CN109374808B - Method for determining aniline genotoxic impurities in new raw material medicine of sodium solitary succinate - Google Patents
Method for determining aniline genotoxic impurities in new raw material medicine of sodium solitary succinate Download PDFInfo
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Abstract
The invention provides a method for determining aniline genotoxic impurities in a new raw material medicine of sodium solitary succinate, which comprises the following steps: preparing 4-chloroaniline and (-) -4 '-chloroaniline tartaric acid amide reference solutions by using 4-chloroaniline and (-) -4' -chloroaniline tartaric acid amide as reference substances and 50% acetonitrile aqueous solution as a solvent, taking a new raw material drug of the succinic acid solisodium, and dissolving the new raw material drug by using 50% acetonitrile aqueous solution to obtain a test solution; detecting by using a UPLC-MS method, respectively obtaining peak areas of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in a reference substance solution, and calculating respective response factors; and (3) detecting the sample solution by using an UPLC-MS method to obtain the peak area of the sample solution, and calculating the contents of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in the sample solution by using the response factors. The invention has the advantages of short detection time, good accuracy, high precision and good repeatability.
Description
Technical Field
The invention belongs to the technical field of medicine detection of a new raw material medicine of sodiumsuccinate, and particularly relates to a method for determining aniline genotoxic impurities in the new raw material medicine of sodiumsuccinate.
Background
4-chloroaniline and (-) -4 '-chloroaniline tartaric acid are toxic impurities of aniline genes and are widely applied as starting materials and intermediates for drug synthesis, but because 4-chloroaniline and (-) -4' -chloroaniline tartaric acid have potential toxicity to cells, the content of the 4-chloroaniline and the (-) -4 '-chloroaniline tartaric acid in the drugs needs to be controlled, but no quality standard is included in the content determination method of the 4-chloroaniline and the (-) -4' -chloroaniline tartaric acid at present.
Therefore, a method for measuring the aniline genotoxic impurities in the new raw material medicine of the sodium solilofenate succinate, which has the advantages of short detection time, good accuracy, high precision and good repeatability, is urgently needed.
Disclosure of Invention
The invention aims to solve the problem that the existing content determination of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid has no quality standard to be checked, and provides a method for determining aniline genotoxic impurities in a new raw material medicine of sodium solitary succinate, which has the advantages of short detection time, good accuracy, high precision and good repeatability.
The invention provides the following technical scheme:
the method for determining the aniline genotoxic impurities in the new raw material medicine of the sodiumsuccinate comprises the following steps:
s1, preparing 4-chloroaniline and (-) -4 '-chloroaniline tartaric acid reference substance solutions by using 4-chloroaniline and (-) -4' -chloroaniline tartaric acid as reference substances and 50% acetonitrile aqueous solution as a solvent, taking a new raw material drug of the succinic acid solisodium, and dissolving the new raw material drug by using 50% acetonitrile aqueous solution to obtain a test solution;
s2, preparing two reference solutions of 4-chloroaniline and (-) -4 ' -chloroaniline tartaric acid in parallel, detecting by using an UPLC-MS method, respectively obtaining peak areas of the 4-chloroaniline and the (-) -4 ' -chloroaniline tartaric acid in the reference solution, and calculating the ratio of the peak areas to the concentration of the reference solution to obtain response factors of the 4-chloroaniline and the (-) -4 ' -chloroaniline tartaric acid;
s3, detecting the sample solution by UPLC-MS method to obtain peak area of the sample solution, and calculating the content of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in the sample solution by using the response factor obtained in S2.
Preferably, the specific conditions of the UPLC-MS method in S2 and S3 are as follows:
the chromatographic conditions are as follows:
a chromatographic column: BEH C18;
column temperature: 40 ℃;
mobile phase A: acid-water;
mobile phase B: acetonitrile;
flow rate of mobile phase: 0.3 mL/min;
the mass spectrum mode is as follows:
in positive ion mode, the 4-chloroaniline quantitative ion is 128, and the (-) -4' -chloroaniline tartaric acid quantitative ion is 260; the gradient elution procedure was:
0-1 min, wherein the volume percentage of the mobile phase B is 10%;
1-4 min, wherein the volume percentage of the mobile phase B is 10-90%;
4-6 min, wherein the volume percentage of the mobile phase B is 90%;
6-6.1 min, wherein the volume percentage of the mobile phase B is from 90% to 10%;
6.1-8 min, and the volume percentage of the mobile phase B is 10%.
Preferably, the mobile phase a is 0.1% aqueous formic acid.
The invention has the beneficial effects that:
1. the invention adopts UPLC-MS method to determine the content of 4-chloroaniline and (-) -4 '-chloroaniline tartaric acid amide, the method selects liquid chromatogram, adopts MS detector at the same time, can accurately position 4-chloroaniline and (-) -4' -chloroaniline tartaric acid amide, has higher response and strong specificity, and can simultaneously detect.
2. The mass spectrum detector is adopted, the sensitivity is high, and ppm-level 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in a sample can be detected.
3. By adopting the UPLC-MS method, the time of the chromatographic method is short, the detection time is saved, the use of organic solvents is greatly reduced, the efficiency is improved, and the harm to the environment is reduced.
4. Under the condition of UPLC-MS provided by the invention, the content of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in the test solution is measured by an external standard point method, the operation is simple, and a series of methodological verifications are carried out, and test results show that the detection method provided by the invention has strong specificity, good accuracy, high precision, good repeatability and good durability, and meets the technical requirements of the quality standard research of medicines.
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The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 is a chromatogram of a control solution of 4-chloroaniline in example 1;
FIG. 2 is a chromatogram of (-) -4' -chloroaniline tartaric acid as a control solution in example 1;
FIG. 3 is a chromatogram of the test solution 4-chloroaniline in example 1;
FIG. 4 is a chromatogram of (-) -4' -chloroaniline tartaric acid as a test solution in example 1;
FIG. 5 is a standard curve of 4-chloroaniline in example 2;
FIG. 6 is a standard graph of (-) -4' -chloroaniline tartaric acid in example 2;
FIG. 7 is a specificity profile of 4-chloroaniline from example 5;
FIG. 8 is a profile of the specificity of (-) -4' -chloroaniline tartaric acid in example 5.
Detailed Description
Example 1
A method for determining genotoxic impurities in a new raw material medicine of sodium solitary succinate comprises the following steps:
s1, preparing 4-chloroaniline and (-) -4 '-chloroaniline tartaric acid reference substance solutions by using 4-chloroaniline and (-) -4' -chloroaniline tartaric acid as reference substances and 50% acetonitrile aqueous solution as a solvent, taking a new raw material drug of the succinic acid solisodium, and dissolving the new raw material drug by using 50% acetonitrile aqueous solution to obtain a test solution;
s2, preparing two reference solutions of 4-chloroaniline and (-) -4 ' -chloroaniline tartaric acid in parallel, detecting by using an UPLC-MS method, respectively obtaining peak areas of the 4-chloroaniline and the (-) -4 ' -chloroaniline tartaric acid in the reference solution, and calculating the ratio of the peak areas to the concentration of the reference solution to obtain response factors of the 4-chloroaniline and the (-) -4 ' -chloroaniline tartaric acid;
s3, detecting the sample solution by UPLC-MS method to obtain peak area of the sample solution, and calculating the content of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in the sample solution by using the response factor obtained in S2.
The specific conditions of the UPLC-MS method in S2 and S3 are as follows:
(1) the chromatographic conditions are as follows:
a chromatographic column: BEH C18;
column temperature: 40 ℃;
mobile phase A: 0.1% aqueous formic acid;
mobile phase B: acetonitrile;
flow rate of mobile phase: 0.3 mL/min;
(2) the mass spectrum mode is as follows:
in the positive ion mode, the 4-chloroaniline quantification ion was 128, and the (-) -4' -chloroaniline tartrate quantification ion was 260.
(3) The experimental data for the gradient elution procedure are shown in table 1:
TABLE 1 gradient elution procedure
| 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 |
The UPLC-MS analysis was performed on the control solution and the test solution using the gradient elution procedure provided in example 1, and the chromatograms obtained are shown in fig. 1 to 4, fig. 1 is 4-chloroaniline as the control solution, fig. 2 is (-) -4 ' -chloroaniline tartrate as the control solution, fig. 3 is 4-chloroaniline as the test solution, fig. 4 is (-) -4 ' -chloroaniline tartrate as the test solution, and the chromatograms show that the retention time of 4-chloroaniline is 2.910min and the retention time of (-) -4 ' -chloroaniline tartrate is 3.010 min.
Example 2
Linear range investigation of the assay provided in example 1.
Placing 10mg of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid amide in a 10mL volumetric flask, dissolving and diluting the volumetric flask to a scale by using 50% acetonitrile, shaking up to be used as a reference stock solution 1; precisely weighing 300 μ L of reference stock solution 1, placing in a 100mL volumetric flask, diluting with 50% acetonitrile to scale mark, shaking up, and using as reference stock solution 2;
0.05mL, 0.25mL, 0.4mL, 0.5mL, 0.75mL, 1mL of the control stock solution 2 were transferred into 10mL volumetric flasks, diluted to the mark with 50% acetonitrile, shaken well and labeled L-10, L-50, L-80, L-100, L-150 and L-200, respectively. 0.1mL of L-100 was transferred to a 10mL volumetric flask, diluted to the mark with 50% acetonitrile and shaken up as L-1%.
The results of the measurement conducted by sequential sampling according to the measurement method provided in example 1, in which the peak area was used as the ordinate and the concentration of the control solution was used as the abscissa (μ g/mL), are shown in Table 2, and the standard curves for 4-chloroaniline and (-) -4' -chloroaniline-tartaric acid are shown in FIGS. 5 and 6.
TABLE 24-Chloranilide and (-) -4' -Chloranilide tartaric acid test values
Example 3
Spiking recovery test for the assay provided in example 1.
The accuracy of the assay provided in example 1 was analyzed by the method of spiking recovery.
Taking 10mg of a new raw material medicine of the sodium solitary succinate, precisely weighing, respectively placing 11 parts in parallel into 10mL volumetric flasks, taking 2 parts of the new raw material medicine, dissolving with 50% acetonitrile, fixing the volume to a scale mark, uniformly mixing, and measuring the contents of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in a sample; taking 3 parts of the crude extract, adding 0.25mL of reference stock solution 2, dissolving with 50% acetonitrile, fixing the volume to the scale mark, and mixing to obtain a solution with the recovery rate of 50% standard addition; taking 3 parts of the crude extract, adding 0.5mL of reference stock solution 2, dissolving with 50% acetonitrile, fixing the volume to the scale mark, and mixing uniformly to obtain a solution with the recovery rate of 100% standard addition; taking 3 parts of the crude extract, adding 0.7mL of reference stock solution 2, dissolving with 50% acetonitrile, fixing the volume to a scale mark, and mixing uniformly to obtain a solution with the recovery rate of 150% standard addition; the results of the UPLC-MS measurement according to the example 1 are shown in tables 3 and 4, and show that the recovery rate of 4-chloroaniline is 91-113%, the recovery rate RSD of 9 pins is 8%, the recovery rate of (-) -4' -chloroaniline tartaric acid is 92-99%, and the recovery rate RSD of 9 pins is 2%, which indicates that the measurement method provided by the example 1 has good accuracy.
TABLE 34 Chloroaniline recovery
TABLE 4 recovery of (-) -4' -chloroaniline tartaric acid
The test result shows that: the recovery rates of the 4-chloroaniline and the (-) -4' -chloroaniline tartaric acid are both in the range of 80-120%, and the RSD is less than 20%, which shows that the determination method provided by the embodiment 1 has better accuracy.
Example 4
Precision testing of the assay provided in example 1.
The precision of the assay provided in example 1 was analyzed by a 100% spiking recovery method.
Taking 10mg of a new raw material medicine of the sodium solitary succinate, precisely weighing, respectively placing 8 parts in parallel into a 10mL volumetric flask, taking 2 parts of the new raw material medicine, dissolving with 50% acetonitrile, fixing the volume to a scale mark, uniformly mixing, and measuring the contents of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in a sample; taking 6 parts of the crude extract, adding 0.5mL of reference stock solution 2, dissolving with 50% acetonitrile, fixing the volume to a scale mark, and mixing uniformly to obtain a solution with the recovery rate of 100% standard addition; the results of the measurement by the UPLC-MS method in example 1 are shown in Table 5 and Table 6, and the results show that the recovery rate of 4-chloroaniline is 91-111%, the recovery rate RSD of 6 needles is 7%, the recovery rate of 4-chloroaniline is 92-101%, and the recovery rate RSD of 6 needles is 3%, which indicates that the measurement method provided in example 1 has good repeatability.
TABLE 54 chloroaniline repeatability results
TABLE 6 repeatability results for (-) -4' -chloroaniline tartrate amide acid
Example 5
Specificity test for the assay methods provided in example 1.
Taking 50% acetonitrile as a blank solvent, respectively injecting 5 μ L of each of the reference solution and the sample solution in example 1 and the 100% recovery solution in example 3 into UPLC-MS, measuring according to the UPLC-MS method in example 1, recording chromatogram, and obtaining results shown in figures 7 and 8, wherein 1 is the sample adding solution, 2 is the reference solution, 3 is the sample solution, and 4 is the blank solution. The result shows that the blank solvent and the test solution have no interference to the determination of the 4-chloroaniline and the (-) -4' -chloroaniline tartaric acid.
Example 6
Stability test of the assay method provided in example 1.
Taking the reference solution in example 1 and the 100% recovery solution in the spiking recovery test, examining the stability of the solution at room temperature, injecting samples according to the UPLC-MS method of example 1, recording the peak areas of 4-chloroaniline and (-) -4 '-chloroaniline tartaric acid, calculating the peak area RSD of the reference solution (19 hours) and the peak area RSD of the 100% recovery solution (16.5 hours), and finding out the results in tables 7-8, wherein the results show that the peak area RSD of 4-chloroaniline in the reference solution is 4% and the peak area RSD of (-) -4' -chloroaniline tartaric acid in the reference solution is 3%; the peak area RSD of 4-chloroaniline in the solution with 100% recovery rate is 4%, and the peak area RSD of (-) -4' -chloroaniline tartaric acid is 2%, which shows that the determination method provided in example 1 has good stability.
TABLE 7 control solution stability results
| Reference substance | 4-chloroaniline | (-) -4' -chloroaniline tartaric acid amide |
| 0h | 82281152 | 6305562 |
| 2.5h | 83596554 | 6120135 |
| 6h | 90647618 | 6372512 |
| 8.5h | 90023943 | 6285737 |
| 19h | 85432185 | 5914390 |
| |
4％ | 3％ |
Table 8100% recovery solution stability results
| 100% tagging | 4-chloroaniline | (-) -4' -chloroaniline tartaric acid amide |
| 0h | 69951262 | 5450109 |
| 2h | 75999917 | 5587629 |
| 5h | 78754471 | 5794257 |
| 6h | 75124155 | 5718373 |
| 16.5h | 73717915 | 5750592 |
| |
4％ | 2％ |
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (2)
1. The method for determining the aniline genotoxic impurities in the new raw material medicine of the sodiumsuccinate is characterized by comprising the following steps:
s1, preparing 4-chloroaniline and (-) -4 '-chloroaniline tartaric acid reference substance solutions by using 4-chloroaniline and (-) -4' -chloroaniline tartaric acid as reference substances and 50% acetonitrile aqueous solution as a solvent, taking a new raw material drug of the succinic acid solisodium, and dissolving the new raw material drug by using 50% acetonitrile aqueous solution to obtain a test solution;
s2, preparing two reference solutions of 4-chloroaniline and (-) -4 ' -chloroaniline tartaric acid in parallel, detecting by using an UPLC-MS method, respectively obtaining peak areas of the 4-chloroaniline and the (-) -4 ' -chloroaniline tartaric acid in the reference solution, and calculating the ratio of the peak areas to the concentration of the reference solution to obtain response factors of the 4-chloroaniline and the (-) -4 ' -chloroaniline tartaric acid;
s3, detecting the sample solution by an UPLC-MS method to obtain the peak area of the sample solution, and calculating the content of 4-chloroaniline and (-) -4' -chloroaniline tartaric acid in the sample solution by using the response factor obtained in S2;
the specific conditions of the UPLC-MS method in S2 and S3 are as follows:
the chromatographic conditions are as follows:
a chromatographic column: BEH C18;
column temperature: 40 ℃;
mobile phase A: an acid-water solution;
mobile phase B: acetonitrile;
flow rate of mobile phase: 0.3 mL/min;
the mass spectrum mode is as follows:
in positive ion mode, the 4-chloroaniline quantitative ion is 128, and the (-) -4' -chloroaniline tartaric acid quantitative ion is 260; the gradient elution procedure was:
0-1 min, wherein the volume percentage of the mobile phase B is 10%;
1-4 min, wherein the volume percentage of the mobile phase B is 10-90%;
4-6 min, wherein the volume percentage of the mobile phase B is 90%;
6-6.1 min, wherein the volume percentage of the mobile phase B is from 90% to 10%;
6.1-8 min, and the volume percentage of the mobile phase B is 10%.
2. The method for determining the genotoxic aniline impurities in the new raw material medicine of solisodium succinate as claimed in claim 1, wherein the mobile phase A is 0.1% formic acid solution in water.
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