CN117647609A - Method for detecting residual solvent of bromfenac sodium - Google Patents
Method for detecting residual solvent of bromfenac sodium Download PDFInfo
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- CN117647609A CN117647609A CN202310795656.6A CN202310795656A CN117647609A CN 117647609 A CN117647609 A CN 117647609A CN 202310795656 A CN202310795656 A CN 202310795656A CN 117647609 A CN117647609 A CN 117647609A
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- bromfenac
- residual solvent
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- 239000013557 residual solvent Substances 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 15
- 229960002716 bromfenac sodium Drugs 0.000 title claims abstract description 13
- HZFGMQJYAFHESD-UHFFFAOYSA-M bromfenac sodium Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 HZFGMQJYAFHESD-UHFFFAOYSA-M 0.000 title claims abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000001514 detection method Methods 0.000 claims abstract description 19
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 18
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 238000004817 gas chromatography Methods 0.000 claims abstract description 4
- 239000000523 sample Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 18
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229960003655 bromfenac Drugs 0.000 claims description 9
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000012159 carrier gas Substances 0.000 claims description 7
- 239000012488 sample solution Substances 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 4
- 239000012085 test solution Substances 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000012088 reference solution Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 238000005070 sampling Methods 0.000 abstract 1
- 238000005259 measurement Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- HCSCWJCZRCSQFA-UHFFFAOYSA-N 1-methylpyrrolidin-2-one;hydrate Chemical compound O.CN1CCCC1=O HCSCWJCZRCSQFA-UHFFFAOYSA-N 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- PPOSVVJOVKVBPW-UHFFFAOYSA-L bromfenac sodium salt sesquihydrate Chemical compound O.O.O.[Na+].[Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1.NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 PPOSVVJOVKVBPW-UHFFFAOYSA-L 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- BIYQNLJPABKADF-UHFFFAOYSA-M sodium;2-[2-amino-3-(4-bromobenzoyl)phenyl]acetate;hydrate Chemical compound O.[Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 BIYQNLJPABKADF-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
- G01N30/6052—Construction of the column body
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Sampling And Sample Adjustment (AREA)
Abstract
The invention discloses a detection method of a bromfenac sodium residual solvent. The method adopts a gas chromatography solution direct sampling method to detect residual solvent in the bromfenac sodium bulk drug. The detection method of the invention realizes the separation and determination of 5 organic solvents such as residual solvents of dichloromethane, 2-methoxyethanol, toluene, acetonitrile, 1, 2-dimethoxyethane and the like, has high sensitivity and good separation degree and reproducibility, and can better realize the quality control of medicines.
Description
Technical Field
The invention belongs to the technical field of medical analysis, and particularly relates to a detection method of a bromfenac sodium residual solvent.
Background
Sodium bromfenac (brifenac sodium) is used for treating inflammatory diseases of external eye and anterior eye such as blepharitis, conjunctivitis, scleritis, postoperative inflammation, etc. Bromfenac sodium hydrate eye drops are marketed in the united states in 3 months 2005 and 10 months 2010, and the importation of japan kiloshou pharmaceutical co.
In the production process of the bromfenac sodium bulk drug, 5 organic solvents such as dichloromethane, 2-methoxyethanol, toluene, acetonitrile, 1, 2-dimethoxyethane and the like are used, and according to the rule in the four-part general rule 0861 residual solvent measuring method of the Chinese pharmacopoeia 2020 edition, the dichloromethane, 2-methoxyethanol, toluene, acetonitrile and 1, 2-dimethoxyethane are second solvents, and the solvents are controlled.
The chemical name of bromfenac sodium is: sodium 2-amino-3- (4-bromobenzoyl) phenylacetate sesquihydrate, and has a chemical structural formula:
disclosure of Invention
In order to ensure the quality of sodium bromfenac medicines, the invention provides a method for detecting residual solvents in sodium bromfenac bulk drugs by using a gas chromatography solution direct injection method.
The detection method of the bromfenac sodium residual solvent comprises the following steps: the residual solvent in the bromfenac sodium bulk drug is detected by adopting a gas chromatography solution direct sample injection method, and the detection conditions are as follows:
chromatographic column: an Agilent HP-INNOWAX (30 m. Times.0.32 mm. Times.0.5 μm) capillary chromatographic column;
a detector: a flame ionization detector;
sample inlet temperature: 280+/-2 ℃;
the detector temperature was 300 ℃;
carrier gas: nitrogen gas;
carrier gas flow rate: 1.5+/-0.2 ml/min;
split ratio: 3:1;
programming temperature: the initial temperature is 40+/-2 ℃, the temperature is kept for 10min, the temperature is increased to 250 ℃ at the rate of 30 ℃ per minute, and the temperature is kept for 5min;
the sample volume was 0.5. Mu.l.
The detection method of the bromfenac sodium residual solvent comprises the following specific steps:
(1) A diluent: a mixed solvent of N-methyl pyrrolidone and water in a volume ratio of 1:1;
(2) Control solution: respectively placing dichloromethane, 2-methoxyethanol, toluene, acetonitrile and 1, 2-dimethoxyethane into the same measuring flask, and adding diluent to quantitatively dilute to obtain solutions containing 0.06mg, 0.005mg, 0.089mg, 0.041mg and 0.01mg of each 1 ml;
(3) Test solution: adding a diluting agent into sodium bromfenac for ultrasonic dissolution and quantitatively diluting to prepare a solution containing 0.1g of sodium bromfenac per 1 ml;
(4) Precisely measuring 0.5 μl of each of the sample solution and the reference solution, respectively injecting into gas chromatograph, and recording chromatogram.
The detection method of the bromfenac sodium residual solvent realizes the separation and determination of 5 organic solvents such as residual solvents of dichloromethane, 2-methoxyethanol, toluene, acetonitrile, 1, 2-dimethoxyethane and the like, and has the advantages of high sensitivity, good separation degree and reproducibility, and better realization of medicine quality control.
Drawings
FIG. 1 is a high performance liquid chromatogram of an embodiment of the present invention; the peak sequence is shown in the figure as 1, 2-dimethoxyethane, dichloromethane, acetonitrile, toluene and 2-methoxyethanol.
Detailed Description
Example 1
Blank solvent (diluent): n-methylpyrrolidone-water (50:50).
Control solution: respectively taking proper amounts of dichloromethane, 2-methoxyethanol, toluene, acetonitrile and 1, 2-dimethoxyethane, precisely weighing, placing into a same measuring flask, and adding a diluent for quantitative dilution to prepare solutions containing 0.06mg, 0.005mg, 0.089mg, 0.041mg and 0.01mg of each 1 ml.
Test solution: and (3) taking a proper amount of bromfenac sodium, precisely weighing, adding a diluent, carrying out ultrasonic dissolution, and quantitatively diluting to prepare a solution containing 0.1g per 1 ml.
The detection conditions are as follows:
chromatographic column: an Agilent HP-INNOWAX (30 m. Times.0.32 mm. Times.0.5 μm) capillary chromatographic column;
a detector: a flame ionization detector;
sample inlet temperature: 280 ℃;
the detector temperature was 300 ℃;
carrier gas: nitrogen gas;
carrier gas flow rate: 1.5ml/min;
split ratio: 3:1;
programming temperature: the initial temperature is 40 ℃, the temperature is kept for 10min, the temperature is increased to 250 ℃ at the rate of 30 ℃ per minute, and the temperature is kept for 5min;
the sample volume was 0.5. Mu.l.
(1) Specificity test
Taking blank solvent, reference substance solution and test substance solution, and analyzing according to the above chromatographic conditions, wherein typical chromatogram is shown in figure 1. The result shows that the blank solvent does not interfere with the content measurement of the residual solvent of the product; the minimum degree of separation of each solvent peak in the control solution is 2.86 (> 1.5); the method has good specificity.
(2) Quantitative limit and detection limit
Gradually diluting the reference substance solution, analyzing according to the chromatographic conditions, and taking the concentration with the signal to noise ratio (S/N) of 10-30 and the concentration with the signal to noise ratio (S/N) of 3-10 as a quantitative limit and a detection limit respectively.
The detection result is as follows: the quantitative limit concentration of 1, 2-dimethoxyethane is 3.0181 mug/ml, which is equivalent to 0.0030 percent of the concentration of a test sample, the average value of signal to noise ratio is 14.4, and the RSD of 6 times of peak areas is 4.53 percent; the detection limit concentration is 0.9054 mug/ml, which is equivalent to 0.0009% of the concentration of the test sample, and the signal to noise ratio is 4.4;
the quantitative limit concentration of dichloromethane is 5.8102 mug/ml, which is equivalent to 0.0058% of the concentration of a test sample, the average value of signal to noise ratio is 10.4, and the RSD of 6 times of continuous measurement peak areas is 4.75%; the detection limit concentration is 1.7431 mug/ml, which is equivalent to 0.0017% of the concentration of the test sample, and the signal-to-noise ratio is 3.5;
the acetonitrile quantitative limit concentration is 4.2230 mug/ml, which is equivalent to 0.0042% of the concentration of the test sample, the average value of the signal to noise ratio is 21.4, and the RSD of the continuous 6 times peak area is 2.47%; the limit concentration is 1.2669 mug/ml, which is equivalent to 0.0013% of the concentration of the test sample, and the signal-to-noise ratio is 7.0;
the quantitative limit concentration of toluene is 0.8774 mug/ml, which is equivalent to 0.0009% of the concentration of the test sample, the average value of signal to noise ratio is 20.6, and the RSD of the continuous 6 times peak area is 1.85%; the detection limit concentration is 0.2632 mug/ml, which is equivalent to 0.0003% of the concentration of the test sample, and the signal to noise ratio is 6.5;
the quantitative limit concentration of the 2-methoxyethanol is 0.4921 mug/ml, which is equivalent to 0.0005% of the concentration of a test sample, the average value of the signal to noise ratio is 13.9, and the RSD of the peak area of 6 times of continuous measurement is 3.86%; the detection limit concentration is 0.1476 mug/ml, which is equivalent to 0.0001% of the concentration of the test sample, and the signal to noise ratio is 4.6.
(3) Linearity and range
6 kinds of linear solutions are prepared at the concentration level of quantitative limit-200%, analysis is carried out according to the chromatographic conditions, standard curves are drawn for the concentration (C) according to the peak area (A), and linear regression analysis is carried out, and the results are shown in Table 1, so that the peak area and the concentration of each solvent have good linear relation.
Table 1 Linear relation and Linear Range of Components
(4) Accuracy test
The standard recovery rates of the test samples were examined at three concentration levels of 80%, 100% and 120% (3 parts prepared in parallel), and the results of analysis under the above chromatographic conditions are shown in Table 2, indicating that the accuracy of the method is good.
Table 2 recovery measurement results (n=9)
(5) Precision test
6 parts of the solution were prepared in parallel according to the 100% standard test solution under the test item "(4) accuracy test", and analyzed according to the above chromatographic conditions, and the results are shown in Table 3, which show that the analytical method is excellent in reproducibility.
Table 3 repeatability test measurement results (n=6)
Another tester, on different dates, used different instruments to prepare 6 parts of 100% standard-added test sample solution, analyzed according to the chromatographic conditions, and the results are shown in table 4, which show that the intermediate precision of the analysis method is good. The measurement results of 12 parts of the labeled sample solution are shown in Table 5, and the method has good precision.
Table 4 results of intermediate precision test (n=6)
Table 5 intermediate precision test measurement results (n=12)
(6) Durability test
The RSD of the 100% standard-added sample solution detection content is examined by fine adjustment of chromatographic conditions such as column temperature change + -2 ℃, carrier gas flow rate change + -0.2 ml/min, sample inlet temperature + -2 ℃, and replacement of chromatographic columns with different numbers (table 6), the durability of the method is measured, and the results are shown in table 7, which show that the durability of the method to minor changes of chromatographic conditions is good.
TABLE 6 chromatographic Standard conditions and variations
TABLE 7 durability test measurement results
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and changes could be made by those skilled in the art without departing from the inventive concept herein, which would fall within the scope of the present invention.
Claims (2)
1. The detection method of the residual solvent of the sodium bromfenac is characterized by adopting a gas chromatography solution direct sample injection method to detect the residual solvent in the sodium bromfenac bulk drug, wherein the detection conditions are as follows:
chromatographic column: an Agilent HP-INNOWAX (30 m. Times.0.32 mm. Times.0.5 μm) capillary chromatographic column;
a detector: a flame ionization detector;
sample inlet temperature: 280+/-2 ℃;
the detector temperature was 300 ℃;
carrier gas: nitrogen gas;
carrier gas flow rate: 1.5+/-0.2 ml/min;
split ratio: 3:1;
programming temperature: the initial temperature is 40+/-2 ℃, the temperature is kept for 10min, the temperature is increased to 250 ℃ at the rate of 30 ℃ per minute, and the temperature is kept for 5min;
the sample volume was 0.5. Mu.l.
2. The method for detecting residual solvent of bromfenac sodium according to claim 1, wherein the detection method comprises the following specific steps:
(1) A diluent: a mixed solvent of N-methyl pyrrolidone and water in a volume ratio of 1:1;
(2) Control solution: respectively placing dichloromethane, 2-methoxyethanol, toluene, acetonitrile and 1, 2-dimethoxyethane into the same measuring flask, and adding diluent to quantitatively dilute to obtain solutions containing 0.06mg, 0.005mg, 0.089mg, 0.041mg and 0.01mg of each 1 ml;
(3) Test solution: adding a diluting agent into sodium bromfenac for ultrasonic dissolution and quantitatively diluting to prepare a solution containing 0.1g of sodium bromfenac per 1 ml;
(4) Precisely measuring 0.5 μl of each of the sample solution and the reference solution, respectively injecting into gas chromatograph, and recording chromatogram.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310795656.6A CN117647609A (en) | 2023-06-30 | 2023-06-30 | Method for detecting residual solvent of bromfenac sodium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310795656.6A CN117647609A (en) | 2023-06-30 | 2023-06-30 | Method for detecting residual solvent of bromfenac sodium |
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| CN117647609A true CN117647609A (en) | 2024-03-05 |
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| CN202310795656.6A Pending CN117647609A (en) | 2023-06-30 | 2023-06-30 | Method for detecting residual solvent of bromfenac sodium |
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| CN (1) | CN117647609A (en) |
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2023
- 2023-06-30 CN CN202310795656.6A patent/CN117647609A/en active Pending
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