CN115343399B - Method for detecting residual solvent of N-alkyl pyrrolidone in bulk drug - Google Patents
Method for detecting residual solvent of N-alkyl pyrrolidone in bulk drug Download PDFInfo
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- CN115343399B CN115343399B CN202211271744.8A CN202211271744A CN115343399B CN 115343399 B CN115343399 B CN 115343399B CN 202211271744 A CN202211271744 A CN 202211271744A CN 115343399 B CN115343399 B CN 115343399B
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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
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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
- G01N30/60—Construction of the column
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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
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
- G01N30/8631—Peaks
Abstract
The invention relates to a method for detecting a residual solvent of N-alkyl pyrrolidone in a bulk drug, which adopts a gas chromatograph to carry out detection and an external standard method to carry out quantitative analysis and comprises the following steps: weighing a test sample in a container, adding a diluent, and uniformly stirring for later use; weighing an object to be measured in a container, adding a diluent, and uniformly stirring; then preparing stock solutions of the substances to be detected with a plurality of concentrations; respectively injecting the test solution and the stock solutions of the substances to be tested with a plurality of concentrations into a gas chromatograph, and recording respective chromatograms; performing linear regression by using concentration data and peak areas of chromatograms obtained by measuring a plurality of concentrations of stock solutions of substances to be measured to obtain a regression equation and a correlation coefficient, and preparing a standard curve; and then calculating the content of the N-alkyl pyrrolidone according to an external standard method by utilizing the peak area in the chromatogram of the test solution. The method has the advantages of simple operation, good precision, high accuracy and low detection limit, and can be used for quality control of the residual solvent of the N-alkyl pyrrolidone.
Description
Technical Field
The invention relates to the technical field of analytical chemistry, in particular to a gas chromatography detection method for a residual solvent of N-alkyl pyrrolidone in a bulk drug.
Background
The use of solvents such as N-methyl pyrrolidone, N-ethyl pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide and the like is limited and controlled by more and more domestic drug administration due to potential reproductive toxicity. N-N-butylpyrrolidone, N-isobutylpyrrolidone, N-t-butylpyrrolidone, N-N-pentylpyrrolidone, N-propylpyrrolidone substituted with a methyl group on the ring, N-butylpyrrolidone substituted with a methyl group on the ring, N-pentylpyrrolidone substituted with a methyl group on the ring, and the like have been shown to be non-reproductive toxic. Since they are high boiling, non-corrosive and polar compounds capable of dissolving a variety of other compounds, they are well suited as alternative solvents to N-methylpyrrolidone and the like, which are miscible with a variety of other solvents, including water, ethanol, diethyl ether, chloroform, benzene, ethyl acetate and carbon disulfide. But because it has no therapeutic effect, it should be removed as much as possible to meet the quality standards of the bulk drug and the preparation or other quality requirements.
At present, no report of quantitative related detection methods for the residual solvents of the N-alkyl pyrrolidone exists in the prior art, so an analysis method for detecting and controlling the residual solvents of the N-alkyl pyrrolidone in the bulk drugs needs to be established.
Disclosure of Invention
The invention aims to provide a method for detecting a residual solvent of N-alkyl pyrrolidone in a raw material medicine, which is simple to operate, accurate in result and high in sensitivity and effectively solves the problem that a related detection method is lacked in the prior art.
In order to solve the technical problems, the invention adopts the following technical scheme:
a detection method of residual solvent of N-alkyl pyrrolidone in bulk drugs adopts a gas chromatograph to carry out detection and an external standard method to carry out quantitative analysis, and comprises the following steps:
s1, preparing a test solution: weighing a test sample in a container, adding a diluent, and uniformly stirring for later use;
s2, preparing stock solution of the substance to be detected: weighing an object to be measured in a container, adding a diluent, and uniformly stirring; then preparing stock solutions of the substances to be detected with a plurality of concentrations;
s3, detecting by using a gas chromatograph: respectively injecting the test solution and the stock solutions of the substances to be tested with a plurality of concentrations into a gas chromatograph, and recording respective chromatograms;
and S4, analyzing the content of the N-alkyl pyrrolidone, and performing linear regression on the mass concentration and the peak area of a chromatogram obtained by measuring the stock solution of the substance to be measured with a plurality of concentrations to obtain a regression equation and a correlation coefficient to prepare a standard curve. And then, in a chromatogram for measuring the solution of the test sample, integrating chromatographic peaks of the N-alkyl pyrrolidone to obtain peak areas, and calculating according to an external standard method to obtain the content of the N-alkyl pyrrolidone.
Wherein the concentration of the test solution in the step S1 is 10-100mg/mL; in step S2, the stock solutions of the analyte have concentrations of 0.01mg/mL,0.05mg/mL,0.08mg/mL,0.1mg/mL,0.12mg/mL,0.15mg/mL and 0.2mg/mL, respectively.
The substance to be detected is one or more of N-N-butyl pyrrolidone, N-isobutyl pyrrolidone, N-tert-butyl pyrrolidone, N-N-amyl pyrrolidone, N-propyl pyrrolidone substituted by methyl on a ring, N-butyl pyrrolidone substituted by methyl on a ring and N-amyl pyrrolidone substituted by methyl on a ring.
And the diluent in the step S1 and the step S2 is one of five of water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and 1,3-dimethylimidazolidinone.
Wherein, the chromatographic conditions of the step S3 are as follows:
stationary phase of chromatographic column: 35% biphenyl/65% dimethylpolysiloxane; a detector: a hydrogen flame ionization detector; temperature programming procedure: starting temperature is 60-80 deg.C, maintaining for 0-1min, heating to 250-260 deg.C at a rate of 15-20 deg.C/min, and maintaining for 8-10 min; sample inlet temperature: 150-200 ℃; detector temperature: 250-300 ℃; carrier gas: nitrogen or helium; flow rate of carrier gas: 1.0-2.5mL/min; the split ratio is as follows: 5:1-20; and (3) sample introduction mode: directly feeding a sample; sample introduction volume: 0.5-10 μ L. The invention takes the boiling point of the object to be detected into full consideration, thereby designing a direct sample injection mode suitable for the detection method, and obtaining better peak shape and separation effect with other impurities under the condition.
According to the detection method for the N-alkyl pyrrolidone residual solvent in the bulk drugs, the conventional gas chromatography is adopted, the polysiloxane capillary column chromatographic column is selected, the test sample and the stock solution of the to-be-detected substance are simple to process, the result is accurate, the sensitivity is high, the stability is good, 0.01mg of N-alkyl pyrrolidone contained in the bulk drugs can be detected, and the quality control problem of the N-alkyl pyrrolidone residual solvent in the bulk drugs is solved.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 is a chromatogram of a blank solution of the present invention;
FIG. 2 is a chromatogram of a test solution according to the present invention;
FIG. 3 is a chromatogram of a stock solution of an analyte of the present invention;
FIG. 4 is a chromatogram of a sample recovery solution according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Instrument and reagent
The instrument comprises the following steps:
gas chromatograph: agilent 7820A/7697 gas chromatograph; parts per million analytical balance: mettler Toledo XSE205DU;
reagent:
n, N-dimethylformamide: j & K chromatographic purity
(II) gas chromatography detection conditions
And (3) chromatographic column: restek RTX-35 Amine (30 m × 0.32mm, 1 μm); a detector: a hydrogen flame ionization detector;
temperature programming procedure: the initial temperature is 80 ℃, the temperature is kept for 0min, the temperature is raised to 260 ℃ at the heating rate of 20 ℃/min, and the temperature is kept for 8 min; sample inlet temperature: 200 ℃; detector temperature: 280 ℃; carrier gas (helium) flow rate: 2.0mL/min; the split ratio is as follows: 15; sample injection volume: 1 μ L.
(III) Experimental part-solution preparation
Preparing a diluent: n, N-dimethylformamide as a diluent;
preparing a blank solution: n, N-dimethylformamide is used as a blank solution;
preparing a test solution: taking 1000mg of a raw material medicine sample, precisely weighing, placing in a 10mL volumetric flask, fixing the volume to a scale with a diluent, and shaking up to be used as a test solution;
preparing stock solution of a substance to be detected: taking 100mg of N-N-butyl pyrrolidone standard substance, precisely weighing, placing in a 10mL volumetric flask, diluting to a constant volume with a diluent, shaking up, and taking as stock solution (1 mg/mL) of the substance to be detected;
test sample recovery rate solution: 1000mg of a raw material medicine sample is taken, precisely weighed and placed in a 10mL volumetric flask, 1mL of stock solution of the substance to be detected is respectively added, and the volume is determined to the scale by using a diluent to be used as a solution with 100% recovery rate.
(IV) methodological investigation
1) Specificity test
And (3) sampling blank solution, test sample solution, stock solution of the substance to be tested and recovery rate solution of the test sample respectively to acquire chromatogram maps, and obtaining results shown in figures 1 to 4. The test result shows that the blank solution has no interference, and other peaks in the sample have no interference to the chromatographic peak of N-N-butyl pyrrolidone, i.e. the method has better specificity.
2) Precision test
Diluting the stock solution of the substance to be detected to 0.1mg/mL, continuously injecting samples for 5 times under the gas chromatography detection condition of the second part, injecting samples with volume of 1 mu L, injecting the samples into a chromatograph, recording retention time and peak area, and evaluating the result, wherein the result is shown in Table 1.
TABLE 1 results of systematic precision test
The result shows that the method has good system precision and meets the test requirement.
3) Linear and range test
Precisely transferring a proper amount of N-N-butyl pyrrolidone stock solution, and diluting with diluent to the concentration of 0.01mg/mL,0.05mg/mL,0.1mg/mL,0.15mg/mL and 0.2mg/mL. The solutions were injected into a gas chromatograph, and the sample injection volume was 1 μ L, and linear regression was performed using the mass concentration and peak area to obtain a regression equation and correlation coefficients y =534.23x-0.5376 and 0.9995, respectively, the results of which are shown in table 2.
TABLE 2N-n-butylpyrrolidone Linear and Range test results
The results show that the linearity of N-N-butylpyrrolidone is good in the range of 0.01mg/mL to 0.2mg/mL.
4) Testing of detection limit and quantification limit
Adjusting the sensitivity of the instrument, taking a proper amount of N-N-butyl pyrrolidone stock solution, gradually diluting and injecting samples with the sample injection volume of 1 mu L to ensure that the main peak height is 2-3 times of the baseline noise, and recording a chromatogram map to obtain the minimum detection limit of the N-N-butyl pyrrolidone of 0.005mg/mL.
Adjusting the sensitivity of the instrument, taking a proper amount of N-N-butyl pyrrolidone stock solution, gradually diluting and injecting samples, injecting the sample with the volume of 1 mu L, enabling the main peak height to be 10 times of the baseline noise, and recording a chromatogram map to obtain the minimum detection limit of the N-N-butyl pyrrolidone to be 0.01mg/mL.
5) Standard recovery test
And (3) injecting the sample solution and the sample recovery rate solution into a gas chromatograph, wherein the sample injection volume is 1 mu L, and the concentration of each peak in the recovery rate solution is calculated according to an external standard method, and the test result is shown in table 3.
TABLE 3 results of the normalized recovery test
The result shows that the method has high accuracy and meets the test requirement.
6) Stability test of solution
The recovery rate solution (100%) was allowed to stand at room temperature for 26 hours, and the stability of the solution was examined. According to the conditions of the gas chromatography in the second part, the mixture was injected into the chromatograph at 0,5, 16, 20 and 26 hours, respectively, the injection volume was 1 μ L, and the chromatogram was recorded, and the results are shown in Table 4.
TABLE 4 recovery rate solution stability test
The result shows that the recovery rate solution is placed for 26 hours at room temperature, and the stability of the solution is good.
The present invention is not limited to the above embodiments, and those skilled in the art can make various equivalent changes and substitutions without departing from the principle of the present invention after learning the content of the present invention, and these equivalent changes and substitutions should be considered as belonging to the protection scope of the present invention.
Claims (4)
1. A method for detecting residual solvent of N-alkyl pyrrolidone in bulk drugs is characterized in that a gas chromatograph is used for detection and an external standard method is used for quantitative analysis, and the method comprises the following steps:
s1, preparing a test solution: weighing a test sample in a container, adding a diluent, and uniformly stirring for later use;
s2, preparing stock solution of the substance to be detected: weighing an object to be measured in a container, adding a diluent, and uniformly stirring; then preparing stock solutions of the substances to be detected with a plurality of concentrations;
s3, detecting by using a gas chromatograph: respectively injecting the test solution and the stock solutions of the substances to be tested with a plurality of concentrations into a gas chromatograph, and recording respective chromatograms;
s4, analyzing the content of N-alkyl pyrrolidone: performing linear regression by using concentration data and peak areas of chromatograms obtained by measuring stock solutions of objects to be measured with a plurality of concentrations to obtain a regression equation and a correlation coefficient, and preparing a standard curve; then, calculating the content of the N-alkyl pyrrolidone according to an external standard method by utilizing the peak area in the chromatogram of the test solution;
the substance to be detected in the step S2 is N-N-butyl pyrrolidone;
the chromatographic conditions of step S3 are:
stationary phase of chromatographic column: 35% biphenyl/65% dimethylpolysiloxane; a detector: a hydrogen flame ionization detector;
temperature programming procedure: the initial temperature is 80 ℃, the temperature is kept for 0min, the temperature is raised to 260 ℃ at the heating rate of 20 ℃/min, and the temperature is kept for 8 min; sample inlet temperature: 200 ℃; detector temperature: 280 ℃; helium as carrier gas, carrier gas flow rate: 2.0mL/min; the split ratio is as follows: 15; sample introduction volume: 1 μ L.
2. The method for detecting the residual solvent of N-alkylpyrrolidone in the bulk drug according to claim 1, which is characterized in that: the concentration of the sample solution in the step S1 is 10-100mg/mL.
3. The method for detecting the residual solvent of N-alkylpyrrolidone in the bulk drug according to claim 1, which is characterized in that: in step S2, the stock solutions of the analyte have concentrations of 0.01mg/mL,0.05mg/mL,0.08mg/mL,0.1mg/mL,0.12mg/mL,0.15mg/mL and 0.2mg/mL, respectively.
4. The method for detecting the residual solvent of N-alkylpyrrolidone in the bulk drug according to claim 1, which is characterized in that: the diluent in the step S1 and the step S2 is one of water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and 1,3-dimethylimidazolidinone.
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Non-Patent Citations (3)
| Title |
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| 毛细管气相色谱法测定JS1-1-01原料药中溶剂残留量;闫丽晔 等;《沈阳药科大学学报》;20200228;第37卷(第2期);摘要，第148页右栏至第149页 * |
| 气质联用法快速测定8种挥发性有机溶剂;俞凌云 等;《印染》;20151231;第7卷;全文 * |
| 花生油香气特征在其属性识别中的初步应用;李苑雯 等;《食品与发酵工业》;20131231;第39卷(第7期);全文 * |
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