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Apixaban crystal form and preparation method therefor

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

Active Publication Date: 2019-11-15
GUANGZHOU BAIYUSN TIANXIN PHARMA
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  • Description
  • Claims
  • Application Information

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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 therefor
  • Apixaban crystal form and preparation method therefor
  • Apixaban crystal form and preparation method therefor

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Experimental program
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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 therefor, belongs to the field of medicinal chemicals and particularly relates to an apixaban nicotinate monohydrate eutecticcrystal with anticoagulation activity and a preparation method therefor. Proven by X-ray powder diffraction spectrum analysis on the disclosed crystal, a 2[theta] value of a characteristic absorptionpeak is located at 5.7+ / -0.2 degrees, 6.0+ / -0.2 degrees, 11.5+ / -0.2 degrees, 13.3+ / -0.2 degrees, 15.4+ / -0.2 degrees, 15.8+ / -0.2 degrees, 17.5+ / -0.2 degrees, 17.7+ / -0.2 degrees, 20.0+ / -0.2 degrees, 22.1+ / -0.2 degrees and 23.4+ / -0.2 degrees. The preparation method has the advantages that reagents are cheap, readily available and environmentally friendly, the preparation method is simple, the crystallization conditions are moderate, and the crystal is easy to separate; and the apixaban nicotinate monohydrate eutectic crystal disclosed by the invention can be used for treating thromboembolism.

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 Applications(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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