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Novel crystal of sacubitril valsartan sodium as well as preparation method and application thereof

A technology of sacubitril valsartan and sartan sodium, which is applied in the field of new crystal form of sacubitril valsartan sodium and its preparation, can solve problems such as poor compressibility, difficulty in direct tablet compression, poor fluidity, etc., and achieve shortening Production time, improvement of hygroscopicity, and high product purity

Active Publication Date: 2019-01-25
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sacubitril-valsartan sodium has the characteristics of relatively sticky properties, easy moisture absorption, and poor fluidity, so it has poor compressibility during tablet preparation, and it is easy to cause stratification between ingredients, making it difficult to directly compress tablets, which is not conducive to Industrial production of preparation technology

Method used

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  • Novel crystal of sacubitril valsartan sodium as well as preparation method and application thereof
  • Novel crystal of sacubitril valsartan sodium as well as preparation method and application thereof
  • Novel crystal of sacubitril valsartan sodium as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 preparation approach ( reference CN200680001733.0 Embodiment 2

[0038] In a 500mL flask, add 9.45g of sacubitril (22.96mmol), 10.0g of valsartan (22.96mmol) and 300mL of acetone, stir to dissolve, add dropwise sodium hydroxide aqueous solution (2.76g, namely 68.90mmol, dissolved in 8mL water), stirred at 20-25°C for 2h. Concentrate under reduced pressure at 15-30°C to a volume of 150 mL. Add 150 mL of isopropyl acetate, and concentrate under reduced pressure at 15-30°C to a volume of 150 mL. Add 150 mL of isopropyl acetate, and concentrate under reduced pressure at 15-30°C to a volume of 150 mL. Stir for 1 h at 20-25°C. Suction filtration, washing with isopropyl acetate, and vacuum drying of the solid at 30-35°C gave 19.51 g of sacubitril-valsartan sodium.

Embodiment 2

[0039] Example 2 Preparation method of sacubitril valsartan sodium crystal form Y

[0040] Add 1 g of sacubitril-valsartan sodium (1.04 mmol, prepared in Example 1), 1 mL of water and 10 mL of ethanol to a 100 mL three-necked flask, stir at room temperature for 1 h, and concentrate to dryness under reduced pressure. Add 8 mL of acetone and 30 mL of methyl tert-butyl ether, and stir at 50°C for 2 hours. Cool down to 10°C and stir for 1h. Suction filtration, washing with methyl tert-butyl ether, and vacuum drying gave 0.908g off-white solid, yield 90.8%, HPLC purity 99.8%, all simple impurities were less than 0.1%, XRD detected as a crystalline solid (see attached figure 1 ).

[0041] Its X-ray diffraction data are shown in the following table:

[0042] serial number

Embodiment 3

[0043] Example 3 : Preparation of existing crystal forms (CN201580002782.5 Crystal Form II, I, CN201510618916.8 Crystal Form A, WO2016151525 Form I)

[0044] Preparation of CN201580002782.5 Crystal Form II: In a 250mL reaction bottle, dissolve 667mg of sacubitril-valsartan sodium in 10mL of methanol and 100mL of toluene, filter, seal with a pinhole-punched parafilm, and volatilize at room temperature. Suction filtration to obtain sacubitril valsartan sodium crystal form II.

[0045] CN201580002782.5 Preparation of crystal form I: Suspend 205 mg of sacubitril-valsartan sodium crystal form II above in 1 mL of cumene and stir at 50°C for 2 days to obtain sacubitril-valsartan sodium crystal form I .

[0046] Preparation of CN201510618916.8 Form A: 2.0 g (4.6 mmol) of valsartan and 1.88 g (4.6 mmol) of sacubitril were dissolved in absolute ethanol (10 mL) at room temperature. Add 0.55 g (13.8 mmol) of sodium hydroxide in 1 mL of an aqueous solution, raise the temperature to 40°...

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Abstract

The invention relates to a novel crystal of sacubitril valsartan sodium as well as a preparation method and application thereof. According to the novel crystal, the hygroscopicity of an existing crystal of the sacubitril valsartan sodium is greatly improved, the fluidity of a pharmaceutical preparation is good, the product purity is high and can reach 99.5% or above, tablets with three specifications can be prepared by adopting a direct tabletting process, the process is simple, the production time can be greatly shortened, the cost is lowered, and the novel crystal is suitable for preparing various stable pharmaceutical preparations.

Description

field of invention [0001] The patent relates to the field of pharmaceutical technology, in particular to a new crystal form of sacubitril-valsartan sodium and its preparation method and application. technical background [0002] Sacubitril valsartan sodium (structural formula shown in formula I), chemical name is octadecadeca sodium hexa(4-{[(1S,3R)-1-([1,1'-biphenyl)-4 -ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoic acid)hexa(N-pentanoyl-N-{[2'-(1H -tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine)) was developed by Novartis Pharmaceuticals Co., Ltd., and its trade name is Nuoxintuo It is a co-crystal drug of a neprilysin inhibitor sacubitril and an angiotensin II receptor blocker (ARB) valsartan, which is suitable for reducing the response to Risk of cardiovascular death and hospitalization in heart failure and reduced ejection fraction. This variety was approved for marketing by the FDA in July 2015, approved by the European Union for marketing in November 20...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04A61K31/41A61P9/04
CPCA61P9/04C07B2200/13C07D257/04
Inventor 龚登凰生丽丹王洁刘晓争邢世昌盖京华马玉秀
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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