CN109374808A - The method for measuring phenyl amines genotoxicity impurity in succinic acid Suo Li sodium new raw material medicine - Google Patents
The method for measuring phenyl amines genotoxicity impurity in succinic acid Suo Li sodium new raw material medicine Download PDFInfo
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- CN109374808A CN109374808A CN201811323357.8A CN201811323357A CN109374808A CN 109374808 A CN109374808 A CN 109374808A CN 201811323357 A CN201811323357 A CN 201811323357A CN 109374808 A CN109374808 A CN 109374808A
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- chloroaniline
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- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- 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
- G01N2030/042—Standards
- G01N2030/045—Standards internal
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- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
- G01N2030/8827—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials involving nucleic acids
Abstract
The present invention provides a kind of method for measuring phenyl amines genotoxicity impurity in succinic acid Suo Li sodium new raw material medicine, comprising steps of using 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid as reference substance, using 50% acetonitrile solution as solvent, prepare 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid reference substance solution, take succinic acid Suo Li sodium new raw material medicine, it is dissolved with 50% acetonitrile solution, obtains test solution；The detection of UPLC-MS method, obtains the peak area of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid in reference substance solution respectively, calculates respective response factor；It takes test solution to detect through UPLC-MS method, obtains the peak area of test solution, the content of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid in test solution is calculated with above-mentioned response factor.The present invention has detection time short, and accuracy is good, and precision is high, reproducible advantage.
Description
Technical field
The invention belongs to succinic acid Suo Li sodium new raw material medicine drug measurement techniques fields, and in particular to a kind of measurement succinic acid
The method of phenyl amines genotoxicity impurity in Suo Li sodium new raw material medicine.
Background technique
4- chloroaniline and (-) -4 '-chloroaniline tartramide acid are phenyl amines genotoxicity impurity, as pharmaceutical synthesis
Starting material and intermediate and be widely used, but because 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid deposit cell
In genotoxic potential, it is therefore desirable to control its content in drug, but having no quality standard includes 4- chloroaniline and (-)-at present
The content assaying method of 4 '-chloroaniline tartramide acid.
Therefore, it is short to be badly in need of a kind of detection time, accuracy is good, and precision is high, reproducible measurement succinic acid Suo Li sodium
The method of phenyl amines genotoxicity impurity in new raw material medicine.
Summary of the invention
Present invention aim to address existing 4- chloroanilines and (-) -4 '-chloroaniline tartramide acid content to measure massless
The problem of standard can be looked into provides a kind of method for measuring phenyl amines genotoxicity impurity in succinic acid Suo Li sodium new raw material medicine, tool
Have that detection time is short, accuracy is good, and precision is high, reproducible advantage.
The present invention provides the following technical solutions:
The method for measuring phenyl amines genotoxicity impurity in succinic acid Suo Li sodium new raw material medicine, comprising the following steps:
S1, using 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid as reference substance, with 50% acetonitrile solution be it is molten
Agent prepares 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid reference substance solution, takes succinic acid Suo Li sodium new raw material medicine, uses
50% acetonitrile solution dissolution, obtains test solution；
S2, two parts of 4- chloroanilines and (-) -4 '-chloroaniline tartramide acid reference substance solution are prepared in parallel, through UPLC-MS
Method detection, obtains the peak area of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid in reference substance solution respectively, calculates peak face
The long-pending ratio with the concentration of reference substance solution, obtains the response factor of 4- chloroaniline He (-) -4 '-chloroaniline tartramide acid；
S3, it takes test solution to detect through UPLC-MS method, obtains the peak area of test solution, with the sound obtained in S2
The factor is answered to calculate the content of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid in test solution.
Preferably, the actual conditions of UPLC-MS method are as follows in the S2 and S3:
Chromatographic condition are as follows:
Chromatographic column: BEH C18；
Column temperature: 40 DEG C；
Mobile phase A: acid-water；
Mobile phase B: acetonitrile；
Flow rate of mobile phase: 0.3mL/min；
Mass spectrum mode are as follows:
Positive ion mode, 4- chloroaniline quota ion are 128, and (-) -4 '-chloroaniline tartramide acid quota ion is
260；Gradient elution program are as follows:
0~1min, the percentage by volume of Mobile phase B are 10%；
1~4min, the percentage by volume of Mobile phase B is by 10% to 90%；
4~6min, the percentage by volume of Mobile phase B are 90%；
6~6.1min, the percentage by volume of Mobile phase B is by 90% to 10%；
6.1~8min, the percentage by volume of Mobile phase B are 10%.
Preferably, the aqueous formic acid that the mobile phase A is 0.1%.
The beneficial effects of the present invention are:
1, the present invention is using UPLC-MS method measurement 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid content, we
Method selects liquid chromatogram, while using MS detector, and 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid can be accurately positioned,
Response is higher, and specificity is strong, can detect simultaneously.
2, using mass detector, high sensitivity can detecte ppm grades in sample of 4- chloroaniline and (-) -4 '-chlorobenzene
Amine tartramide acid.
3, using UPLC-MS method, the chromatographic process time is short, not only saves detection time, and greatly reduces organic
The use of solvent reduces the harm to environment while improving efficiency.
4, under the conditions of UPLC-MS provided by the invention, the 4- chlorobenzene in test solution is measured by one point external standard method
Amine and (-) -4 '-chloroaniline tartramide acid content, it is easy to operate, and carried out the methodology validation of series, test result table
Bright detection method specificity of the invention is strong, accuracy is good, precision is high, reproducible, and durability is good, meets the quality of drug
The technical requirements of research on standard.
Detailed description of the invention
Attached drawing is used to provide further understanding of the present invention, and constitutes part of specification, with reality of the invention
It applies example to be used to explain the present invention together, not be construed as limiting the invention.In the accompanying drawings:
Fig. 1 is the chromatogram of reference substance solution 4- chloroaniline in embodiment 1；
Fig. 2 is reference substance solution (-)-4 ' in embodiment 1-chloroaniline tartramide acid chromatogram；
Fig. 3 is the chromatogram of test solution 4- chloroaniline in embodiment 1；
Fig. 4 is test solution (-)-4 ' in embodiment 1-chloroaniline tartramide acid chromatogram；
Fig. 5 is the canonical plotting of 4- chloroaniline in embodiment 2；
Fig. 6 is the canonical plotting of (-) -4 '-chloroaniline tartramide acid in embodiment 2；
Fig. 7 is the specificity map of 4- chloroaniline in embodiment 5；
Fig. 8 is the specificity map of (-) -4 '-chloroaniline tartramide acid in embodiment 5.
Specific embodiment
Embodiment 1
A method of genotoxicity impurity in measurement succinic acid Suo Li sodium new raw material medicine, comprising the following steps:
S1, using 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid as reference substance, with 50% acetonitrile solution be it is molten
Agent prepares 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid reference substance solution, takes succinic acid Suo Li sodium new raw material medicine, uses
50% acetonitrile solution dissolution, obtains test solution；
S2, two parts of 4- chloroanilines and (-) -4 '-chloroaniline tartramide acid reference substance solution are prepared in parallel, through UPLC-MS
Method detection, obtains the peak area of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid in reference substance solution respectively, calculates peak face
The long-pending ratio with the concentration of reference substance solution, obtains the response factor of 4- chloroaniline He (-) -4 '-chloroaniline tartramide acid；
S3, it takes test solution to detect through UPLC-MS method, obtains the peak area of test solution, with the sound obtained in S2
The factor is answered to calculate the content of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid in test solution.
The actual conditions of UPLC-MS method are as follows in the S2 and S3:
(1) chromatographic condition are as follows:
Chromatographic column: BEH C18；
Column temperature: 40 DEG C；
Mobile phase A: 0.1% aqueous formic acid；
Mobile phase B: acetonitrile；
Flow rate of mobile phase: 0.3mL/min；
(2) mass spectrum mode are as follows:
Positive ion mode, 4- chloroaniline quota ion are 128, and (-) -4 '-chloroaniline tartramide acid quota ion is
260。
(3) test data of gradient elution program is as shown in table 1:
1 gradient elution program of table
| T(min) | A:0.1%HCOOH aqueous solution (%) | B: acetonitrile (%) |
| 0 | 90 | 10 |
| 1 | 90 | 10 |
| 4 | 10 | 90 |
| 6 | 10 | 90 |
| 6.1 | 90 | 10 |
| 8 | 90 | 10 |
Using the gradient elution program provided in embodiment 1, UPLC- is carried out to reference substance solution and test solution respectively
MS analysis, gained chromatogram is as shown in Figures 1 to 4, and Fig. 1 is reference substance solution 4- chloroaniline, and Fig. 2 is reference substance solution (-)-
4 '-chloroaniline tartramide acid, Fig. 3 is test solution 4- chloroaniline, and Fig. 4 is test solution (-) -4 '-chloroaniline winestone
Amic acid, chromatogram shows that the retention time of 4- chloroaniline is 2.910min, when the reservation of (-) -4 '-chloroaniline tartramide acid
Between be 3.010min.
Embodiment 2
The range of linearity for the measuring method that embodiment 1 provides is investigated.
4- chloroaniline and (-) -4 '-chloroaniline tartramide acid 10mg is taken to be placed in 10mL volumetric flask, with 50% acetonitrile
Dissolved dilution shakes up, to scale as reference substance stock solution 1；Precision measures 300 μ L reference substance stock solutions 1 and is placed in 100mL capacity
In bottle, with 50% dilution in acetonitrile to graduation mark, shake up, as reference substance stock solution 2；
0.05mL, 0.25mL, 0.4mL, 0.5mL, 0.75mL, 1mL reference substance stock solution 2 is pipetted respectively is respectively placed in 10mL
In volumetric flask, with 50% dilution in acetonitrile to scale, shakes up, be respectively labeled as L-10, L-50, L-80, L-100, L-150 and L-
200.0.1mL L-100 is pipetted in 10mL volumetric flask, with 50% dilution in acetonitrile to scale, is shaken up, as L-1%.
By the measuring method that embodiment 1 provides, successively sample introduction is measured, using peak area as ordinate, reference substance solution concentration
Standard curve is drawn for abscissa (μ g/mL), the result is shown in table 2, the 4- chloroanilines and (-) -4 '-chloroaniline tartramide of drafting
Acidity scale directrix curve is as shown in Figure 5 and Figure 6.
2 4- chloroaniline of table and (-) -4 '-chloroaniline tartramide acid test value
Embodiment 3
The mark-on reclaims test for the measuring method that embodiment 1 provides.
By the method for mark-on reclaims, the accuracy for the measuring method that embodiment 1 provides is analyzed.
Succinic acid Suo Li sodium new raw material medicine 10mg is taken, accurately weighed, parallel 11 parts are respectively placed in 10mL volumetric flask, take it
In 2 parts, with 50% acetonitrile dissolution be settled to graduation mark, mix, measure sample in 4- chloroaniline and (-) -4 '-chloroaniline winestone
Amide acid content；Wherein 3 parts are taken, 0.25mL reference substance stock solution 2 is added, graduation mark is settled to the dissolution of 50% acetonitrile, mixes,
As 50% recovery of standard addition solution；Wherein 3 parts are taken, 0.5mL reference substance stock solution 2 is added, is settled to the dissolution of 50% acetonitrile
Graduation mark mixes, as 100% recovery of standard addition solution；Wherein 3 parts are taken, 0.7mL reference substance stock solution 2 is added, with 50% second
Nitrile dissolution is settled to graduation mark, mixes, as 150% recovery of standard addition solution；It is measured by the UPLC-MS method of embodiment 1, as a result
3 are shown in Table, table 4, the results show that 4- chloroaniline rate of recovery range is 91%~113%, the rate of recovery RSD of 9 needles is 8%, (-)-
4 '-chloroaniline tartramide acid recovering rate ranges are 92%~99%, and the rate of recovery RSD of 9 needles is 2%, show that embodiment 1 provides
Measuring method have good accuracy.
The 3 4- chloroaniline rate of recovery of table
4 (-) -4 ' of table-chloroaniline tartramide acid recovering rate
Test result shows: the rate of recovery of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid is 80%~120%
In range, and RSD, less than 20%, the measuring method accuracy for illustrating that embodiment 1 provides is preferable.
Embodiment 4
The precision test for the measuring method that embodiment 1 provides.
By the method for 100% mark-on reclaims, the precision for the measuring method that embodiment 1 provides is analyzed.
Succinic acid Suo Li sodium new raw material medicine 10mg is taken, accurately weighed, parallel 8 parts are respectively placed in 10mL volumetric flask, take it
In 2 parts, with 50% acetonitrile dissolution be settled to graduation mark, mix, measure sample in 4- chloroaniline and (-) -4 '-chloroaniline winestone
Amide acid content；Wherein 6 parts are taken, 0.5mL reference substance stock solution 2 is added, graduation mark is settled to the dissolution of 50% acetonitrile, mixes,
As 100% recovery of standard addition solution；It is measured by the UPLC-MS method of embodiment 1, the results are shown in Table 5, table 6, the results show that 4- chlorine
Aniline recovery rate range is 91%~111%, 6 needle rate of recovery RSD be 7%, 4- chloroaniline rate of recovery range be 92%~
101%, 6 needle rate of recovery RSD are 3%, show that the measuring method that embodiment 1 provides has good repeatability.
5 4- chloroaniline repeatability result of table
6 (-) -4 ' of the table-repeated result of chloroaniline tartramide acid
Embodiment 5
The specificity test for the measuring method that embodiment 1 provides.
Take 50% acetonitrile as blank solvent, reference substance solution and test solution in embodiment 1,100% in embodiment 3
Each 5 μ L of rate of recovery solution, is injected separately into UPLC-MS, measures by the UPLC-MS method of the present embodiment 1, records chromatogram, as a result see
Fig. 7, Fig. 8, label 1 is test sample mark-on solution in figure, and 2 be reference substance solution, and 3 be test solution, and 4 be blank solution.Knot
Fruit shows that blank solvent and test solution are noiseless to the measurement of 4- chloroaniline He (-) -4 '-chloroaniline tartramide acid.
Embodiment 6
The stability test for the measuring method that embodiment 1 provides.
100% rate of recovery solution in reference substance solution, mark-on reclaims test in Example 1 is investigated at room temperature
Stability of solution, by the UPLC-MS method of embodiment 1, sample introduction, records 4- chloroaniline and (-) -4 '-chloroaniline tartramide respectively
The peak area of acid, note calculate the peak area RSD (16.5 of peak area RSD (19 hours) and 100% rate of recovery solution of reference substance solution
Hour), it the results are shown in Table 7~8, the results showed that the peak area RSD of 4- chloroaniline is 4% in reference substance solution, (-) -4 '-chloroaniline
The peak area RSD of tartramide acid is 3%；The peak area RSD of 4- chloroaniline is 4% in 100% rate of recovery solution, (-) -4 ' -
The peak area RSD of chloroaniline tartramide acid is 2%, and the measuring method for illustrating that embodiment 1 provides is with good stability.
7 reference substance solution stability result of table
| Reference substance | 4- chloroaniline | (-) -4 '-chloroaniline tartramide acid |
| 0h | 82281152 | 6305562 |
| 2.5h | 83596554 | 6120135 |
| 6h | 90647618 | 6372512 |
| 8.5h | 90023943 | 6285737 |
| 19h | 85432185 | 5914390 |
| RSD | 4% | 3% |
8 100% rate of recovery stability of solution result of table
| 100% mark-on | 4- chloroaniline | (-) -4 '-chloroaniline tartramide acid |
| 0h | 69951262 | 5450109 |
| 2h | 75999917 | 5587629 |
| 5h | 78754471 | 5794257 |
| 6h | 75124155 | 5718373 |
| 16.5h | 73717915 | 5750592 |
| RSD | 4% | 2% |
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, although referring to aforementioned reality
Applying example, invention is explained in detail, for those skilled in the art, still can be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features.It is all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (3)
1. the method for measuring phenyl amines genotoxicity impurity in succinic acid Suo Li sodium new raw material medicine, which is characterized in that including following
Step:
S1, using 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid as reference substance, using 50% acetonitrile solution as solvent,
4- chloroaniline and (-) -4 '-chloroaniline tartramide acid reference substance solution are prepared, succinic acid Suo Li sodium new raw material medicine is taken, with 50%
Acetonitrile solution dissolution, obtain test solution；
S2, two parts of 4- chloroanilines and (-) -4 '-chloroaniline tartramide acid reference substance solution are prepared in parallel, examine through UPLC-MS method
Survey, respectively obtain reference substance solution in 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid peak area, calculating peak area and
The ratio of the concentration of reference substance solution obtains the response factor of 4- chloroaniline He (-) -4 '-chloroaniline tartramide acid；
S3, take test solution to detect through UPLC-MS method, obtain the peak area of test solution, with the response obtained in S2 because
Son calculates the content of 4- chloroaniline and (-) -4 '-chloroaniline tartramide acid in test solution.
2. the method for phenyl amines genotoxicity impurity in measurement succinic acid Suo Li sodium new raw material medicine according to claim 1,
It is characterized in that, the actual conditions of UPLC-MS method are as follows in the S2 and S3:
Chromatographic condition are as follows:
Chromatographic column: BEH C18；
Column temperature: 40 DEG C；
Mobile phase A: acid-water；
Mobile phase B: acetonitrile；
Flow rate of mobile phase: 0.3mL/min；
Mass spectrum mode are as follows:
Positive ion mode, 4- chloroaniline quota ion are 128, and (-) -4 '-chloroaniline tartramide acid quota ion is 260；Ladder
Spend elution program are as follows:
0~1min, the percentage by volume of Mobile phase B are 10%；
1~4min, the percentage by volume of Mobile phase B is by 10% to 90%；
4~6min, the percentage by volume of Mobile phase B are 90%；
6~6.1min, the percentage by volume of Mobile phase B is by 90% to 10%；
6.1~8min, the percentage by volume of Mobile phase B are 10%.
3. the method for phenyl amines genotoxicity impurity in measurement succinic acid Suo Li sodium new raw material medicine according to claim 2,
It is characterized in that, the aqueous formic acid that the mobile phase A is 0.1%.
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Effective date of registration: 20200827 Address after: Block B, 4 / F, Lane 1238, Zhangjiang Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai Applicant after: Shanghai Mingjie Pharmaceutical Technology Co.,Ltd. Address before: 210000 Jiangbei New District, Nanjing City, Jiangsu Province, 3-1 Xinjinhu Road, Zhongdanyuan Phase II, Building C, 6 Floors Applicant before: NANJING MILESTONE PHARMA Co.,Ltd. |
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