A method for separating and measuring lcz696 isomer impurities

A technology for isomers and impurities, which is applied in the field of separation and determination of LCZ696 isomer impurities, can solve problems such as poor baseline, difficulty in meeting detection requirements, and poor peak shape, and achieve high column efficiency, high accuracy, and improved resolution. Effect

Active Publication Date: 2022-04-12
CHONGQING SANSHENG IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For the separation and detection of isomers, especially enantiomers, conventional chiral columns are generally used to separate and detect them by forward chromatography. This detection method forms a poor baseline and poor peak shape, which is very Difficult to meet testing requirements

Method used

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  • A method for separating and measuring lcz696 isomer impurities
  • A method for separating and measuring lcz696 isomer impurities
  • A method for separating and measuring lcz696 isomer impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Take 50 mg of impurity AHUA, impurity AHUB, impurity AHUC, and impurity VAL-A respectively (the purity of AHUA, AHUB, AHUC, and VAL-A are all above 99%), accurately weigh, place in a 50ml measuring bottle, add methanol- Dissolve and dilute to the mark in water (volume ratio 80:20), shake well, and use it as impurity stock solution; take 50 mg of LCZ696, accurately weigh it, place it in a 50ml measuring bottle, add 0.25ml of impurity stock solution precisely, add methanol-water (Volume ratio is 80:20) dissolved and diluted to the scale, shake well, as a mixed control solution, in the solute of the mixed control solution, the concentration of LCZ696 is 1 mg / ml, and the concentration of each known impurity is 5 μg / ml.

[0041] Take methanol-water (volume ratio is 80:20) and mixed control solution respectively, carry out liquid chromatography analysis according to the above-mentioned chromatographic conditions, record the chromatogram, the result is as follows: figure 1 , ...

Embodiment 2

[0044] The mensuration of embodiment two LCZ696 crude drug (provided by Chongqing Sansheng Industrial Co., Ltd.)

[0045] Take 50 mg of LCZ696, weigh it accurately, put it in a 50ml measuring bottle, add methanol-water (volume ratio: 80:20) for ultrasonic treatment to dissolve and dilute to the mark, shake well, and use it as the sample solution; accurately measure 1ml of the sample solution , placed in a 100ml measuring bottle, diluted to the mark with methanol-water (volume ratio of 80:20), shaken up, as a reference solution; liquid chromatography analysis was carried out according to the chromatographic conditions of Example 1. Record the chromatogram, the result is as follows image 3 , Figure 4 shown. The content of each isomer impurity in the test sample was calculated by the self-control method with a correction factor, and the test results are shown in Table 1:

[0046] Table 1

[0047] Impurities Content (wt%) VAI-A 0.0179 AHUC 0.0013 ...

Embodiment 3

[0048] The mensuration of embodiment three LCZ696 sheet (provided by Chongqing Sansheng Industrial Co., Ltd.)

[0049] Take about 210mg of fine powder of LCZ696 tablets (approximately equivalent to 50mg of LCZ696), put it in a 50ml measuring bottle, add methanol-water (volume ratio: 80:20) sonication to dissolve and dilute to the mark, shake well, filter, and take The filtrate is used as the sample solution; accurately measure 1ml of the sample solution, place it in a 100ml measuring bottle, dilute it to the mark with methanol-water (volume ratio: 80:20), shake it well, and use it as a control solution; in addition, take it according to the prescription ratio of LCZ696 tablets An appropriate amount of blank auxiliary material is prepared, and the blank auxiliary material test solution is prepared according to the same method as the sample solution; the liquid chromatography analysis is carried out according to the chromatographic conditions of Example 1. Record the chromatogra...

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Abstract

A method for separating and measuring LCZ696 isomer impurities, comprising the following steps: 1) taking LCZ696 or a preparation containing LCZ696, adding a diluent to dissolve, and obtaining a sample solution with a concentration of 0.1-10 mg / ml; 2) taking step 1) The obtained sample solution is diluted 50-1000 times with a diluent to obtain a control solution; 3) a polysaccharide derivative or a cellulose derivative reversed-phase coating type chiral chromatographic column is used, and the flow rate of the mobile phase is set to 0.4-0.8ml / min, the mobile phase is made up of mobile phase A and mobile phase B, mobile phase A is a buffer solution with a volume concentration of 0.0001-1.0%, mobile phase B is an acetonitrile-methanol mixed solution, and the volume ratio of acetonitrile and methanol is 75 ‑85:25‑15, 100 parts by volume of mobile phase B were added with 0‑1 parts by volume of phosphoric acid, and the mobile phase entered the chromatographic column by gradient elution; 4) were injected into the high performance liquid chromatograph with an equal volume of In step 1) sample solution and step 2) control solution, the injection volume is 5 μl-100 μl, and the wavelength of 200nm to 280nm is used to detect, record the chromatogram, and complete the separation and determination of isomers in the sample solution.

Description

technical field [0001] The invention relates to the field of analytical chemistry, in particular to a method for separating and measuring LCZ696 isomer impurities. Background technique [0002] LCZ696 is a single-molecule prodrug with dual effects of angiotensin receptor blocking and neutral endopeptidase inhibitor (ARB-NEPi). Following oral administration, LCZ696 releases the angiotensin receptor blocker (ARB) valsartan and the neutral endopeptidase inhibitor (NEPi) prodrug AHU377, which is subsequently converted to the active NEP inhibitor LBQ657. Intended for the treatment of hypertension and heart failure. Its molecular formula is C48H55N6O8.2.5(H2O).3Na, and its structural formula is shown in formula (a). [0003] LCZ696 has two chiral centers, that is, valsartan has one chiral center, and AHU377 has one chiral center, so they have enantiomers and diastereoisomers, collectively referred to as isomer impurities, respectively : Impurity AHUA, impurity AHUB, impurity AH...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/28G01N30/16
CPCG01N30/02G01N30/06G01N30/28G01N30/16G01N2030/165G01N2030/027
Inventor 代广会谢青山柳玲何伟彭磊黄雄鸠唐安凤晏香兰
Owner CHONGQING SANSHENG IND CO LTD
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