CN115453000B - Detection method and application of toxic impurities in tenib drug intermediate - Google Patents
Detection method and application of toxic impurities in tenib drug intermediate Download PDFInfo
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- CN115453000B CN115453000B CN202211207115.9A CN202211207115A CN115453000B CN 115453000 B CN115453000 B CN 115453000B CN 202211207115 A CN202211207115 A CN 202211207115A CN 115453000 B CN115453000 B CN 115453000B
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- fluoronitrobenzene
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- 239000012535 impurity Substances 0.000 title claims abstract description 63
- 238000001514 detection method Methods 0.000 title claims abstract description 41
- 239000003814 drug Substances 0.000 title claims abstract description 39
- 231100000331 toxic Toxicity 0.000 title claims abstract description 33
- 230000002588 toxic effect Effects 0.000 title claims abstract description 33
- 229940079593 drug Drugs 0.000 title claims abstract description 32
- 239000000243 solution Substances 0.000 claims abstract description 88
- 239000013558 reference substance Substances 0.000 claims abstract description 73
- NTBYINQTYWZXLH-UHFFFAOYSA-N 1,2-dichloro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(Cl)=C1 NTBYINQTYWZXLH-UHFFFAOYSA-N 0.000 claims abstract description 53
- DPHCXXYPSYMICK-UHFFFAOYSA-N 2-chloro-1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(Cl)=C1 DPHCXXYPSYMICK-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 33
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 23
- RBAHXNSORRGCQA-UHFFFAOYSA-N 1-chloro-2-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Cl)=C1F RBAHXNSORRGCQA-UHFFFAOYSA-N 0.000 claims abstract description 20
- CSSSAKOGRYYMSA-UHFFFAOYSA-N 1-chloro-2-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(F)=C1 CSSSAKOGRYYMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 claims abstract description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012488 sample solution Substances 0.000 claims abstract description 18
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical group N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000005695 Ammonium acetate Substances 0.000 claims abstract description 14
- 229940043376 ammonium acetate Drugs 0.000 claims abstract description 14
- 235000019257 ammonium acetate Nutrition 0.000 claims abstract description 14
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 238000010828 elution Methods 0.000 claims abstract description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 68
- 239000012085 test solution Substances 0.000 claims description 9
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical group NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 claims description 8
- 238000012417 linear regression Methods 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000003908 quality control method Methods 0.000 claims description 4
- 239000012088 reference solution Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 239000000523 sample Substances 0.000 description 33
- 239000000543 intermediate Substances 0.000 description 27
- 238000007865 diluting Methods 0.000 description 23
- 239000011259 mixed solution Substances 0.000 description 18
- 238000011084 recovery Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 231100000024 genotoxic Toxicity 0.000 description 5
- 230000001738 genotoxic effect Effects 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000010812 external standard method Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- 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
Abstract
The invention provides a method for detecting toxic impurities in a tenidine drug intermediate, which comprises the following steps: respectively taking 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene as reference substances to prepare reference substance solutions; taking a to-be-detected product of the tenib drug intermediate, and preparing a to-be-detected product solution; respectively carrying out high performance liquid chromatography detection on the reference substance solution and the sample solution; wherein, the conditions of the high performance liquid chromatography detection include: the mobile phase A is methanol, the mobile phase B is ammonium acetate aqueous solution, and gradient elution is adopted. The detection method has the advantages of quick and simple operation, strong specificity, high sensitivity, and good precision, accuracy and durability.
Description
Technical Field
The invention relates to the technical field of medicine analysis, in particular to a detection method and application of toxic impurities in a tenib drug intermediate.
Background
The tenidine medicine is a common medicine in the field of anticancer medicine, such as gefitinib, canetinib and the like, and an important intermediate for synthesizing the tenidine medicine in the medical industry is 3-chloro-4-fluoroaniline. The synthetic route of 3-chloro-4-fluoroaniline is shown below:
3, 4-dichloronitrobenzene and 3-chloro-4-fluoronitrobenzene are intermediates obtained in the synthesis process of 3-chloro-4-fluoroaniline, and excessive 3, 4-dichloronitrobenzene and 3-chloro-4-fluoronitrobenzene can be introduced into 3-chloro-4-fluoroaniline. Meanwhile, by-products 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene can be generated in the synthetic route, and the three by-products can be introduced into the final 3-chloro-4-fluoroaniline product. The chemical structure of each impurity is as follows:
as the nitro compound is a risk warning structure, the quality control is generally carried out according to genotoxic impurities. In order to ensure the medication safety, the content of nitro impurities in the intermediate of the tenib drugs is required to be detected. However, since 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene are similar in properties to each other, it is difficult to effectively separate all impurities by conventional detection methods.
Disclosure of Invention
Based on the method, the invention provides a method for detecting toxic impurities in a tenib drug intermediate, which has the advantages of rapid and simple operation, strong specificity, high sensitivity, and good precision, accuracy and durability.
The invention is realized by the following technical scheme.
A method for detecting toxic impurities in a tenidine drug intermediate comprises the following steps:
respectively taking 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene as reference substances to prepare reference substance solutions;
taking a to-be-detected product of the tenib drug intermediate, and preparing a to-be-detected product solution;
respectively carrying out high performance liquid chromatography detection on the reference substance solution and the sample solution;
wherein, the conditions of the high performance liquid chromatography detection include: the mobile phase A is methanol, the mobile phase B is ammonium acetate aqueous solution, and gradient elution is adopted; the gradient elution procedure includes: 0 min-33 min, wherein the volume percentage of the mobile phase A is a; 33-33.1 min, the volume percentage of the mobile phase A is changed from a to 85%;33.1 to 40 minutes, the volume percentage of the mobile phase A is kept at 85 percent; 40 min-40.1 min, the volume percentage of the mobile phase A is changed from 85% to a;40.1 to 50 minutes, the volume percentage of the mobile phase A is kept as a; a is 53% + -3%.
In one embodiment, the conditions for high performance liquid chromatography detection further comprise: the column temperature is 35-45 ℃; the flow rate is 0.8 mL/min-1.2 mL/min; the detection wavelength is 271nm + -5 nm.
In one embodiment, the conditions employed for high performance liquid chromatography further comprise: the chromatographic column is octadecylsilane chemically bonded silica column.
In one embodiment, the dimensions of a chromatography column used for high performance liquid chromatography include: the column length is 200 mm-300 mm, the inner diameter is 4 mm-5 mm, and the grain diameter is 4 μm-6 μm.
In one embodiment, the mass percentage of the ammonium acetate in the ammonium acetate aqueous solution is 0.4% -0.8%.
In one embodiment, preparing the control solution comprises the steps of:
3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene, p-fluoronitrobenzene reference and dimethyl sulfoxide are mixed separately.
In one embodiment, preparing a test solution includes the steps of:
and mixing the to-be-detected product of the tenidine drug intermediate with dimethyl sulfoxide.
In one embodiment, the tenidine intermediate is 3-chloro-4-fluoroaniline.
In one embodiment, the high performance liquid chromatography detection of the reference solution and the sample solution is performed separately, and then the method further comprises the following steps:
obtaining peak areas corresponding to the toxic impurities in the reference substance solution respectively; obtaining the concentration of the reference substance solution; calculating a linear regression equation by taking the concentration of the reference substance solution as an abscissa and the peak areas corresponding to the toxic impurities in the reference substance solution as an ordinate respectively;
and obtaining peak areas respectively corresponding to the toxic impurities in the sample solution, and substituting an external standard method into the linear regression equation to calculate and obtain the content of the genotoxic impurities in the sample solution.
The invention also provides an application of the detection method of toxic impurities in the intermediate of the tenib medicament in the quality control of the intermediate of the tenib medicament.
Compared with the prior art, the method for detecting toxic impurities in the tenib drug intermediate has the following beneficial effects:
according to the invention, a high performance liquid chromatography technology is adopted to detect the intermediate of the tenib drug, five impurities are successfully separated by limiting a mobile phase and a gradient elution program, and an effective method for detecting genotoxic impurities of 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene in the intermediate of the tenib drug is established. In addition, the detection method is proved to have strong specificity, high sensitivity, good precision, accuracy and durability by a methodology verification experiment.
Furthermore, the detection method of toxic impurities in the tenib drug intermediate is rapid and simple to operate, does not need complicated operation, and can be popularized and applied.
Drawings
FIG. 1 is a high performance liquid chromatogram of a mixed solution 1 according to example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of the mixed solution 2 according to example 1 of the present invention;
FIG. 3 is a high performance liquid chromatogram of the mixed solution 3 according to example 1 of the present invention;
FIG. 4 is a graph showing the linear relationship of 3-chloro-4-fluoronitrobenzene provided by the invention;
FIG. 5 is a linear relationship diagram of 3, 4-dichloronitrobenzene provided by the invention.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. The drawings illustrate preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise. In the description of the present invention, the meaning of "several" means at least one, such as one, two, etc., unless specifically defined otherwise.
The words "preferably," "more preferably," and the like in the present invention refer to embodiments of the invention that may provide certain benefits in some instances. However, other embodiments may be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values for the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
All percentages, fractions and ratios are calculated on the total mass of the composition of the invention, unless otherwise indicated. All of the mass of the ingredients listed, unless otherwise indicated, are given to the active substance content and therefore they do not include solvents or by-products that may be included in commercially available materials. The term "mass percent" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless indicated otherwise. All formulations and tests herein take place in an environment of 25 ℃, unless otherwise indicated. The terms "comprising," "including," "containing," "having," or other variations thereof herein are intended to cover a non-closed inclusion, without distinguishing between them. The term "comprising" means that other steps and ingredients may be added that do not affect the end result. The compositions and methods/processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as additional or optional ingredients, components, steps, or limitations of any of the embodiments described herein. The terms "efficacy," "performance," "effect," "efficacy" are not differentiated herein.
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. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The invention provides a method for detecting toxic impurities in a tenidine drug intermediate, which comprises the following steps:
respectively taking 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene as reference substances to prepare reference substance solutions;
taking a to-be-detected product of the tenib drug intermediate, and preparing a to-be-detected product solution;
respectively performing high performance liquid chromatography detection on the reference substance solution and the sample solution;
wherein, the conditions of the high performance liquid chromatography detection include: the mobile phase A is methanol, the mobile phase B is ammonium acetate aqueous solution, and gradient elution is adopted; the gradient elution procedure includes: 0 min-33 min, wherein the volume percentage of the mobile phase A is a; 33-33.1 min, the volume percentage of the mobile phase A is changed from a to 85%;33.1 to 40 minutes, the volume percentage of the mobile phase A is kept at 85 percent; 40 min-40.1 min, the volume percentage of the mobile phase A is changed from 85% to a;40.1 to 50 minutes, the volume percentage of the mobile phase A is kept as a; a is 53% + -3%.
In a specific example, the conditions of the high performance liquid chromatography detection further include: the column temperature is 35-45 ℃; the flow rate is 0.8 mL/min-1.2 mL/min; the detection wavelength is 271nm + -5 nm.
It is understood that in the present invention, column temperatures include, but are not limited to, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃;
flow rates include, but are not limited to, 0.8mL/min, 0.9mL/min, 1.0mL/min, 1.1mL/min, 1.2mL/min;
detection wavelengths include, but are not limited to 266nm, 267nm, 268nm, 269nm, 270nm, 271nm, 272nm, 273nm, 274nm, 275nm, 276nm.
In a specific example, the conditions employed in the high performance liquid chromatography further include: the chromatographic column is octadecylsilane chemically bonded silica column.
In a specific example, the size of the column used for high performance liquid chromatography includes: the column length is 200 mm-300 mm, the inner diameter is 4 mm-5 mm, and the grain diameter is 4 μm-6 μm.
More specifically, the chromatographic column is Agilent XDB C 18 Columns (4.6X250 mm,5 μm) or columns of comparable performance.
In a specific example, the mass percentage of ammonium acetate in the ammonium acetate aqueous solution is 0.4% -0.8%.
It is understood that in the present invention, the mass percent of ammonium acetate in the aqueous ammonium acetate solution includes, but is not limited to, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%.
In a specific example, preparing the control solution includes the steps of:
3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene, p-fluoronitrobenzene reference and dimethyl sulfoxide are mixed separately.
More specifically, the preparation of the control solution comprises the following steps:
taking proper amounts of 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene reference substances, precisely weighing, adding dimethyl sulfoxide for dissolving and quantitatively diluting to prepare a solution with about 0.12 mug of each impurity in each 1 ml.
More specifically, the diluent used for quantitative dilution is dimethyl sulfoxide.
In a specific example, preparing a test solution includes the steps of:
mixing the to-be-detected product of the tenidal intermediate with dimethyl sulfoxide.
More specifically, the preparation of the test solution includes the steps of:
taking a proper amount of a to-be-detected product of the intermediate of the tennini, precisely weighing, adding dimethyl sulfoxide for dissolving and quantitatively diluting to prepare a solution containing about 20mg per 1 ml.
More specifically, the diluent used for quantitative dilution is dimethyl sulfoxide.
In a specific example, the tenidine-based drug intermediate is 3-chloro-4-fluoroaniline.
In a specific example, the high performance liquid chromatography detection of the control solution and the sample solution respectively includes the following steps:
obtaining peak areas corresponding to toxic impurities in the reference substance solution respectively; obtaining the concentration of a reference substance solution; calculating a linear regression equation by taking the concentration of the reference substance solution as an abscissa and the peak areas corresponding to toxic impurities in the reference substance solution as an ordinate respectively;
and obtaining peak areas respectively corresponding to toxic impurities in the sample solution, and substituting an external standard method into a linear regression equation to calculate and obtain the content of genotoxic impurities in the sample solution.
The invention also provides an application of the detection method of toxic impurities in the intermediate of the tenib drug in quality control of the intermediate of the tenib drug.
The method for detecting toxic impurities in the intermediate of the tenidine drug of the invention is described in further detail below with reference to specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides a method for detecting toxic impurities in a tenib drug intermediate, which comprises the following steps:
1. instrument and reagent
The names, models or specifications of the instruments and reagents used in this example are shown in Table 1.
TABLE 1
2. Experimental procedure
2.1 liquid chromatography conditions
The chromatographic column is Agilent XDB C 18 (4.6X250 mm,5 μm) column; the mobile phase A is methanol, and the mobile phase B is an ammonium acetate aqueous solution with the mass fraction of 0.6%; gradient elution is adopted, and the gradient elution program is as follows: 0-33 min, wherein the volume percentage of the mobile phase A is 53%; 33-33.1 min, the volume percentage of the mobile phase A is changed from 53% to 85%;33.1 to 40 minutes, the volume percentage of the mobile phase A is kept at 85 percent; 40 min-40.1 min, the volume percentage of the mobile phase A is changed from 85% to 53%; the volume percentage of the mobile phase A is kept at 53% within 40.1 min-50 min, and is shown in Table 2 in detail; the flow rate is 1.0mL/min; column temperature is 40 ℃; the detection wavelength is 271nm; the sample loading was 10. Mu.L.
TABLE 2
| Time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 53 | 47 |
| 33 | 53 | 47 |
| 33.1 | 85 | 15 |
| 40 | 85 | 15 |
| 40.1 | 53 | 47 |
| 50 | 53 | 47 |
2.2 preparation of control solution
Taking proper amounts of 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene reference substances, precisely weighing, adding dimethyl sulfoxide for dissolving and quantitatively diluting to prepare a solution with about 0.12 mug of each impurity in each 1 ml.
More specifically, in step 2.2, a control stock solution is prepared in advance, and the operations are performed according to table 3:
TABLE 3 Table 3
Wherein, the solution 1, the solution 2, the solution 3, the solution 4 and the solution 5 are respectively stock solutions of single impurity reference substances, and the solution 6 is a stock solution of mixed reference substances;
in daily detection, 1ml of solution 6 is removed, diluted and fixed to 20ml to obtain a reference substance solution, wherein the theoretical concentration of the reference substance solution is as follows: the concentration of individual impurities was 0.12. Mu.g/ml.
2.3 preparation of sample solution
Taking a proper amount of a test article (a test article of a tenidine drug intermediate), precisely weighing, adding dimethyl sulfoxide for dissolving and quantitatively diluting to prepare a solution containing about 20mg per 1 ml.
2.4 sample injection
And (3) respectively injecting the solutions prepared in the steps (2.2) and (2.3) into a high performance liquid chromatograph for detection, and recording the chromatograms to obtain peak areas corresponding to the impurities in the reference solution and the sample solution.
Substituting the concentrations of the reference substance solution and the sample solution into peak areas corresponding to the impurities in the reference substance solution and the sample solution, and calculating the content of each genotoxic impurity in the sample according to an external standard method.
3. Results
3.1 retention time
The retention time of each impurity in the method for high performance liquid chromatography detection is shown in table 4:
TABLE 4 Table 4
| Impurity name | Retention time (min) |
| P-fluoronitrobenzene | 8.196 |
| 3-chloro-2-fluoronitrobenzene | 14.548 |
| 3-chloro-4-fluoronitrobenzene | 17.643 |
| 4-chloro-3-fluoronitrobenzene | 17.996 |
| 3, 4-dichloronitrobenzene | 32.234 |
3.2 System applicability investigation
Preparing a mixed solution 1: and (3) taking a sample, a 3-chloro-4-fluoronitrobenzene reference substance and a 3, 4-dichloronitrobenzene reference substance, adding a proper amount of dimethyl sulfoxide, dissolving and diluting to prepare a mixed solution which contains about 20mg of the sample, 0.12 mug of 3-chloro-4-fluoronitrobenzene and 0.12 mug of 3, 4-dichloronitrobenzene per 1ml, and taking the mixed solution as a system applicability solution.
Preparing a mixed solution 2: and (3) taking a sample and a 4-chloro-3-fluoronitrobenzene reference substance, adding a proper amount of dimethyl sulfoxide for dissolving, and diluting to prepare a mixed solution which contains about 20mg of the sample and 0.12 mug of 4-chloro-3-fluoronitrobenzene per 1 ml.
Preparing a mixed solution 3: and (3) taking a sample, a 3-chloro-2-fluoronitrobenzene reference substance and a p-fluoronitrobenzene reference substance, adding a proper amount of dimethyl sulfoxide, dissolving and diluting to prepare a mixed solution containing 20mg of the sample, 0.12 mug of 3-chloro-2-fluoronitrobenzene and 0.12 mug of p-fluoronitrobenzene per 1 ml.
Sample injection detection is carried out on the mixed solution 1, the mixed solution 2 and the mixed solution 3 (chromatographic conditions are consistent with those of 2.1), the obtained chromatograms are shown in fig. 1-3, and the separation degree results with the test sample are shown in table 5.
TABLE 5
| Composition of the components | Retention time (min) | Degree of separation |
| 3-chloro-4-fluoronitrobenzene | 17.643 | 3.37/10.95 |
| 3, 4-dichloronitrobenzene | 32.234 | 7.25/1.98 |
| 4-chloro-3-fluoronitrobenzene | 17.996 | 3.00/7.91 |
| 3-chloro-2-fluoronitrobenzene | 14.548 | 10.48/1.62 |
| P-fluoronitrobenzene | 8.196 | 1.94/1.10 |
Under the chromatographic conditions, each impurity chromatographic peak can be well separated from the adjacent chromatographic peaks, and the method is suitable for detecting the impurities.
3.3 specificity investigation
Blank solvent: dimethyl sulfoxide.
Test solution: taking a proper amount of test sample, precisely weighing, adding dimethyl sulfoxide for dissolving, and quantitatively diluting to obtain a solution containing about 20mg per 1 ml.
3-chloro-4-fluoronitrobenzene positioning solution: taking a proper amount of 3-chloro-4-fluoronitrobenzene reference substance, adding a proper amount of dimethyl sulfoxide for dissolving and diluting to prepare a solution containing about 0.024mg per 1 ml.
3, 4-dichloronitrobenzene positioning solution: taking a proper amount of 3, 4-dichloronitrobenzene reference substance, adding a proper amount of dimethyl sulfoxide for dissolving and diluting to prepare a solution containing about 0.024mg per 1 ml.
4-chloro-3-fluoronitrobenzene positioning solution: taking a proper amount of 4-chloro-3-fluoronitrobenzene reference substance, adding a proper amount of dimethyl sulfoxide for dissolving and diluting to prepare a solution containing about 0.024mg per 1 ml.
3-chloro-2-fluoronitrobenzene positioning solution: taking a proper amount of 3-chloro-2-fluoronitrobenzene reference substance, adding a proper amount of dimethyl sulfoxide for dissolving and diluting to prepare a solution containing about 0.024mg per 1 ml.
P-fluoronitrobenzene positioning solution: taking proper amount of p-fluoronitrobenzene reference substance, adding proper amount of dimethyl sulfoxide for dissolving and diluting to prepare a solution containing about 0.024mg per 1 ml.
Precisely measuring 10 μl of blank solvent, sample solution and impurity positioning solution, and injecting into a liquid chromatograph under the chromatographic conditions consistent with 2.1, and recording the chromatogram, wherein the results are shown in Table 6.
TABLE 6
| Sample name | Retention time (min) |
| Blank solvent | - |
| Test solution | 6.593-7.583 |
| 3-chloro-4-fluoronitrobenzene | 17.653 |
| 3, 4-dichloronitrobenzene | 32.326 |
| P-fluoronitrobenzene | 8.213 |
| 3-chloro-2-fluoronitrobenzene positioning solution | 14.540 |
| 4-chloro-3-fluoronitrobenzene positioning solution | 17.930 |
Conclusion: the blank solvent and other peaks in the sample do not interfere with detection of each impurity, and the method has good specificity.
3.4 detection limit
Taking the stock solution of each impurity reference substance, adding dimethyl sulfoxide to dilute to proper concentration step by step, precisely measuring 10 μl of the stock solution under the chromatographic condition shown in 2.1, injecting into a liquid chromatograph, recording the chromatogram, and taking the signal-to-noise ratio of 3 times as a detection limit, wherein the result is shown in Table 7.
TABLE 7
Conclusion: the detection limits of the impurities 3-chloro-4-fluoronitrobenzene, 3, 4-dichloronitrobenzene, 4-chloro-3-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene and p-fluoronitrobenzene are respectively equivalent to 1.26ppm, 1.30ppm, 1.29ppm, 1.21ppm and 1.41ppm of the normal detection quantity of the sample, which indicates that the chromatographic conditions can detect one part per million equivalent of each impurity, and the method has high sensitivity.
3.5 Linear Range investigation
The linear range was verified by taking 3-chloro-4-fluoronitrobenzene and 3, 4-dichloronitrobenzene as examples.
3-chloro-4-fluoronitrobenzene: taking a proper amount of 3-chloro-4-fluoronitrobenzene reference substance, adding dimethyl sulfoxide for dissolving and diluting to prepare a solution which contains about 0.08 mug, 0.09 mug, 0.12 mug, 0.19 mug and 0.23 mug in each 1ml, and taking the solution as a linear solution;
3, 4-dichloronitrobenzene: taking a proper amount of 3, 4-dichloronitrobenzene reference substance, adding dimethyl sulfoxide for dissolving and diluting to prepare a solution which contains about 0.09 mug, 0.10 mug, 0.13 mug, 0.20 mug and 0.25 mug in each 1ml, and taking the solution as a linear solution.
Precisely measuring 10 μl of the linear solution, measuring with a liquid chromatograph, recording chromatogram under chromatographic conditions consistent with 2.1, calculating linear regression equation and correlation coefficient with concentration as abscissa and peak area as ordinate, and obtaining the results shown in Table 8 and Table 9, and linear relationship diagrams shown in FIGS. 4-5.
Table 8 3-chloro-4-fluoronitrobenzene linear table
TABLE 9 3, 4-dichloronitrobenzene Linear tables
Conclusion: the concentration of 3-chloro-4-fluoronitrobenzene and 3, 4-dichloronitrobenzene is in the range of about 0.08 mu g/ml to 0.25 mu g/ml, the linear relation between the concentration and the peak area is good, and the linear relation coefficient r is not lower than 0.999, and the linear relation is good.
3.6 accuracy
Accuracy was verified by taking 3-chloro-4-fluoronitrobenzene and 3, 4-dichloronitrobenzene as examples.
Control solution: taking appropriate amounts of 3-chloro-4-fluoronitrobenzene reference substance and 3, 4-dichloronitrobenzene reference substance, and diluting to obtain solutions containing about 0.12 μg per 1ml before dissolving in dimethyl sulfoxide.
Test solution: the sample is taken, precisely weighed, dissolved and diluted by dimethyl sulfoxide to prepare a solution containing about 20mg per 1 ml.
Recovery rate 80% solution: and (3) taking a sample, a 3-chloro-4-fluoronitrobenzene reference substance and a 3, 4-dichloronitrobenzene reference substance in proper amounts, and diluting the sample, the 3-chloro-4-fluoronitrobenzene reference substance and the 3, 4-dichloronitrobenzene reference substance before adding dimethyl sulfoxide for dissolution to prepare mixed solutions of 20mg of the sample, 0.096 mug of 3-chloro-4-fluoronitrobenzene and 0.096 mug of 3, 4-dichloronitrobenzene in each 1 ml. 3 parts of the total formulation.
Recovery 100% solution: and (3) taking a sample, a 3-chloro-4-fluoronitrobenzene reference substance and a 3, 4-dichloronitrobenzene reference substance in proper amounts, and diluting the sample, the 3-chloro-4-fluoronitrobenzene reference substance and the 3, 4-dichloronitrobenzene reference substance before adding dimethyl sulfoxide for dissolution to prepare mixed solutions containing 20mg of the sample, 0.12 mug of 3-chloro-4-fluoronitrobenzene and 0.12 mug of 3, 4-dichloronitrobenzene in each 1 ml. 3 parts of the total formulation.
Recovery rate 120% solution: and (3) taking a sample, a 3-chloro-4-fluoronitrobenzene reference substance and a 3, 4-dichloronitrobenzene reference substance in proper amounts, and diluting the sample, the 3-chloro-4-fluoronitrobenzene reference substance and the 3, 4-dichloronitrobenzene reference substance before adding dimethyl sulfoxide for dissolution to prepare mixed solutions containing 20mg of the sample, 0.144 mug of 3-chloro-4-fluoronitrobenzene and 0.144 mug of 3, 4-dichloronitrobenzene in each 1 ml. 3 parts of the total formulation.
10. Mu.l of each solution was measured precisely, and the solution was injected into a liquid chromatograph to measure the concentration, the chromatographic conditions were 2.1, the chromatogram was recorded, and the recovery rate of the impurity sample was calculated, and the results were shown in Table 10 and Table 11.
TABLE 10 recovery results of 3-chloro-4-fluoronitrobenzene
TABLE 11 recovery results of 3, 4-dichloronitrobenzene
Conclusion: the recovery rate of the 3-chloro-4-fluoronitrobenzene is 90% -110%, the average recovery rate is 103.00%, and the RSD is 4.12%; the recovery rate of the 3, 4-dichloronitrobenzene is 90% -110%, the average recovery rate is 99.05%, and the RSD is 2.15%. The detection method has good accuracy.
3.7 precision
The precision was verified by taking 3-chloro-4-fluoronitrobenzene and 3, 4-dichloronitrobenzene as examples.
Control solution: taking proper amounts of 3-chloro-4-fluoronitrobenzene reference substance and 3, 4-dichloronitrobenzene reference substance, adding dimethyl sulfoxide, dissolving, and diluting to obtain solutions containing about 0.12 μg per 1ml, and taking as reference substance solution.
Test solution: and (3) taking a sample, a 3-chloro-4-fluoronitrobenzene reference substance and a 3, 4-dichloronitrobenzene reference substance in proper amounts, and diluting the sample, the 3-chloro-4-fluoronitrobenzene reference substance and the 3, 4-dichloronitrobenzene reference substance before adding dimethyl sulfoxide for dissolution to prepare mixed solutions containing 20mg of the sample, 0.12 mug of 3-chloro-4-fluoronitrobenzene and 0.12 mug of 3, 4-dichloronitrobenzene in each 1 ml. 6 parts of the total formulation.
Precisely measuring 10 μl of each solution, injecting into a liquid chromatograph, keeping chromatographic conditions consistent with 2.1, recording chromatogram, and calculating impurity content. The above solutions were repeatedly prepared at different times by different laboratory workers and tested using different instruments, the results of which are shown in table 12.
Table 12
| Impurity name | 3-chloro-4-fluoronitrobenzene content (ppm) | 3, 4-dichloronitrobenzene content (ppm) |
| Laboratory staff A-1 | 6.18 | 6.08 |
| Laboratory staff A-2 | 6.30 | 5.88 |
| Laboratory staff A-3 | 5.56 | 6.31 |
| Laboratory staff A-4 | 6.12 | 6.58 |
| Laboratory staff A-5 | 5.52 | 6.72 |
| Laboratory staff A-6 | 6.32 | 6.19 |
| Laboratory staff B-1 | 5.71 | 6.19 |
| Laboratory staff B-2 | 5.51 | 6.49 |
| Laboratory staff B-3 | 5.71 | 6.11 |
| Laboratory staff B-4 | 5.44 | 6.01 |
| Experimental staff B-5 | 5.47 | 6.67 |
| Laboratory staff B-6 | 5.83 | 6.08 |
| Average of | 5.81 | 6.27 |
| RSD(％) | 5.82 | 4.40 |
Conclusion: the 3-chloro-4-fluoronitrobenzene content RSD is 5.82% and the 3, 4-dichloronitrobenzene content RSD is 4.40%, which indicates that the method has good precision.
3.8 durability
Durability was demonstrated using 3-chloro-4-fluoronitrobenzene and 3, 4-dichloronitrobenzene as examples.
Control solution: taking proper amounts of 3-chloro-4-fluoronitrobenzene reference substance and 3, 4-dichloronitrobenzene reference substance, adding dimethyl sulfoxide, dissolving, and diluting to obtain solutions containing about 0.12 μg per 1ml, and taking as reference substance solution.
Test solution: and (3) taking a sample, a 3-chloro-4-fluoronitrobenzene reference substance and a 3, 4-dichloronitrobenzene reference substance in proper amounts, and diluting the sample, the 3-chloro-4-fluoronitrobenzene reference substance and the 3, 4-dichloronitrobenzene reference substance before adding dimethyl sulfoxide for dissolution to prepare mixed solutions containing 20mg of the sample, 0.12 mug of 3-chloro-4-fluoronitrobenzene and 0.12 mug of 3, 4-dichloronitrobenzene in each 1 ml.
The results of the measurement of the above solutions under slight changes in chromatographic conditions, such as column temperature, flow rate and wavelength, are shown in Table 13.
TABLE 13
Selecting the conditions: the column temperature is 40 ℃, the flow rate is 1.0ml/min, the wavelength is 271nm, and the initial proportion of the mobile phase A is 53% -B47%.
Conclusion: when the column temperature, the flow rate, the wavelength and the initial flow phase ratio change slightly, the separation degree of the 3-chloro-4-fluoronitrobenzene peak and the front and back impurity peaks is more than 1.5, and the content is basically consistent; the separation degree of the 3, 4-dichloronitrobenzene peak and the front and back impurity peaks is more than 1.5, and the content is basically consistent. The method has good durability.
Comparative example 1
The comparative example provides a method for detecting toxic impurities in a tenib drug intermediate, which comprises the following steps:
the liquid chromatography condition is that the chromatographic column is Agilent XDB C 18 (4.6X250 mm,5 μm) column; the mobile phase A is methanol, and the mobile phase B is an ammonium acetate aqueous solution with the mass fraction of 0.6%; isocratic elution (mobile phase A:58%; mobile phase B: 42%); the flow rate is 1.0mL/min; column temperature is 40 ℃; the detection wavelength is 271nm; the sample loading was 10. Mu.L.
Other conditions and procedures were the same as in example 1.
Detection result: the impurities cannot be separated effectively.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.
Claims (9)
1. The method for detecting toxic impurities in the intermediate of the tenidine is characterized by comprising the following steps of:
respectively taking 3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene and p-fluoronitrobenzene as reference substances to prepare reference substance solutions;
taking a to-be-detected product of the tenib drug intermediate, and preparing a to-be-detected product solution;
respectively carrying out high performance liquid chromatography detection on the reference substance solution and the sample solution;
wherein, the conditions of the high performance liquid chromatography detection include: the mobile phase A is methanol, the mobile phase B is ammonium acetate aqueous solution, and gradient elution is adopted; the gradient elution procedure includes: 0 min-33 min, wherein the volume percentage of the mobile phase A is a;33 min-33.1 min, wherein the volume percentage of the mobile phase A is changed from a to 85%;33.1 min-40 min, and the volume percentage of the mobile phase A is kept to be 85%;40 min-40.1 min, wherein the volume percentage of the mobile phase A is changed from 85% to a;40.1 min-50 min, and keeping the volume percentage of the mobile phase A as a; a is 53% ± 3%; the detection wavelength of the high performance liquid chromatography is 271nm plus or minus 5nm; in the ammonium acetate aqueous solution, the mass percentage of ammonium acetate is 0.4% -0.8%.
2. The method for detecting toxic impurities in a tenidine intermediate according to claim 1, wherein the conditions for high performance liquid chromatography detection further comprise: the column temperature is 35-45 ℃; the flow rate is 0.8mL/min to 1.2mL/min.
3. The method for detecting toxic impurities in a tenidine intermediate according to claim 1, wherein the conditions adopted by the high performance liquid chromatography further comprise: the chromatographic column is octadecylsilane chemically bonded silica column.
4. The method for detecting toxic impurities in a tenidine intermediate according to claim 1, wherein the size of a column used for high performance liquid chromatography comprises: the column length is 200 mm-300 mm, the inner diameter is 4 mm-5 mm, and the particle size is 4 μm-6 μm.
5. The method for detecting toxic impurities in a tenidine drug intermediate according to claim 1, wherein the preparation of the reference solution comprises the following steps:
3, 4-dichloronitrobenzene, 3-chloro-4-fluoronitrobenzene, 3-chloro-2-fluoronitrobenzene, 4-chloro-3-fluoronitrobenzene, p-fluoronitrobenzene reference and dimethyl sulfoxide are mixed separately.
6. The method for detecting toxic impurities in a tenidine intermediate according to claim 1, wherein the preparation of the test solution comprises the steps of:
and mixing the to-be-detected product of the tenidine drug intermediate with dimethyl sulfoxide.
7. The method for detecting toxic impurities in a tenidine drug intermediate according to any one of claims 1 to 6, wherein the tenidine drug intermediate is 3-chloro-4-fluoroaniline.
8. The method for detecting toxic impurities in a tinib-based drug intermediate according to any one of claims 1 to 6, wherein the steps of performing high performance liquid chromatography detection on the reference solution and the sample solution respectively are as follows:
obtaining peak areas corresponding to the toxic impurities in the reference substance solution respectively; obtaining the concentration of the reference substance solution; calculating a linear regression equation by taking the concentration of the reference substance solution as an abscissa and the peak areas corresponding to the toxic impurities in the reference substance solution as an ordinate respectively;
and obtaining peak areas respectively corresponding to the toxic impurities in the sample solution, and substituting the peak areas into the linear regression equation to calculate and obtain the content of the toxic impurities in the sample solution.
9. The application of the detection method of toxic impurities in the intermediate of the tenidine drugs according to any one of claims 1-8 in quality control of the intermediate of the tenidine drugs.
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