CN110632211A - Method for measuring migration quantity of 2-mercaptobenzothiazole in medicine - Google Patents
Method for measuring migration quantity of 2-mercaptobenzothiazole in medicine Download PDFInfo
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- CN110632211A CN110632211A CN201910995204.6A CN201910995204A CN110632211A CN 110632211 A CN110632211 A CN 110632211A CN 201910995204 A CN201910995204 A CN 201910995204A CN 110632211 A CN110632211 A CN 110632211A
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- mercaptobenzothiazole
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
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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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
Abstract
The invention provides a method for measuring the migration quantity of 2-mercaptobenzothiazole in a medicament, which comprises the following steps of 1): preparing a test solution: taking 2-mercaptobenzothiazole, taking acetonitrile-water (1:1) solution as a solvent, preparing a reference substance solution, taking the packaged drug to be detected, redissolving the drug by pure water, and diluting the drug by acetonitrile-water (1: 1); step 2): and (3) preparing two reference substance solutions in parallel, detecting by an LC-MS/MS method, respectively obtaining response values of the 2-mercaptobenzothiazole in the reference substance solutions, and calculating the ratio of the response values of the 2-mercaptobenzothiazole to the concentration of the reference substance solutions to obtain corresponding response factors. Step 3): and (3) detecting the test solution by an LC-MS/MS method to obtain the peak area of the test solution, and calculating the migration amount of the 2-mercaptobenzothiazole in the test solution by using a response factor. The invention has the advantages of short detection time, strong specificity, good accuracy, high precision and good repeatability.
Description
Technical Field
The invention belongs to the technical field of detection of migration quantity of packaging materials in a medicine, relates to a method for detecting the migration quantity of 2-mercaptobenzothiazole in the medicine, and particularly designs a method for detecting the migration quantity of 2-mercaptobenzothiazole in the medicine by using an LC-MS/MS method, wherein the medicine is esomeprazole sodium for injection.
Background
The list of carcinogens published by international cancer research institution of world health organization international in 2017, 10 and 27 is preliminarily collated, and 2-mercaptobenzothiazole is in the list of 2A carcinogens. In order to guide the compatibility research work of medicines and packaging container systems and establish and perfect a medicine and packaging compatibility research guiding principle system, the national medicine supervision and administration organization sets out a technical guiding principle (trial) of compatibility research on chemical medicines and elastomer sealing elements. As a medicine packaging component, on one hand, a sealing member should meet the requirement of a packaging system on sealing performance, provide protection for medicines and meet the expected use function of packaging; on the other hand, the extract has good compatibility with the medicine, namely, the extract with safety risk cannot be introduced, or the extract level meets the safety requirement, and the quality, the curative effect and the safety of the medicine cannot be influenced by adsorbing the active ingredients or the functional auxiliary materials in the medicine. Therefore, the migration amount of 2-mercaptobenzothiazole in the medicine needs to be controlled. However, no quality standard exists at present and a method for measuring the migration quantity of 2-mercaptobenzothiazole is included.
Disclosure of Invention
Aiming at the defects, the invention aims to provide a method for measuring the content of 2-mercaptobenzothiazole in a medicament, which has the advantages of strong specificity, good accuracy, high precision and good repeatability.
The invention provides the following technical scheme:
a method for measuring the migration quantity of 2-mercaptobenzothiazole in a medicament is characterized by comprising the following steps:
step 1): preparing a reference solution: taking 2-mercaptobenzothiazole, taking acetonitrile-water (1:1) solution as a solvent, preparing a reference substance solution, taking the packaged drug to be detected, redissolving the drug by pure water, and diluting the drug by acetonitrile-water (1: 1);
step 2): and (3) preparing two reference substance solutions in parallel, detecting by an LC-MS/MS method, respectively obtaining response values of the 2-mercaptobenzothiazole in the reference substance solutions, and calculating the ratio of the response values of the 2-mercaptobenzothiazole to the concentration of the reference substance solutions to obtain corresponding response factors.
Step 3): detecting the test solution by an LC-MS/MS method to obtain the peak area of the test solution, and calculating the migration amount of the 2-mercaptobenzothiazole in the test solution by using a response factor:
preferably, the control solution is prepared as follows:
11.12mg of 2-mercaptobenzothiazole control was weighed out precisely, dissolved in 50mL of acetonitrile, and diluted with acetonitrile-water (1:1) to make a solution containing 2.2084ng of 2-mercaptobenzothiazole per 1mL, to obtain control solution 1.
10.94 mg of 2-mercaptobenzothiazole control was weighed out precisely, dissolved in 50mL of acetonitrile, and diluted with acetonitrile-water (1:1) to make 2.1727ng of 2-mercaptobenzothiazole per 1mL, to obtain control solution 2.
The preparation method of the test solution comprises the following steps:
packaged esomeprazole sodium for injection 1 bottle (about 40 mg) is taken, 1mL of water is added for redissolution, and acetonitrile-water (1:1) solution is used for diluting 1000 times to obtain a test solution.
Preferably, the parameters of the LC-MS/MS method in step 2) and step 3) are: an electrospray ion source (ESI) is adopted, an MRM negative ion mode is adopted, an ion pair is 165.8/133.8, the collision energy CE is-29V, and the cluster removing voltage DP is-59V;
the invention has the beneficial effects that:
1. the method for determining the migration quantity of the 2-mercaptobenzothiazole by adopting the sample pretreatment and the LC-MS/MS method has the following remarkable characteristics. Firstly, pure water is adopted to directly redissolve the medicine, and acetonitrile-water (1:1) solution is adopted to dilute the medicine redissolution, so that errors caused by liquid-liquid extraction and solid-phase extraction are avoided, the operation steps are greatly reduced, and the sample pretreatment is very simple and convenient. Secondly, the LC-MS/MS method is adopted to determine the 2-mercaptobenzothiazole, the detection time is short, and the detection efficiency is greatly improved. Thirdly, the mass spectrum detector is adopted, so that the sensitivity is high, the specificity is strong, and the ng-grade 2-mercaptobenzothiazole in the sample can be detected.
2. Under the LC-MS/MS condition provided by the invention, the 2-mercaptobenzothiazole migration amount in the test solution is determined by an external standard one-point method, the operation is simple, a series of methodological verifications are carried out, and test results show that the detection method provided by the invention has strong specificity, good accuracy, high sensitivity and good repeatability, and meets the technical requirements of the quality standard research of medicines.
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 an specificity graph;
FIG. 2 is a standard curve for 2-mercaptobenzothiazole.
Detailed Description
The reagents and reference substances used in the detection method provided by the invention can be purchased from the market. Esomeprazole sodium for injection is available from tehrey pharmaceutical ltd, suzhou.
Example 1:
11.12mg of 2-mercaptobenzothiazole control was weighed out precisely, dissolved in 50mL of acetonitrile, and diluted with acetonitrile-water (1:1) to make a solution containing 2.2084ng of 2-mercaptobenzothiazole per 1mL, to obtain control solution 1.
10.94 mg of 2-mercaptobenzothiazole control was weighed out precisely, dissolved in 50mL of acetonitrile, and diluted with acetonitrile-water (1:1) to make 2.1727ng of 2-mercaptobenzothiazole per 1mL, to obtain control solution 2.
The preparation method of the test solution comprises the following steps:
packaged esomeprazole sodium for injection 1 bottle (about 40 mg) is taken, 1mL of water is added for redissolution, and acetonitrile-water (1:1) solution is used for diluting 1000 times to obtain a test solution.
The parameters of the LC-MS/MS method are as follows: the electrospray ionization source (ESI) is adopted, the MRM negative ion mode is adopted, the ion pair is 165.8/133.8, the collision energy CE is-29V, and the cluster removing voltage DP is-59V.
The LC-MS/MS analysis is respectively carried out on the reference solution and the test solution by adopting the LC-MS/MS conditions provided by the invention. The results of the obtained specificity are shown in FIG. 1.
Test results show that the blank solution and the test solution have no interference on the determination of the target compound.
Example 2:
this example provides a linear range investigation of the method.
Reference stock solution 1-1: precisely weighing 11.12mg of 2-mercaptobenzothiazole, placing the weighed solution in a 50mL measuring flask, dissolving the solution with acetonitrile, diluting the solution to a scale, and uniformly mixing.
Reference stock solution 2-1: precisely measuring 0.1mL of reference stock solution 1-1, placing in a 10mL measuring flask, diluting with acetonitrile-water (1:1) solution to scale, and mixing.
Control stock solution 3-1: precisely measuring 0.5mL of reference stock solution 2-1, placing in a 50mL measuring flask, diluting with acetonitrile-water (1:1) solution to scale, and mixing.
BLK: acetonitrile-water (1:1) solution.
L-200: precisely measuring 2mL of reference stock solution in a measuring flask of 3-1 to 10mL, diluting to scale with acetonitrile-water (1:1), and mixing.
L-150: precisely measuring 1.5mL of reference stock solution in a measuring flask of 3-1 to 10mL, diluting to scale with acetonitrile-water (1:1), and mixing.
L-100: precisely measuring 1mL of reference stock solution in a measuring flask of 3-1 to 10mL, diluting to scale with acetonitrile-water (1:1), and mixing.
L-50: precisely measuring 0.5mL of reference stock solution in a measuring flask of 3-1 to 10mL, diluting to scale with acetonitrile-water (1:1), and mixing.
L-20: accurately weighing 1mL L-100-5 mL measuring flask, diluting with acetonitrile-water (1:1) solution to scale, and mixing.
The BLK, linear solution, was injected into LC-MS/MS separately and the chromatographic peak area was recorded. The test results are shown in table 1 and fig. 2.
TABLE 12 results of standard curves for mercaptobenzothiazole
Example 3:
the sample collection test according to the method provided in this example:
the accuracy of the method provided by the invention is analyzed by a sample adding and recovering method.
Stock solution for test article-1: taking 1 bottle of the sample, adding 1mL of water for redissolving, and mixing uniformly.
Stock solution for test article-2: precisely measuring 0.5mL of a test sample stock solution-1 in a 50mL measuring flask, and diluting to scale with a diluent.
Test solution: precisely weighing 1mL of a test sample stock solution-2 into a 10mL measuring flask, diluting the test sample stock solution to a scale with a diluent, and preparing 2 parts in parallel as a test sample solution. Wherein 1 part is the test solution under the term of '5.3 speciality'.
50% recovery solution: precisely measuring 1mL of a test article stock solution-2 into a 10mL measuring flask, adding 0.5mL of a reference article stock solution 3-1, diluting to scale with a diluent, and uniformly mixing to obtain a solution with the recovery rate of 50%. 3 parts are prepared in parallel.
100% recovery solution: precisely measuring 1mL of a test article stock solution-2 into a 10mL measuring flask, adding 1mL of a reference article stock solution 3-1, diluting to scale with a diluent, and uniformly mixing to obtain a solution with 100% recovery rate. 3 parts are prepared in parallel. Wherein 1 part is the standard solution of the sample under the item of '5.2 speciality'.
150% recovery solution: precisely measuring 1mL of a test article stock solution-2 into a 10mL measuring flask, adding 1.5mL of a reference article stock solution 3-1, diluting to scale with a diluent, and uniformly mixing to obtain a 150% recovery solution. 3 parts are prepared in parallel.
The results of the LC-MS/MS method are shown in Table 2, and the results show that the recovery rate of the 2-mercaptobenzothiazole is 80-120%. The method provided by the invention has good accuracy.
TABLE 22 Mercaptobenzothiazole recovery results
Test results show that the recovery rate of the 2-mercaptobenzothiazole is within the range of 80-120%, and the RSD is less than 10%, which indicates that the method has good accuracy.
Example 4:
the example provides a reproducibility test of the method:
repeatability: 6 parts of 100% recovery solution were prepared in parallel as a repetitive solution by a 100% loading recovery method.
The repeatability of the method provided by the invention is analyzed. The results of the measurement by the LC-MS/MS method of the invention are shown in Table 3, and the results show that the recovery rate of 2-mercaptobenzothiazole is 70-130%, and the recovery rate of 6 needles RSD% is 3. The method provided by the invention has good repeatability.
TABLE 32 Mercaptobenzothiazole repeatability results
Example 5:
stability test of the method provided in this example
The control solution in example 1 and the 100% recovery solution in example 3 were used to examine the stability of the solutions at 10 ℃. According to the LC-MS/MS method, samples are respectively injected, the response value of the 2-mercaptobenzothiazole is recorded, and the recovery rates of the reference substance solution and the 100 percent recovery rate solution relative to the 0h point are recorded. The results are shown in tables 4 to 5. The result shows that the control solution is placed for 5.1h at 10 ℃, the solution with 100 percent recovery rate is placed for 3.9h at 10 ℃, the stability of the solution is good, and the recovery rate is in the range of 70-130 percent compared with the peak area recovery rate of 0 h. The method provided by the invention has good stability.
TABLE 4 control solution stability results
TABLE 5100% recovery solution stability results
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A method for measuring the migration quantity of 2-mercaptobenzothiazole in a medicament is characterized by comprising the following steps:
step 1): preparing a test solution: taking 2-mercaptobenzothiazole, taking acetonitrile-water (1:1) solution as a solvent, preparing a reference substance solution, taking the packaged drug to be detected, redissolving the drug by pure water, and diluting the drug by acetonitrile-water (1: 1);
step 2): and (3) preparing two reference substance solutions in parallel, detecting by an LC-MS/MS method, respectively obtaining response values of the 2-mercaptobenzothiazole in the reference substance solutions, and calculating the ratio of the response values of the 2-mercaptobenzothiazole to the concentration of the reference substance solutions to obtain corresponding response factors.
Step 3): and (3) detecting the test solution by an LC-MS/MS method to obtain the peak area of the test solution, and calculating the migration amount of the 2-mercaptobenzothiazole in the test solution by using a response factor.
2. A method for measuring the migration quantity of 2-mercaptobenzothiazole in a medicament is characterized in that,
the preparation method of the reference solution comprises the following steps:
control 2-mercaptobenzothiazole was weighed precisely 5 to 15 mg, dissolved in 45 to 55 mL of acetonitrile, and diluted with acetonitrile-water (1:1) to a solution containing about 2ng of 2-mercaptobenzothiazole per 1mL, to obtain control solution 1.
Control 2 was obtained by precisely weighing 5 to 15 mg of 2-mercaptobenzothiazole as a control, dissolving it in 45 to 55 mL of acetonitrile, and diluting it with acetonitrile-water (1:1) to obtain a solution containing about 2ng of 2-mercaptobenzothiazole per 1 mL.
The preparation method of the test solution comprises the following steps:
35 to 45 mg of packaged esomeprazole sodium for injection is taken, 1mL of water is added for redissolution, and acetonitrile-water (1:1) solution is used for diluting 1000 times to be used as a test solution.
3. The method for determining the migration amount of 2-mercaptobenzothiazole in medicine according to claim 1, wherein the parameters of the LC-MS/MS method in step 2) and step 3) are as follows: the electrospray ionization source (ESI) is adopted, the MRM negative ion mode is adopted, the ion pair is 165.8/133.8, the collision energy CE is-29V, and the cluster removing voltage DP is-59V.
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Citations (4)
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| JP3390695B2 (en) * | 1999-05-19 | 2003-03-24 | アサヒビール株式会社 | Microanalysis of 3-methyl-2-butene-1-thiol, a trace sun odor component in beer |
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| CN105974019A (en) * | 2016-05-11 | 2016-09-28 | 上海瀚海检测技术股份有限公司 | Method for quantitatively analyzing sulfur-containing thiazole additive in styrene-butadiene rubber |
| CN109374805A (en) * | 2018-11-02 | 2019-02-22 | 南京明捷生物医药检测有限公司 | A kind of method of 12 kinds of residual metal contents in measurement drug |
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2019
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| JP3390695B2 (en) * | 1999-05-19 | 2003-03-24 | アサヒビール株式会社 | Microanalysis of 3-methyl-2-butene-1-thiol, a trace sun odor component in beer |
| CN104334525A (en) * | 2012-05-24 | 2015-02-04 | 奥赖恩公司 | Catechol o-methyltransferase activity inhibiting compounds |
| CN105974019A (en) * | 2016-05-11 | 2016-09-28 | 上海瀚海检测技术股份有限公司 | Method for quantitatively analyzing sulfur-containing thiazole additive in styrene-butadiene rubber |
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Application publication date: 20191231 |