CN107688065B - Gas chromatography-mass spectrometry combined detection method for chloromethyl methyl ether residue in bulk drug - Google Patents
Gas chromatography-mass spectrometry combined detection method for chloromethyl methyl ether residue in bulk drug Download PDFInfo
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Abstract
The invention discloses a gas chromatography-mass spectrometry combined detection method for chloromethyl methyl ether residue in bulk drugs, which adopts alcohol as a solvent and a derivatization reagent, adopts a capillary gas chromatographic column, adopts direct sample injection, adopts temperature programming and is matched with a mass spectrometry detector for detection. The method can effectively detect chloromethyl methyl ether in the bulk drugs, and the spectrogram base line is stable and does not drift; the method has simple and convenient sample treatment process, uses alcohol as a solvent and simultaneously as a derivatization reagent, and has mild, rapid and complete derivatization reaction. The method greatly simplifies the sample preparation process, avoids the interference of complex derivatization reagents on detection, and improves the detection precision and accuracy; the method disclosed by the invention is used for measuring the residue of chloromethyl methyl ether in the bulk drugs, has good linear relation, precision, accuracy and sensitivity, and has important research values in the aspects of bulk drug quality research, impurity analysis, control research and the like.
Description
Technical Field
The invention relates to the technical field of drug analysis, in particular to a gas chromatography-mass spectrometry (GC-MS) detection method for chloromethyl methyl ether residue in bulk drugs.
Background
Pharmaceutical impurities are active pharmaceutical ingredients (API, drug substance) or undesired chemical components in a pharmaceutical preparation. Impurities in the raw material drug may originate from the synthetic process or from starting materials, intermediates, solvents, catalysts, reaction by-products, unstable ingredients of the raw material drug, incompatibility with auxiliary materials, or from reactions with packaging materials, etc. Various impurities in the drug have a great influence on the safety of the final drug. Among them, Genotoxic impurities (GTI) mean that the compound itself directly damages cellular DNA, causes gene mutation or in vivo mutagenesis, and has carcinogenic potential or propensity. It features that at very low concentration, the genetic matter of human body is damaged to result in gene mutation and promote tumor, and its toxicity is high to threaten the safety of medicine.
Chloromethyl methyl ether is often used as a chloromethylating agent in the process of synthesizing drugs, and sometimes exists as a solvent or an active organic intermediate, such as the production of sulfadiazine drugs. Chloromethyl methyl ether is currently listed as a human carcinogen by the international cancer research institution, and residues in raw material medicines are typical genotoxic impurities.
The detection of chloromethyl methyl ether in the bulk drugs has no relevant report. Chloromethyl methyl ether is very difficult to directly detect because of its active chemical property and poor stability. The prior art reports about the determination of chloromethyl methyl ether in air, and the detection method is to use sodium methoxide solution of 2,4, 6-trichlorophenol sodium salt to perform derivatization reaction with the sodium methoxide solution to generate a derivatization product with strong electronegativity, extract the derivatization product with n-hexane, and then use an electron capture detector to perform determination. The inventor determines the residue of chloromethyl methyl ether in the bulk drugs according to the method, finds that the sample preparation process is more complicated and takes longer, and the precision and the accuracy in quantitative analysis are not high.
Disclosure of Invention
The invention aims to solve the technical problem of providing a detection method of chloromethyl methyl ether, which is simple, convenient and easy to operate and has higher precision and accuracy.
In order to solve the technical problems, the gas chromatography-mass spectrometry (GC-MS) detection method of chloromethyl methyl ether provided by the invention is characterized in that a sample is dissolved by using alcohol as a solvent to obtain a sample solution, and the alcohol is simultaneously used as the solvent and a derivatization reagent of chloromethyl methyl ether.
The inventor unexpectedly finds that chloromethyl methyl ether can react mildly, quickly and completely at normal temperature when being dissolved in an alcohol solvent during developing a detection method, and the detection can be directly carried out after the solution is prepared without adopting complex derivatization reagents and extraction operations in the prior art. The method is suitable for all crude drugs which can be dissolved in alcohol. The alcohol is an alcohol solvent commonly used in analytical experiments, such as methanol, ethanol, isopropanol and the like, and can be used as a solvent and a derivatization reagent to react with chloromethyl methyl ether rapidly and completely.
(1) Preparation of control solution and sample solution: precisely weighing a proper amount of chloromethyl methyl ether reference substances, dissolving the chloromethyl methyl ether reference substances by using alcohol and fixing the volume to obtain a plurality of reference substance solutions with a certain concentration gradient; accurately weighing a proper amount of raw material medicine samples, dissolving the raw material medicine samples in alcohol and fixing the volume to obtain a sample solution with a certain concentration;
(2) sequentially injecting the plurality of reference substance solutions and the plurality of sample solutions according to the chromatographic conditions in the step (2), and recording chromatograms; GC-MS method conditions:
the chromatographic column adopts DB-624 capillary gas chromatographic column, and has a length of 30m, an inner diameter of 0.32mm, and a film thickness of 1.8 μm. (ii) a
Helium is used as carrier gas, and the flow rate of the carrier gas is 1.5 mL/min;
adopting direct sample introduction, wherein the sample introduction amount is 1 mu L, and the sample introduction port temperature is 200 ℃;
split-flow sample injection is adopted, and the split-flow ratio is 5: 1;
adopting temperature programming, wherein the temperature programming comprises the following steps: the initial temperature is 40 deg.C, maintained for 3min, increased to 110 deg.C at 15 deg.C/min, maintained for 0min, increased to 220 deg.C at 40 deg.C/min, and maintained for 2 min.
Adopting a quadrupole mass spectrometer, wherein the temperature of a quadrupole is 150 ℃;
adopting an EI ion source, wherein the energy of the ion source is 70ev, and the temperature of the ion source is 280 ℃;
qualitative detection is carried out by adopting a Scan mode, and the scanning quality range is 50-500 m/z;
and (5) carrying out quantitative detection in an SIM mode, wherein the quantitative ion is 89 m/z.
(3) And (4) calculating a result:
and preparing a linear correlation working curve according to the spectrum data and the concentration data of the plurality of reference substance solutions, substituting the spectrum data of the sample for calculation to obtain the concentration of the sample solution, and completing the determination of chloromethyl methyl ether residue.
The GC-MS detection method of chloromethyl methyl ether provided by the invention has the technical advantages that:
1. the method uses alcohol as a solvent and a derivatization reagent simultaneously, the solution preparation is simple and convenient, the operation is easy, the sample preparation process is greatly simplified, the detection efficiency is improved, and the reagent cost is reduced. In the prior art, the derivatization mode for detecting chloromethyl methyl ether by using the GC method is complex, and the detection is not suitable for detecting the chloromethyl methyl ether residue in the raw material medicine because a special derivatization reagent is needed to be used for derivatization and then extraction in an alkaline environment.
2. The method can effectively detect the residue of chloromethyl methyl ether in the bulk drugs, and the limit of quantitation reaches 60 ng/mL.
3. The method for determining the GC-MS spectrum has stable baseline and does not drift. The mass spectrum detector has strong selectivity and less interference, and improves the precision and the accuracy of the method.
4. The method disclosed by the invention is used for measuring the residue of chloromethyl methyl ether, has good sensitivity, linear relation, precision, accuracy and stability, and has important research values in the aspects of raw material medicine quality research, impurity analysis and control research and the like.
Drawings
FIGS. 1A-1B are mass spectra of CMME-DCM solution and CMME-IPA solution, respectively.
FIG. 2 is a GC-MS chromatogram of a blank solution, a sensitivity solution and a control solution.
Fig. 3 is a working curve of the linear test of the present method.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The invention is further described below with reference to examples (figures) without restricting the invention thereto.
Example 1 specificity study of chloromethyl methyl ether residue assay in drug substance:
approximately 100mg of chloromethyl methyl ether (CMME) was weighed precisely into a 100mL volumetric flask containing approximately 10mL of dichloromethane, made up to the mark with dichloromethane, and shaken well, and labeled as CMME-DCM solution. Chloromethyl methyl ether was stable in dichloromethane.
Approximately 100mg of chloromethyl methyl ether was precisely weighed into a 100mL volumetric flask containing approximately 10mL of isopropanol, and the volume was measured to a scale with the isopropanol and shaken up, and the solution was labeled as CMME-IPA solution. Chloromethyl methyl ether reacts with isopropanol in isopropanol solution as follows:
performing GC-MS analysis on the CMME-DCM solution and the CMME-IPA solution respectively, wherein the method conditions are as follows:
the chromatographic column adopts DB-624 capillary gas chromatographic column, and has a length of 30m, an inner diameter of 0.32mm, and a film thickness of 1.8 μm. (ii) a
Helium is used as carrier gas, and the flow rate of the carrier gas is 1.5 mL/min;
adopting direct sample introduction, wherein the sample introduction amount is 1 mu L, and the sample introduction port temperature is 200 ℃;
split-flow sample injection is adopted, and the split-flow ratio is 5: 1;
adopting temperature programming, wherein the temperature programming comprises the following steps: the initial temperature is 40 deg.C, maintained for 3min, increased to 110 deg.C at 15 deg.C/min, maintained for 0min, increased to 220 deg.C at 40 deg.C/min, and maintained for 2 min.
Adopting a quadrupole mass spectrometer, wherein the temperature of a quadrupole is 150 ℃;
adopting an EI ion source, wherein the energy of the ion source is 70ev, and the temperature of the ion source is 280 ℃;
qualitative detection is carried out by adopting a Scan mode, and the scanning quality range is 50-500 m/z;
the mass spectra of the CMME-DCM solution and CMME-IPA solution are shown in FIG. 1, the CMME is completely converted in IPA, and the derivatization reaction is mild, rapid and complete.
Example 2 study of sensitivity, precision, linearity, accuracy and stability of chloromethyl methyl ether residue determination in bulk drug:
precisely weighing about 100mg of chloromethyl methyl ether into a 100mL volumetric flask containing about 10mL of isopropanol, using the isopropanol to fix the volume to the scale, shaking up, precisely transferring 0.6mL of the solution into the 100mL volumetric flask, using the isopropanol to fix the volume to the scale, shaking up, and marking as a reference substance storage solution.
GC-MS analysis method conditions:
the chromatographic column adopts DB-624 capillary gas chromatographic column, and has a length of 30m, an inner diameter of 0.32mm, and a film thickness of 1.8 μm. (ii) a
Helium is used as carrier gas, and the flow rate of the carrier gas is 1.5 mL/min;
adopting direct sample introduction, wherein the sample introduction amount is 1 mu L, and the sample introduction port temperature is 200 ℃;
split-flow sample injection is adopted, and the split-flow ratio is 5: 1;
adopting temperature programming, wherein the temperature programming comprises the following steps: the initial temperature is 40 deg.C, maintained for 3min, increased to 110 deg.C at 15 deg.C/min, maintained for 0min, increased to 220 deg.C at 40 deg.C/min, and maintained for 2 min.
Adopting a quadrupole mass spectrometer, wherein the temperature of a quadrupole is 150 ℃;
adopting an EI ion source, wherein the energy of the ion source is 70ev, and the temperature of the ion source is 280 ℃;
and (5) carrying out quantitative detection in an SIM mode, wherein the quantitative ion is 89 m/z.
And (3) testing the sensitivity:
precisely transferring 1mL of the control stock solution into a 100mL volumetric flask, adding isopropanol to the volume to a scale, shaking up, and marking as a sensitive solution (60 ng/mL).
In a GC-MS chromatogram of a sensitivity solution test, the signal-to-noise ratio of a target peak is 36, and the requirement on the limit of quantitation in Chinese pharmacopoeia is completely met (S/N is more than or equal to 10).
And (3) testing precision:
precisely transferring 1mL of the reference stock solution into a 10mL volumetric flask, adding isopropanol to a constant volume to a scale, shaking up, and marking as a reference solution (600 ng/mL).
The control solution was continuously injected 6 times, and in the GC-MS chromatogram, the Relative Standard Deviation (RSD) of the retention time of the 6-pin control solution was 0.02%, and the Relative Standard Deviation (RSD) of the peak area of the 6-pin control solution was 0.5%. It can be seen that the precision of the method is good. The stack of the sensitivity solution and the control solution is shown in FIG. 2.
And (3) linear testing:
precisely transferring 0.1mL, 0.5mL, 1mL, 1.5mL and 2mL of reference substance stock solutions into 5 10mL volumetric flasks respectively, metering to a scale with isopropanol, and shaking up to obtain linear test solutions with the concentrations of 60, 300, 600, 900 and 1200ng/mL in sequence.
In the GC-MS chromatogram of the linear test, the linear correlation coefficient r of the peak area of the test solution at 5 concentrations is 0.9997. It can be seen that the method has good linearity in the range of 60ng/mL to 1200ng/mL for CMME testing (FIG. 3).
And (3) testing accuracy:
9 parts of a raw material drug sample with the known CMME residual quantity of 100mg are precisely weighed into a 5mL volumetric flask, and are dissolved and fixed to the constant volume by using reference solutions of 50% (300ng/mL), 100% (600ng/mL) and 150% (900ng/mL) respectively. Each of the solutions was prepared in 3 portions for testing. The recovery of 9 solutions is shown in the table below and has an average recovery of 102% and a relative standard deviation of 3%. It can be seen that the accuracy of this method is good.
And (3) stability testing:
and taking the same reference substance solution, injecting samples for 0h, 6h, 12h, 18h and 24h respectively, and determining. As a result, the ratios of the peak areas measured at 6h, 12h, 18h and 24h to the peak area at 0h were 100.1%, 98.0%, 98.9% and 99.2%, respectively. Indicating that the control solution was stable over 24 hours.
In summary, the above embodiments and drawings are only preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (11)
1. A gas chromatography-mass spectrometry combined detection method for chloromethyl methyl ether residue in bulk drugs is characterized in that a sample is dissolved by taking alcohol as a solvent to obtain a sample solution, and the alcohol is simultaneously taken as the solvent and a derivatization reagent of chloromethyl methyl ether; the detection method comprises the following steps:
1) preparation of control solution and sample solution: dissolving chloromethyl methyl ether reference substances by using alcohol and fixing the volume to obtain a plurality of reference substance solutions with a certain concentration gradient; taking a raw material medicine sample, dissolving the raw material medicine sample in alcohol and fixing the volume to obtain a sample solution with a certain concentration;
2) sequentially injecting a plurality of reference substance solutions and raw material sample solutions prepared in the step 1) according to the following chromatographic mass spectrometry conditions, and recording GC-MS spectrograms;
the chromatographic conditions were as follows: the chromatographic column adopts a capillary gas chromatographic column; helium is used as carrier gas; direct sample introduction is adopted; adopting split-flow sample introduction; adopting a programmed temperature rise;
the mass spectrum parameters were as follows: a quadrupole mass spectrometer is adopted; adopting an EI ion source; qualitative detection is carried out by adopting a Scan mode; carrying out quantitative detection by adopting an SIM mode;
3) and (4) calculating a result: drawing a linear relevant working curve according to the spectrum data and the concentration data of the multiple reference substance solutions obtained in the step 2), and taking in and calculating the spectrum data of the raw material medicine sample to obtain the concentration of the residual reference substance in the sample, so as to complete the residual determination of chloromethyl methyl ether in the raw material medicine; the alcohol is selected from methanol, ethanol or isopropanol.
2. The assay of claim 1 wherein the control solution has a concentration gradient of 60, 300, 600, 900, 1200ng/mL in sequence.
3. The detection method according to claim 1, wherein the chromatography column is of type DB-624, has a column length of 30m, an inner diameter of 0.32mm, and a film thickness of 1.8 μm.
4. The detection method according to claim 1, wherein the carrier gas is in a constant flow mode and has a flow rate of 1.0 to 2.0 mL/min.
5. The detection method according to claim 1, wherein the amount of the sample is 1 to 2. mu.L, and the temperature of the sample inlet is 200 ℃.
6. The detection method according to claim 1, wherein the split ratio of the split sample introduction is 5:1 to 50: 1.
7. The detection method according to claim 1, wherein the temperature raising program: the initial temperature is 40 ℃, and the temperature is kept for 3 min; raising the temperature to 110 ℃ at a speed of 15 ℃/min, and keeping the temperature for 0 min; raising the temperature to 220 ℃ at a speed of 40 ℃/min, and keeping the temperature for 2 min.
8. The method of claim 1, wherein the temperature of the quadrupole rods is set at 150 ℃.
9. The detection method of claim 1, wherein the EI ion source has an energy of 70ev and an ion source temperature of 280 ℃.
10. The detection method according to claim 1, wherein the Scan quality range of the Scan pattern is 50 to 500 m/z.
11. The detection method according to claim 1, wherein the quantitative ion of the SIM mode is 89 m/z.
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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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| 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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