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Eutectic of apixaban and fumaric acid as well as preparation method and application thereof

A technology of apixaban and fumaric acid, which is applied in the field of co-crystals formed by apixaban and fumaric acid and its preparation, can solve the problem of low crystal form dissolution rate, limited clinical application of new product development, and difficulty in obtaining ideal It can improve the bioavailability, the best purification and impurity removal effect, and the effect of easy operation.

Active Publication Date: 2022-08-09
TIANJIN CREATRON BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some of these existing technologies have improved the dissolution rate to a certain extent, but the re-introduced co-crystal ligand or the new crystal form prepared by the ligand has a strong spring effect on the dissolution rate, or brings about enhanced wettability of the drug or physical / chemical For issues such as stability or safety, the dissolution rate of some new crystal forms or co-crystals is slightly improved compared with the N-1 anhydrate crystal form, but if a once-a-day sustained-release product is developed, the requirements for raw materials are in the Under the high pH condition of the colon, the drug should not crystallize out, otherwise it is difficult to obtain the desired effect
[0009]The crystalline form used in the currently marketed product ELIQUIS® has a low dissolution rate, so it is necessary to strictly control the particle size of the raw material drug, and the limit The development of new products and the clinical application of existing products as emergency medicine

Method used

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  • Eutectic of apixaban and fumaric acid as well as preparation method and application thereof
  • Eutectic of apixaban and fumaric acid as well as preparation method and application thereof
  • Eutectic of apixaban and fumaric acid as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1: Preparation of co-crystals of apixaban and fumaric acid

[0117] Add 400 mL of acetonitrile to a 1000 mL three-necked bottle, and add 40.00 g of crude apixaban (Suzhou Capwell Pharmaceutical Technology Co., Ltd., HPLC: 99.08%, see details for details). Figure 8 ), turn on stirring, take another 250mL beaker, add 5.05g fumaric acid and 100mL purified water, stir and dissolve, add the purified aqueous solution of fumaric acid to the above three-necked flask, heat the system to reflux, and cool down to 20 after the system is dissolved. ℃~30℃, stir for 1~2 hours and then filter, collect the solid and dry it under vacuum at 40℃~60℃ for 4 hours to obtain 40.10g of white solid, the melting point is 242.5~244.5℃, the purity detected by HPLC is: 99.67%, see details for details Figure 9 .

[0118] By X-ray powder diffraction (XRPD), infrared spectroscopy (IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hydrogen nuclear magnetic resona...

Embodiment 2

[0119] Example 2: Preparation of co-crystals of apixaban and fumaric acid

[0120] Add 50 mL of acetonitrile to a 100 mL three-necked flask, add 5.00 g of apixaban, turn on stirring, add 0.13 g of fumaric acid and 10 mL of purified water to another 50 mL beaker, stir to dissolve, and add the prepared purified aqueous solution of fumaric acid to the above three-necked flask. In the bottle, the system was heated to 50°C, the system was dissolved and then cooled to 30°C~40°C, and the mixture was stirred for 1~2 hours, filtered, and the collected solid was vacuum-dried at 20°C~40°C for 8 hours to obtain 0.37g of white solid. The melting point is 243.0~244.5°C, and it is confirmed to be a new crystal form of apixaban. The purity detected by HPLC is: 99.73%.

Embodiment 3

[0121] Example 3: Preparation of co-crystals of apixaban and fumaric acid

[0122] Add 50 mL of acetonitrile to a 100 mL three-necked flask, add 5.00 g of apixaban, turn on stirring, add 1.26 g of fumaric acid and 20 mL of purified water to another 50 mL beaker, and stir to dissolve, add the fumaric acid aqueous solution to the above-mentioned there-necked flask, and the system Heated to 65°C, the system was dissolved and then cooled to -10°C ~ 0°C, kept stirring for 1~2 hours, filtered, collected the solid at 60°C-70°C ~ vacuum-dried for 4 hours to obtain 4.97g of white solid, the detected melting point was : 243.0~244.0 ℃, confirmed to be the new crystal form of apixaban, and the purity detected by HPLC was: 99.52%.

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Abstract

The invention relates to an apixaban and fumaric acid eutectic and a preparation method and application thereof, and belongs to the technical field of chemical pharmacy. By using Cu-Kalpha radiation, the X-ray powder diffraction pattern of apixaban and fumaric acid disclosed by the invention has characteristic peaks at positions with diffraction angles 2 theta of 5.7 + / -0.2 degrees, 7.2 + / -0.2 degrees, 8.7 + / -0.2 degrees, 11.4 + / -0.2 degrees, 13.2 + / -0.2 degrees, 16.5 + / -0.2 degrees, 17.6 + / -0.2 degrees, 18.5 + / -0.2 degrees, 20.1 + / -0.2 degrees, 20.7 + / -0.2 degrees, 21.9 + / -0.2 degrees, 23.2 + / -0.2 degrees and 25.1 + / -0.2 degrees. The prepared eutecticum of apixaban and fumaric acid is good in physical stability and chemical stability, and meanwhile, compared with an apixaban N-1 anhydrous crystal form, the dissolution rate is remarkably improved, so that the in-vivo bioavailability is further improved.

Description

technical field [0001] The invention relates to the technical field of chemical pharmacy, in particular to a co-crystal formed by apixaban and fumaric acid and a preparation method and application thereof. Background technique [0002] Cardiovascular and cerebrovascular diseases are a general term for cardiovascular and cerebrovascular diseases, which generally refer to ischemic or hemorrhagic diseases of the heart, brain and whole body caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. disease. Cardiovascular and cerebrovascular disease is a common disease that seriously threatens the health of human beings, especially the middle-aged and elderly people over 50 years old. It has the characteristics of high morbidity, high disability and high mortality. Every year, cardiovascular and cerebrovascular diseases such as cerebral thrombosis, cerebral infarction, various embolisms, myocardial infarction, coronary heart disease, atherosclerosis and othe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4545C07C57/15C07C51/43A61P7/02A61P9/00A61P9/10A61P13/12
CPCC07D471/04C07C57/15A61P7/02A61P9/00A61P9/10A61P13/12C07B2200/13
Inventor 贾慧娟任晓慧杜海艳翟华坤张加晏侯伟
Owner TIANJIN CREATRON BIOTECHNOLOGY CO LTD
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