 / 0160841.

[0042] Add 0.182g of nicotinic acid and 0.68g of apixaban into 7ml of 0.5% water-containing trifluoroethanol, stir at 30°C for 24 hours, then add 15ml of ethyl acetate dropwise, stir at the same temperature for 30 minutes, filter to obtain white crystals, and place in a drying oven Vacuum-dried at 40°C for 4 hours to obtain 0.66 g of white crystals. The molar yield is 74%. Melting point: 191.0~197℃. 1 H NMR (500MHz, DMSO-d 6 )δ: 13.42(s, 1H), 9.06(s, 1H), 8.77(d, J=3.8Hz, 1H), 8.25(d, J=7.9Hz, 1H), 7.70(s, 1H), 7.53( dd,J=7.8,4.9Hz,1H),7.49(d,J=8.8Hz,2H),7.43(s,1H),7.33(d,J=8.6Hz,2H),7.26(d,J=8.6 Hz, 2H), 6.98(d, J=8.9Hz, 2H), 4.03(t, J=6.5Hz, 2H), 3.78(s, 3H), 3.57(t, J=5.5Hz, 2H), 3.19( t, J = 6.5Hz, 2H), 2.37 (t, J = 6.2Hz, 2H), 1.82 (dd, J = 12.4, 7.1Hz, 4H). 13 C NMR (125MHz, DMSO-d 6 )δ: 168.9, ...

Embodiment 2

[0055] Apixaban N-1 crystal form is prepared by the method disclosed in the patent US2006 / 0160841.

[0056] Add 0.182g of nicotinic acid and 0.68g of apixaban into 7ml of 0.5% water-containing trifluoroethanol, stir at 20°C for 24 hours, then add 15ml of acetone dropwise, stir at the same temperature for 30 minutes, filter to obtain white crystals, and place them in a drying oven for 40 °C and vacuum-dried for 4 hours to obtain 0.75 g of white crystals. The molar yield is 84%. Melting point: 191.0~197℃.

[0057] The obtained crystals were analyzed by X-ray powder diffraction spectrum, and the 2θ values ​​of the characteristic absorption peaks were located at 5.7±0.2゜, 6.0±0.2゜, 11.5±0.2゜, 13.3±0.2゜, 15.4±0.2゜, 15.8±0.2゜, 17.5± 0.2°, 17.7±0.2°, 20.0±0.2°, 22.1±0.2°, 23.4±0.2°. and figure 1 The result is almost the same.

[0058] Differential scanning calorimetry (DSC) test analysis showed that the first endothermic peak was the loss of crystallization water peak at 60±2°C...

Embodiment 3

[0060] Apixaban N-1 crystal form is prepared by the method disclosed in Chinese patent ZL200580040778.4.

[0061] Add 0.182g of nicotinic acid and 0.68g of apixaban into 4ml of 0.5% water-containing trifluoroethanol, stir at 40°C for 24 hours, then add 6ml of acetone, stir at the same temperature for 2 hours, filter to obtain white crystals, and place in a drying oven Vacuum-dried at 40°C for 4 hours to obtain 0.79 g of white crystals. The molar yield is 89%. Melting point: 191.0~197℃.

[0062] The obtained crystals were analyzed by X-ray powder diffraction spectrum, and the 2θ values ​​of the characteristic absorption peaks were located at 5.7±0.2゜, 6.0±0.2゜, 11.5±0.2゜, 13.3±0.2゜, 15.4±0.2゜, 15.8±0.2゜, 17.5± 0.2°, 17.7±0.2°, 20.0±0.2°, 22.1±0.2°, 23.4±0.2°. and figure 1 The result is almost the same.

[0063] Differential scanning calorimetry (DSC) test analysis showed that the first endothermic peak was the loss of crystallization water peak at 60±2°C. There is a char...

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Abstract

The invention relates to an apixaban crystal form and a preparation method thereof, belonging to the field of medicine and chemical industry, in particular to an apixaban nicotinic acid monohydrate eutectic with anticoagulant activity and a preparation method thereof. It is disclosed that the obtained crystals are analyzed by X-ray powder diffraction spectrum, and the 2θ values ​​of the characteristic absorption peaks are located at 5.7±0.2゜, 6.0±0.2゜, 11.5±0.2゜, 13.3±0.2゜, 15.4±0.2゜, 15.8±0.2゜, 17.5±0.2゜, 17.7±0.2゜, 20.0±0.2゜, 22.1±0.2゜, 23.4±0.2゜. The preparation method has the advantages of cheap and easy-to-obtain reagents, environmental friendliness, simple preparation method, mild crystallization conditions and easy crystal separation. The apixaban nicotinic acid monohydrate cocrystal of the invention can be used for treating thromboembolic diseases.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a co-crystal of an anticoagulant drug apixaban and a preparation method thereof. Background technique [0002] Apixaban (Apixaban, formula 1), is a novel oral direct factor Xa inhibitor with a chemical formula of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo Substituted piperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, a product of Bristol-Myers Squibb and Pfizer The co-developed anticoagulant drugs directly act on coagulation factor Xa and are used to treat venous thrombosis diseases including deep venous thrombosis (DVT) and pulmonary embolism (PE). In May 2011, the European Union approved the oral direct factor Xa inhibitor apixaban (trade name ) for the prevention of venous thromboembolic events (VTE) in adult patients undergoing elective hip or knee replacement surgery. In December 2012, the US FDA officially approved apixaban to re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D213/80C07D213/803A61P9/00A61P9/04A61P9/10A61P7/02A61P7/06A61P7/00
CPCA61P7/00A61P7/02A61P7/06A61P9/00A61P9/04A61P9/10C07B2200/13C07D213/80C07D213/803C07D471/04
Inventor 黄小光郭泽彬何凯思陈昆南
Owner GUANGZHOU BAIYUSN TIANXIN PHARMA
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