CN114594188A - Method for screening unknown acylated gene toxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry - Google Patents
Method for screening unknown acylated gene toxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry Download PDFInfo
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Abstract
The invention discloses a non-targeted screening method of alkylation genotoxic impurities, which comprises the following steps: (1) and (3) performing acylation reaction on the amine derivative reagent and the unknown acylated genotoxic impurity to generate a product carrying the amine derivative reagent. (2) Separating the product from a reaction system, analyzing a sample by using an ultra-high performance liquid chromatography-triple quadrupole mass spectrometry combination method, and screening unknown acylated genotoxic impurities by using characteristic ion fragments to perform parent ion scanning. The invention takes the amine derivative reagent as the marker to react with the acylated genotoxic impurities to generate the product carrying the derivative product, and has the characteristic that the amine derivative reagent can generate common ion fragments after the amine derivative reagent is taken as the marker to react with different types of unknown acylated genotoxic impurities, thereby conveniently and quickly realizing the screening of the unknown acylated genotoxic impurities.
Description
Technical Field
The invention relates to the technical field of genotoxic impurity detection, in particular to a method for screening unknown acylated genotoxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry.
Background
The information disclosed in this background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
The acylation reagent is a reagent commonly used in the synthesis of medicines, and a trace amount of residue may exist in the medicines; acylated impurities may also be produced during the production and storage of pharmaceuticals. The acylation reagent can react with electron-rich groups in DNA, protein and the like to generate amide substances, thereby causing gene mutation and carcinogenesis. The acylation reagent is a common genotoxic impurity, strict requirements are put forward on the control of genotoxicity according to the guidance principles of medicine quality control such as ICH and FDA, the safety threshold of the genotoxic impurity in the medicine is 1.5 mu g/day, but the method is only suitable for predictable impurities, and no effective evaluation method is available for unknown impurities.
Disclosure of Invention
Aiming at the problems, the invention provides a method for screening unknown acylated genotoxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry, which realizes the screening of the unknown acylated genotoxic impurities by utilizing the characteristic of the reaction of amine compounds and the acylated genotoxic impurities. In order to achieve the purpose, the technical scheme of the invention is as follows:
in a first aspect, the invention discloses an application of an amine derivative reagent as a marker in detection of unknown acylated genotoxic impurities.
Further, the amine-based derivatizing agent includes 3-amino-N- (4-methoxyphenyl) propionamide and the like.
Further, the unknown acylated genotoxic impurity is an impurity capable of performing an acylation reaction with an amine derivative reagent; optionally, the unknown acylated genotoxic impurity comprises: pivaloyl chloride, thiopheneacetyl chloride, cefixime active ester (methyl ester), and the like.
In a second aspect, the invention discloses a method for screening unknown acylated genotoxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry, which comprises the following steps:
(1) and (3) performing acylation reaction on the amine derivative reagent and the unknown acylated genotoxic impurity to generate a product carrying the amine derivative reagent.
(2) Separating the product from a reaction system, analyzing a sample by using an ultra-high performance liquid chromatography-triple quadrupole mass spectrometry combination method, and screening unknown acylated genotoxic impurities by using characteristic ion fragments to perform parent ion scanning.
In a further scheme, in the step (1), the unknown acylated genotoxic impurity is dissolved in a solvent, and then the amine derivative reagent is added for reaction.
Preferably, the solvent includes any one of acetonitrile, dimethyl sulfoxide, N-dimethylformamide, and the like.
In a further aspect, in step (1), the amine derivatizing reagent comprises 3-amino-N- (4-methoxyphenyl) propanamide, and the like.
In a further embodiment, in step (1), the unknown acylated genotoxic impurity is an impurity capable of undergoing an acylation reaction with an amine derivative reagent; optionally, the unknown acylated genotoxic impurity comprises: pivaloyl chloride, thiopheneacetyl chloride, cefixime active ester (methyl ester), and the like.
Further, in the step (1), the reaction temperature is 40-80 ℃, and the reaction time is 1 hour. The reaction is preferably carried out at 60 ℃ for 1 hour.
Further, in the step (2), derivative products in the reaction system are separated by an ultra-high performance liquid chromatography technology. Preferably, the chromatographic column of the ultra performance liquid chromatography technology is Thermo Hypersil Gold C18(2.1X100mm, 3 μm); the column temperature was 40 ℃; the mobile phase A is 0.1% acetic acid water solution; the mobile phase B is 0.1 percent acetic acid acetonitrile solution; gradient elution: 0-3min, 2% B, 3-50mi, 2% → 90% B, 50-55min, 98% B, 55.1-60min, 2% B; the flow rate is 0.3 mL/h; the sample injection amount is 1 mu L;
further, in the step (2), the product carrying the amine derivative reagent is fragmented by using a triple quadrupole mass spectrometry to generate an ion fragment, and when a chromatographic peak of m/z279.17 and/or m/z319.11 exists in the obtained ion fragment, the existence of the unknown acylated genotoxic impurity is determined.
Preferably, the mass spectrum conditions of the triple quadrupole mass spectrometry are as follows: and (4) carrying out primary ion scanning detection in an ESI positive ion detection mode.
Preferably, the parent ion scanning detection conditions are as follows: the daughter ion was m/z178.08, and the parent ion scanned over a range of m/z190-m/z 600.
Compared with the prior art, the invention has the following beneficial effects: the invention provides a method for screening unknown acylated genotoxic impurities by using derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry, which discovers that: the method has the advantages that the amine derivative reagent is used as a marker to react with the acylated genotoxic impurities to generate a product carrying a derivative product, parent ion scanning is further carried out on characteristic fragment ions related to the derivative reagent generated by the product under the triple quadrupole mass spectrometry condition, and due to the characteristic that common ion fragments can be generated after the amine derivative reagent is used as the marker to react with different types of unknown acylated genotoxic impurities, the screening of the unknown acylated genotoxic impurities can be conveniently and quickly realized. In addition, test results show that the method provided by the invention has a technical advantage of good specificity for screening unknown acylated genotoxic impurities.
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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 exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a schematic diagram of screening for unknown acylated genotoxic impurities in an embodiment of the present invention.
Detailed Description
In the following description, further specific details of the invention are set forth in order to provide a thorough understanding of the invention. The terminology used in the description of the invention herein is for the purpose of describing particular advantages and features of the invention only and is not intended to be limiting of the invention.
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. Unless otherwise indicated, the drugs or agents used in the present invention are used according to the instructions of the product or by the conventional methods in the art. The process of the present invention will now be further described with reference to the drawings and the detailed description.
First embodiment
A method for screening unknown acylated genotoxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry is disclosed, and with reference to figure 1, the method comprises the following steps:
(1) taking four measuring flasks with the volume of 10ml, taking 3-amino-N- (4-methoxyphenyl) propionamide as a derivatization reagent or a marker, and adding 100mg of the derivatization reagent into each measuring flask.
(2) And (2) adding solvents acetonitrile, DMSO, water and DMF into the four measuring flasks in the step (1) respectively, and diluting to a scale to obtain four derivative reagent solutions with the concentration of 10mg/ml, which are respectively marked as a derivative reagent 1, a derivative reagent 2, a derivative reagent 3 and a derivative reagent 4 for later use.
(3) Taking four measuring bottles with the volume of 10ml, adding 10mg of pivaloyl chloride (acylation gene toxic impurities) into each measuring bottle, adding acetonitrile, DMSO, water and DMF (dimethyl formamide) as solvents into the four measuring bottles respectively, diluting to a scale, diluting the obtained mixed solution to the concentration of 10 mu g/ml to obtain four kinds of acylation reagent solutions, and marking the four kinds of acylation reagent solutions as an acylation reagent 1, an acylation reagent 2, an acylation reagent 3 and an acylation reagent 4 respectively for later use.
(4) 1ml of the derivatization reagent 1 is taken and added with 1ml of the acylation reagent 1, and the mixture is uniformly mixed and reacted for 1h at 40 ℃.
1ml of the derivatization reagent 2 is taken and added with 1ml of the acylation reagent 2, and the mixture is uniformly mixed and reacts for 1h at 40 ℃.
1ml of the derivatization reagent 3 is taken and added with 1ml of the acylation reagent 3, and the mixture is reacted for 1h at 40 ℃ after being mixed uniformly.
1ml of the derivatization reagent 4 is taken and added with 1ml of the acylation reagent 4, and the mixture is uniformly mixed and reacts for 1h at 40 ℃.
(5) And (4) after the four groups of reactions in the step (4) are finished, precisely measuring 1 mu l of reaction liquid, injecting the reaction liquid into an ultra-high performance liquid chromatography-triple quadrupole mass spectrometer, and analyzing the amount of the generated derivative products. Wherein: the liquid chromatography conditions were: the chromatographic column is Thermo Hypersil Gold C18(2.1X100mm, 3 μm); the column temperature was 40 ℃; the mobile phase A is 0.1% acetic acid water solution; the mobile phase B is 0.1 percent acetonitrile acetate solution; gradient elution: 0-3min, 2% B, 3-50mi, 2% → 90% B, 50-55min, 98% B, 55.1-60min, 2% B; the flow rate is 0.3 mL/h; the amount of sample was 1. mu.L. The mass spectrum conditions are as follows: ESI positive ion detection mode, carry out mother ion scanning and detect, the scanning condition is: the daughter ion is m/z178.08, and the parent ion scans over the range of m/z190-m/z 600.
The amounts of the derived products formed for the different reaction solutions are shown in table 1. From the results of the table it can be seen that: because the acylation reagent is easy to decompose when meeting water, water is used as a reaction solvent, derivative products are not detected, and the water has great influence on the reaction of the acylation reagent and the derivative reagent. Acetonitrile, DMSO and DMF are used as reaction solvents, have no significant difference and can effectively react, and acetonitrile, DMSO and DMF are preferably used as the reaction solvents.
TABLE 1
| Different reaction solvents | Peak area of derivative |
| Acetonitrile | 46113 |
| DMSO | 47432 |
| Water (W) | Not detected out |
| DMF | 49273 |
Second embodiment
A method for screening unknown acylated genotoxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry comprises the following steps:
(1) taking a measuring flask with the volume of 10ml, taking 3-amino-N- (4-methoxyphenyl) propionamide as a derivatization reagent or a marker, adding 100mg of the derivatization reagent into the measuring flask, then adding acetonitrile to fully dissolve the derivatization reagent and diluting to a scale, and obtaining a derivatization reagent solution with the concentration of 10mg/ml for later use.
(2) Taking a measuring flask with the volume of 10ml, adding 10mg of pivaloyl chloride (acylation gene toxic impurities) into the measuring flask, then adding acetonitrile to fully dissolve the pivaloyl chloride and diluting to a scale, and diluting the obtained mixed solution to the concentration of 10 mu g/ml to obtain an acylation reagent solution for later use.
(3) Measuring 1ml of the derivatization reagent solution, adding 1ml of the acylation reagent solution, mixing the two solutions uniformly, and reacting at 20 ℃, 40 ℃, 60 ℃ and 80 ℃ for 1h respectively.
(4) And (4) precisely measuring 1 mu l of reaction liquid after the reaction in the step (3) is finished, and injecting the reaction liquid into an ultra-high performance liquid chromatography-triple quadrupole mass spectrometer for analyzing the amount of the generated derivative product. Wherein: the liquid chromatography conditions were: the chromatographic column is Thermo Hypersil Gold C18(2.1X100mm, 3 μm); the column temperature was 40 ℃; the mobile phase A is 0.1% acetic acid water solution; the mobile phase B is 0.1 percent acetic acid acetonitrile solution; gradient elution: 0-3min, 2% B, 3-50mi, 2% → 90% B, 50-55min, 98% B, 55.1-60min, 2% B; the flow rate is 0.3 mL/h; the amount of sample was 1. mu.L. The mass spectrum conditions are as follows: ESI positive ion detection mode, carry out mother ion scanning and detect, the scanning condition is: the daughter ion is m/z178.08, and the parent ion scans over the range of m/z190-m/z 600.
The amounts of the derived products formed for the different reaction solutions are shown in table 2. It can be seen that: the derivatization reaction efficiency obtained by the reaction at 20 ℃ is lower, the reaction efficiency at 40 ℃, 60 ℃ and 80 ℃ is higher, the site where genotoxic impurities act is a physiological environment, and the temperature of 40 ℃ is preferably used as the derivatization reaction temperature.
TABLE 2
| Different reaction temperatures | Peak area of derivative |
| 20℃ | 25611 |
| 40℃ | 46113 |
| 60℃ | 48991 |
| 80℃ | 45234 |
Third embodiment
A method for screening unknown acylated genotoxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry comprises the following steps:
(1) pivaloyl chloride, thiopheneacetyl chloride and cefixime active ester (methyl ester) are respectively added into cefuroxime axetil to respectively prepare a cefuroxime axetil sample 1 and a cefuroxime axetil sample 2 with the impurity contents of 100 mu g/g for later use.
(2) Adding 100mg of 3-amino-N- (4-methoxyphenyl) propionamide into a measuring flask with a solvent of 10ml, adding acetonitrile to dissolve the 3-amino-N- (4-methoxyphenyl) propionamide and diluting to a scale to obtain a derivative reagent solution with the concentration of 10mg/ml for later use.
(3) Taking 1g of each of the cefuroxime axetil sample 1 and the cefuroxime axetil sample 2, adding the cefuroxime axetil sample 1 and the cefuroxime axetil sample 2 into measuring bottles with the volume of 10ml, and adding acetonitrile to dissolve the samples to obtain a sample solution 1 and a sample solution 2 for later use.
(4) 1ml of the derivatization reagent solution was measured, and 1ml of cefuroxime axetil sample 1 was added thereto, mixed well and reacted at 40 ℃ for 1 hour. 1ml of the derivatization reagent solution was measured, and 1ml of cefuroxime axetil sample 2 was added thereto, mixed well and reacted at 40 ℃ for 1 hour.
(5) And (4) after the two groups of reactions in the step (4) are finished, precisely measuring 1 mu l of reaction liquid, and injecting the reaction liquid into an ultra-high performance liquid chromatography-triple quadrupole mass spectrometer for analyzing the amount of the generated derivative products. Wherein: the liquid chromatography conditions were: the chromatographic column is Thermo Hypersil Gold C18(2.1X100mm, 3 μm); the column temperature was 40 ℃; the mobile phase A is 0.1% acetic acid water solution; the mobile phase B is 0.1 percent acetic acid acetonitrile solution; gradient elution: 0-3min, 2% B, 3-50mi, 2% → 90% B, 50-55min, 98% B, 55.1-60min, 2% B; the flow rate is 0.3 mL/h; the amount of sample was 1. mu.L. The mass spectrum conditions are as follows: ESI positive ion detection mode, carry out mother ion scanning and detect, the scanning condition is: the daughter ion is m/z178.08, and the parent ion scans over the range of m/z190-m/z 600.
The test results are shown in table 3, and it can be seen that: chromatographic peaks at m/z279.17, m/z319.11 and m/z436.13 were detected in the samples added with pivaloyl chloride, thiopheneacetyl chloride and cefixime active ester (methyl ester), respectively, and were consistent with the theoretical molecular weight of the derivative product. The fact that the undetected daughter ion in the blank sample is a parent ion of m/z178.08 indicates that the detection method of the present embodiment has good specificity for detecting the acylated genotoxic impurity, because the acylated genotoxic impurity (known or unknown) reacts to generate a corresponding ion fragment when encountering the derivatization reagent, thereby indicating that the acylated genotoxic impurity exists in the detected sample, and it should be noted that the detection method only needs to detect the presence of the acylated genotoxic impurity, and does not need to confirm that the acylated genotoxic impurity is specific.
TABLE 3
The above description is only illustrative of several embodiments of the present invention and should not be taken as limiting the scope of the invention. It should be noted that other persons skilled in the art can make modifications, substitutions, improvements and the like without departing from the spirit and scope of the present invention, and all of them belong to the protection scope of the present invention. Therefore, the scope of the invention is to be defined by the claims appended hereto.
Claims (10)
1. The application of amine derivative reagent as a marker in the detection of unknown acylated genotoxic impurities.
2. The use according to claim 1, wherein the amine derivatizing agent comprises any one of 3-amino-N- (4-methoxyphenyl) propionamide, p-anisidine.
3. The use according to claim 1 or 2, wherein the unknown acylated genotoxic impurity is an impurity capable of undergoing an acylation reaction with an amine derivatizing agent.
4. The use of claim 3, wherein the unknown acylgenotoxic impurity comprises: at least one of pivaloyl chloride, thiopheneacetyl chloride and cefixime active ester (methyl ester).
5. A method for screening unknown acylated genotoxic impurities by derivatization-ultra-high performance liquid chromatography-triple quadrupole mass spectrometry is characterized by comprising the following steps:
(1) performing acylation reaction on an amine derivative reagent and an unknown acylated genotoxic impurity to generate a product carrying the amine derivative reagent;
(2) separating the product from a reaction system, analyzing a sample by using an ultra-high performance liquid chromatography-triple quadrupole mass spectrometry combination method, and screening unknown acylated genotoxic impurities by using characteristic ion fragments to perform parent ion scanning.
6. The method for screening the unknown acylated genotoxic impurity according to claim 5, wherein in the step (1), the unknown acylated genotoxic impurity is dissolved in a solvent and then the amine derivative reagent is added for reaction; preferably, the solvent comprises any one of acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide;
alternatively, in the step (1), the amine derivatization reagent comprises any one of 3-amino-N- (4-methoxyphenyl) propionamide and p-anisidine.
7. The method for screening unknown acylated genotoxic impurities as claimed in claim 5, wherein in step (1), the unknown acylated genotoxic impurities are impurities capable of undergoing acylation reaction with amine derivative reagents; preferably, the unknown acylated genotoxic impurities include: at least one of pivaloyl chloride, thiopheneacetyl chloride and cefixime active ester (methyl ester).
8. The method for screening the unknown acylated genotoxic impurities according to claim 5, wherein in the step (1), the reaction temperature is 40-80 ℃, and the reaction time is 1 hour; the reaction is preferably carried out at 60 ℃ for 1 hour.
9. The method for screening unknown acylated genotoxic impurities as claimed in any one of claims 5 to 8, wherein in step (2), the derivative products in the reaction system are separated by ultra high performance liquid chromatography; preferably, the chromatographic column of the ultra-high performance liquid chromatography technology is Thermo Hypersil Gold C18(2.1X100mm, 3 μm); the column temperature was 40 ℃; the mobile phase A is 0.1% acetic acid aqueous solution; the mobile phase B is 0.1 percent acetic acid acetonitrile solution; gradient elution: 0-3min, 2% B, 3-50mi, 2% → 90% B, 50-55min, 98% B, 55.1-60min, 2% B; the flow rate is 0.3 mL/h; the sample size is 1 mu L.
10. The method for screening unknown acylated genotoxic impurities according to any one of claims 5 to 8, wherein in the step (2), the product carrying the amine derivative reagent is fragmented by using a triple quadrupole mass spectrometry method to generate ion fragments, and when chromatographic peaks of m/z279.17 and/or m/z319.11 exist in the obtained ion fragments, the unknown acylated genotoxic impurities are judged to exist;
preferably, the mass spectrum conditions of the triple quadrupole mass spectrometry are as follows: carrying out primary ion scanning detection in an ESI positive ion detection mode;
preferably, the parent ion scanning detection conditions are as follows: the daughter ion was m/z178.08, and the parent ion scan ranged from m/z190-m/z 600.
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