CN111266094B - Method for analyzing genotoxic impurities of synthetic drugs based on solid-phase microextraction - Google Patents
Method for analyzing genotoxic impurities of synthetic drugs based on solid-phase microextraction Download PDFInfo
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Abstract
The invention relates to a method for analyzing genotoxic impurities of synthetic drugs based on solid-phase microextraction. The solid-phase microextraction fiber comprises covalent organic framework nano microspheres and a fiber carrier, wherein the covalent organic framework nano microspheres are loaded on the surface of the fiber carrier. The covalent organic framework nano microsphere is formed by combining three- (4-aminophenyl) -amine and three- (4-formylphenyl) -amine. Realizes the determination of genotoxic impurities in the raw material medicine. The solid phase micro-extraction fiber has the characteristics of high temperature resistance, high repeated use frequency and strong adsorption capacity.
Description
Technical Field
The invention belongs to the technical field of genotoxic impurity detection, and particularly relates to solid-phase microextraction fiber, a preparation method thereof and application thereof in genotoxic impurity analysis of synthetic drugs.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Currently, most drugs are produced by chemical synthesis or by modification of natural products. In either mode, a variety of reagents are used in the synthesis. These reagents often remain in small amounts or produce a number of by-products during the manufacturing process, forming impurities with some unknown toxicity, especially genotoxicity. Small molecular substances affecting genetic materials exist in raw medicines and finished medicines, which have attracted extensive attention from regulatory departments, pharmaceutical companies, hospitals, and patients of various countries.
The mechanism of action of genotoxic impurities that result in mutation of genetic material is not complex, and these impurities typically have electrophilic groups or are capable of being metabolized to a material having electrophilic groups and then reacting with nucleophilic groups on the DNA. Adenine, guanine, cytosine, thymine and phosphate skeletons in a DNA structure are all rich in electrons, and when an electron-deficient reagent is encountered, a substitution reaction is easy to occur. The electron-deficient reagents mainly comprise alkyl halides, alkyl sulfates, epoxides, hydrazines, tetramethylpiperidine nitroxide, aromatic amines, boric acids and the like. The practical difficulty in completely removing these genotoxic impurities during the pharmaceutical production process is very high. Therefore, the U.S. food and drug administration and other agencies issue relevant guidelines and give key thresholds for toxicology to control the residual genotoxic magazines generated during production. In the detection method of the actual genotoxic impurities, a limit inspection method is often used. There are three main types of genotoxic impurity sources in the medicine. (1) The genotoxic agents are mainly derived from residues of raw materials, reaction reagents, catalysts and the like used in the synthesis process. (2) The intermediate process synthesizes the product, and various reagents or intermediates react to generate impurity components with warning structures in the synthesis process. (3) Degradation products often lead to chemical reactions of some components of the drug due to adverse conditions during storage or transportation, thereby producing impurity components with alarming structures. The genotoxic impurities have various structures, and the development of a suitable analysis method aiming at one class of genotoxic impurities becomes a key point and a difficulty point of research. The conventional solid phase extraction method has the defects of low sensitivity, large matrix interference and the like.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a solid phase micro-extraction fiber, a preparation method thereof and application thereof in analysis of genotoxic impurities of synthetic drugs. The method adopts a headspace solid-phase microextraction method and adopts covalent organic framework nano microspheres as an adsorbent to quantitatively analyze various genotoxic impurities, and the method meets quantitative requirements in the aspects of precision, reproducibility, sensitivity and the like.
In order to solve the technical problems, the technical scheme of the invention is as follows:
in a first aspect, a solid-phase microextraction fiber comprises covalent organic framework nano microspheres (CONs) and a fiber carrier, wherein the covalent organic framework nano microspheres are loaded on the surface of the fiber carrier.
The covalent organic framework nanosphere material provided by the invention can be used for detecting electron-deficient reagents, namely residues or byproducts in the raw material medicines, has a wider detection range, and can be used for analyzing various electron-deficient compounds with genotoxicity, such as various solvent residues, byproducts and the like in the raw material medicines.
In some embodiments of the invention, the covalent organic framework nanospheres are formed by binding of two ligands, tris- (4-aminophenyl) -amine and tris- (4-formylphenyl) -amine.
Preferably, the mass ratio of the two ligands of the tri- (4-aminophenyl) -amine and the tri- (4-formylphenyl) -amine is: 0.5-1: 1; further preferably 0.8 to 0.9: 1.
In some embodiments of the invention, the fibrous support is stainless steel fibers, glass fibers, or the like.
In a second aspect, a method for preparing the solid-phase micro-extraction fiber comprises the following steps: and etching the fiber carrier, adhering the sealant to the surface of the etched fiber carrier, then placing the fiber carrier in the dispersion liquid of the covalent organic framework nano microspheres for dipping, taking out, drying and aging to obtain the covalent organic framework nano fibers. Covalent organic framework nanofibers are also known as solid phase microextraction fibers.
In some embodiments of the invention, the stainless steel fibers have a diameter of 100-150 microns.
In some embodiments of the invention, the solvent of the dispersion of covalent organic-framework nanospheres is ethanol, and the concentration of the ethanol dispersion is 90-110 mg/mL.
In some embodiments of the invention, the covalent organic framework nanosphere material is aged at the gas chromatography injection port for 2-4h at a temperature of 200-300 ℃.
In some embodiments of the present invention, a method for preparing covalent organic framework nanospheres, the method comprising: mixing two ligands of tri (4-aminophenyl) amine and tri (4-formylphenyl) amine with a solvent to obtain a reaction solution, and mixing the reaction solution with methanol; then adding glacial acetic acid into the mixed solution; and (3) carrying out water bath reaction on the obtained solution, removing redundant solution after reaction to obtain precipitate, and washing and drying the precipitate to obtain the covalent organic framework nano-microsphere.
In some embodiments of the invention, the mass ratio of the two ligands tris- (4-aminophenyl) -amine and tris- (4-formylphenyl) -amine is: 0.5-1: 1; further preferably 0.8 to 0.9: 1.
In some embodiments of the invention, the solvent of the reaction solution is N, N-dimethylformamide, and the mass of tris- (4-aminophenyl) -amine and tris- (4-formylphenyl) -amine dissolved in 1mL of solvent is 50-60mg and 60-70mg, respectively.
In some embodiments of the invention, the temperature of the water bath is 70-90 ℃ and the reaction time of the water bath is 20-40 min.
In a third aspect, the solid phase micro-extraction fiber is used for analyzing genotoxic impurities of synthetic drugs.
In some embodiments of the invention, the genotoxic impurities are alkyl halides, alkyl sulfates, epoxides, hydrazines, tetramethylpiperidine nitroxide, aromatic amines, boronic acids, and the like.
In a fourth aspect, the method for analyzing genotoxic impurities of synthetic drugs by using the solid-phase microextraction fiber comprises the steps of mixing and sealing the raw material drug and a sodium chloride solution to serve as a test solution, carrying out solid-phase microextraction on the test solution and the organic framework nanosphere material by using a headspace method, and then detecting by using a gas chromatography-mass spectrometer.
In some embodiments of the invention, the ratio of bulk drug to sodium chloride solution is 1 g: 90-110mL, and the mass percent of sodium chloride is 9-12%.
In some embodiments of the invention, the solid phase microextraction is carried out at a temperature of 50-100 deg.C for a period of 20-40 min.
In some embodiments of the present invention, the sample inlet temperature of the gas chromatography-mass spectrometer is 240-.
In some embodiments of the invention, the column box is heated at 40 ℃ for 1min, and at 20 ℃/min to 280 ℃ for 10 min.
In some embodiments of the invention, the chromatography column is a 5% phenyl-95% dimethylpolysiloxane quartz capillary column DB-5(30m x 0.25mm i.d.,0.25 μm), with a carrier gas flow rate of 0.7-1.3 mL/min.
In some embodiments of the invention, the mass spectrometry conditions are: the ion source is an electron ionization source (EI), the temperature is 230 ℃, and the temperature of the quadrupole rod is 150 ℃.
The invention has the beneficial effects that:
the solid-phase microextraction fiber based on the covalent organic framework nano-microsphere prepared by the invention has the advantages of stable structure, high temperature resistance, high repeated use frequency and strong adsorption capacity. The extraction mode of headspace solid-phase microextraction can greatly reduce the interference caused by the matrix of the bulk drug, has the advantages of high sensitivity, good reproducibility, small usage amount of organic solvent and the like compared with the traditional methods such as solid-phase extraction, derivatization and the like, and greatly reduces the cost while improving the extraction efficiency. The established GC-MS/MS high-sensitivity genotoxic impurity analysis method has good linear correlation (>0.99) and good reproducibility (< 15%, n ═ 6); the detection limit of the method is far smaller than the limit threshold of each target object. The method can successfully realize the determination of genotoxic impurities in the raw material medicaments. Can provide powerful technical support for safety supervision and law enforcement in the drug production process.
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The accompanying drawings, which are incorporated in and constitute a part of this specification, 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 invention and not to limit the invention.
FIG. 1 is a diagram of a co-solid phase microextraction fiber preparation process;
FIG. 2 is a scanning electron microscope and a transmission electron microscope image of the covalent organic framework nano-microsphere in example 1;
FIG. 3 is a Fourier transform infrared spectrum of the covalent organic framework nanospheres of example 1;
FIG. 4 is an XRD pattern of the solid phase microextraction fiber of example 1;
FIG. 5 is a thermogravimetric analysis of the covalent organic framework nanospheres of example 1.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The preparation process of the covalent organic framework nano microsphere comprises the following steps:
in some embodiments of the present invention, the washing reagent for the covalent organic framework nano-microsphere is absolute ethyl alcohol, absolute acetone, absolute dichloromethane, and absolute ethyl alcohol in sequence.
In some embodiments of the present invention, the covalent organic framework nano-microsphere is washed and then dried under vacuum at 40-60 ℃ for 10-15 h.
The invention will be further illustrated by the following examples
Example 1
And (3) preparation of covalent organic framework nano microspheres.
First, two ligands, 116.1mg of tris- (4-aminophenyl) -amine and 130.6mg of tris- (4-formylphenyl) -amine, were diluted into 2mL of a solution of N, N-dimethylformamide, and the reaction solution was added to 25mL of methanol and stirred at room temperature for 10 minutes; then, toTo this solution was added 0.01mL of glacial acetic acid solution. The above reaction solution was reacted in a water bath at 80 ℃ for 30 minutes. After the reaction was completed, the excess reaction solution was removed, and a dark yellow precipitate remained. Finally, the precipitate is washed with absolute ethyl alcohol, absolute acetone, absolute dichloromethane and absolute ethyl alcohol in sequence to remove residual solvent and redundant raw materials remained on the surface of the material. The washed material was dried under vacuum at 50 ℃ overnight. The synthesized material is characterized, and as can be seen from a scanning electron microscope and a transmission electron microscope in FIG. 2, the material is in a spherical structure, the diameter is about 400nm, and the shape is uniform. Fourier transform Infrared Spectroscopy (FTIR) see FIG. 3, C-N (1269 cm)-1),aromatic C＝C(1431cm-1),C＝N(1619cm-1),C＝O(1695cm-1) Characteristic absorption peaks of the functional groups can be seen in the infrared spectrogram. No significant weight loss was observed below 300 ℃ in the thermogravimetric plot (as shown in figure 5), demonstrating that the material was able to withstand the high temperature conditions at the injection port. The XRD pattern of the obtained covalent organic framework nanosphere is shown in fig. 4.
Example 2
Preparing solid phase micro-extraction fiber.
And (3) cleaning the stainless steel fiber with the diameter of 120 microns by using absolute ethyl alcohol and deionized water in sequence, etching the cleaned stainless steel fiber according to the figure 1, wherein the etching solution is hydrofluoric acid, and the etching time is 1 hour. Adhering high-temperature-resistant silicone sealant to the surface of the etched stainless steel fiber, placing the treated fiber in an ethanol dispersion liquid (the dispersion concentration is 100mg/mL) of the covalent organic framework nano-microsphere, standing for one minute, taking out, and uniformly distributing the material on the surface of the stainless steel fiber. After the fiber surface is dried, aging is carried out for 3 hours at the gas chromatography sample inlet, and the aging temperature is 250 ℃. Taking out for later use.
Example 3
The solid phase micro-extraction fiber prepared in example 2 is used for quantitative analysis of 9 genotoxic impurities in the bulk drug.
The instrument comprises the following steps: shimadzu GC-MS QP2020 NX gas chromatography-mass spectrometer;
a sample inlet: the temperature is 250 ℃, the shunting mode is non-shunting sample injection, and the carrier gas is high-purity helium;
column box: keeping the temperature at 40 ℃ for 1min, raising the temperature to 280 ℃ at 20 ℃/min, and keeping the temperature for 10 min.
A chromatographic column: 5% phenyl-95% dimethyl polysiloxane quartz capillary column DB-5(30m × 0.25mm i.d.,0.25 μm), carrier gas flow rate 1 mL/min.
Mass spectrum conditions: the ion source is an electron ionization source (EI), the temperature is 230 ℃, and the temperature of the quadrupole rod is 150 ℃. The mass spectrometry conditions for each genotoxic impurity are shown in Table 1.
Preparing a raw material medicine test sample: accurately weighing 0.1g of raw material medicine, placing the raw material medicine into a 20mL headspace bottle, precisely weighing 10mL 10% sodium chloride aqueous solution, placing the solution into the headspace bottle, covering, sealing and uniformly mixing to obtain a test solution. The solid phase microextraction conditions were as follows: the temperature is 65 ℃, the time is 30 minutes, and the mass concentration of the NaCl solution is 15 percent. The salt solution concentration is the concentration of the sodium chloride solution in the aqueous solution.
Solid phase microextraction process: inserting solid-phase microextraction fibers of the covalent organic framework nano microspheres into a headspace bottle containing 20mL of test solution, inserting a CONs fiber coating into the upper layer gas of the headspace bottle, and controlling the temperature and speed by heating a magnetic stirrer. And after extraction is finished, placing the solid-phase micro-extraction device in a gas sample inlet for headspace-mode sample injection. Before each extraction, the self-made solid phase micro-extraction device needs to be aged for 10 minutes at 250 ℃ under the protection of nitrogen. The extraction was repeated 10 times using the same coatings of the CONs fibers, and the results showed RSD between 5.02% and 8.90%.
The method for detecting genotoxic impurities in 9 in the bulk drugs by using the CONs fiber solid-phase microextraction is optimized as follows: taking the average value of the areas of 9 genotoxic impurities as an index for measuring the extraction efficiency, optimizing by using Design-Expert statistical analysis software according to Box-Behnken test Design to obtain the best extraction parameters: the extraction time is 30 minutes, and the extraction temperature is 65 ℃; the pH value is 6; NaCl ionic strength was 15%.
And (3) verification of methodology: the raw drugs were stored in a refrigerator prior to analysis. The method detection limits, linear relationship, precision in the daytime and precision in the daytime are shown in Table 2.
TABLE 1 Mass Spectrometry parameters
TABLE 2 method detection limit, linearity and precision experiment
As can be seen from Table 1, the covalent organic framework nanofibers of the present invention can quantitatively detect a variety of genotoxic substances in the bulk drug. The linear correlation of the detection of various genotoxic substances was greater than 0.99 as shown in Table 2.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. 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 (13)
1. The application of solid phase micro-extraction fiber in the analysis of genotoxic impurity of synthetic drug,
the genotoxic impurities are alkyl halides, alkyl sulfates, epoxides, hydrazines, tetramethylpiperidine nitroxide, aromatic amines and boric acids;
the solid-phase microextraction fiber comprises covalent organic framework nano microspheres and a fiber carrier, wherein the covalent organic framework nano microspheres are loaded on the surface of the fiber carrier;
the covalent organic framework nano microsphere is formed by combining three- (4-aminophenyl) -amine and three- (4-formylphenyl) -amine.
2. Use according to claim 1, wherein the mass ratio of the two ligands tris- (4-aminophenyl) -amine and tris- (4-formylphenyl) -amine is between 0.5 and 1: 1.
3. Use according to claim 2, wherein the mass ratio of the two ligands tris- (4-aminophenyl) -amine and tris- (4-formylphenyl) -amine is between 0.8 and 0.9: 1.
4. The use according to claim 1, wherein the fibrous support is stainless steel fibers or glass fibers.
5. The use according to claim 1, wherein the solid phase microextraction fiber is prepared by a process comprising: and etching the fiber carrier, adhering the sealant to the surface of the etched fiber carrier, then placing the fiber carrier in a dispersion liquid of covalent organic framework nano microspheres for dipping, taking out, drying and aging to obtain the solid-phase micro-extraction fiber.
6. The use according to claim 4, wherein the stainless steel fibers have a diameter of 100-150 μm.
7. The use according to claim 5, wherein the solvent of the dispersion of covalent organic-framework nanospheres is ethanol, and the concentration of the ethanol dispersion is 90-110 mg/mL.
8. The use according to claim 5, wherein the covalent organic framework nanospheres are prepared by a method comprising: mixing two ligands of tri (4-aminophenyl) amine and tri (4-formylphenyl) amine with a solvent to obtain a reaction solution, and mixing the reaction solution with methanol; then adding glacial acetic acid into the mixed solution; and (3) carrying out water bath reaction on the obtained solution, removing redundant solution after reaction to obtain precipitate, and washing and drying the precipitate to obtain the covalent organic framework nano-microsphere.
9. The use according to claim 8, wherein the mass ratio of the two ligands tris- (4-aminophenyl) -amine and tris- (4-formylphenyl) -amine is: 0.5-1: 1;
or the solvent of the reaction solution is N, N-dimethylformamide, and the mass of the tri- (4-aminophenyl) -amine and the mass of the tri- (4-formylphenyl) -amine dissolved in 1mL of the solvent are respectively 50-60mg and 60-70 mg;
or the temperature of the water bath is 70-90 ℃, and the reaction time of the water bath is 20-40 min.
10. The use according to claim 9, wherein the mass ratio of the two ligands tris- (4-aminophenyl) -amine and tris- (4-formylphenyl) -amine is: 0.8-0.9: 1;
or the solvent of the reaction solution is N, N-dimethylformamide, and the mass of the tri- (4-aminophenyl) -amine and the mass of the tri- (4-formylphenyl) -amine dissolved in 1mL of the solvent are respectively 50-60mg and 60-70 mg;
or the temperature of the water bath is 70-90 ℃, and the reaction time of the water bath is 20-40 min.
11. A method for analyzing genotoxic impurities of synthetic drugs by solid-phase microextraction fibers is characterized in that the solid-phase microextraction fibers comprise covalent organic framework nano microspheres and a fiber carrier, and the covalent organic framework nano microspheres are loaded on the surface of the fiber carrier;
the covalent organic framework nano-microsphere is formed by combining two ligands of tri- (4-aminophenyl) -amine and tri- (4-formylphenyl) -amine;
the method comprises the following steps: mixing and sealing the raw material medicine and a sodium chloride solution to serve as a test solution, carrying out solid-phase micro-extraction on the test solution and the organic framework nanosphere material by using a headspace method, and then detecting by using a gas chromatography mass spectrometer.
12. The method of claim 11, wherein the ratio of bulk drug to sodium chloride solution is 1 g: 90-110mL, and the mass percent of sodium chloride is 9-12%.
13. The process according to claim 11, characterized in that the solid phase microextraction is carried out at a temperature of 50 to 100 ℃ for a time of 20 to 40 min.
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| CN114949930B (en) * | 2022-04-24 | 2023-03-24 | 湖州市食品药品检验研究院(湖州市药品和医疗器械不良反应监测中心、湖州市医疗器械监督检验中心、湖州市食品认证审评和粮油质量监测中心) | Preparation method of nanofiber solid-phase extraction column and extraction column prepared by same |
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| CN105536745B (en) * | 2015-12-16 | 2017-09-12 | 中国烟草总公司郑州烟草研究院 | A kind of metal organic framework solid-phase micro-extraction fibre and preparation method thereof |
| CN108543527B (en) * | 2018-03-23 | 2020-01-03 | 江南大学 | Covalent organic framework compound solid phase micro-extraction fiber head and preparation method thereof |
| CN108543519B (en) * | 2018-04-24 | 2020-10-09 | 福州大学 | Simple and rapid preparation method and application of covalent organic framework compound solid-phase microextraction coating |
| CN109912807B (en) * | 2019-02-18 | 2021-12-10 | 山东省分析测试中心 | Preparation method and application of covalent organic framework material |
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