CN117825546A - GC-MS method for separating genotoxic impurities in clotrimazole and measuring content thereof - Google Patents
GC-MS method for separating genotoxic impurities in clotrimazole and measuring content thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 100
- 238000000034 method Methods 0.000 title claims abstract description 46
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960004022 clotrimazole Drugs 0.000 title claims abstract description 44
- 231100000024 genotoxic Toxicity 0.000 title claims abstract description 41
- 230000001738 genotoxic effect Effects 0.000 title claims abstract description 41
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 title claims abstract description 13
- 238000001514 detection method Methods 0.000 claims abstract description 19
- 238000001819 mass spectrum Methods 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract description 3
- -1 polysiloxane Polymers 0.000 claims abstract description 3
- 229920001296 polysiloxane Polymers 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 73
- 239000013558 reference substance Substances 0.000 claims description 26
- 239000000523 sample Substances 0.000 claims description 20
- 239000012488 sample solution Substances 0.000 claims description 14
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- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000010586 diagram Methods 0.000 claims description 4
- 230000014759 maintenance of location Effects 0.000 claims description 4
- 230000006399 behavior Effects 0.000 claims description 2
- 239000012159 carrier gas Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000004949 mass spectrometry Methods 0.000 claims description 2
- 230000000717 retained effect Effects 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 4
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- 229940079593 drug Drugs 0.000 abstract 1
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- 238000003908 quality control method Methods 0.000 abstract 1
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- 239000007858 starting material Substances 0.000 description 20
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- 238000005303 weighing Methods 0.000 description 7
- 238000007865 diluting Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005259 measurement Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012088 reference solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical group ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
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- 201000002563 Histoplasmosis Diseases 0.000 description 1
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- 208000002474 Tinea Diseases 0.000 description 1
- 206010067197 Tinea manuum Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
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- 238000004817 gas chromatography Methods 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
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- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 201000003875 tinea corporis Diseases 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
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- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry analysis, and particularly relates to a GC-MS method for separating genotoxic impurities in clotrimazole and determining the content of the genotoxic impurities. The genotoxic impurity is impurity SM 1 And impurity Z 1f . According to the invention, 5% phenyl-methyl polysiloxane is adopted as chromatographic column fixing liquid, the chromatographic column is a capillary column, genetic toxic impurities in clotrimazole are separated by utilizing temperature programming, and the chromatographic column is detected by a mass spectrum detector to obtain a GC spectrum; finally, according to the result of the map, the impurity SM in the clotrimazole 1 And impurity Z 1f Qualitative and quantitative detection is carried out. The method has the advantages of strong specificity, high accuracy and good stability, and can realize the aim of the clotrimazole within 13.5 minutesSeparation of genotoxic impurities; and the detection limit is as low as 3ng/ml, and the method has the characteristic of high sensitivity. The invention provides a new method and thinking for quality control of the clotrimazole bulk drug and the preparation.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry analysis, and particularly relates to a GC-MS method for separating genotoxic impurities in clotrimazole and determining the content of the genotoxic impurities.
Background
Clotrimazole (Clotrimazole) belongs to pyrrole broad-spectrum antifungal agents, and has a structural formula shown in formula III, and is mainly used for treating deep and shallow mycosis caused by sensitive bacteria, such as cryptococcus meningitis, candida pneumonia, enteritis, histoplasmosis, tinea corporis, tinea manus and pedis, and the like. Clotrimazole has a good antibacterial effect on various fungi, especially candida albicans, and the action mechanism is to inhibit the synthesis of fungal cell membranes and influence the metabolic process of the fungi. Kemyclobutanil intermediate Z 1 Is a key intermediate in the synthesis process of clotrimazole, wherein the civilian chemical name is 1-chloro-2- (chlorodiphenylmethyl) benzene, and the molecular formula is C 19 H 14 C l2 The molecular weight is 313.22, the CAS number is 42074-68-0, and the clotrimazole intermediate Z 1 The structural formula of (C) is shown as formula IV.
Impurity SM 1 Use of the starting material as the main starting material for the synthesis of clotrimazole intermediate Z 1 Ke myc zole intermediate Z 1 With a small amount of impurities SM 1 Detecting; and impurity Z 1f To synthesize clotrimazole intermediate Z 1 By-products of the process, in order to better control the impurity level, ensure the medicine quality, the impurity SM is needed to be treated 1 And impurity Z 1f Strict control is performed.
In the prior art, the invention patent with publication number of CN113834885A discloses an HPLC detection method for genotoxic impurities of clotrimazole raw materials, wherein the genotoxic impurities are formaldehyde and glyoxal. At present, the impurity SM which can be used in clotrimazole is not inquired 1 And impurity Z 1f Related methods of control of (a).
Disclosure of Invention
Therefore, one of the purposes of the invention is to provide a method for separating the genotoxic impurities in the clotrimazole by a GC-MS method, which has strong specificity, high accuracy and good stability, can separate the genotoxic impurities in the clotrimazole within 13.5 minutes, and provides technical support for the subsequent detection of the genotoxic impurities in the clotrimazole.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
method for separating genotoxic impurities in clotrimazole by GC-MS method, wherein the genotoxic impurities comprise impurity SM 1 And impurity Z 1f Any one or more of the following; the impurity SM 1 The structural formula of the catalyst is shown as formula I, and the impurity Z 1f The structural formula of the clotrimazole is shown as a formula II, and the structural formula of the clotrimazole is shown as a formula III; the method comprises the following steps: adopting 5% phenyl-methyl polysiloxane as chromatographic column fixing liquid, adopting helium as carrier gas, and adopting programmed temperature to separate genotoxic impurities in clotrimazole;
impurity SM 1 To synthesize clotrimazole intermediate Z 1 Is the main starting material of the clotrimazole intermediate Z 1 With a small amount of impurities SM 1 Detection, thus selecting the impurity SM in the finished product 1 Strictly controlling Z 1f To synthesize Z 1 The by-products of the process are controlled in the finished product for better control of impurity levels.
Further, the temperature programming includes: the initial temperature is 70-90 ℃, and the operation is maintained for 1-3 minutes; heating to 180-220 ℃ at a speed of 5-15 ℃/min; and (3) post-operation: maintaining at 280-320 deg.C for 5-10min.
Preferably, the temperature programming is: the initial temperature is 80 ℃, and the operation is maintained for 2 minutes; heating to 200 ℃ at a rate of 10 ℃/min; and (3) post-operation: kept at 300℃for 6min.
Further, the column flow rate is 0.8 to 1.2ml/min, more preferably 1ml/min.
Further, the split ratio is 5:1
Preferably, the inlet temperature is 230-270 ℃, more preferably 250 ℃.
Preferably, the sample volume is 1.5. Mu.l.
Further, the chromatographic column is a capillary column.
Preferably, the mass spectrum is a single quadrupole mass spectrum.
Preferably, the chromatographic column specification is: 30m 0.25mm 0.25 μm.
The second object of the invention is to provide a method for qualitatively identifying the genotoxic impurities in the clotrimazole, which can effectively identify whether the genotoxic impurities are contained in the clotrimazole or not, has the detection limit as low as 3ng/ml, and has the characteristic of high sensitivity.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the method for qualitatively identifying the genotoxic impurities in the clotrimazole comprises the steps of separating the genotoxic impurities in the clotrimazole by adopting the method, and detecting by adopting a mass spectrum detector to obtain a GC diagram; judging whether the detection product contains genotoxic impurities according to the consistency of chromatographic behaviors of the control product and the detection product.
Further, the mass spectrometry conditions include: and (3) detecting by adopting an EI ion source and a SIM scanning mode, wherein the temperature of the ion source is 210-250 ℃, the temperature of a four-stage rod is 130-170 ℃, the temperature of a heating auxiliary device is 260-300 ℃, the solvent delay is 6-10 minutes, and the gain factor is 8-12.
Preferably, the ion source temperature is 230 ℃, the quaternary rod temperature is 150 ℃, the heating aid temperature is 280 ℃, the solvent delay is 8 minutes, and the gain factor is 10.
Further, the impurity SM 1 The quantitative ion of (2) is 195m/z, the qualitative ion is 193m/z, and the residence time is 100ms; the impurity Z 1f The quantitative ion of (2) was 167m/z, the qualitative ion was 202m/z, and the residence time was 100ms.
Further, the retention time was 10.8.+ -. 0.5min, which is the impurity SM 1 The method comprises the steps of carrying out a first treatment on the surface of the The retention time was 12.9.+ -. 0.5min for the impurity Z 1f 。
The invention further aims to provide a method for judging whether the content of the genotoxic impurities in the clotrimazole is qualified or not, and the method utilizes a limit method to quantify the genotoxic impurities in the clotrimazole, so that the accuracy is high and the repeatability is good.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the method for judging whether the content of the genotoxic impurities in the clotrimazole is qualified or not comprises the following steps:
(1) Preparing a sample to be detected and a reference substance by taking dichloromethane as a solvent;
(2) Detecting the sample to be detected and the reference substance in the step (1) by using the method of any one of claims 5 to 7 to obtain a GC diagram;
(3) Establishing a chromatographic model;
(4) And (3) judging whether the content of the genotoxic impurities in the sample to be detected is qualified or not according to the chromatographic model obtained in the step (3).
Further, if the peak areas of the genotoxic impurities in the sample solution are smaller than the peak areas of the corresponding impurities in the reference substance solution, the sample is qualified; if the peak area of any impurity in the genotoxic impurities in the sample solution is larger than the peak area of the corresponding impurity in the reference substance solution, the sample is unqualified.
As a preferred embodiment:
1. precisely weighing the product, such as 200mg, placing into a 50ml volumetric flask, adding dichloromethane to dissolve, fixing volume to scale, and shaking to obtain sample solution;
2. accurate weighing of impurity SM 1 Placing control, such as 30mg, in 50ml volumetric flask; precisely weighing, adding dichloromethane for dissolving and fixing volume to obtain impurity SM 1 Stock solution I of control; taking stock solution I such as 0.1ml, placing into a 50ml volumetric flask, adding dichloromethane, dissolving, diluting and fixing volume to obtain impurity SM 1 Stock solution II of reference substance; precisely measuring stock solution II such as 0.5ml, placing into 50ml volumetric flask, diluting with dichloromethane to desired volume, and shaking to obtain impurity SM 1 Is a reference solution;
3. preparing impurity Z according to the method in step 2 1f Is a reference solution;
4. taking the sample solution and the reference substance solution prepared in the step 1-3, for example, 1.5 mu l, respectively carrying out sample injection detection, and recording a chromatogram. According to the result of the map, the impurity SM in the sample solution 1 And impurity Z 1f Qualitative and quantitative analysis were performed.
The invention has the beneficial effects that:
1. the book is provided withThe GC-MS method established by the invention can successfully separate the genotoxic impurity SM in the clotrimazole 1 And Z 1f And determining the content of each impurity, impurity SM 1 And impurity Z 1f All are genotoxic impurities containing warning structures, the limit is 3ppm (12 ng/ml), and the sensitivity of the conventional LC or GC method cannot meet the requirement; the GC-MS method provided by the invention has the characteristics of low detection limit of 3ng/ml (0.75 ppm) and high sensitivity.
2. The invention ensures the impurity SM by adjusting the temperature rise program of the GCMS column incubator 1 And impurity Z 1f The method can well separate two impurities, and the clotrimazole, other impurities and matrixes do not interfere with measurement, and has the characteristics of strong specificity, high accuracy and good stability.
3. The method can realize the genotoxic impurity SM in the clotrimazole within 13.5 minutes 1 And Z 1f The measurement of (2) has the characteristic of short analysis time.
Drawings
FIG. 1 shows a blank solvent (SM 1 Channel) chromatogram;
FIG. 2 blank solvent (Z) 1f Channel) chromatogram;
FIG. 3 shows a control solution (12 ng/ml, SM 1 Channel) chromatogram;
FIG. 4 shows the control solution (12 ng/ml, Z 1f Channel) chromatogram;
FIG. 5 shows LOD solution (3 ng/ml, SM 1 Channel) chromatogram;
FIG. 6 shows LOD solution (3 ng/ml, Z 1f Channel) chromatogram;
FIG. 7 shows a sample solution (SM 1 Channel) chromatogram;
FIG. 8 shows a sample solution (Z 1f ) Is a chromatogram of (2).
Detailed Description
The technical scheme of the present invention will be further clearly and completely described in connection with specific embodiments. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. Therefore, all other embodiments obtained by those skilled in the art without undue burden are within the scope of the invention based on the embodiments of the present invention.
In the embodiment of the invention, the measurement is strictly carried out according to gas chromatography-mass spectrometry (Chinese pharmacopoeia 2020 edition four general rules 0521 and 0431).
In the embodiment of the invention, the GC-MS method for separating and measuring the content of genotoxic impurities in clotrimazole comprises the following steps:
1. preparing a solution to be tested
Test solution: 200mg of the product is taken, precisely weighed, placed in a 50ml volumetric flask, added with dichloromethane to dissolve, fixed in volume to scale, and uniformly shaken to obtain the product.
Control solution: SM taking 1 And Z 1f And (3) accurately weighing a proper amount of the reference substance, adding dichloromethane to dissolve and dilute the reference substance to prepare a solution containing about 12ng per 1ml, and shaking the solution uniformly to obtain the reference substance.
2. Chromatographic conditions
As shown in tables 1 and 2.
TABLE 1 chromatographic conditions
TABLE 2 parameters of the compounds
3. Measurement
System applicability requirements: and proper mass spectrum conditions are selected, and the signal to noise ratio of an impurity peak in a reference substance solution chromatogram is not less than 10.
Assay: taking sample solution and reference solution, directly introducing sample, recording chromatogram, and sequentially taking SM as peak sequence 1 And Z 1f 。
Limit: calculated according to peak area, SM in sample solution 1 And Z 1f The peaks were not greater than the corresponding chromatographic peaks (0.0003%) in the control solution, respectively.
Embodiments of the inventionThe preparation of the reference substance solution is preferably as follows: SM taking 1 And Z 1f 30mg of reference substance is precisely weighed in each 50ml volumetric flask, and methylene dichloride is added for dissolution and volume fixation to obtain a stock solution I; SM taking 1 And Z 1f 0.1ml of each stock solution I is put in a 50ml volumetric flask, and methylene dichloride is added for dissolving dilution and volume fixing to obtain stock solution II; precisely measuring 0.5ml of stock solution II, placing into a 50ml volumetric flask, adding dichloromethane to dilute and fix volume, and shaking uniformly to obtain the final product.
EXAMPLE 1 specificity
1. Preparing a solution to be tested
Blank solution: dichloromethane.
Control stock solution: SM taking 1 And Z 1f 30mg of reference substance, respectively placing into 50ml measuring flask, precisely weighing, adding dichloromethane to dissolve and dilute to scale, and shaking to obtain stock solution I; respectively taking SM 1 And Z 1f Stock solution I0.1 ml was placed in a 50ml measuring flask, diluted to scale with dichloromethane, and shaken well to give stock solution II.
Control solution: taking 0.5ml of reference stock solution II, placing into a 50ml measuring flask, diluting to scale with dichloromethane, and shaking.
Adding a labeled test sample solution: 200mg of the product is taken, precisely weighed, placed in a 50ml volumetric flask, added with 0.5ml of reference substance stock solution II, dissolved by methylene dichloride, fixed in volume to scale and shaken uniformly to obtain the product.
2. Detection of
Taking blank solution, reference substance solution and sample solution, respectively injecting into GC-MS chromatograph, detecting according to the chromatographic conditions, and recording chromatogram.
Results: the retention time of the control solution and the labeled test solution are consistent, and the blank solvent and sample matrix do not interfere with the determination of impurities, as shown in graph 3, figures 1-4, 7 and 8.
TABLE 3 specificity detection results Table
Example 2 System applicability
SM taking 1 And Z 1f And (3) a proper amount of a reference substance is precisely weighed, dissolved and diluted by adding dichloromethane to prepare a solution containing about 12ng per 1ml, shaking uniformly, obtaining the sample, continuously injecting the sample for 6 times, recording a chromatogram, and calculating the RSD of the peak area.
Results: as shown in table 4, the system applicability sample test results were satisfactory.
TABLE 4 System applicability test results Table
Example 3 detection Limit
SM taking 1 And Z 1f And (3) accurately weighing a proper amount of the reference substance, adding dichloromethane for dissolving and diluting to prepare a solution containing about 3ng per 1ml, and shaking uniformly to obtain the product. The samples were continuously injected 3 times in parallel and the chromatograms were recorded.
Results: as shown in table 5, fig. 5 and fig. 6, impurity SM 1 The detection limit of (C) is 2.95ng/ml, and the impurity Z 1f The detection limit of (2) is 2.97ng/ml, and the limit requirement is met.
TABLE 5 test limit experiment results Table
EXAMPLE 4 Standard addition test
1. Preparing a solution to be tested
Control stock solution: SM taking 1 And Z 1f 30mg of reference substance is respectively placed in 50ml measuring flask, precisely weighed, dissolved and diluted to scale by adding dichloromethane, and uniformly shaken to obtainStock solution I; respectively taking SM 1 And Z 1f Stock solution I0.1 ml was placed in a 50ml measuring flask, diluted to scale with dichloromethane, and shaken well to give stock solution II.
Control solution: taking 0.5ml of reference stock solution II, placing into a 50ml measuring flask, diluting to scale with dichloromethane, and shaking.
Standard addition of solution: 200mg of the product is taken, precisely weighed, placed in a 50ml volumetric flask, added with 0.5ml of reference substance stock solution II, dissolved by methylene dichloride, fixed in volume to scale and shaken uniformly to obtain the product.
2. Detection of
Taking reference substance solution, sample solution and standard solution for sample injection, measuring each sample in parallel for 2 times, and calculating recovery rate.
Results: as shown in Table 6, impurity SM 1 Accuracy of (2) is 106.3%, impurity Z 1f The accuracy of (2) was 99.3%.
TABLE 6 Standard addition test results Table
EXAMPLE 5 solution stability
1. Preparing a solution to be tested
Control stock solution: SM taking 1 And Z 1f 30mg of reference substance, respectively placing into 50ml measuring flask, precisely weighing, adding dichloromethane to dissolve and dilute to scale, and shaking to obtain stock solution I; respectively taking SM 1 And Z 1f Stock solution I0.1 ml was placed in a 50ml measuring flask, diluted to scale with dichloromethane, and shaken well to give stock solution II.
Control solution: taking 0.5ml of reference stock solution II, placing into a 50ml measuring flask, diluting to scale with dichloromethane, and shaking.
Standard addition of solution: 200mg of the product is taken, precisely weighed, placed in a 50ml volumetric flask, added with 0.5ml of reference substance stock solution II, dissolved by methylene dichloride, fixed in volume to scale and shaken uniformly to obtain the product.
2. Detection of
Taking standard adding solution and reference substance solution, recording chromatograms at 0h, 2h, 5h and 8h respectively, and calculating peak area RSD.
Results: as shown in Table 7, the process of the present invention has good solution stability.
TABLE 7 solution stability test results Table
Claims (10)
- A method for separating genotoxic impurities in clotrimazole by a GC-MS method, which is characterized in that the genotoxic impurities comprise impurity SM 1 And impurity Z 1f Any one or more of the following; the impurity SM 1 The structural formula of the catalyst is shown as formula I, and the impurity Z 1f The structural formula of the clotrimazole is shown as a formula II, and the structural formula of the clotrimazole is shown as a formula III; the method comprises the following steps: adopting 5% phenyl-methyl polysiloxane as chromatographic column fixing liquid, adopting helium as carrier gas, and adopting programmed temperature to separate genotoxic impurities in clotrimazole;
- 2. the method of claim 1, wherein the temperature programming comprises: the initial temperature is 70-90 ℃, and the operation is maintained for 1-3 minutes; heating to 180-220 ℃ at a speed of 5-15 ℃/min; and (3) post-operation: maintaining at 280-320 deg.C for 5-10min.
- 3. The process of claim 1, wherein the column flow rate is 0.8-1.2ml/min and the split ratio is 5:1.
- 4. the method of claim 1, wherein the sample inlet temperature is 230-270 ℃.
- 5. A method for qualitatively identifying genotoxic impurities in clotrimazole, characterized in that the method according to one of claims 1-4 is used for separating the genotoxic impurities in clotrimazole and detecting them by a mass spectrum detector to obtain GC diagram; judging whether the detection product contains genotoxic impurities according to the consistency of chromatographic behaviors of the control product and the detection product.
- 6. The method of claim 5, wherein the mass spectrometry conditions comprise: and (3) detecting by adopting an EI ion source and a SIM scanning mode, wherein the temperature of the ion source is 210-250 ℃, the temperature of a four-stage rod is 130-170 ℃, the temperature of a heating auxiliary device is 260-300 ℃, the solvent delay is 6-10 minutes, and the gain factor is 8-12.
- 7. The method according to claim 5, characterized in that the impurity SM 1 The quantitative ion of (2) is 195m/z, the qualitative ion is 193m/z, and the residence time is 100ms; the impurity Z 1f The quantitative ion of (2) was 167m/z, the qualitative ion was 202m/z, and the residence time was 100ms.
- 8. The method according to claim 5, wherein the impurity SM is retained for a period of 10.8+ -0.5 min 1 ；The retention time was 12.9.+ -. 0.5min for the impurity Z 1f 。
- 9. The method for judging whether the content of the genotoxic impurities in the clotrimazole is qualified is characterized by comprising the following steps:(1) Preparing a sample to be detected and a reference substance by taking dichloromethane as a solvent;(2) Detecting the sample to be detected and the reference substance in the step (1) by using the method of any one of claims 5 to 7 to obtain a GC diagram;(3) Establishing a chromatographic model;(4) And (3) judging whether the content of the genotoxic impurities in the sample to be detected is qualified or not according to the chromatographic model obtained in the step (3).
- 10. The method of claim 9, wherein if the peak areas of the genotoxic impurities in the sample solution are smaller than the peak areas of the corresponding impurities in the control solution, indicating that the sample is acceptable; if the peak area of any impurity in the genotoxic impurities in the sample solution is larger than the peak area of the corresponding impurity in the reference substance solution, the sample is unqualified.
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