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Sulfonylurea compound and metformin salts, preparation method and application

A technology for metformin and a compound, applied in the field of chemical synthesis and crystallization, can solve the problems of poor pharmaceutical properties, low solubility, large oral dose and the like, and achieve the effects of easy control of the crystallization process, improved hygroscopic stability, and simple preparation method.

Inactive Publication Date: 2020-02-18
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, glibenclamide and glibenclamide are class II drugs (BCSII) in the biopharmaceutical classification system and have low solubility, so their pharmaceutical properties are not good. It has been reported in the literature that their solubility can be improved through different preparation methods. But the end result is not ideal
Metformin (C 4 h 11 N 5 ) is a biguanide oral hypoglycemic drug against type 2 diabetes, but metformin is unstable and easily absorbs moisture, which is not conducive to the storage and transportation of drugs. It is common to improve stability by forming a salt with hydrochloric acid, but the oral dose of metformin hydrochloride Larger, the daily dose is about 500-1000mg, and patients have to take hydrochloride ions with no hypoglycemic effect in an equimolar ratio while taking metformin
Therefore, the problems of gliquidone, glibenclamide and metformin itself have not been well resolved

Method used

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  • Sulfonylurea compound and metformin salts, preparation method and application
  • Sulfonylurea compound and metformin salts, preparation method and application
  • Sulfonylurea compound and metformin salts, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Take 52.7mg of gliquidone and 13.0mg of metformin (the molar ratio is 1:1) and put them in a 4mL sample bottle, add 2mL of acetonitrile, sonicate, make it dissolve and be in a supersaturated state, and react and crystallize at room temperature for 24 hours. The suspension is centrifuged, the supernatant is discarded, and the centrifuged solid is dried in a 40°C forced air oven for 3 hours to obtain the gliquidone-metformin salt. The diffraction angle represented by the 2θ angle in the XRPD result is 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20°, There are characteristic peaks at 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, 30.78±0.20°, such as figure 1 . The chemical structural formula is as follows:

[0053]

Embodiment 2

[0055] Take 52.7mg of gliquidone and 13.0mg of metformin (the molar ratio is 1:1) and place them in a 4mL sample bottle, add 2mL of ethanol, ultrasonicate, make it decompose and be in a supersaturated state, and react and crystallize at room temperature for 24 hours. The suspension was centrifuged, the supernatant was discarded, and the centrifuged solid was dried in a 40°C forced air oven for 3 hours to obtain the gliquidone-metformin salt. The diffraction angle represented by the 2θ angle in the XRPD result was at 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20°, There are characteristic peaks at 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, 30.78±0.20°, such as figure 2 .

Embodiment 3

[0057] Take 52.7mg of gliquidone and 12.0mg of metformin (molar ratio is 1:0.92) into a 4mL sample bottle, add 2mL of acetone, sonicate to dissolve and become supersaturated, react and crystallize at 40°C for 12 hours, Centrifuge the suspension, discard the supernatant, and dry the centrifuged solid in a forced air oven at 60°C for 1 hour to obtain the gliquidone-metformin salt. The diffraction angle expressed by the 2θ angle in the XRPD result is At 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20° , 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, 30.78±0.20° have characteristic peaks, such as image 3 .

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Abstract

The invention relates to sulfonylurea compound and metformin salts, a preparation method and application. The preparation method comprises the following steps: dissolving a sulfonylurea compound and metformin into a solvent according to a mole ratio of (1:0.9):(1:1.1) so as to obtain a mixture; performing reaction crystallization on the mixture under a condition of 25-50 DEG C for 12-48 hours; andperforming solid-liquid phase separation on the obtained product, and performing drying, so as to obtain a salt type solid product. The sulfonylurea compound is gliquidone or glibenclamide. The gliquidone-metformin salt and the glibenclamide-metformin salt provided by the invention are applied to medicines for preventing and treating diabetes. The wet absorption capacities of the salt type products provided by the invention are greatly increased when being compared with that of metformin, that is, the hygroscopy gain of the metformin is 35% when the relative humidity is 75%, and the hygroscopy gains of the salt type products are smaller than 1%; and the dissolubility of the salt type products is greatly improved when being compared with that of the sulfonylurea compound, that is, the dissolubility of the sulfonylurea compound in water is smaller than 0.03mg / ml, and the dissolubility after salt formation is 10.61mg / ml and 16.78mg / ml respectively.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis and crystallization, and specifically relates to the salt formation, preparation method and application of a sulfonylurea compound and metformin; the sulfonylurea compound includes glibenclamide and glibenclamide, and the formed salt is glibenclamide - metformin salts and glibenclamide-metformin salts. Background technique [0002] According to statistics, about 70-80% of drug candidates fail to be marketed due to defects in physical and chemical properties. Therefore, improving the physical and chemical properties of drugs is of great significance for the development of new drugs. In the preclinical research and development stage of drugs, new drug R&D companies usually use the active ingredients of drugs to form salts to improve the drug's solubility, dissolution rate, hygroscopicity, stability and bioavailability and other pharmaceutical properties. In the first half of 2017, the U....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/24C07C277/08C07C279/26C07C303/40C07C311/59A61P3/10A61K31/155A61K31/64
CPCA61K31/155A61K31/64A61P3/10C07B2200/13C07C277/08C07C279/26C07C303/40C07C311/59C07D217/24A61K2300/00
Inventor 龚俊波贾丽娜吴送姑侯宝红尹秋响王静康
Owner TIANJIN UNIV
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