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Fenofibric acid salt of berberine and analogue thereof, crystal form, preparation method and applications thereof

A technology of fenofibric acid and berberine, which is applied in the field of fenofibric acid salt crystalline salt and crystalline salt, can solve problems such as inability to screen salts, achieve the effect of avoiding harmful effects and improving pharmaceutical properties

Active Publication Date: 2020-05-12
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This may be due to the fact that berberine in the market usually exists in the form of salts, such as hydrochloride or bisulfate, etc., which cannot be directly used in traditional salt screening

Method used

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  • Fenofibric acid salt of berberine and analogue thereof, crystal form, preparation method and applications thereof
  • Fenofibric acid salt of berberine and analogue thereof, crystal form, preparation method and applications thereof
  • Fenofibric acid salt of berberine and analogue thereof, crystal form, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Exemplary preparation and characterization of berberine fenofibrate salt (A crystalline salt)

[0203] 74.2 mg (0.20 mmol) of berberine hydrochloride was suspended in 1.0 ml of MeOH, and then 2.0 ml of 0.1 N NaOH (0.2 mmol) was added to obtain a suspension. To the suspension was added 64.1 mg (0.20 mmol) of fenofibric acid. After stirring the suspension at 60°C for 30 minutes, a clear orange solution was obtained. The solution was cooled to room temperature, and yellow fenofibrate berberine salt (crystal form A salt) was precipitated from the orange solution. It is separated by filtration, washed with water, and then dried in air. Obtained 83.2 mg of crystalline form A salt (60% yield). Such as figure 1 As shown, the salt of crystal form A is in D 2 In O 1 The H-NMR spectrum indicated that, for the A crystal salt, the molar ratio of berberine and fenofibric acid was about 1:1. 1 H NMR (300MHz, DMSO) 1.41 (s, 6H), 3.21 (t, J = 6.0 Hz, 2H), 4.07 (s, 3H), 4.10 (s, 3H), 4.9...

Embodiment 2

[0209] Exemplary preparation of berberine fenofibrate salt (crystal B salt):

[0210] 100 mg of berberine fenofibrate (crystal form A salt, other amorphous or crystalline forms) was suspended in 1.0 ml of water to produce a suspension. The suspension was then stirred at room temperature for 1 day. The solid was collected by filtration and dried in air. 75 mg of yellow crystalline material of the B crystal form salt was obtained. (Yield: 75%).

[0211] The crystal form B salt was analyzed by XRPD, and the results are listed in Table 2. See XRPD of B crystal salt Figure 4 .

[0212] Table 2 XRPD key peaks of B crystal salt

[0213] Angle(2θ±0.2°) Intensity(%) 8.0100.0 15.979.1 17.367.0 12.455.0 6.252.9 20.949.2 25.541.8 19.834.8 18.730.0 12.928.9

[0214] The characteristic of Type B salt is that when measured with CuKα radiation, at least one of the following 2θ±0.2° values ​​will be displayed: 6.2, 12.4 and 20.9°.

[0215] The type B salt was also analyzed by thermal technique...

Embodiment 3

[0217] Exemplary preparation of berberine fenofibrate salt (C crystalline salt):

[0218] 318.2 mg of fenofibric acid (1.0 mmol) was suspended in 5.0 ml of water, and 1.0 ml of 1N NaOH aqueous solution was added to obtain a clear and colorless solution. 384.7 mg of berberine hemisulfate (1.0 mmol) was dissolved in 10.0 ml of water to obtain a clear orange solution. The colorless solution of fenofibric acid and NaOH was slowly added to the orange solution of berberine, and a yellow solid was precipitated first, and then a double layer solution was formed. 5.0 ml of ethanol was added to the bilayer solution, the yellow crystalline form of Celite solid began to precipitate out, and the slurry was stirred at room temperature for 1 day. 530 mg of yellow crystalline substance of type C salt was obtained (yield: 82%).

[0219] Analyze crystal form C salt by XRPD. For the XRPD pattern of crystal form C, see Image 6 , The results are listed in Table 3.

[0220] Table 3 Key XRPD peaks of C...

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Abstract

The invention discloses fenofibric acid salts of berberine and analogues thereof, a crystal form, a preparation method and applications thereof, wherein the fenofibric acid salt comprises fenofibric acid serving as an anion and berberine or a berberine analogue serving as a cation. According to the invention, the fenofibric acid salt of berberine or analogue thereof can be used for removing unnecessary cations from commercially available medicines, ie., choline cations in choline fenofibrate and / or chlorine ions in berberine hydrochloride, so that a certain side effect, including gastrointestinal irritation due to instability property of choline as an anion and high acidity of berberine hydrochloride, caused by the two pairing ions can be reduced.

Description

Technical field [0001] The present disclosure relates to fenofibrate salts of berberine and its analogs, especially crystalline salts, which can be used in medicines or health food ingredients for the treatment or prevention of cardiovascular diseases or other diseases. The present disclosure also relates to a method for preparing a crystalline salt using berberine or its analogue as a cation, particularly a method for preparing a crystalline salt of fenofibrate salt of berberine or its analogue. Background technique [0002] Fenofibrate, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propionic acid-1-methylethyl ester, is a lipid regulator. It can lower the total cholesterol and triglyceride levels in the body. Fenofibrate is usually administered orally. After oral administration, fenofibrate is metabolized into fenofibrate acid in the body. In fact, fenofibrate acid is a biologically active molecule of fenofibrate. Therefore, the more soluble fenofibric acid is a new chemical enti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03C07C59/90C07C51/41A61K31/192A61K31/4375A61P9/00
CPCC07D455/03C07C59/90C07C51/412A61K31/192A61K31/4375A61P9/00C07B2200/13A61K2300/00C07D217/24C07D491/147C07C59/88
Inventor 谢永居汤玉涛赵宗敏卓晨吴德冬
Owner JIANGXI FUSHINE PHARMA CO LTD
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