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High-stability LCZ696 crystallized powder and a preparing method thereof

A technology of crystalline powder and preparation process, which is applied in the field of medicine, and can solve the problems of undisclosed LCZ696 preparation scale-up solution, product becoming sticky, unfavorable preparation of preparation products, etc.

Inactive Publication Date: 2017-02-15
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Patent WO2007056546 Example 1-Example 3 discloses the preparation method of LCZ696. The LCZ696 prepared according to this method is in the form of very fine powder, which makes its suction filtration speed extremely slow in the post-treatment process, especially in the amplification reaction. Obviously, even if nitrogen protection is used throughout the suction filtration process, the obtained product still has the possibility of becoming sticky due to moisture absorption, thereby affecting the process stability. In addition, the extremely fine powder is not conducive to the preparation of preparation products in the subsequent preparation process
[0009] Patent WO2009061713 discloses a series of preparations of LCZ696. This series of preparations has the characteristics of good dissolution performance and high stability. However, in the field of preparations, for specific products with multiple specifications at the same time, from the perspective of clinical medication and process simplification , the established prescription and process need to be enlarged / reduced in proportion at the same time, that is, without changing the prescription and process, the formulation specification can be enlarged / reduced by equal multiples, and the dissolution performance of the preparation still meets the clinical drug requirements. At the same time, the dissolution performance of the preparation has no Excessive fluctuations, but the drawings of patent WO2009061713 show that the preparations of various specifications have not achieved proportional amplification, and the prior art has not disclosed a solution to realize the proportional enlargement / reduction of LCZ696 preparations
[0010] In summary, the prior art does not provide LCZ696 crystalline powder obtained by direct synthesis, which is beneficial to the synthesis and preparation process, and has not realized the optimization of LCZ696 preparation formulation and process. The optimization of the process is a technical problem that the existing technology does not solve

Method used

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  • High-stability LCZ696 crystallized powder and a preparing method thereof
  • High-stability LCZ696 crystallized powder and a preparing method thereof
  • High-stability LCZ696 crystallized powder and a preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Preparation of AHU377 free acid:

[0078] Add 100g of AHU377 calcium salt and 1000ml of isopropyl acetate into a 2L three-necked flask, add 240ml of 2mol / L hydrochloric acid dropwise under an ice bath; stir to dissolve; separate the liquids, collect the organic layer, and wash it twice with 600ml of water; Under reduced pressure at 38°C, the free acid of AHU377 was obtained;

[0079] Preparation of LCZ696:

[0080] At room temperature, add AHU377 free acid, 100g valsartan, 880ml acetone, and 220ml isopropanol to a 3L three-necked flask and dissolve; add dropwise an aqueous solution of sodium hydroxide with an equivalent concentration of 0.9g / ml relative to valsartan 2.85 , heat up to 50°C and react for 20 minutes; cool down to 45°C, add about 2.0 g of seed crystals, the solution becomes cloudy after stirring, then lower the external temperature to 35°C at a rate of 1.0°C / 10min, and then move the reaction solution to 15°C Stir at high temperature for 2h; then add 1120m...

Embodiment 2

[0083] Preparation of AHU377 free acid:

[0084] Add 100g of AHU377 calcium salt and 1000ml of isopropyl acetate into a 2L three-neck flask, add 230ml of 2mol / L hydrochloric acid dropwise under ice bath; stir to dissolve; separate the liquid, collect the organic layer, and wash it twice with 600ml of water; Desolvation under reduced pressure at 38°C to obtain AHU377 free acid, add 250ml of isopropanol to dissolve, then desolventize under reduced pressure again and repeat once;

[0085] Preparation of LCZ696:

[0086] At room temperature, add AHU377 free acid, 100g valsartan, 800ml acetone, and 220ml isopropanol to a 3L three-necked flask and dissolve; add dropwise at room temperature an aqueous solution of sodium hydroxide with an equivalent concentration of 0.85g / ml relative to valsartan 2.95 , raised the temperature to 53°C for 30 minutes; then lowered the external temperature to 30°C at a rate of 1.0°C / 10min, added about 1.0 g of seed crystals, moved the reaction solution ...

Embodiment 3

[0089] Since the crystalline powder obtained in Examples 1 and 2 has a moderate particle size and shape, rapid filtration can be achieved during the reaction. In order to reflect its advantages in filtration compared with the prior art, the reaction scale of embodiment 1 and embodiment 2 is enlarged by 20 times, and it is compared with patent CN200680001733.0 embodiment 3 (hereinafter referred to as "comparative implementation Example 1") for comparison, the results are as follows:

[0090] project Suction time (min) D90(μm) Example 1 about 20min 44.68 Example 2 <20min

47.36 Comparative Example 1 about 55min 16.80

[0091] In particular, the crystalline powder obtained in Comparative Example 1 has a more serious caking phenomenon (appearance such as Figure 6 shown), showing that the passing rate through the 80 mesh sieve is only about 25%, and the particle size distribution of the resulting crystalline powder is as follows Figure...

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Abstract

High-stability LCZ696 crystallized powder and a preparing method thereof are provided. According to the LCZ696 crystallized powder, through controlling the using amount and the concentration of sodium hydroxide, contents of hydrolysis impurities in the prepared LCZ696 crystallized powder are controlled to a relatively low range. The LCZ696 crystallized powder has higher stability.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a highly stable LCZ696 crystalline powder which can be used for treating heart failure and a preparation method thereof. Background technique [0002] Heart failure (referred to as heart failure) is a group of complex clinical syndromes due to any structural or functional abnormality of the heart that leads to impaired ventricular filling or ejection ability. The main clinical manifestations of heart failure are dyspnea and fatigue (limited exercise tolerance), and fluid retention (pulmonary congestion and peripheral edema). Heart failure is the severe and terminal stage of various heart diseases with a high incidence rate and is one of the most important cardiovascular diseases today ("Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2014"). [0003] Since 2005, due to the prevalence of cardiovascular disease risk factors, the incidence of cardiovascular d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C231/24C07C233/47C07D257/04A61K31/41A61K31/216A61K9/36A61P9/04
CPCA61K9/2009A61K9/2027A61K9/2054A61K9/2866A61K31/216A61K31/41C07B2200/13C07C231/12C07C231/24C07C233/47C07D257/04A61K2300/00
Inventor 李松许文杰华怀杰
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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