Eutectic crystal formed by apixaban and carboxylic acid and preparation method thereof

A technology of apixaban and carboxylic acid, applied in the field of apixaban/carboxylic acid co-crystal and preparation thereof, can solve the problems of slow dissolution rate and low dissolution rate of apixaban

Active Publication Date: 2020-03-27
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to overcome the deficiencies of the prior art, develop a novel apixaban / carboxylic acid co-crystal with a specific molecular ratio and a preparation method thereof, and improve the dissolution rate of apixaban while satisfying safe medication, Solve the shortcomings of slow dissolution rate and low dissolution rate of apixaban, and improve its bioavailability

Method used

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  • Eutectic crystal formed by apixaban and carboxylic acid and preparation method thereof
  • Eutectic crystal formed by apixaban and carboxylic acid and preparation method thereof
  • Eutectic crystal formed by apixaban and carboxylic acid and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1: Preparation of Apixaban / malonic acid co-crystal form I

[0093]At room temperature, add 10.2g of malonic acid, 60g of apixaban, 350ml of trifluoroethanol, and 170mL of methanol into the reaction bottle. After stirring for 1 hour to dissolve, keep the resulting solution at 30-35°C and continue stirring for 18 hours. Control the cooling rate at 10-15°C / hour, cool the crystallization solution to 0-5°C to crystallize, crystallize for 5 hours, a large number of crystals precipitate, filter the obtained crystals and wash with a small amount of methanol, and then vacuum dry at 55°C for 24 hours to obtain 53.5 g Apixaban / malonic acid co-crystal. After detection, the obtained co-crystal is Apixaban / malonic acid co-crystal form I. The X-ray powder diffraction data of the samples are as figure 1 And shown in table 1; TGA collection of illustrative plates such as figure 2 Shown; DSC spectrum such as image 3 shown.

[0094] Table 1

[0095] 2θ(°) Relat...

Embodiment 2

[0096] Example 2: Preparation of Apixaban / D-malic acid cocrystal form II

[0097] At room temperature, add 13.2g of D-malic acid, 60g of apixaban, 350ml of trifluoroethanol, and 170mL of methanol into the reaction flask. After stirring for 1 hour to dissolve, keep the resulting solution at 30-35°C and continue stirring for 18 hours. Then control the cooling rate of 10-15°C / hour, cool the crystallization solution to 0-5°C to crystallize, crystallize for 6 hours, a large number of crystals precipitate, filter the obtained crystals and wash with a small amount of methanol, and then vacuum dry at 55°C for 24 hours 48.6 g of apixaban / D-malic acid co-crystals were obtained. After testing, the obtained co-crystal was Apixaban / D-malic acid co-crystal form II. The X-ray powder diffraction data of the samples are as Figure 4 And shown in table 2; TGA collection of illustrative plates such as Figure 5 Shown; DSC spectrum such as Figure 6 shown.

[0098] Table 2

[0099]

Embodiment 3

[0100] Example 3: Preparation of Apixaban / Maleic Acid Cocrystal Form III

[0101] At room temperature, add 11.3g of maleic acid, 60g of apixaban, 350ml of trifluoroethanol, and 170mL of methanol into the reaction flask. After stirring for 1 hour to dissolve, keep the resulting solution at 30-35°C and continue stirring for 18 hours. Control the cooling rate at 10-15°C / hour, cool the crystallization solution to 0-5°C to crystallize, crystallize for 5 hours, a large number of crystals precipitate, filter the obtained crystals and wash with a small amount of methanol, and then vacuum dry at 55°C for 24 hours to obtain 45.3 g Apixaban / maleic acid co-crystal. After detection, the obtained co-crystal is apixaban / maleic acid co-crystal form III. The X-ray powder diffraction data of the samples are as Figure 7 And shown in table 3; TGA collection of illustrative plates such as Figure 8 Shown; DSC spectrum such as Figure 9 shown.

[0102] table 3

[0103] 2θ(°) Rela...

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Abstract

The invention provides an apixaban/carboxylic acid eutectic crystal which comprises an apixaban/malonic acid eutectic crystal, an apixaban/D-malic acid eutectic crystal, an apixaban/maleic acid eutectic crystal, an apixaban/L-proline eutectic crystal and an apixaban/L-tartaric acid eutectic crystal. According to the apixaban/carboxylic acid eutectic crystal, the dissolution rate of apixaban is improved while safe medication is met, the defects of low solution rate and low dissolution rate of apixaban are overcome and the bioavailability of apixaban is improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an apixaban / carboxylic acid co-crystal and a preparation method thereof. Background technique [0002] Apixaban, its English name is Apixaban (trade name: Eliquis), its chemical name is 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6 -[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, CAS: 503612-47-3, its chemical structure as follows: [0003] [0004] Apixaban is a new generation of antithrombotic drugs. It is a new type of direct inhibitor of factor Xa jointly developed by Bristol-Myers Squibb and Pfizer. It is currently clinically used to prevent elective hip or knee replacement. Venous thromboembolism (VTE) in adult patients. [0005] Apixaban is almost insoluble in water, and has the disadvantages of slow dissolution rate, which is not conducive to the absorption of drugs in the body. It is urgent to find a method to improve the dissolution r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07C51/43C07C55/08C07C59/245C07C57/02C07C59/255C07D207/16
CPCC07D471/04C07C55/08C07C59/245C07C57/02C07C59/255C07D207/16C07B2200/13C07C57/145
Inventor 朱国荣柯春龙王臻屠勇军张鹏
Owner ZHEJIANG TIANYU PHARMA
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