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Novel crystal form of sartan drug as well as preparation method and application thereof

A technology of sartans and drugs, which is applied in the direction of drug combination, organic chemical methods, and active ingredients of heterocyclic compounds, etc., can solve the problems of unfavorable oral solid preparation production and storage, restriction of drug application, poor water solubility, etc., and achieve physical and chemical drug properties Superior, environment-friendly, good stability

Active Publication Date: 2020-06-09
GUANGZHOU BAIYUSN TIANXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]Sacubitril, English common name: sacubitril, also known as: AHU-377, chemical name: 3-((1S,3R)-1-biphenyl- 4-ylmethyl-3-ethoxycarbonyl-1-butylaminoacyl)propionic acid is a kind of neprilysin inhibitor, reported in Chinese patent application CN106146333A and US5217996A, sacubitril has a low melting point and is water soluble Poor, not suitable for oral solid preparations; although sacubitril sodium is solid under normal temperature conditions, it has strong hygroscopicity (or called hygroscopicity), which is not conducive to the production and storage of oral solid preparations, which greatly limits Clinical application of this drug

Method used

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  • Novel crystal form of sartan drug as well as preparation method and application thereof
  • Novel crystal form of sartan drug as well as preparation method and application thereof
  • Novel crystal form of sartan drug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of co-crystal of sacubitril-valsartan trisodium trihydrate

[0043] Sacubitril-valsartan trisodium 2.5 hydrate co-crystal was prepared by referring to the method reported by Novartis in Chinese patent ZL200680001733.0 (PCT patent WO2007 / 056546)

[0044] Take 0.98401 g (1.027 mmol) of sacubitril valsartan trisodium 2.5 hydrate eutectic, spread it into a thickness of about 1 mm, place it at 25 ° C, 60 ± 2% relative humidity for 24 hours, collect the material, and obtain sacubitril Trivalsartan trisodium trihydrate co-crystal with quantitative molar yield.

[0045] Karl Fischer method test moisture measured value (calculated value): 5.69% (5.58%).

[0046] Elemental analysis (C 48 h 61 N 6 Na 3 o 11 ) found (calculated value, %): C 59.83 (59.62), H 6.37 (6.36), N 8.73 (8.69).

[0047] The obtained crystals were subjected to X-ray powder diffraction, using Cu target Kɑ rays, voltage 40kV, current 40mA, divergence slit 1 / 8°, anti-scatter slit 1 / 4°, anti-sc...

Embodiment 2

[0052] Preparation of co-crystal of sacubitril-valsartan trisodium trihydrate

[0053] Sacubitril-valsartan trisodium 2.5 hydrate co-crystal was prepared by referring to the method reported by Novartis in Chinese patent ZL200680001733.0 (PCT patent WO2007 / 056546)

[0054] Take 1.02736 g (1.072 mmol) of sacubitril valsartan trisodium 2.5 hydrate eutectic, spread it to a thickness of about 1 mm, place it at 25 ° C, 40 ± 2% relative humidity for 24 hours, collect the material, and obtain sacubitril Trivalsartan trisodium trihydrate co-crystal with quantitative molar yield.

[0055] Karl Fischer method test moisture measured value (calculated value): 5.67% (5.58%).

[0056]The obtained crystals were analyzed by X-ray powder diffraction spectrum, and the 2θ values ​​of the characteristic absorption peaks were located at 4.2±0.2゜, 5.0±0.2゜, 5.4±0.2゜, 9.7±0.2゜, 12.6±0.2゜, 17.0±0.2゜, 18.1± 0.2°, 19.4±0.2°, 21.3±0.2°, 23.0±0.2°.

[0057] Differential scanning calorimetry (DSC) test ...

Embodiment 3

[0059] Preparation of co-crystal of sacubitril-valsartan trisodium trihydrate

[0060] Sacubitril-valsartan trisodium 2.5 hydrate co-crystal was prepared by referring to the method reported by Novartis in Chinese patent ZL200680001733.0 (PCT patent WO2007 / 056546)

[0061] Take 1.06124 g (1.108 mmol) of sacubitril valsartan trisodium 2.5 hydrate eutectic, spread it to a thickness of about 1 mm, place it at 35 ° C, 54 ± 2% relative humidity for 24 hours, collect the material, and obtain sacubitril Trivalsartan trisodium trihydrate co-crystal with quantitative molar yield.

[0062] Karl Fischer method test moisture measured value (calculated value): 5.55% (5.58%).

[0063] The obtained crystals were analyzed by X-ray powder diffraction spectrum, and the 2θ values ​​of the characteristic absorption peaks were located at 4.2±0.2゜, 5.0±0.2゜, 5.4±0.2゜, 9.7±0.2゜, 12.6±0.2゜, 17.0±0.2゜, 18.1± 0.2°, 19.4±0.2°, 21.3±0.2°, 23.0±0.2°.

[0064] Differential scanning calorimetry (DSC) test...

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Abstract

The invention relates to a new crystal form of a sartan drug as well as a preparation method and application thereof, and belongs to the field of pharmaceutical chemicals. The invention discloses a sacubitril valsartan trisodium trihydrate eutectic composed of an angiotensin receptor antagonist and an enkephalinase inhibitor for treating hypertension or heart failure and a preparation method of the sacubitril valsartan trisodium trihydrate eutectic. The obtained crystal is analyzed by an X-ray powder diffraction spectrogram, and the characteristic absorption peaks 2 theta are located at 4.2 + / -0.2 degrees, 5.0 + / -0.2 degrees, 5.4 + / -0.2 degrees, 9.7 + / -0.2 degrees, 12.6 + / -0.2 degrees, 17.0 + / -0.2 degrees, 18.1 + / -0.2 degrees, 19.4 + / -0.2 degrees, 21.3 + / -0.2 degrees and 23.0 + / -0.2 degrees. The new eutectic crystal form disclosed by the invention is simple in preparation method, the crystal is easy to separate, and experiments show that the hygroscopicity and the stability of the neweutectic crystal form are superior to those of the existing eutectic crystal form, so that the new eutectic crystal form is favorable for being prepared into an oral solid preparation and processing and producing the oral solid preparation, and can be used for treating hypertension or heart failure.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a co-crystal of sacubitril-valsartan trisodium trihydrate, a drug for treating hypertension or heart failure, and a preparation method thereof. Background technique [0002] Angiotensin II is a hormone that causes blood vessels to constrict, which in turn leads to high blood pressure and heart strain. Angiotensin II is known to interact with receptors on the surface of target cells. Two receptor subtypes of angiotensin II have been identified, called AT1 and AT2. Over the past two decades, great efforts have been made to identify substances capable of binding to the AT1 receptor. It is now known that angiotensin receptor blockers (ARBs, angiotensin II antagonists) can reduce blood pressure by preventing angiotensin II from binding to its receptors on blood vessel walls. Due to their ability to inhibit AT1 receptors, such antagonists can be used in antihypertensive...

Claims

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Application Information

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IPC IPC(8): C07D257/04A61K31/41A61P9/12A61P9/04A61P9/00A61P9/06A61P3/10
CPCC07D257/04A61P9/12A61P9/04A61P9/00A61P9/06A61P3/10C07B2200/13
Inventor 黄小光麦桁棠何凯思文青陈昆南
Owner GUANGZHOU BAIYUSN TIANXIN PHARMA
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