CN114814050A - Impurity detection method of 3-amino-1-adamantanol - Google Patents
Impurity detection method of 3-amino-1-adamantanol Download PDFInfo
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- CN114814050A CN114814050A CN202210341542.XA CN202210341542A CN114814050A CN 114814050 A CN114814050 A CN 114814050A CN 202210341542 A CN202210341542 A CN 202210341542A CN 114814050 A CN114814050 A CN 114814050A
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- 239000012535 impurity Substances 0.000 title claims abstract description 61
- DWPIPTNBOVJYAD-BQKDNTBBSA-N (5s,7r)-3-aminoadamantan-1-ol Chemical compound C([C@H](C1)C2)[C@@H]3CC2(N)CC1(O)C3 DWPIPTNBOVJYAD-BQKDNTBBSA-N 0.000 title claims abstract description 30
- 238000001514 detection method Methods 0.000 title claims abstract description 20
- 239000003085 diluting agent Substances 0.000 claims abstract description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 21
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 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 abstract description 10
- 235000019253 formic acid Nutrition 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 238000004458 analytical method Methods 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 claims abstract description 7
- 238000010828 elution Methods 0.000 claims abstract description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 6
- 238000002347 injection Methods 0.000 claims abstract description 6
- 239000007924 injection Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000011259 mixed solution Substances 0.000 claims abstract description 4
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical group O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000000523 sample Substances 0.000 claims description 22
- 238000007865 diluting Methods 0.000 claims description 21
- 239000011550 stock solution Substances 0.000 claims description 21
- 238000005303 weighing Methods 0.000 claims description 14
- 239000012490 blank solution Substances 0.000 claims description 11
- 239000012488 sample solution Substances 0.000 claims description 11
- 239000012086 standard solution Substances 0.000 claims description 10
- 238000001819 mass spectrum Methods 0.000 claims description 9
- OTHKXWALZCWLGM-UHFFFAOYSA-N 5-aminoadamantane-1,3-diol Chemical compound C1C(C2)CC3(O)CC1(N)CC2(O)C3 OTHKXWALZCWLGM-UHFFFAOYSA-N 0.000 claims description 8
- 239000013558 reference substance Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 abstract description 5
- 229960001254 vildagliptin Drugs 0.000 abstract description 5
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 description 8
- 239000007789 gas Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- 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 an impurity detection method of 3-amino-1-adamantanol, which comprises the steps of detecting the content of impurities by using high performance liquid chromatography-mass spectrometry, dissolving a sample to be detected by using a diluent, and then carrying out sample injection analysis; the mobile phase of the high performance liquid chromatography system is a mixed solution of an acid aqueous solution and an organic solvent, the diluent is a methanol-aqueous solution with the volume ratio of 1:1, and the chromatographic column is a C18 chromatographic column; the mobile phase is formic acid water solution with the volume concentration of 0.1 percent of formic acid and acetonitrile, and the flow rate is 0.3mL per minute; the mobile phase was subjected to gradient elution. The method detects the impurities of the 3-amino-1-adamantanol by liquid chromatography-mass spectrometry, and has the advantages of strong specificity, high sensitivity, 0.016 percent of limit of quantitation and 0.005 percent of limit of detection; meanwhile, the detection precision is improved, the method has good reproducibility, the relative standard deviation of continuous sample injection is 0.92%, and convenience is provided for the analysis of the 3-amino-1-adamantanol, so that the quality of the 3-amino-1-adamantanol is controllable, and conditions are provided for the industrial production of vildagliptin.
Description
Technical Field
The invention relates to the field of pharmaceutical analysis, in particular to a method for detecting impurities of 3-amino-1-adamantanol.
Background
Vildagliptin is an orally administered dipeptidyl peptidase-iv inhibitor developed and marketed by nova pharmaceuticals, inc, and is commonly used to treat type 2 diabetes. Numerous processes for the synthesis of vildagliptin are disclosed in the prior art, wherein 3-amino-1-adamantanol is an important starting material for the synthesis of vildagliptin, whereas in the commercially available 3-amino-1-adamantanol, 5-amino-adamantane-1, 3-diol is an impurity present therein. According to the ICH Q3A (impurity in new drug substance) guideline, the impurity of the starting material needs to be confirmed and controlled.
In the prior art, no analytical method for detecting 5-amino-adamantane-1, 3-diol exists.
The molecular weight of the 5-amino-adamantane-1, 3-diol is only 183.25, and the molecular weight is small; no retention in liquid chromatography, peak at dead volume, no detection; the commercial 5-amino-adamantane-1, 3-diol control was hydrochloride, and it was difficult to peak in the gas phase. That is, the content of the impurity 5-amino-adamantane-1, 3-diol cannot be accurately detected by the conventional chromatographic monitoring method.
Disclosure of Invention
The invention aims to solve the technical problem of providing an impurity detection method of 3-amino-1-adamantanol capable of conveniently and accurately measuring the content of impurities so as to provide reference for controlling the content of impurities in the current state of the prior art.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the impurity detection method of 3-amino-1-adamantanol uses high performance liquid chromatography-mass spectrometry to detect the impurity content, and comprises the following steps:
(1) dissolving a sample to be detected by using a diluent, and then carrying out sample injection analysis;
(2) the mobile phase of the high performance liquid chromatography system is a mixed solution of an acid aqueous solution and an organic solvent, the diluent is a methanol-aqueous solution with the volume ratio of 1:1, and the chromatographic column is a C18 chromatographic column; the mobile phase comprises aqueous formic acid solution with the volume concentration of formic acid of 0.1 percent and acetonitrile, and the flow rate is 0.3mL per minute; the mobile phase was subjected to gradient elution.
The steps are as follows:
dissolving a sample to be detected by using a diluent, and detecting by using a high performance liquid chromatography-mass spectrometry instrument containing a triple quadrupole and an electrospray ion source, wherein the quantitative parent ion of impurities is 184.1, the child ions are 107.1, 109.1 and 167.1, the stationary phase of the high performance liquid chromatography is a C18 chromatographic column, the mobile phase is a mixed solution of an aqueous solution of acid and an organic solvent, the volume percentage of the acid is 60-94%, the volume percentage of the organic solvent is 6-40%, the acid is a volatile acid, and the organic solvent is acetonitrile; the acid is acetic acid or formic acid. The concentration of the acid aqueous solution is 0.01-0.1%.
The chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: InfinityLab Poroshell 120 EC-C18;
mobile phase: a-0.1% formic acid, B-acetonitrile;
flow rate: 0.3 mL/min;
column temperature: 25 ℃;
sample introduction amount: 2 μ L.
The elution gradient of the mobile phase was:
| time (min) | 0.1% aqueous formic acid solution% | Acetonitrile% |
| 0 | 94 | 6 |
| 5 | 94 | 6 |
| 9 | 60 | 40 |
| 12 | 60 | 40 |
| 12.1 | 94 | 6 |
| 20 | 94 | 6 |
。
The mass spectrum chromatographic conditions are as follows:
| an ion source: | electrospray ionization source ESI |
| Atomizing: | nitrogen gas N 2 |
| Gas temperature: | 350℃ |
| gas flow rate: | 11L/min |
| atomizerPressure: | 45psi |
| capillary voltage: | 4000V |
| the scanning type is as follows: | MRM |
| polarity: | is just for |
。
The invention also comprises blank control detection, wherein the preparation process of the blank control solution comprises the following steps:
diluent agent: water methanol 50:50 (V/V);
blank solution: a diluent;
impurity stock solution: accurately weighing 2.5mg of impurity reference substance (the impurity name is 5-amino-adamantane-1, 3-diol, namely the impurity of the aforementioned 3-amino-1-adamantanol) in a 50mL volumetric flask, dissolving and diluting the reference substance to a scale by using a diluent, and shaking up; concentration of impurity reference: 0.05 mg/mL;
standard solution: precisely transferring 1.0mL of impurity stock solution into a 25mL volumetric flask, dissolving and diluting a diluent to a scale, and shaking up; concentration of impurity reference: 0.002 mg/mL;
sample solution: accurately weighing 50mg of a sample in a 50mL volumetric flask, ultrasonically dissolving the sample by using a diluent, diluting the sample to a scale, shaking the sample uniformly, and preparing two parts in parallel; 3-amino-1-adamantanol concentration: 2.0 mg/mL;
precisely measuring blank solution, standard solution, sample solution, and impurity-added sample solution 2 μ L each, injecting into high performance liquid chromatography-mass spectrometry, and recording mass spectrum.
Compared with the prior art, the invention has the advantages that: the method detects the impurities of the 3-amino-1-adamantanol by liquid chromatography-mass spectrometry, and has the advantages of strong specificity, high sensitivity, 0.016 percent of limit of quantitation and 0.005 percent of limit of detection; meanwhile, the detection precision is improved, the method has good reproducibility, the relative standard deviation of continuous injection is 0.92%, and convenience is provided for the analysis of 3-amino-1-adamantanol, so that the quality of the 3-amino-1-adamantanol is controllable, and conditions are provided for realizing the industrial production of vildagliptin.
Drawings
FIG. 1 is a mass spectrum of a blank solution according to an example of the present invention;
FIG. 2 is a mass spectrum of a standard solution according to an example of the present invention;
FIG. 3 is a mass spectrum of a sample solution according to an embodiment of the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
In the embodiment of the invention, the method for detecting the content of 5-amino-adamantane-1, 3-diol serving as an impurity of 3-amino-1-adamantanol comprises the following steps: detecting impurity content by using high performance liquid chromatography-mass spectrometry, dissolving a sample to be detected by using a diluent, carrying out sample injection analysis, and carrying out gradient elution on a mobile phase.
Wherein, the chromatographic conditions are as follows:
a chromatographic column: InfinityLab Poroshell 120 EC-C18;
mobile phase: a-0.1% formic acid, B-acetonitrile;
flow rate: 0.3 mL/min;
column temperature: 25 ℃;
sample introduction amount: 2 μ L.
The mass spectrum detection conditions are as follows:
an ion source: electrospray ion source ESI;
atomizing: nitrogen gas
Gas temperature: 350 deg.C
Gas flow rate: 11L/min;
atomizing gas pressure: 45 psi;
capillary voltage: 4000V;
the scanning type is as follows: MRM;
polarity: is positive.
Diluent agent: water methanol 50:50 (V/V);
blank solution: a diluent.
Impurity stock solution: precisely weighing about 2.5mg of impurity reference substance into a 50mL volumetric flask, dissolving and diluting the diluent to a scale, and shaking up. (concentration: 0.05mg/mL)
Standard solution: precisely transferring 1.0mL of the impurity stock solution into a 25mL volumetric flask, dissolving and diluting the diluent to a scale, and shaking up. (concentration: 0.002mg/mL)
Sample solution: precisely weighing about 50mg of a sample in a 50mL volumetric flask, ultrasonically dissolving the sample by using a diluent, diluting the sample to a scale, shaking the sample uniformly, and preparing two parts in parallel. (3-amino-1-adamantanol concentration: 2.0mg/mL)
Precisely measuring blank solution, standard solution, sample solution and impurity-added sample solution 2 μ L each, injecting into a liquid chromatograph-mass spectrometer, and recording mass spectrogram.
As shown in FIGS. 1-3, the blank solution is free of interference, the retention time of impurities is 1.823min, the mass spectrum parent ions are 184.1, and the daughter ions are 107.1, 109.1 and 167.1, which meets the requirements and proves that the method provided by the embodiment of the invention has specificity.
Detection limit and quantitation limit tests were performed according to this example.
Blank solution Blank: a diluent;
impurity stock solution: precisely weighing about 2.5mg of impurity reference substance into a 50mL volumetric flask, dissolving and diluting the diluent to a scale, and shaking up. (concentration: 0.05mg/mL)
Standard solution SS: precisely transferring 1.0mL of the impurity stock solution into a 25mL volumetric flask, diluting the impurity stock solution to a scale mark with a diluent, and shaking up. (concentration: 0.002mg/mL)
Limit of quantitation solution LOQ solution: precisely transferring 0.2mL of impurity stock solution into a 25mL volumetric flask, diluting to the scale with a diluent, and shaking up. 6 parts are prepared in parallel.
Limit of detection solution LOD solution: precisely transferring 3.0mL of quantitative limiting solution-1 into a 10mL volumetric flask, diluting to the scale with a diluent, and shaking up.
According to the detection result, the detection limit is 0.005 percent, and the signal-to-noise ratio is 378.5; the quantitation limit is 0.016% and the signal-to-noise ratio is 1308.2; the relative standard deviation of the impurity peak area of the 6-needle quantitative limiting solution is 7.39%, so that the method has good sensitivity.
The linear test was carried out according to this example.
Blank solution Blank: a diluent;
impurity stock solution: precisely weighing about 2.5mg of impurity reference substance into a 50mL volumetric flask, dissolving and diluting the diluent to a scale, and shaking up. (concentration: 0.05mg/mL)
Standard solution SS: precisely transferring 1.0mL of the impurity stock solution into a 25mL volumetric flask, diluting the impurity stock solution to a scale mark with a diluent, and shaking up. (concentration: 0.002mg/mL)
Linear solutions at each concentration level were prepared as follows:
| serial number | Volume of impurity stock solution removed (mL) | Dilution volume (mL) | |
| 1 | 0.2 | 25 | |
| 2 | 0.6 | 25 | 60％ |
| 3 | 1.0 | 25 | 100％ |
| 4 | 1.5 | 25 | 150％ |
| 5 | 2.5 | 25 | 250％ |
According to the detection result, the correlation coefficient of the linear equation is 0.9998 and is more than 0.990; the intercept of the linear equation is 1440.1019, and the requirement of the intercept limit +/-1667.0500 is met, so that the method has good linearity.
The recovery test was carried out according to this example.
Blank solution Blank: a diluent;
impurity stock solution: precisely weighing about 2.5mg of impurity reference substance into a 50mL volumetric flask, dissolving and diluting the diluent to a scale, and shaking up. (concentration: 0.05mg/mL)
Standard solution SS: precisely transferring 1.0mL of the impurity stock solution into a 25mL volumetric flask, diluting the impurity stock solution to a scale mark with a diluent, and shaking up. (concentration: 0.002mg/mL)
Sample solution SaS: precisely weighing about 50mg of 3-amino-1-adamantanol in a 25mL volumetric flask, adding a diluent to dissolve and fix the volume, uniformly mixing, and preparing two parts in parallel. (3-amino-1-adamantanol: 2.0mg/mL)
LOQ Accuracy solution Accuracy LOQ: precisely weighing about 50mg of 3-amino-1-adamantanol in a 25mL volumetric flask, adding a proper amount of diluent for dissolution, adding 0.2mL of impurity stock solution, diluting the diluent to a scale, and shaking up. 3 parts are prepared in parallel.
50% Accuracy solution Accuracy 50%: precisely weighing about 50mg of 3-amino-1-adamantanol in a 25mL volumetric flask, adding a proper amount of diluent for dissolution, adding 0.5mL of impurity stock solution, diluting the diluent to a scale, and shaking up. 3 parts are prepared in parallel.
100% Accuracy solution Accuracy 100%: precisely weighing about 50mg of 3-amino-1-adamantanol in a 25mL volumetric flask, adding a proper amount of diluent for dissolution, adding 1.0mL of impurity stock solution, diluting the diluent to a scale, and shaking up. 6 parts are prepared in parallel.
150% Accuracy solution Accuracy 150%: precisely weighing about 50mg of 3-amino-1-adamantanol in a 25mL volumetric flask, adding a proper amount of diluent for dissolution, adding 1.5mL of impurity stock solution, diluting the diluent to a scale, and shaking up. 3 parts are prepared in parallel.
According to the detection result, the recovery rate of the LOQ concentration level is 122.24-128.53%, the recovery rate of the 50% concentration level is 101.82-117.93%, the recovery rate of the 100% concentration level is 92.10-93.02%, the recovery rate of the 150% concentration level is 93.38-94.71%, and the test result of the impurity accuracy recovery rate is within an acceptable range, so that the analysis method has good accuracy.
Claims (5)
1. The impurity detection method of 3-amino-1-adamantanol is characterized by detecting the impurity content by using high performance liquid chromatography-mass spectrometry, and comprising the following steps of:
(1) dissolving a sample to be detected by using a diluent, and then carrying out sample injection analysis;
(2) the mobile phase of the high performance liquid chromatography system is a mixed solution of an acid aqueous solution and an organic solvent, the diluent is a methanol-aqueous solution with the volume ratio of 1:1, and the chromatographic column is a C18 chromatographic column; the mobile phase is formic acid water solution with the volume concentration of 0.1 percent of formic acid and acetonitrile, and the flow rate is 0.3mL per minute; the mobile phase was subjected to gradient elution.
2. The method of detecting an impurity of 3-amino-1-adamantanol according to claim 1, characterized in that: the chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: InfinityLab Poroshell 120 EC-C18;
mobile phase: a-0.1% formic acid, B-acetonitrile;
flow rate: 0.3 mL/min;
column temperature: 25 ℃;
sample introduction amount: 2 μ L.
3. The method of detecting an impurity of 3-amino-1-adamantanol according to claim 1 or 2, characterized in that: the elution gradient of the mobile phase is:
。
4. The method of detecting an impurity of 3-amino-1-adamantanol according to claim 1, characterized in that: the mass spectrum chromatographic conditions are as follows:
5. the method of detecting an impurity of 3-amino-1-adamantanol according to claim 1, characterized in that: the method also comprises blank control detection, wherein the preparation process of the blank control solution is as follows:
diluent agent: water methanol 50:50 (V/V);
blank solution: a diluent;
impurity stock solution: accurately weighing 2.5mg of an impurity reference substance 5-amino-adamantane-1, 3-diol in a 50mL volumetric flask, dissolving and diluting a diluent to a scale, and shaking up; concentration of impurity reference: 0.05 mg/mL;
standard solution: precisely transferring 1.0mL of impurity stock solution into a 25mL volumetric flask, dissolving and diluting a diluent to a scale, and shaking up; concentration of impurity reference: 0.002 mg/mL;
sample solution: accurately weighing 50mg of a sample in a 50mL volumetric flask, ultrasonically dissolving the sample by using a diluent, diluting the sample to a scale, shaking the sample uniformly, and preparing two parts in parallel; 3-amino-1-adamantanol concentration: 2.0 mg/mL;
precisely measuring blank solution, standard solution, sample solution, and impurity-added sample solution 2 μ L each, injecting into high performance liquid chromatography-mass spectrometry, and recording mass spectrum.
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|---|---|---|---|---|
| CN117074578A (en) * | 2023-10-16 | 2023-11-17 | 瀚盟测试科技（天津）有限公司 | LC-MS/MS quantitative detection method of 2- (methylamino) -ethanol |
| CN117074578B (en) * | 2023-10-16 | 2024-02-09 | 瀚盟测试科技（天津）有限公司 | LC-MS/MS quantitative detection method of 2- (methylamino) -ethanol |
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