CN110133150B - Method for separating and measuring LCZ696 isomer impurities - Google Patents
Method for separating and measuring LCZ696 isomer impurities Download PDFInfo
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- CN110133150B CN110133150B CN201910469003.2A CN201910469003A CN110133150B CN 110133150 B CN110133150 B CN 110133150B CN 201910469003 A CN201910469003 A CN 201910469003A CN 110133150 B CN110133150 B CN 110133150B
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- 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
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- 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
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- G—PHYSICS
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- 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
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- G—PHYSICS
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- 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
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Abstract
A method for separating and determining LCZ696 isomer impurities, comprising the steps of: 1) dissolving LCZ696 or preparation containing LCZ696 with diluent to obtain sample solution with concentration of 0.1-10 mg/ml; 2) taking the sample solution obtained in the step 1), and adding a diluent to dilute the sample solution by 50-1000 times to obtain a control solution; 3) adopting a polysaccharide derivative or cellulose derivative reverse-phase coating type chiral chromatographic column, setting the flow rate of a mobile phase to be 0.4-0.8ml/min, wherein the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is a buffer solution with the volume concentration of 0.0001-1.0%, the mobile phase B is an acetonitrile-methanol mixed solution, the volume ratio of acetonitrile to methanol is 75-85:25-15, 100 parts by volume of the mobile phase B is added with 0-1 part by volume of phosphoric acid, and the mobile phase enters the chromatographic column by adopting a gradient elution mode; 4) injecting equal volumes of the sample solution in the step 1) and the control solution in the step 2) into a high performance liquid chromatograph respectively, wherein the injection amount is 5-100 mu l, detecting by using the wavelength of 200-280 nm, recording a chromatogram, and completing the separation and determination of the isomer in the sample solution.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a method for separating and determining LCZ696 isomer impurities.
Background
LCZ696 is a single molecule prodrug with both angiotensin receptor blocking and central endopeptidase inhibitor dual action (ARB-NEPi). Upon oral administration, LCZ696 releases Angiotensin Receptor Blocker (ARB) valsartan and the neutral endopeptidase inhibitor (NEPi) prodrug AHU377, which is subsequently converted to the active NEP inhibitor LBQ 657. Intended for the treatment of hypertension and heart failure. The molecular formula is C48H55N6O8.2.5(H2O). sub.3 Na, and the structural formula is shown as a formula (a).
LCZ696 has two chiral centers, namely valsartan has one chiral center and AHU377 has one chiral center, so it has enantiomers and diastereomers, collectively referred to as isomeric impurities, which are respectively: the structural formulas of the impurity AHUA, the impurity AHUB, the impurity AHUC and the impurity VAI-A are respectively shown as the formulas (b), (c), (d) and (e).
Wherein the impurity AHUA and the impurity VAI-A are enantiomers, and the impurity AHUB and the impurity AHUC are diastereoisomers. For the separation and detection of isomers, particularly enantiomers, a conventional chiral column is generally adopted, and the separation and detection are carried out by utilizing a forward chromatography, and the detection method has the defects of poor formed base line and poor peak shape, so that the detection requirement is difficult to achieve.
In order to accurately control the quality of LCZ696, it is necessary to find an HPLC assay method that can effectively separate LCZ696 from its isomers, and achieving separation of LCZ696 from its isomers is of great significance in the synthesis of LCZ696 and in the quality control of formulations.
Disclosure of Invention
The invention aims to provide a method for separating and measuring LCZ696 isomer impurities, which is simple and convenient to operate, can effectively separate and measure the LCZ696 isomer impurities and effectively control the quality of LCZ696 and products thereof, aiming at the defects of the prior art.
The technical scheme of the invention is as follows: a method for separating and measuring LCZ696 isomer impurities comprises the following steps,
1) preparation of sample solution
Dissolving LCZ696 or preparation containing LCZ696 with diluent to obtain sample solution with concentration of 0.1-10 mg/ml;
2) preparation of control solutions
Taking the sample solution obtained in the step 1), and adding a diluent to dilute the sample solution by 50-1000 times to obtain a control solution;
3) adopting a polysaccharide derivative reverse phase coating type chiral chromatographic column or a cellulose derivative reverse phase coating type chiral chromatographic column, setting the flow rate of a mobile phase to be 0.4-0.8ml/min, wherein the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is a buffer solution with the volume concentration of 0.0001-1.0%, the mobile phase B is an acetonitrile-methanol mixed solution, the volume ratio of acetonitrile to methanol is 75-85:25-15, 100 parts by volume of the mobile phase B is added with 0-1 part by volume of phosphoric acid, the mobile phase enters the chromatographic column by adopting a gradient elution mode for 0 minute, the volume percentage of the mobile phase A is 65-75%, and the volume percentage of the mobile phase B is 35-25%; from 0 minute to 50 minutes, the volume percent of mobile phase a decreased linearly to 55% -45%, and the volume percent of mobile phase B increased linearly to 45% -55%; from 50 minutes to 50.1 minutes, the volume percent of mobile phase a increased linearly to 65% -75%, and the volume percent of mobile phase B decreased linearly to 35% -25%; 50.1 to 60 minutes, the volume percentage of the mobile phase A is 65 to 75 percent, and the volume percentage of the mobile phase B is 35 to 25 percent;
4) injecting equal volumes of the sample solution in the step 1) and the control solution in the step 2) into a high performance liquid chromatograph respectively, wherein the injection amount is 5-100 mu l, detecting by using the wavelength of 200-280 nm, recording a chromatogram, and completing the separation and determination of the isomer in the sample solution.
The diluent in the step 1) and the step 2) is a mixture of methanol and water, and the volume ratio of the methanol to the water is 75-95: 25-5.
The volume ratio of methanol to water is 80: 20.
step 3) the mobile phase A is a buffer solution with the volume concentration of 0.001-0.2%.
And 3) the buffer solution is phosphoric acid or a phosphate solution or a mixture of the phosphoric acid and the phosphate, and the phosphate is monopotassium phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate or a mixture of the phosphate and the diammonium hydrogen phosphate.
Step 3) the polysaccharide derivative is amylose or cellulose derivative; the cellulose derivative is cellulose-tris (3-chloro-4-methylphenyl carbamate, cellulose-tris (3, 5-dimethylphenyl carbamate), cellulose-tris (4-chloro-3-methylphenyl carbamate), cellulose-tris (4-methylbenzoate).
Step 3), the mobile phase enters a chromatographic column by adopting a gradient elution mode for 0 minute, wherein the volume percentage of the mobile phase A is 70 percent, and the volume percentage of the mobile phase B is 30 percent; from 0 minutes to 50 minutes, the volume percent of mobile phase a decreased linearly to 550%, and the volume percent of mobile phase B increased linearly to 50%; from 50 minutes to 50.1 minutes, the volume percent of mobile phase a increased linearly to 70%, and the volume percent of mobile phase B decreased linearly to 30%; from 50.1 minutes to 60 minutes, the volume percent of mobile phase a was 70% and the volume percent of mobile phase B was 30%.
And 4) during sample injection, the sample injection amount is 10 mu l, the detection is carried out by using the wavelength of 255nm, and the column temperature of the chromatographic column is 15-40 ℃.
The column temperature of the column was 30 ℃.
Adopt above-mentioned technical scheme to have following beneficial effect:
1. the separation and determination method adopts high performance liquid chromatography, takes polysaccharide derivative reverse phase coating type chiral chromatographic column, takes buffer solution as mobile phase A and acetonitrile-methanol mixed solution as mobile phase B, can effectively separate and determine LCZ696 isomer impurities, and has strong specificity and meets the requirements on the separation degree of main peak and isomer impurity peak and the separation degree between isomer impurities.
2. The separation and determination method of the invention adopts a self-contrast method of adding correction factors to calculate the impurity content of each isomer in the sample, the accuracy is high, the minimum relative detection limit of each impurity is 0.002 percent, which indicates that more than 0.002 percent of the impurities can be detected.
3. The mobile phase A and the mobile phase B used in the separation and determination method are simple and convenient to prepare, and the used reagents are common reagents, so that the method is economical and practical. The mixed solution of water and methanol is selected as a diluent to dissolve the sample, so that the sample can be prevented from being separated out in a mobile phase; the volume ratio of the mobile phase A to the mobile phase B is adjusted by adopting a gradient elution mode, so that the LCZ696 and the isomer can be effectively separated; the mobile phase A is matched, so that retention can be enhanced, the separation degree is improved, good symmetry and high column efficiency of chromatographic peaks are ensured, the number of theoretical plates of the product and each impurity is more than 15000, and tailing factors of known impurity peaks are all between 0.95 and 1.05. If the volume ratio of the mobile phase A to the mobile phase B is not adjusted in a gradient manner, or the ratio of acetonitrile to methanol in the mobile phase B is not 75-85:25-15, the separation degree of a main peak and an isomer impurity peak is poor, or even the main peak and the isomer impurity peak cannot be separated.
The separation and determination method effectively solves the problem that LCZ696 and isomers thereof are difficult to separate, and can accurately determine the content of LCZ696 and isomer impurities thereof, thereby ensuring the controllable quality of LCZ696 and preparations thereof.
The following further description is made with reference to the accompanying drawings and detailed description.
Drawings
FIG. 1 is a liquid chromatogram of a methanol-water mixture of example one;
FIG. 2 is a liquid chromatogram of a mixed control solution of example one;
FIG. 3 is a liquid chromatogram of a sample solution of example two;
FIG. 4 is a liquid chromatogram of the control solution of the example;
FIG. 5 is a liquid chromatogram of a sample solution of the third example;
FIG. 6 is a liquid chromatogram of a control solution of the third example;
FIG. 7 is a liquid chromatogram of a test solution of the third blank adjuvant of the example.
Detailed Description
Apparatus and conditions
The HPLC adopts Shimadzu LC-16 type liquid chromatograph and chemical workstation, and is set as automatic sample introduction. An CHIRALCEL OJ-RH column (5 μm, 150X 4.6mm) was used as a column. Wavelength of ultraviolet detector: 255 nm. Mobile phase: phosphoric acid solution with volume concentration of 0.01% is used as mobile phase A, and acetonitrile-methanol-phosphoric acid (with volume ratio of 800: 200: 1) is used as mobile phase B. Gradient elution mode: 0 minute, the volume percent of mobile phase a was 70%, and the volume percent of mobile phase B was 30%; from 0 minutes to 50 minutes, the volume percent of mobile phase a decreased linearly to 50%, and the volume percent of mobile phase B increased linearly to 50%; from 50 minutes to 50.1 minutes, the volume percent of mobile phase a increased linearly to 70%, and the volume percent of mobile phase B decreased linearly to 30%; from 50.1 minutes to 60 minutes, the volume percent of mobile phase a was 70% and the volume percent of mobile phase B was 30%. Column temperature 35 ℃, flow rate: 0.6 ml/min. The injection volume was 10. mu.l.
The first embodiment is as follows:
respectively taking 50mg of impurities AHUA, AHUB, AHUC and VAL-A (the purity of AHUA, AHUB, AHUC and VAL-A is more than 99%), precisely weighing, placing in a 50ml measuring flask, adding methanol-water (volume ratio of 80: 20) to dissolve and dilute to scale, shaking uniformly to obtain an impurity stock solution; LCZ 69650 mg is precisely weighed and placed in a 50ml measuring flask, 0.25ml of impurity stock solution is precisely added, methanol-water (volume ratio is 80: 20) is added for dissolution and dilution to scale, shaking is carried out uniformly to serve as a mixed control solution, the concentration of LCZ696 is 1mg/ml, and the known impurity concentration is 5 mug/ml.
The liquid chromatography analysis was carried out under the above-mentioned chromatographic conditions using methanol-water (volume ratio 80: 20) and a mixed control solution, and chromatograms were recorded, and the results are shown in fig. 1 and 2.
Figure 1 shows that the methanol-water mixture and the chromatographic system do not interfere with the assay.
In FIG. 2, the order of successive peaks is valsartan, impurity VAL-A, AHU377, impurity AHUC, impurity AHUA, impurity AHUB. Fig. 2 shows that the separation and determination method of the present invention can effectively separate LCZ696 and isomers thereof, and can be used for determination of isomers in LCZ 696.
EXAMPLE determination of drug substance LCZ696 (supplied by Chongqing san Sheng industries, Ltd.)
Precisely weighing LCZ 69650 mg, placing in a 50ml measuring flask, adding methanol-water (volume ratio of 80: 20) for ultrasonic treatment, dissolving and diluting to scale, and shaking up to obtain sample solution; precisely measuring 1ml of sample solution, placing in a 100ml measuring flask, diluting to scale with methanol-water (volume ratio of 80: 20), and shaking to obtain control solution; liquid chromatography was performed according to the chromatographic conditions of example one. The chromatograms were recorded, and the results are shown in fig. 3 and 4. Calculating the content of each isomer impurity in the sample by adopting a self-contrast method with correction factors, wherein the detection results are shown in table 1:
TABLE 1
| Impurities | Content (wt%) |
| VAI-A | 0.0179 |
| AHUC | 0.0013 |
| AHUB | 0.0052 |
| AHUA | 0.0099 |
EXAMPLE determination of three LCZ696 tablets (supplied by Chongqing san Sheng industries, Ltd.)
Taking about 210mg (about equal to LCZ 69650 mg) of the fine powder of the LCZ696 tablet, putting the fine powder into a 50ml measuring flask, adding methanol-water (the volume ratio is 80: 20) for ultrasonic treatment, dissolving and diluting to scale, shaking up, filtering, and taking the filtrate as a sample solution; precisely measuring 1ml of sample solution, placing in a 100ml measuring flask, diluting to scale with methanol-water (volume ratio of 80: 20), and shaking to obtain control solution; taking a proper amount of blank auxiliary materials according to the formula proportion of the LCZ696 tablets, and preparing a blank auxiliary material test solution according to the same method of the sample solution; liquid chromatography was performed according to the chromatographic conditions of example one. The chromatograms were recorded, and the results are shown in fig. 5, 6, and 7. Calculating the content of each isomer impurity in the sample by adopting a self-contrast method with correction factors, wherein the detection results are shown in a table 2:
TABLE 2
| Impurities | Content (wt%) |
| VAI-A | 0.0154 |
| AHUC | 0.0011 |
| AHUB | 0.0022 |
| AHUA | 0.0112 |
Claims (7)
1. A method for separating and measuring LCZ696 isomer impurities is characterized by comprising the following steps,
1) preparation of sample solution
Dissolving LCZ696 or preparation containing LCZ696 with diluent to obtain sample solution with concentration of 0.1-10mg/ml, wherein LCZ696 or preparation containing LCZ696 contains isomer impurities (b), (c), (d), (e) with following structural formula,
2) preparation of control solutions
Taking the sample solution obtained in the step 1), and adding a diluent to dilute the sample solution by 50-1000 times to obtain a control solution;
3) adopting a cellulose-tris (4-methyl benzoate) reverse-phase coating type chiral chromatographic column, setting the flow rate of a mobile phase to be 0.4-0.8ml/min, wherein the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is a phosphoric acid solution with the volume concentration of 0.0001-1.0%, the mobile phase B is an acetonitrile-methanol mixed solution, the volume ratio of acetonitrile to methanol is 75-85:25-15, 100 parts by volume of the mobile phase B is added with 0-1 part by volume of phosphoric acid, the mobile phase enters the chromatographic column by adopting a gradient elution mode for 0 minute, the volume percentage of the mobile phase A is 65-75%, and the volume percentage of the mobile phase B is 35-25%; from 0 minute to 50 minutes, the volume percent of mobile phase a decreased linearly to 55% -45%, and the volume percent of mobile phase B increased linearly to 45% -55%; from 50 minutes to 50.1 minutes, the volume percent of mobile phase a increased linearly to 65% -75%, and the volume percent of mobile phase B decreased linearly to 35% -25%; 50.1 to 60 minutes, the volume percentage of the mobile phase A is 65 to 75 percent, and the volume percentage of the mobile phase B is 35 to 25 percent;
4) injecting equal volumes of the sample solution in the step 1) and the control solution in the step 2) into a high performance liquid chromatograph respectively, wherein the injection amount is 5-100 mu l, detecting by using the wavelength of 200-280 nm, recording a chromatogram, and completing the separation and determination of the isomer in the sample solution.
2. The method as claimed in claim 1, wherein the diluent in step 1) and step 2) is a mixture of methanol and water, and the volume ratio of methanol to water is 75-95: 25-5.
3. The method of claim 2, wherein the volume ratio of methanol to water is 80: 20.
4. the method according to claim 1, wherein the mobile phase A in the step 3) is a phosphoric acid solution with a volume concentration of 0.001-0.2%.
5. The method according to claim 1, wherein the mobile phase in step 3) enters the chromatographic column by adopting a gradient elution mode, and the volume percentage of the mobile phase A is 70 percent and the volume percentage of the mobile phase B is 30 percent in 0 minute; from 0 minutes to 50 minutes, the volume percent of mobile phase a decreased linearly to 50%, and the volume percent of mobile phase B increased linearly to 50%; from 50 minutes to 50.1 minutes, the volume percent of mobile phase a increased linearly to 70%, and the volume percent of mobile phase B decreased linearly to 30%; from 50.1 minutes to 60 minutes, the volume percent of mobile phase a was 70% and the volume percent of mobile phase B was 30%.
6. The method according to claim 1, wherein the sample is injected in step 4), the sample injection amount is 10 μ l, the detection is carried out by using a wavelength of 255nm, and the column temperature of the chromatographic column is 15-40 ℃.
7. The method of claim 6, wherein the column temperature of the chromatography column is 30 ℃.
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| 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 |
| CN112666294B (en) * | 2020-12-29 | 2022-08-16 | 重庆三圣实业股份有限公司 | Method for separating and determining Shakubatu calcium salt and impurities 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 |
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