CN118112144A - Method for detecting succinic acid in artesunate - Google Patents
Method for detecting succinic acid in artesunate Download PDFInfo
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- CN118112144A CN118112144A CN202410389481.3A CN202410389481A CN118112144A CN 118112144 A CN118112144 A CN 118112144A CN 202410389481 A CN202410389481 A CN 202410389481A CN 118112144 A CN118112144 A CN 118112144A
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- succinic acid
- artesunate
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 title claims abstract description 117
- 239000001384 succinic acid Substances 0.000 title claims abstract description 57
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 title claims abstract description 45
- 229960004991 artesunate Drugs 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000001514 detection method Methods 0.000 claims abstract description 25
- 238000001819 mass spectrum Methods 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000004811 liquid chromatography Methods 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 239000003085 diluting agent Substances 0.000 claims abstract description 8
- 238000005516 engineering process Methods 0.000 claims abstract description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 20
- 150000002500 ions Chemical class 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 238000013467 fragmentation Methods 0.000 claims description 5
- 238000006062 fragmentation reaction Methods 0.000 claims description 5
- 230000001133 acceleration Effects 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 239000006199 nebulizer Substances 0.000 claims 2
- 230000008569 process Effects 0.000 abstract description 8
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 238000004458 analytical method Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000000523 sample Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000007865 diluting Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000012088 reference solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229960002521 artenimol Drugs 0.000 description 2
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229930016266 dihydroartemisinin Natural products 0.000 description 1
- JYGAZEJXUVDYHI-UHFFFAOYSA-N dihydroartemisininic acid Natural products C1CC(C)=CC2C(C(C)C(O)=O)CCC(C)C21 JYGAZEJXUVDYHI-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
-
- 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
- G01N30/72—Mass spectrometers
-
- 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
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
- G01N30/8631—Peaks
Landscapes
- 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)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention relates to a method for detecting succinic acid in artesunate, which adopts a liquid chromatography-mass spectrometry technology to detect, and dissolves artesunate bulk drug into a diluent to obtain a solution to be detected; and separating each component of the solution to be detected through liquid chromatography, then entering a mass spectrum detector, adopting a selective ion detection mode to obtain a mass spectrum, and calculating according to the peak area of succinic acid in the mass spectrum to obtain the succinic acid content in the artesunate bulk drug. The invention ensures the high-efficiency separation of artesunate and succinic acid through the establishment of a proper analysis method, such as the selection of a mobile phase and various detection conditions; the detection method established by the invention has high sensitivity, accuracy and reliability and good repeatability, and the specificity, the accuracy, the detection limit and the quantitative limit of the method are verified by the method; the invention avoids the problem that artesunate is degraded into succinic acid to interfere with the detection result in the detection process, and can accurately quantify the content of the residual succinic acid in the artesunate process.
Description
Technical Field
The invention relates to the technical field of biological medicine analysis, in particular to a method for detecting succinic acid in artesunate.
Background
Artesunate is a dihydroartemisinin hemisuccinate derivative, and is one of main derivatives of artemisinin. It is white crystal, odorless and bitter; has wide pharmacological action and remarkable medicinal activity, and also has strong effect in the fields of viruses, tumors and other parasites. Artesunate for injection is recommended by the world health organization as the first drug to be used in the treatment of severe malaria and is listed in the national guidelines for drug administration by some malaria-high countries.
In the preparation process of artesunate, succinic anhydride is often used as a raw material, and finally, a byproduct succinic acid remains in the artesunate finished product. Succinic acid has no therapeutic effect and has certain toxicity to human bodies, but no detection method for the succinic acid is carried out in the current pharmacopoeia standards of various countries. In addition, how to avoid degradation of artesunate into succinic acid during detection is a difficult problem in accurately quantifying the succinic acid remained in the artesunate synthesis process when artesunate is degraded into succinic acid in water or high Wen Junyi.
In conclusion, the development of the detection method of succinic acid has important significance for guiding the synthesis process of artesunate and guaranteeing the quality and safety of medicines.
Disclosure of Invention
The invention aims to provide a method for detecting succinic acid in artesunate, which has the advantages of high sensitivity, strong specificity, good precision, high accuracy and the like, and solves the problems that the artesunate is degraded to produce succinic acid in the detection process, so that the detection result is interfered.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
The invention provides a method for detecting succinic acid in artesunate, which adopts a liquid chromatography-mass spectrometry technology to detect, and dissolves artesunate bulk drug into a diluent to obtain a solution to be detected; and separating each component of the solution to be detected through liquid chromatography, then entering a mass spectrum detector, adopting a selective ion detection mode to obtain a mass spectrum, and calculating according to the peak area of succinic acid in the mass spectrum to obtain the succinic acid content in the artesunate bulk drug.
The invention adopts the liquid chromatography-mass spectrometry technology to measure the residual succinic acid in the artesunate preparation process. And the liquid chromatography part uses acetonitrile as a diluent to avoid the degradation of artesunate in the sample preparation process, and the liquid chromatography part can separate succinic acid from artesunate. And in the mass spectrum part, ESI is used as an ion source, the mass-to-charge ratio is set to be 116.8 by SIM scanning in a negative ion mode, and in the mass spectrum part, although artesunate is subjected to high temperature drop Jie Cheng succinic acid, two succinic acid peaks are shown in a chromatogram, wherein the front succinic acid is free succinic acid, the rear succinic acid is succinic acid degraded by artesunate, and the residual succinic acid in the artesunate process can be accurately quantified by detecting the front succinic acid peak.
Specifically, agilent Poroshell EC-C18.1X105 mm,1.9 μm chromatographic column is selected for the liquid chromatography.
Specifically, a mixed solution of formic acid aqueous solution with the mass fraction of 0.1% and acetonitrile is selected as a mobile phase in the liquid chromatography; wherein the volume ratio of the formic acid aqueous solution to the acetonitrile is 50:50.
Specifically, in the liquid chromatography, the sample volume is 3 to 10. Mu.L, preferably 5. Mu.L.
Specifically, in the liquid chromatography, the flow rate of the mobile phase is 0.1 to 0.5mL/min, preferably 0.3mL/min.
Specifically, the ion source of the mass spectrum detector is ESI.
Specifically, the scanning mode of the mass spectrum detector is SIM, and the collected ions are negative ions 116.8.
Specifically, the fragmentation voltage of the mass spectrum detector is 135V, and the collision cell acceleration voltage is 5V.
Specifically, the atomizer temperature of the mass spectrum detector is 300 ℃, and the flow rate of the atomizer air flow is 5L/min.
Compared with the prior art, the invention has the following beneficial effects:
1. The invention provides a method for detecting succinic acid in artesunate, which ensures the high-efficiency separation of artesunate and succinic acid through the establishment of a proper analysis method, such as the selection of a mobile phase and various detection conditions;
2. the detection method established by the invention has high sensitivity, accuracy and reliability and good repeatability, and the specificity, the accuracy, the detection limit and the quantitative limit of the method are verified by the method;
3. The invention avoids the problem that artesunate is degraded into succinic acid to interfere with the detection result in the detection process, and can accurately quantify the content of the residual succinic acid in the artesunate process.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
The example provides a method for detecting succinic acid in artesunate, and the chromatographic conditions are as follows: HPLC chromatographic parameters
| Instrument for measuring and controlling the intensity of light | High performance liquid chromatography-triple quadrupole mass spectrometer |
| Chromatographic column | Agilent Poroshell 120EC-C18 2.1×50mm，1.9μm |
| Flow rate | 0.3ml/min |
| Column temperature | 40℃ |
| Mobile phase | 0.1% Formic acid in water: acetonitrile=50:50 |
| Sample injection amount | 5μl |
| Run time | For 5 minutes |
Mass spectral parameters
| Scanning mode | MS2 SIM |
| Polarity pattern | Negative ion mode |
| Mass | 116.8 |
| Residence time | 200 |
| Fracture voltage | 135V |
| Acceleration voltage of collision cell | 5V |
Ion source parameters
| Ion source | ESI |
| Atomizer temperature | 300℃ |
| Atomizer air flow | 5L/min |
| Atomizer | 45psi |
| Sheath air temperature | 250℃ |
| Sheath air flow rate | 11L/min |
| Capillary voltage | 3500V |
| Nozzle voltage | 500V |
| Cavity current | 0.22μA |
According to the content calculation formula: succinic acid content (%) = (a1×c2)/(a2×c1);
wherein A1 is the peak area of succinic acid in the sample to be detected;
a2 is the peak area of succinic acid in the reference solution;
C1 concentration of artesunate (mg/ml) in the sample to be tested;
c2 is the concentration (mg/ml) of succinic acid in the reference solution;
And carrying out data to obtain the succinic acid content.
Preparing a reference substance solution: precisely weighing succinic acid about 50mg, placing into a 50ml measuring flask, adding appropriate amount of acetonitrile to dissolve it, diluting with acetonitrile to scale, and shaking; transferring 1ml of the solution, placing in a 100ml measuring flask, diluting to scale with acetonitrile, and shaking; then 1ml of the solution is removed, the solution is placed in a 10ml measuring flask, diluted to a scale with acetonitrile, and shaken uniformly, and the concentration of succinic acid in the reference solution is 1 mug/ml.
Preparing a sample solution to be tested: precisely weighing artesunate about 25mg, placing into 25ml measuring flask, adding acetonitrile to dissolve, diluting with acetonitrile to scale, shaking, and keeping artesunate concentration at 1mg/ml.
Respectively taking 5 mu l of a reference substance solution and 5 mu l of a sample solution to be detected, sequentially injecting into a liquid chromatograph, separating each component through the liquid chromatograph, then entering a mass spectrum detector, adopting a selective ion detection mode to obtain a mass spectrum, and calculating according to the peak area of succinic acid in the mass spectrum to obtain the succinic acid content in the artesunate bulk drug. 1. The specificity test is specifically as follows:
And under the chromatographic conditions, taking blank solution and reference solution for sample injection respectively, and recording a chromatogram. The results show that the blank solution has no interference at the peak position of the target solvent peak.
2. Accuracy test, in particular as follows
To the test solution, succinic acid limits of 50%, 100% and 150% were added, respectively, and 3 parts of the solution were prepared for each concentration. And sequentially sampling, recording a chromatogram, and calculating the succinic acid content. Comparing the actual measurement value with the theoretical value, calculating the recovery rate, wherein 9 parts of recovery rate is between 84.4 and 130.5 percent, the average recovery rate is 108.7 percent, the RSD is 15.0 percent, and the results all meet the acceptable standard, thus indicating that the accuracy is good.
3. The quantitative limit test is specifically as follows:
preparing quantitative limiting solution: precisely measuring 3ml of succinic acid control solution, placing in a 10ml measuring flask, diluting to scale with a diluent, and shaking to obtain quantitative limiting solution.
And (3) detection: and (5) continuously injecting the quantitative limiting solution into 6 needles, and recording a chromatogram. The quantitative limit concentration of succinic acid was 0.30mg/L (relative concentration was 0.03%), the signal-to-noise ratio was between 22.3 and 31.6, and the 6-needle peak area RSD was 12.5%, and it was considered that the concentration level could be reliably quantified.
| Number of sample injections | 1 | 2 | 3 | 4 | 5 | 6 | RSD％ |
| Peak area | 6899 | 6487 | 6941 | 7134 | 5147 | 5687 | 12.5％ |
| Signal to noise ratio | 31.6 | 27.7 | 28.1 | 26.1 | 22.3 | 23.3 | N/A |
4. The detection limit test is specifically as follows:
Preparing a detection limit solution: taking the quantitative limiting solution and diluting the quantitative limiting solution by one time to obtain the detection limiting solution. 1 needle was introduced, the chromatogram was recorded, the succinic acid detection limit concentration was 0.152mg/L (relative concentration was 0.015%), and the signal-to-noise ratio was 10.6, which was considered to be reliably detectable.
Comparative example 1
The example provides a method for detecting succinic acid in artesunate, which is different from the diluent in the example 1, when the diluent is a mixture of acetonitrile and water, and the volume ratio is 1:1, the artesunate is easy to degrade into dihydroartemisinin and succinic acid, and the residual succinic acid in the artesunate cannot be accurately detected.
Comparative example 2
This example provides a method for detecting succinic acid in artesunate, which is different from the detector in example 1 in that when the detector is an ultraviolet-visible spectroscopic detector, the succinic acid chromatographic peak has a solvent effect, the peak shape is distorted, the sensitivity is low, and accurate quantification is not possible.
Comparative example 3-comparative example 5
This example provides a method for detecting succinic acid in artesunate which is different from the fragmentation voltage of the mass spectrum parameters in example 1 in that the response to succinic acid is weaker than the response at the fragmentation voltage of 135V when the fragmentation voltages are selected from 90V (comparative example 3), 110V (comparative example 4) and 120V (comparative example 5).
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that fall within the technical scope of the present invention disclosed herein are within the scope of the present invention.
Claims (10)
1. A method for detecting succinic acid in artesunate is characterized in that a liquid chromatography-mass spectrometry technology is adopted for detection, and artesunate bulk drugs are dissolved in a diluent to obtain a solution to be detected; and separating each component of the solution to be detected through liquid chromatography, then entering a mass spectrum detector, adopting a selective ion detection mode to obtain a mass spectrum, and calculating according to the peak area of succinic acid in the mass spectrum to obtain the succinic acid content in the artesunate bulk drug.
2. The method of claim 1, wherein the diluent is acetonitrile.
3. The method according to claim 1, wherein Agilent Poroshell 120 EC-C18.1X105 mm,1.9 μm column is used in the liquid chromatography.
4. The method according to claim 1, wherein the liquid chromatograph is eluted with a mixture of an aqueous formic acid solution and acetonitrile as a flow equality, and the mass fraction of formic acid in the aqueous formic acid solution is 0.1%; wherein the volume ratio of the formic acid aqueous solution to the acetonitrile is 50:50.
5. The method according to claim 1, wherein the sample volume in the liquid chromatograph is 3-10 μl.
6. The method according to claim 1, wherein the flow rate of the mobile phase in the liquid chromatograph is 0.1 to 0.5ml/min.
7. The method of claim 1, wherein the ion source of the mass spectrum detector is ESI.
8. The method of claim 1, wherein the scanning mode of the mass spectrum detector is SIM and the collected ions are negative ions 116.8.
9. The method of claim 1, wherein the fragmentation voltage of the mass spectrum detector is 135V and the collision cell acceleration voltage is 5V.
10. The method of claim 1, wherein the mass spectrum detector has a nebulizer temperature of 300 ℃ and a nebulizer gas flow rate of 5L/min.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410389481.3A CN118112144A (en) | 2024-04-02 | 2024-04-02 | Method for detecting succinic acid in artesunate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410389481.3A CN118112144A (en) | 2024-04-02 | 2024-04-02 | Method for detecting succinic acid in artesunate |
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| CN202410389481.3A Pending CN118112144A (en) | 2024-04-02 | 2024-04-02 | Method for detecting succinic acid in artesunate |
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