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Epalrestat-metformin salt hydrate as well as preparation method and application thereof

A technology of metformin salt and epalrestat, which is applied in the field of medicine and chemical industry, can solve the problems of toxicity, poor physical and chemical properties, and no therapeutic effect of diabetes treatment, etc., to achieve reduced hygroscopicity, easy control of the crystallization process, and improved dissolution Effects of Rate and Solubility

Active Publication Date: 2021-08-20
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Relevant researchers have tried to improve the adverse physical and chemical properties of epalrestat by forming multi-component crystals. Chinese patent (CN201410190918.7) provides a solid form of epalrestat crystalline salt hydrate and hydroxypiperidine cocrystal , the Chinese patent (CN200980143667.4) provides a solid form of epalrestat choline co-crystal, although the solubility of epalrestat has been improved to a certain extent, the selected ligand has no effect on the treatment of diabetes. The therapeutic effect is even toxic

Method used

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  • Epalrestat-metformin salt hydrate as well as preparation method and application thereof
  • Epalrestat-metformin salt hydrate as well as preparation method and application thereof
  • Epalrestat-metformin salt hydrate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Take 32.0mg of epalrestat and 12.9mg of metformin (the molar ratio is 1:1) and place them in a 4mL sample bottle, add 2mL of acetone-water (v:v=4:1) mixed solvent, sonicate to dissolve and In a supersaturated state, react and crystallize at 30°C for 24 hours, centrifuge the suspension, discard the supernatant, and dry the centrifuged solid at room temperature for 3 hours to obtain epalrestat-metformin salt hydrate. Its XRPD results are as follows figure 1 .

[0048] figure 1 Prepare the XRD figure of product for embodiment 1, from figure 1 It can be seen that the diffraction angle is 2θ, which means that there are characteristic peaks at 4.93, 11.85, 12.96, 13.29, 13.90, 14.89, 15.34, 16.22, 17.88, 19.87, 21.45, 22.92, 23.77, and 25.43.

[0049] figure 2 Prepare the crystal structure figure of product for embodiment 1, from figure 2 It can be seen that the crystallographic characteristics of this product are: the bond length is a=7.8711 (4), b=8.3789 (4), c=18.34...

Embodiment 2

[0058] Take 32.0mg of epalrestat and 11.9mg of metformin (molar ratio is 1:0.92) and place them in a 4mL sample bottle, add 2mL of acetone-water (v:v=1:1) mixed solvent, sonicate to dissolve and In a supersaturated state, react and crystallize at 45°C for 12 hours, centrifuge the suspension, discard the supernatant, and dry the centrifuged solid in a blast drying oven at 40°C for 1 hour to obtain epalrestat- Metformin Salt Hydrate.

[0059] Carry out XRD test to the product that embodiment 2 obtains, test product has characteristic peak at 4.93, 11.85, 12.96, 13.29, 13.98, 14.89, 15.34, 16.22, 17.88, 19.87, 21.55, 22.92, 23.77, 25.43 at diffraction angle 2θ .

[0060] The product that embodiment 2 obtains is carried out crystallographic test, finds that its crystallographic feature is: bond length is a=7.8711 (4), b=8.3789 (4), c=18.3489 (8), and bond angle is α=77.437 ( 4), β=82.244(4), γ=66.896(4), V=1084.7(6).

[0061] The product obtained in Example 2 was subjected to t...

Embodiment 3

[0065] Take 32.0mg of epalrestat and 15.5mg of metformin (molar ratio is 1:1.2) and place them in a 4mL sample bottle, add 2mL of acetone-water (v:v=4.5:1) mixed solvent, sonicate to dissolve and In a supersaturated state, react and crystallize at 60°C for 12 hours, centrifuge the suspension, discard the supernatant, and dry the centrifuged solid at room temperature 25°C for 12 hours to obtain epalrestat-metformin salt hydrate .

[0066] Carry out XRD test to the product that embodiment 3 obtains, test product has characteristic peak at 4.93, 11.85, 12.96, 13.29, 14.08, 14.89, 15.34, 16.22, 18.05, 19.87, 21.45, 23.02, 23.77, 25.43 at diffraction angle 2θ .

[0067] The product that embodiment 3 is obtained carries out crystallographic test, finds that its crystallographic feature is: bond length is a=7.8711 (4), b=8.3789 (4), c=18.3489 (8), and bond angle is α=77.437 ( 4), β=82.244(4), γ=66.896(4), V=1084.7(6).

[0068] The product obtained in Example 3 was subjected to the...

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Abstract

The invention relates to an epalrestat-metformin salt hydrate crystal form and a preparation method thereof. The molecular formula of the hydrate is C19H26N6O4S2, and the molecular weight is 466.6. The crystallographic characteristics of the hydrate are as follows: the bond length a is 7.8711 (4), the bond length b is 8.3789 (4), the bond length c is 18.3489 (8), the bond angle alpha is 77.437 (4), the bond angle beta is 82.244 (4), the bond angle gamma is 66.896 (4), and V is 1084.7 (6). Compared with epalrestat, the epalrestat-metformin salt hydrate provided by the invention has the advantages that the dissolution rate and solubility are greatly improved, the problem of high hygroscopicity of metformin at the present stage is well solved, meanwhile, the preparation method is simple to operate, the crystallization process is easy to control, and the epalrestat-metformin salt hydrate is suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to epalrestat-metformin salt hydrate and its preparation method and application. Background technique [0002] Epalrestat (C 15 h 13 NO 3 S 2 ) carboxylic acid anti-type 2 diabetes drugs, metformin (C 4 h 11 N 5 ) is a biguanide oral hypoglycemic agent, and the two have a synergistic effect on drug efficacy. However, due to the low solubility of epalrestat itself and the high hygroscopicity of metformin itself, the efficacy and production cost of these two drugs are greatly limited. [0003] Multi-component crystals provide a new idea for improving the physical and chemical properties of drugs. The preparation of two drugs with complementary physical and chemical properties into co-crystals or salts or solvates can significantly improve the physical and chemical properties of these two drugs. lack of. Relevant researchers have tried to improve the a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/26C07D277/36C07C277/08A61P3/10
CPCC07C279/265C07D277/36C07C277/08A61P3/10C07B2200/13
Inventor 龚俊波孙晶晶贾丽娜吴送姑韩丹丹刘裕
Owner TIANJIN UNIV
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