CN107688065A - The gas chromatography combined with mass spectrometry detection method that chloromethyl methyl ether remains in bulk drug - Google Patents
The gas chromatography combined with mass spectrometry detection method that chloromethyl methyl ether remains in bulk drug Download PDFInfo
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- CN107688065A CN107688065A CN201710812848.8A CN201710812848A CN107688065A CN 107688065 A CN107688065 A CN 107688065A CN 201710812848 A CN201710812848 A CN 201710812848A CN 107688065 A CN107688065 A CN 107688065A
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- detection method
- bulk drug
- methyl ether
- chloromethyl methyl
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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
Abstract
The present invention discloses the gas chromatography combined with mass spectrometry detection method that chloromethyl methyl ether remains in a kind of bulk drug, derivatization reagent is used as using alcohol simultaneously as solvent, using capillary gas chromatographic column, using direct injected, using temperature programming, and coordinate mass detector to be detected.This method can effectively detect the chloromethyl methyl ether in bulk drug, and spectrogram baseline is steady, does not drift about；The sample handling processes of this method are simple and convenient, and alcohol is used as derivatization reagent simultaneously as solvent, and derivative reaction is gently, quickly, completely.This method enormously simplify Sample Preparation Procedure, avoids the interference that the derivatization reagent of complexity comes to detection band, improves detection preci-sion and accuracy；The method of the present invention is used for the residues detecton of chloromethyl methyl ether in bulk drug, has good linear relationship, precision, the degree of accuracy and sensitivity, in bulk drug quality research and impurity analysis with controlling research etc. to have important research value.
Description
Technical field
The present invention relates to Pharmaceutical Analysis technical field, and in particular to the gas phase color that chloromethyl methyl ether remains in a kind of bulk drug
Compose mass spectrometry (GC-MS) detection method.
Background technology
Impurity of the drug is to be not intended to existing chemical composition in active pharmaceutical ingredient (API, bulk drug) or pharmaceutical preparation.It is former
Impurity in material medicine may come from building-up process or starting material, intermediate, solvent, catalyst, byproduct of reaction, bulk drug
Composition is unstable, incompatible with auxiliary material, or is reacted etc. with packaging material.Various impurity are for final medicine in medicine
The security of thing has a great impact.Wherein, genotoxicity impurity (Genotoxic Impurity, GTI) refers to compound sheet
Body directly hinders cell DNA, produces gene mutation or mutagenesis in vivo, may or be inclined to carcinogenic.It is characterized in very low dense
The damage of human genetic material can be caused when spending, and then causes gene mutation and tumour may be promoted, because its toxicity compared with
Strong threat is generated to the security of medication by force.
Chloromethyl methyl ether is passed through during pharmaceutical synthesis frequently as chloromethyl agent, sometimes having also as solvent or vivaciously
Machine intermediate is present, such as the production of sulphadiazine medicine.Chloromethyl methyl ether has been classified as confirmation by international cancer research institution at present
Human carcinogen, the residual in bulk drug are then typical genotoxicity impurity.
The detection of chloromethyl methyl ether there are no the report of correlation in bulk drug.Because chloromethyl methyl ether chemical property is active,
Less stable, directly it is detected very difficult.On the measure of chloromethyl methyl ether in air, existing technology has been reported
Road, its detection method be the sodium methoxide solution with 2,4,6- trichlorophenol, 2,4,6,-T sodium salts in derivative reaction occurs with it, generation has
The derivatization product of strong electronegativity, then with after n-hexane extraction, be measured with electron capture detector.Inventor is in this way
The residual of chloromethyl methyl ether in bulk drug is measured, it is found that sample making course is relatively complicated, it is time-consuming longer, and during quantitative analysis
Preci-sion and accuracy it is not high.
The content of the invention
The technical problem to be solved by the invention is to provide a kind of simple and convenient, easily operated, precision and accurately
The detection method of Du Genggao chloromethyl methyl ether.
In order to solve the above technical problems, gas chromatography combined with mass spectrometry (GC-MS) inspection of chloromethyl methyl ether provided by the invention
Survey method, sample are to dissolve to obtain sample solution as solvent using alcohol, and alcohol is simultaneously as solvent and the derivatization of chloromethyl methyl ether
Reagent.
When inventor has been surprisingly found that chloromethyl methyl ether is dissolved in alcoholic solvent when developing detection method, detection finds it normal
Can gently, quickly and completely it be reacted under temperature, solution can be detected directly after preparing, without in the prior art using complexity
Derivatization reagent and extracting operation.This method is suitable for all bulk drugs that can be dissolved alcohol.The alcohol is tested for analysis
In the alcoholic solvent commonly used, such as methanol, ethanol, isopropanol, could act as solvent and derivatization reagent it is quick with chloromethyl methyl ether,
It is completely carried out reacting.
(1) preparation of reference substance solution and sample solution：Precision weighs appropriate chloromethyl methyl ether reference substance, with alcohol dissolving simultaneously
Constant volume is into multiple reference substance solutions with finite concentration gradient；Precision weighs appropriate bulk drug sample, with alcohol dissolving and constant volume
Obtain certain density sample solution；
(2) the multiple reference substance solution and sample solution are pressed into described (2) chromatographic condition sample introduction successively, records chromatogram
Figure；GC-MS method conditions：
Chromatographic column uses DB-624 capillary gas chromatographic columns, column's length 30m, internal diameter 0.32mm, and thickness is
1.8μm.；
Using helium as carrier gas, flow rate of carrier gas 1.5mL/min；
Using direct injected, sample size is 1 μ L, and injector temperature is 200 DEG C；
Using split sampling, split ratio 5:1；
Using temperature programming, heating schedule：40 DEG C of initial temperature, 3min is kept, rise to 110 DEG C with 15 DEG C/min, keep
0min, 220 DEG C are risen to 40 DEG C/min, keeps 2min.
Using level Four bar mass detector, level Four bar temperature is 150 DEG C；
Using EI ion guns, ion gun energy is 70ev, and ion source temperature is 280 DEG C；
Qualitative detection is carried out using Scan patterns, quality of scanning scope is 50~500m/z；
Quantitative detection, quota ion 89m/z are carried out using SIM patterns.
(3) result calculates：
Linear related work curve is prepared according to the spectrum data of multiple reference substance solutions and concentration data, substitutes into sample
Spectrum data calculates and draws sample solution concentration, completes the measure of chloromethyl methyl ether residual.
Chloromethyl methyl ether provided by the invention GC-MS detection methods it is a technical advantage that：
1. this method is using alcohol simultaneously as solvent and derivatization reagent, solution preparation is simple and convenient, easily operated, significantly
Simplify sample making course, improve detection efficiency, and reduce reagent cost.GC methods detection chloromethyl first in the prior art
Ether derivatization mode is complicated, and using special derivatization reagent need to derive under alkaline environment and then be extracted again,
Be not suitable for the detection that chloromethyl methyl ether remains in bulk drug
2. the method for the present invention can effectively detect residual of the chloromethyl methyl ether in bulk drug, quantitative limit reaches 60ng/
mL。
3. the method measure GC-MS spectrum baselines of the present invention are steady, do not drift about.Mass detector is selectively strong, interference
It is few, improve the preci-sion and accuracy of method.
4. the method for the present invention is used for the residues detecton of chloromethyl methyl ether, there is good sensitivity, linear relationship, precision
Degree, the degree of accuracy and stability, in bulk drug quality research and impurity analysis with controlling research etc. that there is important research valency
Value.
Brief description of the drawings
Figure 1A~1B is the mass spectrogram of CMME-DCM solution and CMME-IPA solution respectively.
Fig. 2 is the GC-MS chromatograms of blank solution, sensitivity solution and reference substance solution.
Fig. 3 is the working curve that this method is linearly tested.
Embodiment
Clear, complete description is carried out to technical scheme below in conjunction with accompanying drawing, it is clear that described implementation
Example is the part of the embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, the common skill in this area
The every other embodiment that art personnel are obtained on the premise of creative work is not made, belong to the model that the present invention protects
Enclose.
(accompanying drawing) is described further the present invention with reference to embodiments, but does not limit the present invention.
The exclusive Journal of Sex Research of chloromethyl methyl ether residues detecton in the bulk drug of embodiment 1：
Precision weighs about 100mg chloromethyl methyl ethers (CMME) into the 100mL volumetric flasks containing about 10mL dichloromethane,
With being shaken up after dichloromethane constant volume to scale, labeled as CMME-DCM solution.Chloromethyl methyl ether is stable in dichloromethane.
Precision weighs about 100mg chloromethyl methyl ethers into the 100mL volumetric flasks containing about 10mL isopropanols, uses isopropanol
Constant volume is to shaking up after scale, labeled as CMME-IPA solution.Chloromethyl methyl ether reacts in aqueous isopropanol with isopropanol,
Reaction is as follows：
GC-MS analyses, method condition are carried out to CMME-DCM solution and CMME-IPA solution respectively：
Chromatographic column uses DB-624 capillary gas chromatographic columns, column's length 30m, internal diameter 0.32mm, and thickness is
1.8μm.；
Using helium as carrier gas, flow rate of carrier gas 1.5mL/min；
Using direct injected, sample size is 1 μ L, and injector temperature is 200 DEG C；
Using split sampling, split ratio 5:1；
Using temperature programming, heating schedule：40 DEG C of initial temperature, 3min is kept, rise to 110 DEG C with 15 DEG C/min, keep
0min, 220 DEG C are risen to 40 DEG C/min, keeps 2min.
Using level Four bar mass detector, level Four bar temperature is 150 DEG C；
Using EI ion guns, ion gun energy is 70ev, and ion source temperature is 280 DEG C；
Qualitative detection is carried out using Scan patterns, quality of scanning scope is 50~500m/z；
The mass spectrogram of gained CMME-DCM solution and CMME-IPA solution is as shown in figure 1, CMME turns completely in IPA
Change, this derivative reaction is gentle, quick, complete.
The sensitivity of chloromethyl methyl ether residues detecton, precision, the linear, degree of accuracy and stability in the bulk drug of embodiment 2
Research：
Precision weighs about 100mg chloromethyl methyl ethers into the 100mL volumetric flasks containing about 10mL isopropanols, uses isopropanol
For constant volume to shaking up after scale, precision pipettes the 0.6mL solution into 100mL volumetric flasks, with being shaken up after isopropanol constant volume to scale,
Labeled as reference substance stock solution.
GC-MS analysis method conditions：
Chromatographic column uses DB-624 capillary gas chromatographic columns, column's length 30m, internal diameter 0.32mm, and thickness is
1.8μm.；
Using helium as carrier gas, flow rate of carrier gas 1.5mL/min；
Using direct injected, sample size is 1 μ L, and injector temperature is 200 DEG C；
Using split sampling, split ratio 5:1；
Using temperature programming, heating schedule：40 DEG C of initial temperature, 3min is kept, rise to 110 DEG C with 15 DEG C/min, keep
0min, 220 DEG C are risen to 40 DEG C/min, keeps 2min.
Using level Four bar mass detector, level Four bar temperature is 150 DEG C；
Using EI ion guns, ion gun energy is 70ev, and ion source temperature is 280 DEG C；
Quantitative detection, quota ion 89m/z are carried out using SIM patterns.
Sensitivity test：
Precision pipettes 1mL reference substances stock solution into 100mL volumetric flasks, with being shaken up after isopropanol constant volume to scale, marks
It is designated as sensitivity solution (60ng/mL).
In the GC-MS chromatograms of sensitivity solution testing, the signal to noise ratio of target peak is 36, and it is right in Chinese Pharmacopoeia to be fully achieved
In the requirement (S/N >=10) of quantitative limit.
Precision is tested：
Precision pipettes 1mL reference substances stock solution into 10mL volumetric flasks, with being shaken up after isopropanol constant volume to scale, marks
For reference substance solution (600ng/mL).
6 reference substance solutions of continuous sample introduction, in GC-MS chromatograms, the relative standard of the retention time of 6 pin reference substance solutions
Deviation (RSD) is 0.02%, and the relative standard deviation (RSD) of the peak area of 6 pin reference substance solutions is 0.5%.As can be seen here, should
The precision of method is fine.Sensitivity solution and the folded figure of reference substance solution are as shown in Figure 2.
Linear test：
Precision pipettes 0.1mL, 0.5mL, 1mL respectively, 1.5mL, 2mL reference substances stock solution into 5 10mL volumetric flasks,
With being shaken up after isopropanol constant volume to scale, the concentration of resulting linear test solution is followed successively by 60,300,600,900,
1200ng/mL。
In the GC-MS chromatograms linearly tested, the linearly dependent coefficient r=of the test solution peak area of 5 concentration
0.9997.As can be seen here, test of this method for CMME be in the range of 60ng/mL-1200ng/mL, has good linear
(Fig. 3).
The degree of accuracy is tested：
Precision weighs 9 parts of the bulk drug sample of CMME residual quantities known to 100mg in 5mL volumetric flasks, respectively with 50%
(300ng/mL), 100% (600ng/mL), 150% (900ng/mL) reference substance solution dissolving and constant volume.It is each to prepare 3 parts times
Yield solution is tested.The rate of recovery statistics of 9 parts of solution such as following table, its rate of recovery average value are 102%, relative standard deviation
For 3%.As can be seen here, the degree of accuracy of this method is good.
Stability test：
Same reference substance solution is taken, respectively at 0h, 6h, 12h, 18h, 24h sample introductions, measure.As a result 6h, 12h, 18h, 24h
The peak area of measure is respectively 100.1%, 98.0%, 98.9%, 99.2% relative to the ratio of 0h peak areas.Show reference substance
Solution is stable in 24 hours.
In summary, the various embodiments described above and accompanying drawing are only presently preferred embodiments of the present invention, not limiting this
The protection domain of invention, within the spirit and principles of the invention, any modification, equivalent substitution and improvements done etc., all should
Comprising within the scope of the present invention.
Claims (14)
1. in a kind of bulk drug chloromethyl methyl ether remain gas chromatography combined with mass spectrometry detection method, it is characterised in that sample with
Alcohol dissolves to obtain sample solution as solvent, and alcohol is simultaneously as solvent and the derivatization reagent of chloromethyl methyl ether.
2. detection method as claimed in claim 1, it is characterised in that the alcohol is alcohols solvent conventional in analysis experiment,
Including methanol, ethanol, isopropanol.
3. detection method as claimed in claim 1, it is characterised in that the detection method comprises the following steps：
1) preparation of reference substance solution and sample solution：Chloromethyl methyl ether reference substance is taken, with alcohol dissolving and constant volume is into certain
Multiple reference substance solutions of concentration gradient；Bulk drug sample is taken, certain density sample solution is obtained with alcohol dissolving and constant volume；
2) by the multiple reference substance solutions 1) prepared and bulk drug sample solution by following chromatographic mass spectrometry condition successively sample introduction, note
Record GC-MS spectrograms；
Chromatographic condition is as follows：Chromatographic column uses capillary gas chromatographic column；Using helium as carrier gas；Using direct injected；Adopt
Use split sampling；Using temperature programming；
Mass spectrometry parameters are as follows：Using level Four bar mass detector；Using EI ion guns；Qualitative detection is carried out using Scan patterns；
Quantitative detection is carried out using SIM patterns；
3) result calculates：Linearly related work is drawn according to the spectrum data of the multiple reference substance solutions 2) obtained and concentration data
Curve, the spectrum data of bulk drug sample is brought into and residual reference substance concentration in sample is calculated, so as to complete bulk drug
The residues detecton of middle chloromethyl methyl ether.
4. detection method as claimed in claim 3, it is characterised in that the alcohol is selected from methanol, ethanol or isopropanol.
5. detection method as claimed in claim 3, it is characterised in that the concentration gradient of the reference substance solution is followed successively by 60,
300、600、900、1200ng/mL。
6. detection method as claimed in claim 3, it is characterised in that the chromatographic column model DB-624, column length 30m,
Internal diameter is 0.32mm, and thickness is 1.8 μm.
7. detection method as claimed in claim 3, it is characterised in that the carrier gas is constant current mode, flow velocity is 1.0~
2.0mL/min。
8. detection method as claimed in claim 3, it is characterised in that sample size is 1~2 μ L, and injector temperature is 200 DEG C.
9. detection method as claimed in claim 3, it is characterised in that the split ratio of the split sampling is 5:1~50:1.
10. detection method as claimed in claim 3, it is characterised in that heating schedule：40 DEG C of initial temperature, keep 3min；With
15 DEG C/min rises to 110 DEG C, keeps 0min；220 DEG C are risen to 40 DEG C/min, keeps 2min.
11. detection method as claimed in claim 3, it is characterised in that the temperature of the level Four bar is set to 150 DEG C.
12. detection method as claimed in claim 3 is characterized in that, the energy of the EI ion guns is 70ev, ion gun temperature
Spend for 280 DEG C.
13. detection method as claimed in claim 3, it is characterised in that the quality of scanning scope of the Scan patterns be 50~
500m/z。
14. detection method as claimed in claim 3, it is characterised in that the quota ion of the SIM patterns is 89m/z.
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| CN201710812848.8A CN107688065B (en) | 2017-09-11 | 2017-09-11 | Gas chromatography-mass spectrometry combined detection method for chloromethyl methyl ether residue in bulk drug |
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| CN201710812848.8A CN107688065B (en) | 2017-09-11 | 2017-09-11 | Gas chromatography-mass spectrometry combined detection method for chloromethyl methyl ether residue in bulk drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110068627A (en) * | 2019-05-16 | 2019-07-30 | 江苏出入境检验检疫局轻工产品与儿童用品检测中心 | A kind of method of derivative-pyrolysis-high resolution gas chromatography-mass spectrometry identification cashew nut paint |
| CN113252809A (en) * | 2021-04-25 | 2021-08-13 | 英格尔检测技术服务（上海）有限公司 | Method for detecting residues of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate |
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| CN104502487A (en) * | 2014-12-29 | 2015-04-08 | 通标标准技术服务(上海)有限公司 | Method for determining chloromethyl methyl ether in automotive materials |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104502487A (en) * | 2014-12-29 | 2015-04-08 | 通标标准技术服务(上海)有限公司 | Method for determining chloromethyl methyl ether in automotive materials |
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|---|
| MARSHAL. LANGHORST 等: "Reactive adsorbent derivative collection and gas chromatographic determination of chloromethyl methyl ether in air", 《AMERICAN INDUSTRIAL HYGIENE ASSOCIATION JOURNAL》 * |
| 徐以盛 等: "空气中氯甲甲醚检测方法的研究", 《劳动医学》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110068627A (en) * | 2019-05-16 | 2019-07-30 | 江苏出入境检验检疫局轻工产品与儿童用品检测中心 | A kind of method of derivative-pyrolysis-high resolution gas chromatography-mass spectrometry identification cashew nut paint |
| CN113252809A (en) * | 2021-04-25 | 2021-08-13 | 英格尔检测技术服务（上海）有限公司 | Method for detecting residues of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate |
| CN113252809B (en) * | 2021-04-25 | 2022-10-14 | 英格尔检测技术服务（上海）有限公司 | Method for detecting residues of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate |
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