CN117761175A - Method for detecting impurity C of vonolamine fumarate intermediate - Google Patents
Method for detecting impurity C of vonolamine fumarate intermediate Download PDFInfo
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- CN117761175A CN117761175A CN202311480113.1A CN202311480113A CN117761175A CN 117761175 A CN117761175 A CN 117761175A CN 202311480113 A CN202311480113 A CN 202311480113A CN 117761175 A CN117761175 A CN 117761175A
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- 239000012535 impurity Substances 0.000 title claims abstract description 83
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 30
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000001514 detection method Methods 0.000 claims abstract description 32
- 239000000243 solution Substances 0.000 claims description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 75
- 239000012088 reference solution Substances 0.000 claims description 40
- 239000011550 stock solution Substances 0.000 claims description 39
- 239000012085 test solution Substances 0.000 claims description 36
- 239000003085 diluting agent Substances 0.000 claims description 34
- 239000012490 blank solution Substances 0.000 claims description 22
- 238000007865 diluting Methods 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 18
- 230000035945 sensitivity Effects 0.000 claims description 16
- 238000005303 weighing Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 239000013558 reference substance Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 238000004811 liquid chromatography Methods 0.000 abstract description 5
- 238000004458 analytical method Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- IXCSYEVJOAWXRH-UHFFFAOYSA-N 5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrole-3-carbaldehyde Chemical compound FC1=CC=CC=C1C1=CC(C=O)=CN1S(=O)(=O)C1=CC=CN=C1 IXCSYEVJOAWXRH-UHFFFAOYSA-N 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- 238000012544 monitoring process Methods 0.000 abstract 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 229950003825 vonoprazan Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000011418 maintenance treatment Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940125422 potassium channel blocker Drugs 0.000 description 1
- 239000003450 potassium channel blocker Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
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- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention belongs to the field of medicine analysis, and aims to provide a liquid chromatography detection method for detecting an intermediate impurity 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-formaldehyde (hereinafter referred to as impurity C) of vonolamine fumarate. The method can be used for monitoring the content of the intermediate impurity C in the vonula fumarate, has high chromatographic peak separation degree and high system applicability to the intermediate impurity C in the vonula fumarate, and has the characteristics of specificity, repeatability, quantitative limit, detection limit, accuracy, linearity, range, durability and the like which meet the standards. The method overcomes the defects of the existing method for detecting the impurity C, is simple to operate, has short time and low cost, and ensures the quality controllability of the impurity C in the vonolamine fumarate.
Description
Technical Field
The invention belongs to the technical field of medicine analysis, and particularly provides a detection method of a sulfonyl intermediate impurity C in vonolamine fumarate.
Background
Fu Nuola is a novel potassium channel blocker for treating non-erosive gastroesophageal reflux disease, duodenal ulcer, gastric ulcer and erosive esophagitis (healing and maintenance treatment), and is developed by the pharmaceutical of Wuta in Japan and is first marketed in Japan in 12 months in 2014 under the trade name Takecab with the specification of 10mg and 20mg, and is originally called Vonoprazan fumarate. In 10 months 2018, the Wuta-tsu pharmaceutical submitted a naming application of TAK-438 tablets with the Chinese common name to the national formulary committee, formally more funula tablet with the English name Vonoprazan Fumarate Tablets.5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-formaldehyde (hereinafter referred to as impurity C) is an intermediate impurity of vonolamine fumarate, is a key intermediate for preparing the crude drug, belongs to genotoxic substances, has CAS number of 881677-11-8 and molecular formula of C 16 H 11 FN 2 O 3 S, molecular weight is 330.33, and chemical structure is as follows:the intermediate impurities can be brought into raw materials or preparations along with the subsequent process flow, and the quality, safety and effectiveness of the final product can be directly influenced. The prior art does not disclose a method for detecting the intermediate impurity, so that an effective, stable and reliable detection method for the vonolamine fumarate intermediate impurity C is required.
Disclosure of Invention
The invention aims to provide an effective, stable and reliable liquid chromatography detection method for the intermediate impurity C aiming at the blank of the detection of the intermediate impurity C in the prior detection method.
The technical scheme of the invention is as follows:
(1) Preparing a solution: a diluent, a blank solution, an impurity stock solution, a reference solution, a sensitivity solution, a test solution, and a selectivity solution; the diluent comprises acetonitrile solution; the blank solution comprises a diluent; the impurity stock solution comprises an impurity C stock solution; the reference solution comprises an impurity C stock solution and an acetonitrile solution; the sensitivity solution comprises an impurity C stock solution and an acetonitrile solution; the test solution comprises Fu Nuola raw fumaric acid solution and acetonitrile solution; the selective solution comprises fumaric acid Fu Nuola raw solution and impurity C stock solution and acetonitrile solution;
(2) The measuring method comprises the following steps: after the system is stable, a blank solution 1 needle, a sensitivity solution 1 needle, a reference solution 6 needle, a test solution 1 needle are fed, a chromatogram is recorded, and the chromatographic conditions are as follows: chromatographic column: octadecylsilane chemically bonded silica is used as a filler; flow rate: 1.0ml/min; detection wavelength: 245nm; column temperature: 35 ℃; sample injection amount: 20 μl; mobile phase a:0.01mol/L potassium dihydrogen phosphate solution; mobile phase B: acetonitrile, elution was performed according to the following gradient:
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 3 | 70 | 30 |
| 15 | 20 | 80 |
| 16 | 70 | 30 |
| 25 | 70 | 30 |
Further, the preparation steps of the diluent are as follows: the dilution liquid is acetonitrile and the water volume ratio is 30:70 in acetonitrile;
further, the blank solution is prepared by the following steps: the blank solution is a diluent, and the ratio of acetonitrile to water is 30:70 in acetonitrile;
further, the preparation of the impurity stock solution: taking a 100ml volumetric flask, precisely weighing an impurity C reference substance, dissolving with a diluent, diluting to a scale, and shaking uniformly; precisely measuring the solution, placing in a 50ml volumetric flask, adding diluent, diluting to scale, and shaking;
further, the reference solution is formulated: precisely measuring the impurity C stock solution, placing the stock solution in a 50ml volumetric flask, diluting to a scale with a diluent, and shaking uniformly;
further, the preparation of the sensitivity solution comprises the following steps: precisely measuring a reference solution, placing the reference solution in a 10ml volumetric flask, diluting the reference solution to a scale with a diluent, and shaking the reference solution uniformly;
further, the test solution is formulated: precisely weighing a Vonopraz fumarate sample, placing the Vonopraz fumarate sample in a 10ml volumetric flask, dissolving and diluting the Vonopraz fumarate sample to a scale with a diluent, and shaking the Vonopraz fumarate sample evenly;
further, the preparation of the selective solution comprises the following steps: precisely weighing a voronoi fumarate raw sample, placing the sample in a 10ml volumetric flask, adding a proper amount of diluent for dissolution, precisely weighing an impurity stock solution, placing the impurity stock solution in the flask, diluting to a scale with the diluent, and shaking uniformly;
(3) Impurity(s)
Wherein, ru: testing the peak area of impurity C in the solution; rs:6 mean peak area of impurity C in the reference solution;
cs: concentration of impurity C in the reference solution (. Mu.g/ml); cu: concentration of test solution (g/ml).
The beneficial effects of the invention are as follows:
the invention aims to provide a liquid chromatography detection method for a fumag intermediate impurity C, which has high chromatographic peak separation degree and higher system applicability to the impurity C in fumag, and meets the standards in terms of specificity, precision, quantitative limit, detection limit, accuracy, linearity and range, and durability.
The method for detecting the impurity C further comprises method verification before detection, and the analysis method verification measurement results are shown in the following table 1:
TABLE 1 analysis method validation results summary
Drawings
FIG. 1 example 2 sensitivity solution chromatograms
FIG. 2 example 2 reference solution chromatogram
FIG. 3 example 3 blank solution chromatogram
FIG. 4 example 3 test solution chromatogram
FIG. 5 example 3 Selective test solution chromatography
FIG. 6 test solution (labeled) chromatogram of comparative example 1
FIG. 7 test solution (labeled) chromatogram of comparative example 2
FIG. 8 is a linear relationship between impurity C concentration and peak area
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1
(1) The measuring method comprises the following steps: after the system is stable, a blank solution 1 needle, a sensitivity solution 1 needle, a reference solution 6 needle, a test solution 1 needle are fed, a chromatogram is recorded, and the chromatographic conditions are as follows: chromatographic column: agilent ZORBAX SB-C18,4.6 mm. Times.250 mm,5.0 μm; flow rate: 1.0ml/min; detection wavelength: 245nm; column temperature: 35 ℃; sample injection amount: 20 μl; mobile phase a:0.01mol/L potassium dihydrogen phosphate solution; mobile phase B: acetonitrile, elution was performed according to the following gradient:
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 3 | 70 | 30 |
| 15 | 20 | 80 |
| 16 | 70 | 30 |
| 25 | 70 | 30 |
(2) Solution preparation
Preparing a diluent: the dilution liquid is acetonitrile and the water volume ratio is 30:70 in acetonitrile;
preparing a blank solution: the blank solution is a diluent, and the ratio of acetonitrile to water is 30:70 in acetonitrile;
preparing an impurity stock solution: taking a 100ml volumetric flask, taking about 28mg of impurity C reference substance, precisely weighing, dissolving with diluent, diluting to scale, and shaking; precisely measuring 1.0ml of the solution, placing the solution in a 50ml volumetric flask, adding diluent to dilute to a scale, and shaking uniformly;
preparation of a reference solution: precisely measuring 5.0ml of impurity C stock solution, placing into a 50ml volumetric flask, diluting to scale with diluent, and shaking;
preparation of a sensitivity solution: precisely measuring 3.0ml of reference solution, placing in a 10ml volumetric flask, diluting to scale with diluent, and shaking;
preparing a positioning solution:
preparing an impurity C positioning solution: precisely transferring 1.0ml of impurity C stock solution, placing into a 10ml volumetric flask, and shaking uniformly;
preparation of test solution: taking about 100mg of a voronoi fumarate sample, precisely weighing, placing into a 10ml volumetric flask, dissolving with a diluent, diluting to a scale, and shaking uniformly;
preparation of the selective solution: taking about 100mg of a voronoi fumarate sample, precisely weighing, placing into a 10ml volumetric flask, adding a proper amount of diluent for dissolution, precisely weighing 1.0ml of impurity C stock solution, placing into the flask, diluting to a scale with the diluent, and shaking uniformly;
preparation of LOQ solution: precisely measuring 1.0ml of impurity C stock solution, placing in a 10ml volumetric flask, diluting to scale with diluent, and shaking;
preparation of LOD solution: precisely measuring 3.0ml of impurity C stock solution, placing in a 100ml volumetric flask, diluting to scale with diluent, and shaking;
preparation of a linear 50% solution: precisely measuring 1.0ml dimethylamine stock solution, placing the dimethylamine stock solution in a 20ml volumetric flask, and shaking uniformly;
preparation of a linear 80% solution: precisely measuring 2.0ml dimethylamine stock solution, placing the dimethylamine stock solution in a 25ml volumetric flask, and shaking uniformly;
preparation of a linear 100% solution: precisely measuring 1.0ml dimethylamine stock solution, placing the dimethylamine stock solution in a 10ml volumetric flask, and shaking uniformly;
preparation of linear 120% solution: precisely measuring 3.0ml dimethylamine stock solution, placing the dimethylamine stock solution in a 25ml volumetric flask, and shaking uniformly;
preparation of linear 150% solution: precisely measuring 3.0ml dimethylamine stock solution, placing the dimethylamine stock solution in a 20ml volumetric flask, and shaking uniformly;
after the system is stable, a blank solution 1 needle, a sensitivity solution 1 needle, a reference solution 6 needle, a test solution 1 needle are fed, and a chromatogram is recorded. Impurity(s)Wherein, ru: testing the peak area of impurity C in the solution; rs:6 mean peak area of impurity C in the reference solution; cs: concentration of impurity C in the reference solution (. Mu.g/ml); cu: concentration of test solution (g/ml).
Example 2 System applicability test of the detection method according to the invention
The system applicability is realized by measuring the S/N value of the impurity C in the sensitivity solution and the RSD of the peak area of the impurity C in the 6-needle reference solution, wherein the S/N value of the impurity C in the sensitivity solution is more than or equal to 10, and the RSD of the peak area of the impurity C in the 6-needle reference solution is more than or equal to 10.0%.
Preparing a sensitivity solution and a reference solution as shown in example 1, feeding a sensitivity solution 1 needle and a reference solution 6 needle under the chromatographic conditions described in example 1, recording chromatograms as shown in fig. 1 and 2, and converting the results according to the formulas as shown in the following table 2:
TABLE 2 System applicability determination results
Example 3A test method specific to the detection method according to the invention
The specificity is realized by measuring whether the blank solution has interference on the detection of the impurity C and selectively measuring the separation degree between the impurity C and adjacent peaks in the solution. The blank solution is required to have no interference to the detection of the impurity C, and the separation degree between the impurity C and the adjacent peaks in the selective solution is required to be more than or equal to 1.5.
Blank solution, reference solution, test solution and selective solution were prepared as described in example 1, and after the system was equilibrated, blank solution 1 needle, reference solution 3 needle, test solution 1 needle, selective solution 3 needle were entered, chromatograms were recorded as shown in fig. 3, 2, 4 and 5, and selective detection results were obtained as described in table 3 below:
TABLE 3 determination of specificity
Example 4 test for reproducibility of the detection method according to the invention
Repeatability is achieved by measuring the RSD of the result of the impurity C measurement in 6 parts of the test solution (labeled), and the RSD of the result of the impurity C measurement in 6 parts of the test solution (labeled) is required to be less than or equal to 10.0%.
A blank solution, impurity C stock solution, reference solution, test solution (labeled) were prepared as described in example 1. After the system was equilibrated, 1 needle of blank solution, 1 needle of reference solution, 6 portions of test solution (labeled) were entered, each 1 needle, chromatograms were recorded, as shown in fig. 3, 2 and 4, and the results obtained by conversion according to the formula are shown in the following table 4:
TABLE 4 repeatability test results
Example 5 quantitative limit and detection limit of the detection method of the present invention
The detection limit is obtained by detecting the ratio (S/N) of the response signal to the noise not less than 3, and the quantitative limit is obtained by detecting the ratio (S/N) of the response signal to the noise not less than 10. At this concentration level, 6 LOQ solutions were repeatedly examined, requiring RSD of less than or equal to 10.0% of the area of impurity C peak in 6 LOQ solutions; LOQ is less than or equal to 0.05 percent, and (S/N) is more than or equal to 10; RSD of the peak area of impurity C in 6 parts of LOQ solution is less than or equal to 10.0%, and LOD is less than LOQ; the (S/N) of the impurity C in the LOD solution is more than or equal to 3.
Blank solution, impurity C stock solution, LOQ solution, and LOD solution were formulated as described in example 1. After the system was equilibrated, 1 needle of blank solution, 1 needle of 6 portions of LOQ solution, 1 needle of LOD solution, record chromatograms, limit of quantification, limit of detection, and LOQ reproducibility results are shown in tables 5, 6 below:
TABLE 5 quantitative limit, detection line measurement results
TABLE 6 LOQ repeatability results
Example 6 linearity and Range of the detection method according to the invention
6 concentration points are selected within the limit concentration range of LOQ-150%, a curve is drawn by taking the concentration as the abscissa and the peak area as the ordinate, and the linear correlation coefficient square (R) of the curve is required to be linear within the limit concentration range of LOQ-150% 2 ) Should be greater than or equal to 0.99, the absolute value of the y-axis intercept should be within 25% of the 100% concentration response value.
After the system was stable, 3 needles of each concentration solution were introduced and the chromatograms were recorded to give the following table 7 results:
TABLE 7 Linear detection results of impurity C
The impurity C concentration-peak area linear relationship of FIG. 8 can be obtained.
Example 7 accuracy of the detection method of the present invention
Accuracy is achieved by measuring the recovery rate between the measured concentration and the theoretical concentration of the measured component and the total RSD of the recovery rate (n=9). The recovery rate of impurity C in the solution with accuracy of LOQ limit concentration, 100% limit concentration and 150% limit concentration is required to be 80.0% -120.0%, and the total RSD (n=9) of the recovery rate is required to be less than or equal to 10.0%.
After the system was stable, 3 needles of each concentration solution were introduced and the chromatograms were recorded to give the following table 8 results:
TABLE 8 accuracy measurement results
Example 8 durability (solution stability) of the detection method according to the present invention
The durability is to examine the sample injection of the reference solution, the test solution and the selective solution in a period of time at room temperature, and the change rule of the detection result along with time provides a basis for the placement time of the reference solution and the test solution during detection.
The requirements are: compared with 0h, the recovery rate of the impurity C is between 90.0 and 110.0 percent when the reference solution is placed at room temperature for a period of time, so that the reference solution is stable during the investigation period; if the impurity C is detected in the test solution for 0h, the test solution is placed at room temperature for a period of time, and the variation value of the measurement result is within 20% of the limit, so that the test solution is stable in the room temperature investigation period; if the impurity C is not detected in the test solution for 0h, the test solution is placed at room temperature for a period of time, and the impurity C is still not detected, so that the test solution is stable in the room temperature investigation period; the selective solution is placed at room temperature for a certain time, the recovery rate of the impurity C is 80.0% -120.0%, and the selective solution is stable in the investigation period.
Preparing a reference solution and a test solution according to the embodiment 1, respectively standing for several hours at room temperature, after the system is stable, feeding one needle of the reference solution and the test solution with different standing time, and recording chromatograms to obtain the following results in tables 9, 10 and 11:
TABLE 9 stability of reference solutions results
TABLE 10 test solution stability determination results
TABLE 11 Selective solution stability determination results
Comparative example 1
Changing the column manufacturer.
Comparative example 1 the detection method differs from example 1 in that the liquid chromatography condition column in example 1 is changed to MNNucleosil 100-5C18, the remaining parameters being referred to example 1. The peak shape of impurity C is not as good as this protocol, see fig. 6 for the chromatogram results of the labeled test solution.
Comparative example 2
Changing the manufacturer of chromatographic column and the sample feeding amount.
Comparative example 2 the detection method was different from example 1 in that the liquid chromatography condition column in example 1 was changed to MN nucleic 100-5C18, and the sample injection amount was changed to 10 μl, and the remaining parameters were referred to example 1. The chromatogram results of the labeled test solution are shown in fig. 7, and the impurity C peak and the adjacent peak are not separated and interfere with each other.
The invention is not a matter of the known technology.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (2)
1. A method for detecting a vonolamine fumarate intermediate impurity C, comprising the steps of:
(1) Preparing a solution: a diluent, a blank solution, an impurity stock solution, a reference solution, a sensitivity solution, a test solution, and a selectivity solution; the diluent comprises acetonitrile solution; the blank solution comprises a diluent; the impurity stock solution comprises an impurity C stock solution; the reference solution comprises an impurity C stock solution and an acetonitrile solution; the sensitivity solution comprises an impurity C stock solution and an acetonitrile solution; the test solution comprises Fu Nuola raw fumaric acid solution and acetonitrile solution; the selective solutions include Fu Nuola raw fumaric acid solution and impurity C stock solution and acetonitrile solution;
(2) The measuring method comprises the following steps: after the system is stable, a blank solution 1 needle, a sensitivity solution 1 needle, a reference solution 6 needle, a test solution 1 needle are fed, a chromatogram is recorded, and the chromatographic conditions are as follows: chromatographic column: octadecylsilane chemically bonded silica is used as a filler; flow rate: 1.0ml/min; detection wavelength: 245nm; column temperature: 35 ℃; sample injection amount: 20 μl; mobile phase a:0.01mol/L potassium dihydrogen phosphate solution; mobile phase B: acetonitrile, elution was performed according to the following gradient:
2. The method of detecting according to claim 1, wherein: the dilution liquid is acetonitrile and the water volume ratio is 30:70 in acetonitrile;
the blank solution is a diluent, and the ratio of acetonitrile to water is 30:70 in acetonitrile;
preparing the impurity stock solution: taking a 100ml volumetric flask, precisely weighing an impurity C reference substance, dissolving with a diluent, diluting to a scale, and shaking uniformly; precisely measuring the solution, placing in a 50ml volumetric flask, adding diluent, diluting to scale, and shaking;
the preparation of the reference solution comprises the following steps: precisely measuring the impurity stock solution, placing the stock solution in a 50ml volumetric flask, diluting to a scale with a diluent, and shaking uniformly;
preparing the sensitivity solution: precisely measuring a reference solution, placing the reference solution in a 10ml volumetric flask, diluting the reference solution to a scale with a diluent, and shaking the reference solution uniformly;
preparing the test solution: precisely weighing a Vonopraz fumarate sample, placing the Vonopraz fumarate sample in a 10ml volumetric flask, dissolving and diluting the Vonopraz fumarate sample to a scale with a diluent, and shaking the Vonopraz fumarate sample evenly;
preparing the selective solution: precisely weighing a Vonopraz fumarate sample, placing in a 10ml volumetric flask, adding a proper amount of diluent for dissolution, precisely weighing an impurity stock solution, placing in the flask, diluting to a scale with the diluent, and shaking uniformly.
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