CN110133149A - A kind of method of separation determination LCZ696 and its impurity - Google Patents
A kind of method of separation determination LCZ696 and its impurity Download PDFInfo
- Publication number
- CN110133149A CN110133149A CN201910468999.5A CN201910468999A CN110133149A CN 110133149 A CN110133149 A CN 110133149A CN 201910468999 A CN201910468999 A CN 201910468999A CN 110133149 A CN110133149 A CN 110133149A
- Authority
- CN
- China
- Prior art keywords
- mobile phase
- volume
- percentage
- impurity
- minutes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/16—Injection
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/16—Injection
- G01N2030/165—Injection retention gaps
Landscapes
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The method of a kind of separation determination LCZ696 and its impurity, have follow steps, 1) LCZ696 or the preparation containing LCZ696 are taken, add diluent to dissolve, obtains the sample solution that concentration is 0.1-10mg/ml；2) sample solution for taking step 1) to obtain adds 50-1000 times of dilution agent of dilution, obtains contrast solution；3) use octadecylsilane chemically bonded silica for the chromatographic column of filler, the flow velocity that mobile phase is arranged is 0.8-1.2ml/min, the mobile phase is made of mobile phase A and Mobile phase B, mobile phase A is the buffer solution that concentration is 0.0001-1.0mol/L, the triethylamine of 0.0001-10 parts by volume is added in the buffer solution of 100 parts by volume, Mobile phase B is acetonitrile-methanol mixed liquor, acetonitrile, methanol volume ratio be 55-45:45-55, mobile phase enters chromatographic column using gradient elution mode；4) respectively to the isometric step 1) sample solution of high performance liquid chromatograph sample introduction, step 2) contrast solution, sample volume is 5 μ l-100 μ l, using 200nm to 280nm wavelength detecting, chromatogram is recorded, completes the separation determination of impurity in sample solution.
Description
Technical field
The present invention relates to analytical chemistry field, in particular to the method for a kind of separation determination LCZ696 and its impurity.
Background technique
LCZ696 is that one kind has both angiotensin receptor blocking effect and neutral endopeptidase inhibitor double action
(ARB-NEPi) unimolecular precursors medicine.After oral administration, LCZ696 discharges angiotensin receptor blocker (ARB) Valsartan
With neutral endopeptidase inhibitor (NEPi) pro-drug AHU377, the latter is subsequently converted to active nep inhibitor LBQ657.
It is envisaged for treatment hypertension and heart failure.Its molecular formula is C48H55N6O8.2.5 (H2O) .3Na, chemical name are as follows: L- figured silk fabrics ammonia
Acid, N- (1- oxopentyl)-N [[2 '-(2H- tetrazolium -5- base) [1 ' 1- biphenyl] base -4- base] methyl -, compound, with α-ethyl
(α R, γ S)-γ [(3- carboxyl -1- oxopropyl) amino]-Alpha-Methyl-[1 ' 1- xenyl] -4- valerate, sodium salt, hydrate
Shown in (2:2:6:5) structural formula such as formula (a).
During synthesizing the compound, the intermediate and unknown impuritie for having several steps important may be endless due to removing
Purity and quality complete and that influence drug, these known intermediates and unknown impuritie and the catabolite of generation are medicinal substances
Usually said related substance (i.e. impurity) in amount control.The known impurities mainly controlled for the synthesis of LCZ696 have 21
It is a, be respectively: impurity SM1, impurity IPA, impurity A HUD, impurity IPE, impurity A HUE, impurity IPC, impurity VAL-2, impurity E-
VAL-4-Z, impurity VAL-C, impurity A HUF, impurity A HUG, impurity A HUH, impurity A HUI, impurity A HUJ, impurity A HUK, impurity
AHUL, impurity A HUM, impurity A HUN, impurity A HUO, impurity A HUP, impurity A HUQ, structural formula respectively as formula (b), (c), (d),
(e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), (r), (s), (t), (u), (v) are shown.
As it can be seen that the impurity of LCZ696 is more, and structure is similar, brings difficulty to separation.In addition, the polarity of each impurity is respectively not
It is identical, under the premise of meeting LCZ696 and separating with each impurity, also to meet the separation between impurity and impurity, cause detection difficult
It spends larger.Effectively dividing between LCZ696 and impurity and impurity and impurity is difficult to realize using conventional detection means method
From the quality for seriously affecting LCZ696 and its preparation controls.
In order to accurately control the quality of LCZ696 and formulation products, it is necessary to study it is a kind of can be simple, quickly and accurately
Separation detection goes out the method for LCZ696 and its preparation in relation to substance.
Summary of the invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide the sides of a kind of separation determination LCZ696 and its impurity
Method, it is simple, convenient, measurement LCZ696 and its impurity can be efficiently separated, the quality of LCZ696 and products thereof is effectively controlled.
The technical scheme is that the method for a kind of separation determination LCZ696 and its impurity, have follow steps,
1) sample solution is prepared
LCZ696 or the preparation containing LCZ696 are taken, diluent is added to dissolve, it is molten to obtain the sample that concentration is 0.1-10mg/ml
Liquid；
2) contrast solution is prepared
The sample solution that step 1) obtains is taken, adds 50-1000 times of dilution agent of dilution, obtains contrast solution；
3) use octadecylsilane chemically bonded silica for the chromatographic column of filler, the flow velocity that mobile phase is arranged is 0.8-1.2ml/
Min, the mobile phase are made of mobile phase A and Mobile phase B, mobile phase A be concentration be 0.0001-1.0mol/L buffering it is molten
Liquid, the triethylamine of 0.0001-10 parts by volume is added in the buffer solution of 100 parts by volume, and Mobile phase B is that acetonitrile-methanol mixes
Liquid, acetonitrile, methanol volume ratio be 55-45:45-55, mobile phase enters chromatographic column using gradient elution mode, 0 minute, flowing
The percentage by volume of phase A is 58%~62%, and the percentage by volume of Mobile phase B is 42%~38%；0 minute to 20 minutes, stream
The percentage by volume of dynamic phase A is linearly reduced to 42%~38%, and the percentage by volume of Mobile phase B is linearly increasing to 58%~
62%；20 minutes to 50 minutes, the percentage by volume of mobile phase A was linearly reduced to 22%~18%, the volume basis of Mobile phase B
Number is linearly increasing to 78%~82%；50 minutes to 55 minutes, the percentage by volume of mobile phase A was 22%~18%, Mobile phase B
Percentage by volume be 78%~82%；55 minutes to 55.1 minutes, the percentage by volume of mobile phase A is linearly increasing to 58%~
62%, the percentage by volume of Mobile phase B is linearly reduced to 42%~38%；55.1 minutes to 60 minutes, the volume hundred of mobile phase A
Score is 58%~62%, and the percentage by volume of Mobile phase B is 42%~38%；
4) respectively to the isometric step 1) sample solution of high performance liquid chromatograph sample introduction, step 2) contrast solution, sample introduction
Amount is 5 μ l-100 μ l, using 200nm to 280nm wavelength detecting, records chromatogram, and the separation for completing impurity in sample solution is surveyed
It is fixed.
Step 1), step 2) diluent are the mixture of first alcohol and water, and the volume ratio of methanol and water is 65-95:35-
5。
The volume ratio of methanol and water is 80:20.
It is 0.001-0.01mol/L that mobile phase A, which is concentration, in step 3).
Step 3) the buffer solution is the mixture of phosphoric acid or phosphate solution or both, and phosphate is biphosphate
Potassium, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate or any mixing, buffer solution
PH value be 2.0-3.5.
Step 3) mobile phase enters chromatographic column using gradient elution mode, and 0 minute, the percentage by volume of mobile phase A was
60%, the percentage by volume of Mobile phase B is 40%；0 minute to 20 minutes, the percentage by volume of mobile phase A linearly reduce to
40%, the percentage by volume of Mobile phase B is linearly increasing to 60%；20 minutes to 50 minutes, the percentage by volume of mobile phase A was linear
It reduces to 20%, the percentage by volume of Mobile phase B is linearly increasing to 80%；50 minutes to 55 minutes, the volume basis of mobile phase A
Number is 20%, and the percentage by volume of Mobile phase B is 80%；55 minutes to 55.1 minutes, the percentage by volume of mobile phase A linearly increased
60% is added to, the percentage by volume of Mobile phase B is linearly reduced to 40%；55.1 minutes to 60 minutes, the volume basis of mobile phase A
Number is 60%, and the percentage by volume of Mobile phase B is 40%；
When step 4) sample introduction, sample volume is 10 μ l, and using 255nm wavelength detecting, the column temperature of chromatographic column is 20-40 DEG C.
The column temperature of chromatographic column is 30 DEG C.
It has the advantages that by adopting the above technical scheme
1, method of separating and assaying of the present invention uses octadecylsilane chemically bonded silica for the chromatographic column of filler, is washed using gradient
Off-square formula, it is ensured that can make to be efficiently separated between LCZ696 and impurity, impurity and impurity；In the mobile phase A of 100 parts by volume
The triethylamine for adding 0.0001-10 parts by volume, effectively improves the peak shape of impurity, and reservation can be enhanced, and improves separating degree, it is ensured that
The good symmetry of chromatographic peak and higher column effect.It selects methanol and water mixed liquid as diluent sample dissolution, eliminates molten
The interference and solvent effect at agent peak.
2, method of separating and assaying of the present invention is using mobile phase A (buffer solution+triethylamine), Mobile phase B (acetonitrile+methanol) ladder
The impurity for spending type of elution measurement LCZ696 and its preparation, avoiding traditional mobile phase cannot be divided completely using a kind of organic phase
LCZ696 effectively can be effectively separated and be measured with known impurities and unknown impuritie by impurity similar from polarity, be solved
The problem of separation determination LCZ696 is separated with its impurity difficulty, to ensure that the quality controllable of LCZ696 and its preparation.
3, the diluent that method of separating and assaying of the present invention uses does not interfere impurity determination, and specificity is strong；Each impurity sensitivity
Meet the requirements.Impurity content is calculated by the Self-control method of the correction up factor, is divided between main peak and other impurities and other impurities
It meets the requirements from degree.This product and each impurity minimum detection are limited to 0.0006%, show that the impurity greater than 0.0006% can quilt
Detection, accuracy are higher.
It is further described with reference to the accompanying drawings and detailed description.
Detailed description of the invention
Fig. 1 is the liquid chromatogram of one methanol-water mixture of embodiment；
Fig. 2 is the liquid chromatogram that embodiment one mixes contrast solution；
Fig. 3 is the liquid chromatogram of two sample solution of embodiment；
Fig. 4 is the liquid chromatogram of two contrast solution of embodiment；
Fig. 5 is the liquid chromatogram of three sample solution of embodiment；
Fig. 6 is the liquid chromatogram of three contrast solution of embodiment；
Fig. 7 is the liquid chromatogram of three blank auxiliary test liquid of embodiment.
Specific embodiment
Instrument and condition
High performance liquid chromatograph selects 1260 type liquid chromatograph of Agilent and chem workstation, be set as automatically into
Sample.With (3.5 μm, 100 × 4.6mm) of column of ZORBAX Eclipse Plus C18 for separation chromatography column.UV detector wavelength:
255nm.Mobile phase: with 0.02mol/L potassium dihydrogen phosphate, (1ml triethylamine is added in 100ml potassium dihydrogen phosphate, uses phosphorus
2.5) it is mobile phase A that acid, which is adjusted to pH value to be, with methanol-acetonitrile (volume ratio 50:50) for Mobile phase B, progress gradient elution: 0
Minute, the percentage by volume of mobile phase A is 60%, and the percentage by volume of Mobile phase B is 40%；0 minute to 20 minutes, mobile phase
The percentage by volume of A is linearly reduced to 40%, and the percentage by volume of Mobile phase B is linearly increasing to 60%；20 minutes to 50 minutes,
The percentage by volume of mobile phase A is linearly reduced to 20%, and the percentage by volume of Mobile phase B is linearly increasing to 80%；50 minutes extremely
55 minutes, the percentage by volume of mobile phase A was 20%, and the percentage by volume of Mobile phase B is 80%；55 minutes to 55.1 minutes,
The percentage by volume of mobile phase A is linearly increasing to 60%, and the percentage by volume of Mobile phase B is linearly reduced to 40%；55.1 minutes
To 60 minutes, the percentage by volume of mobile phase A was 60%, and the percentage by volume of Mobile phase B is 40%.Column temperature is 35 DEG C, flow velocity:
0.6ml/min.Sampling volume is 10 μ l.
Embodiment one:
Impurity SM1, impurity IPA, impurity A HUD, impurity IPE, impurity A HUE, impurity IPC, impurity VAL-2, miscellaneous is taken respectively
Matter E-VAL-4-Z, impurity VAL-C, impurity A HUF, impurity A HUG, impurity A HUH, impurity A HUI, impurity A HUJ, impurity A HUK,
Impurity A HUL, impurity A HUM, impurity A HUN, impurity A HUO, impurity A HUP, impurity A HUQ (purity of each impurity 99% with
On) each 20mg, precision weighing is placed in 100ml measuring bottle, adds methanol-water (volume ratio 80:20) to dissolve and be diluted to scale,
It shakes up, as impurity stock solution；LCZ696 about 100mg is taken, it is accurately weighed, it is placed in 50ml measuring bottle, impurity reserve is added in precision
Liquid 2.5ml adds methanol-water (volume ratio 80:20) to dissolve and is diluted to scale, shakes up, as mixing contrast solution.
Diluent (methanol: water=80:20), mixing contrast solution are taken respectively, carry out liquid chromatogram by above-mentioned chromatographic condition
Analysis records chromatogram, as a result as shown in Figure 1 and Figure 2.
Fig. 1 shows the mixture and chromatographic system not interference measurement of methanol-water.
Successively the sequence of appearance is impurity VAL-2, impurity IPA, impurity A HUE, impurity VAL-C, VAL, impurity in Fig. 2
AHUQ, impurity IPE, impurity A HUH, impurity A HUP, AHU377, impurity E-VAL-4-Z, impurity A HUJ, impurity A HUD, impurity
AHUM, impurity A HUN, impurity SM1, impurity A HUO, impurity A HUG, impurity A HUK, impurity A HUI, impurity A HUL, impurity A HUF,
Impurity IPC.Fig. 2 shows that method of separating and assaying of the present invention can efficiently separate the miscellaneous of unknown structure that may be present in LCZ696
The impurity of matter and known structure, and each defects inspecting sensitivity can meet the requirements, between main peak and other impurities and each impurity
Separating degree meets the requirements, i.e. this method measurement for can be used for the impurity of LCZ696 and its preparation.
The measurement of two LCZ696 bulk pharmaceutical chemicals of embodiment (holy Industry Co., Ltd provides by Chongqing three)
LCZ696 100mg is taken, it is accurately weighed, it is placed in 50ml measuring bottle, adds at methanol-water (volume ratio 80:20) ultrasound
Reason dissolves and is diluted to scale, shakes up, as sample solution；Precision measures sample solution 0.5ml, is placed in 100ml measuring bottle, uses first
Alcohol-water (volume ratio 80:20) is diluted to scale, shakes up, as contrast solution；Liquid phase is carried out by the chromatographic condition of embodiment one
Chromatography records chromatogram.In the chromatogram of sample solution if any impurity peaks (in addition to solvent peak), by the correction up factor from
Body counter point calculates impurity content.As a result as shown in Figure 3, Figure 4.Testing result such as table 1:
Table 1
| Impurity title | Content (calculates) relative to Valsartan |
| VAL-2 | It is not detected |
| IPA | It is not detected |
| AHUE | 0.035% |
| VAL-C | It is not detected |
| AHUQ | It is not detected |
| IPE | 0.015% |
| AHUH | It is not detected |
| AHUP | It is not detected |
| E-VAL-4-Z | It is not detected |
| AHUJ | It is not detected |
| AHUD | It is not detected |
| AHUM | It is not detected |
| AHUN | It is not detected |
| SM1 | It is not detected |
| AHUO | It is not detected |
| AHUG | 0.020% |
| AHUK | It is not detected |
| AHUI | It is not detected |
| AHUL | It is not detected |
| AHUF | It is not detected |
| IPC | It is not detected |
| It is total miscellaneous | 0.07% |
The measurement of three LCZ696 piece of embodiment (holy Industry Co., Ltd provides by Chongqing three)
It takes LCZ696 piece appropriate (being approximately equivalent to LCZ696 100mg), is placed in 50ml measuring bottle, adds methanol-water (volume ratio
It is ultrasonically treated for 80:20) and dissolves and be diluted to scale, shaken up, filtered, take filtrate as sample solution；It is molten that precision measures sample
Liquid 0.5ml is placed in 100ml measuring bottle, is diluted to scale with methanol-water (volume ratio 80:20), shakes up, as contrast solution；Separately
It takes blank auxiliary appropriate in LCZ696 tablet recipe ratio, prepares blank auxiliary test liquid according to the identical method of sample solution；By reality
The chromatographic condition for applying example one carries out liquid-phase chromatographic analysis.Chromatogram is recorded, as a result as shown in Fig. 5, Fig. 6, Fig. 7.Using correction up
The Self-control method of the factor calculates Isomers impurity content in test product, testing result such as table 2:
Table 2
| Impurity title | Content (calculates) relative to Valsartan |
| VAL-2 | It is not detected |
| IPA | It is not detected |
| AHUE | 0.036% |
| VAL-C | It is not detected |
| AHUQ | It is not detected |
| IPE | 0.015% |
| AHUH | It is not detected |
| AHUP | It is not detected |
| E-VAL-4-Z | It is not detected |
| AHUJ | It is not detected |
| AHUD | 0.003% |
| AHUM | It is not detected |
| AHUN | 0.003% |
| SM1 | It is not detected |
| AHUO | It is not detected |
| AHUG | 0.019% |
| AHUK | It is not detected |
| AHUI | It is not detected |
| AHUL | It is not detected |
| AHUF | It is not detected |
| IPC | It is not detected |
| Unknown single maximum | 0.010% |
| It is total miscellaneous | 0.11% |
Claims (8)
1. the method for a kind of separation determination LCZ696 and its impurity, which is characterized in that it has follow steps,
1) sample solution is prepared
LCZ696 or the preparation containing LCZ696 are taken, diluent is added to dissolve, obtains the sample solution that concentration is 0.1-10mg/ml；
2) contrast solution is prepared
The sample solution that step 1) obtains is taken, adds 50-1000 times of dilution agent of dilution, obtains contrast solution；
3) use octadecylsilane chemically bonded silica for the chromatographic column of filler, the flow velocity that mobile phase is arranged is 0.8-1.2ml/min,
The mobile phase is made of mobile phase A and Mobile phase B, mobile phase A be concentration be 0.0001-1.0mol/L buffer solution, 100
The triethylamine of 0.0001-10 parts by volume is added in the buffer solution of parts by volume, Mobile phase B is acetonitrile-methanol mixed liquor, second
Nitrile, methanol volume ratio be 55-45:45-55, mobile phase enters chromatographic column using gradient elution mode, 0 minute, mobile phase A
Percentage by volume is 58%~62%, and the percentage by volume of Mobile phase B is 42%~38%；0 minute to 20 minutes, mobile phase A
Percentage by volume linearly reduce to 42%~38%, the percentage by volume of Mobile phase B is linearly increasing to 58%~62%；20 points
Clock was to 50 minutes, and the percentage by volume of mobile phase A is linearly reduced to 22%~18%, and the percentage by volume of Mobile phase B linearly increases
Add to 78%~82%；50 minutes to 55 minutes, the percentage by volume of mobile phase A was 22%~18%, the volume hundred of Mobile phase B
Score is 78%~82%；55 minutes to 55.1 minutes, the percentage by volume of mobile phase A was linearly increasing to 58%~62%, stream
The percentage by volume of dynamic phase B is linearly reduced to 42%~38%；55.1 minutes to 60 minutes, the percentage by volume of mobile phase A was
58%~62%, the percentage by volume of Mobile phase B is 42%~38%；
4) respectively to the isometric step 1) sample solution of high performance liquid chromatograph sample introduction, step 2) contrast solution, sample volume 5
μ l-100 μ l records chromatogram using 200nm to 280nm wavelength detecting, completes the separation determination of impurity in sample solution.
2. the method according to claim 1, wherein step 1), step 2) diluent are first alcohol and water
The volume ratio of mixture, methanol and water is 65-95:35-5.
3. according to the method described in claim 2, it is characterized in that, the volume ratio of methanol and water is 80:20.
4. the method according to claim 1, wherein it is 0.001- that mobile phase A, which is concentration, in step 3)
0.01mol/L。
5. the method according to claim 1, wherein the step 3) buffer solution is that phosphoric acid or phosphate are molten
The mixture of liquid or both, phosphate are potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphoric acid hydrogen two
Sodium, diammonium hydrogen phosphate or any mixing, the pH value of buffer solution are 2.0-3.5.
6. the method according to claim 1, wherein step 3) mobile phase enters chromatography using gradient elution mode
Column, 0 minute, the percentage by volume of mobile phase A was 60%, and the percentage by volume of Mobile phase B is 40%；0 minute to 20 minutes, stream
The percentage by volume of dynamic phase A is linearly reduced to 40%, and the percentage by volume of Mobile phase B is linearly increasing to 60%；20 minutes to 50
Minute, the percentage by volume of mobile phase A is linearly reduced to 20%, and the percentage by volume of Mobile phase B is linearly increasing to 80%；50 points
For clock to 55 minutes, the percentage by volume of mobile phase A was 20%, and the percentage by volume of Mobile phase B is 80%；55 minutes to 55.1 points
Clock, the percentage by volume of mobile phase A are linearly increasing to 60%, and the percentage by volume of Mobile phase B is linearly reduced to 40%；55.1 points
For clock to 60 minutes, the percentage by volume of mobile phase A was 60%, and the percentage by volume of Mobile phase B is 40%.
7. utilizing 255nm the method according to claim 1, wherein sample volume is 10 μ l when step 4) sample introduction
Wavelength detecting, the column temperature of chromatographic column are 20-40 DEG C.
8. the method according to the description of claim 7 is characterized in that the column temperature of chromatographic column is 30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910468999.5A CN110133149B (en) | 2019-05-31 | 2019-05-31 | Method for separating and measuring LCZ696 and impurities thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910468999.5A CN110133149B (en) | 2019-05-31 | 2019-05-31 | Method for separating and measuring LCZ696 and impurities thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110133149A true CN110133149A (en) | 2019-08-16 |
| CN110133149B CN110133149B (en) | 2022-05-24 |
Family
ID=67583462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910468999.5A Active CN110133149B (en) | 2019-05-31 | 2019-05-31 | Method for separating and measuring LCZ696 and impurities thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110133149B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112415114A (en) * | 2021-01-22 | 2021-02-26 | 方达医药技术(上海)有限公司 | Method for determining concentration of valsartan and sabotarol in human plasma and application thereof |
| CN112666294A (en) * | 2020-12-29 | 2021-04-16 | 重庆三圣实业股份有限公司 | Method for separating and determining Shakubatu calcium salt and impurities thereof |
| CN112730721A (en) * | 2020-12-29 | 2021-04-30 | 重庆三圣实业股份有限公司 | Method for separating and measuring Shakubatroxa calcium salt and isomer thereof |
| CN113816871A (en) * | 2021-08-23 | 2021-12-21 | 江苏开放大学（江苏城市职业学院） | LCZ696 impurity and preparation method thereof |
| CN114814060A (en) * | 2021-01-28 | 2022-07-29 | 上海博志研新药物技术有限公司 | Detection method of valsartan amlodipine tablet related substances |
| CN116930370A (en) * | 2023-07-28 | 2023-10-24 | 辽源市百康药业有限责任公司 | Method for measuring parachloroaniline in paracetamol |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330609A (en) * | 2015-12-07 | 2016-02-17 | 南京正大天晴制药有限公司 | Method for preparing LCZ696 |
| CN106458857A (en) * | 2014-08-27 | 2017-02-22 | 上海翰森生物医药科技有限公司 | Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof |
| CN106770855A (en) * | 2016-12-30 | 2017-05-31 | 江苏开元医药化工有限公司 | A kind of method for separating and detecting of Sha Kubi song intermediates and its optical isomer based on high performance liquid chromatography |
| CN107935958A (en) * | 2017-11-30 | 2018-04-20 | 中国药科大学 | A kind of Valsartan Puerarin sodium salt compound and preparation method thereof |
| CN108047092A (en) * | 2018-01-12 | 2018-05-18 | 重庆市碚圣医药科技股份有限公司 | A kind of synthetic method of LCZ696 intermediates |
-
2019
- 2019-05-31 CN CN201910468999.5A patent/CN110133149B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106458857A (en) * | 2014-08-27 | 2017-02-22 | 上海翰森生物医药科技有限公司 | Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof |
| CN105330609A (en) * | 2015-12-07 | 2016-02-17 | 南京正大天晴制药有限公司 | Method for preparing LCZ696 |
| CN106770855A (en) * | 2016-12-30 | 2017-05-31 | 江苏开元医药化工有限公司 | A kind of method for separating and detecting of Sha Kubi song intermediates and its optical isomer based on high performance liquid chromatography |
| CN107935958A (en) * | 2017-11-30 | 2018-04-20 | 中国药科大学 | A kind of Valsartan Puerarin sodium salt compound and preparation method thereof |
| CN108047092A (en) * | 2018-01-12 | 2018-05-18 | 重庆市碚圣医药科技股份有限公司 | A kind of synthetic method of LCZ696 intermediates |
Non-Patent Citations (2)
| Title |
|---|
| BAHIA A. MOUSSA ET AL: "Experimental Design Approach in HPLC Method Development:Application for the Simultaneous Determination of Sacubitril and Valsartan in Presence of Their Impurities and Investigation of Degradation Kinetics", 《CHROMATOGRAPHIA》 * |
| 朱功凤 等: "HPLC 法测定沙库必曲缬沙坦原料药的含量及有关物质", 《广东化工》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112666294A (en) * | 2020-12-29 | 2021-04-16 | 重庆三圣实业股份有限公司 | Method for separating and determining Shakubatu calcium salt and impurities thereof |
| CN112730721A (en) * | 2020-12-29 | 2021-04-30 | 重庆三圣实业股份有限公司 | Method for separating and measuring Shakubatroxa calcium salt and isomer thereof |
| CN112415114A (en) * | 2021-01-22 | 2021-02-26 | 方达医药技术(上海)有限公司 | Method for determining concentration of valsartan and sabotarol in human plasma and application thereof |
| CN114814060A (en) * | 2021-01-28 | 2022-07-29 | 上海博志研新药物技术有限公司 | Detection method of valsartan amlodipine tablet related substances |
| CN114814060B (en) * | 2021-01-28 | 2024-05-10 | 上海博志研新药物研究有限公司 | Detection method of valsartan amlodipine tablet related substances |
| CN113816871A (en) * | 2021-08-23 | 2021-12-21 | 江苏开放大学（江苏城市职业学院） | LCZ696 impurity and preparation method thereof |
| CN116930370A (en) * | 2023-07-28 | 2023-10-24 | 辽源市百康药业有限责任公司 | Method for measuring parachloroaniline in paracetamol |
| CN116930370B (en) * | 2023-07-28 | 2024-05-28 | 辽源市百康药业有限责任公司 | Method for measuring parachloroaniline in paracetamol |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110133149B (en) | 2022-05-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110133149A (en) | A kind of method of separation determination LCZ696 and its impurity | |
| CN106940355B (en) | A kind of brufen, the detection method of its sodium salt and its preparation in relation to substance | |
| CN108627597A (en) | A kind of detection method of the salbutamol sulfate in relation to substance | |
| CN106146332A (en) | Separate and measure Linezolid raw material X3 and the method for process contaminants X2 thereof | |
| CN114651177A (en) | Carbocisteine raw material and quality control method and application of preparation thereof | |
| CN110133150A (en) | A kind of method of separation determination LCZ696 isomer impurities | |
| CN112666294B (en) | Method for separating and determining Shakubatu calcium salt and impurities thereof | |
| CN107525877A (en) | A kind of method using liquid chromatography for separating and determining according to a piperazine azoles and its impurity | |
| CN106153795A (en) | Measure chenodeoxycholic acid crude drug content and the method having related substance thereof | |
| CN110057943A (en) | A kind of efficient liquid phase chromatographic analysis detection method of Amlodipine Besylate Tablet intermediate | |
| CN112034066B (en) | Method for separating and measuring Ribociclib and impurities | |
| CN104297354A (en) | Detection method for determining impurities in penehyclidine hydrochloride through high performance liquid chromatography (HPLC) | |
| CN108872406A (en) | HPLC analyzing detecting method in relation to substance in a kind of L-aminobutanedioic acid bulk pharmaceutical chemicals | |
| CN114518413A (en) | Method for measuring content of proline in captopril raw material medicine | |
| CN110095554B (en) | Method for analyzing milrinone related substances by high performance liquid chromatography | |
| CN116735746B (en) | Method for separating and measuring clopidodine hydrochloride and impurities thereof | |
| Magiera et al. | A rapid method for determination of 22 selected drugs in human urine by UHPLC/MS/MS for clinical application | |
| CN110133168A (en) | HPLC method measures method of the Cabazitaxel in relation to substance | |
| CN109265496A (en) | A kind of synthetic method of glucoside-containing component | |
| CN108226346A (en) | A kind of analysis method for detecting aspartic acid ornithine specific impurities | |
| CN115236255B (en) | Method for detecting related substances of loxoprofen sodium | |
| CN114200050B (en) | HPLC detection method for content of related substances in p-bromoanisole | |
| CN107656005A (en) | Separation and assay method of the erlotinib Hydrochloride with potential impurity | |
| CN114839286B (en) | Method for measuring related substances in glimepiride bulk drug | |
| CN115420823B (en) | Method for measuring related substances in roflumilast |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |