CN116990417A - Detection method of bromoalkane genotoxic impurities in irbesartan and intermediate thereof - Google Patents
Detection method of bromoalkane genotoxic impurities in irbesartan and intermediate thereof Download PDFInfo
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- 239000002947 C09CA04 - Irbesartan Substances 0.000 title claims abstract description 97
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 229960002198 irbesartan Drugs 0.000 title claims abstract description 97
- 238000001514 detection method Methods 0.000 title claims abstract description 47
- 239000012535 impurity Substances 0.000 title claims abstract description 43
- 231100000024 genotoxic Toxicity 0.000 title claims abstract description 26
- 230000001738 genotoxic effect Effects 0.000 title claims abstract description 26
- 239000000543 intermediate Substances 0.000 claims abstract description 43
- 239000013558 reference substance Substances 0.000 claims abstract description 34
- JFOGXCVQPLGLLD-UHFFFAOYSA-N 2-[4-(dibromomethyl)phenyl]benzonitrile Chemical group C1=CC(C(Br)Br)=CC=C1C1=CC=CC=C1C#N JFOGXCVQPLGLLD-UHFFFAOYSA-N 0.000 claims abstract description 31
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 102
- 239000000243 solution Substances 0.000 claims description 76
- 238000000034 method Methods 0.000 claims description 39
- 239000012071 phase Substances 0.000 claims description 34
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000007865 diluting Methods 0.000 claims description 20
- 238000004090 dissolution Methods 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000012544 monitoring process Methods 0.000 claims description 8
- 238000000132 electrospray ionisation Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 4
- 239000012085 test solution Substances 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000007791 liquid phase Substances 0.000 claims description 3
- 238000004949 mass spectrometry Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000004811 liquid chromatography Methods 0.000 claims description 2
- 239000012088 reference solution Substances 0.000 claims description 2
- YGVGITVCEHRBDK-UHFFFAOYSA-N 1-aminocyclopentane-1-carboxamide Chemical class NC(=O)C1(N)CCCC1 YGVGITVCEHRBDK-UHFFFAOYSA-N 0.000 abstract description 9
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 125000000950 dibromo group Chemical group Br* 0.000 description 37
- 239000000523 sample Substances 0.000 description 32
- 238000011084 recovery Methods 0.000 description 25
- 239000011550 stock solution Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 12
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 239000012488 sample solution Substances 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010200 validation analysis Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- -1 dibromo Chemical compound 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 230000009946 DNA mutation Effects 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 1
- 102000010913 Type 1 Angiotensin Receptor Human genes 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000005526 organic bromine compounds Chemical class 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
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- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
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- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
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- Pathology (AREA)
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Abstract
The application relates to a detection method of bromoalkane genotoxic impurities in irbesartan and intermediates thereof, which relates to the technical field of organic impurity detection and comprises the steps of selecting reference substances of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl, and preparing a reference substance solution; respectively selecting an irbesartan sample and an irbesartan intermediate sample, and preparing a sample to-be-detected liquid; and respectively carrying out liquid chromatography-mass spectrometry detection on the reference substance solution and the liquid to be detected, establishing a standard curve, calculating the contents of the 2-cyano-4 '-bromomethyl biphenyl and the 2-cyano-4' -dibromomethyl biphenyl according to the standard curve, and judging whether the contents of the 2-cyano-4 '-bromomethyl biphenyl and the 2-cyano-4' -dibromomethyl biphenyl are within a standard limit range. The liquid chromatograph provided by the application has lower quantitative limit and detection limit, and can further accurately detect the residual quantity of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl in irbesartan and irbesartan intermediates, and has the advantages of high detection sensitivity, high accuracy and strong specificity.
Description
Technical Field
The application relates to the technical field of organic impurity detection, in particular to a detection method of brominated alkanes genotoxic impurities in irbesartan and an intermediate thereof.
Background
Irbesartan is an angiotensin receptor antagonist antihypertensive agent used for treating primary hypertension and type 2 diabetic nephropathy accompanied with hypertension. The product can inhibit binding of angiotensin I and AT1 receptor, inhibit vasoconstriction, reduce vascular resistance, reduce aldosterone secretion, and increase blood plasma angiotensin sub-level, thereby exerting protuberance pressure effect.
Haloalkanes are very widely used alkylating agents in drug synthesis reactions, and are listed in the guidelines for limitation of genotoxic impurities issued by EMEA in 2006 and in the raw materials and genotoxic impurities in formulations issued by FDA: as mentioned in the recommended methods, the haloalkane is active, and can directly react with bioactive macromolecules (such as DNAs, RNAs and proteins) through nucleophilic substitution reaction, or can generate free radicals under the action of illumination or other excitation energy. Both of these methods directly or indirectly act on DNA, which may cause DNA mutation, and contact with such agents may present some carcinogenic risk, which seriously jeopardizes human health, so that control of the content of such substances is particularly important.
In the process of synthesizing irbesartan, brominated alkanes are present as genotoxic impurities, which are mainly 2-cyano-4 '-bromomethylbiphenyl (hereinafter abbreviated as monobromide) and 2-cyano-4' -dibromomethylbiphenyl (hereinafter abbreviated as dibromo). Monobromo is a key starting material of irbesartan, dibromo is a main impurity in monobromo, and both structures contain the same warning structure, namely halogenated hydrocarbon. The application provides a method for effectively detecting the residual quantity of two brominated alkanes in irbesartan and an intermediate thereof, and further lacks quality control standards for genetic toxic impurities of the two brominated alkanes, which definitely increases the biosafety of irbesartan related medicaments.
Disclosure of Invention
In order to solve the problems in the prior art, the application provides a method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof, which adopts liquid chromatography-mass spectrometry to detect the residual amounts of two brominated alkanes in irbesartan and irbesartan intermediates, accurately controls quality control standards of two brominated alkanes in controlled irbesartan and irbesartan intermediates, and provides guidance for biosafety of irbesartan related medicines.
Firstly, the application provides a method for detecting bromoalkane genotoxic impurities in irbesartan and intermediates thereof, which comprises the steps of selecting reference substances of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl, and preparing a reference substance solution; respectively selecting an irbesartan sample and an irbesartan intermediate sample, and preparing a sample to-be-detected liquid;
and respectively carrying out liquid chromatography-mass spectrometry detection on the reference substance solution and the liquid to be detected, recording chromatograms, establishing a standard curve by taking the liquid chromatogram peak areas of the 2-cyano-4 '-bromomethylbiphenyl and the 2-cyano-4' -dibromomethylbiphenyl as the ordinate and the concentration as the abscissa, calculating the contents of the 2-cyano-4 '-bromomethylbiphenyl and the 2-cyano-4' -dibromomethylbiphenyl according to the standard curve, and judging whether the contents of the 2-cyano-4 '-bromomethylbiphenyl and the 2-cyano-4' -dibromomethylbiphenyl are within the standard limit range.
Further, the standard limit ranges are:
2-cyano-4' -bromomethylbiphenyl content omega in irbesartan 1 2-cyano-4' -dibromomethylbiphenyl content omega in irbesartan less than or equal to 5ppm 2 Less than or equal to 5ppm and omega 1 +ω 2 ≤5ppm；
2-cyano-4' -bromomethylbiphenyl content omega in irbesartan intermediates 11 2-cyano-4' -dibromomethylbiphenyl content omega in irbesartan intermediate less than or equal to 20ppm 22 Less than or equal to 20ppm and omega 11 +ω 22 ≤20ppm。
Further, the above-mentioned 2-cyano-4' -bromomethylbiphenyl LOQ 1 2.53ng/ml, limit of detection LOD 1 1.01ng/ml; quantitative limit LOQ of 2-cyano-4' -dibromomethyl biphenyl 2 2.47ng/ml, limit of detection LOD 2 0.99ng/ml.
Further, the liquid chromatography conditions in the liquid chromatography-mass spectrometry detection process include:
chromatographic column: a C18 chromatographic column;
mobile phase: the phase A is ammonium acetate solution with the concentration of 0.01mol/L, and the phase B is methanol solution;
flow rate: 0.3-0.5ml/min;
sample injection amount: 4-6 μl, sample injection temperature: 2-8 ℃;
column temperature: 28-32 ℃.
Further, the elution procedure of the liquid phase is as follows:
0min, 40% by volume of phase A and 60% by volume of phase B;
0-10min, the volume of the A phase is changed from 40% to 30%, and the volume of the B phase is changed from 60% to 70%;
10-12min, the volume of the A phase is changed from 30% to 0%, and the volume of the B phase is changed from 70% to 100%;
12-22min, wherein the volume of the phase A is 0% and the volume of the phase B is 100%;
22-22.01min, the volume of the A phase is changed from 0% to 40%, and the volume of the B phase is changed from 100% to 60%;
22.01-30min, the volume of the A phase is 40% and the volume of the B phase is 60%.
Further, mass spectrum conditions in the liquid chromatography-mass spectrometry detection process include:
ion source: an electrospray ionization source; scanning mode: a positive ion scanning mode; monitoring mode: monitoring multiple reactions;
parameters of the electrospray ionization source include: a sprayer: 55-65psi; capillary voltage: 5500-6500V; nozzle voltage: 450-550V.
Further, the parameters of the electrospray ionization source further include:
drying gas temperature: 350 ℃; gas flow rate: 13L/min; sheath temperature: 100 ℃; sheath air flow rate: 12L/min.
Further, the preparation steps of the reference substance solution comprise:
respectively taking 20-30mg of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl, adding acetonitrile for dissolution, and diluting with methanol to a series of concentrations to obtain a reference substance solution for preparing a standard curve.
Further, the concentration of the reference substance in the reference substance solution is 2.5-125%.
Further, the step of preparing the sample to be measured solution includes:
respectively taking 80-120mg of irbesartan and irbesartan intermediates, and adding methanol for dissolution to prepare a sample to-be-detected liquid;
and diluting the concentration of the sample to be tested to 3-8% by using methanol.
In summary, the present application includes at least one of the following beneficial technical effects:
1. according to the application, a detection method of liquid chromatography-mass spectrometry is adopted, and the contents of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl in irbesartan and irbesartan intermediates are accurately detected by designing detection parameters and detection reagents, and the quality control range for controlling the contents of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl is strictly controlled, so that a beneficial guidance is provided for the biosafety of irbesartan related medicine;
2. the liquid chromatograph provided by the application has lower quantitative limit and detection limit, and can further accurately detect the residual quantity of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl in irbesartan and irbesartan intermediates, and has the advantages of high detection sensitivity, high accuracy and strong specificity.
Drawings
FIG. 1 is a diagram of a linear relationship versus accuracy part of a monobromo linear relationship in an embodiment of the present application;
FIG. 2 is a graph of linear relationship versus dibromo of the accuracy component of an embodiment of the present application;
FIG. 3 is a graph showing the monobromolinear relationship of the intermediate precision fraction in an embodiment of the present application;
FIG. 4 is a graph showing the dibromo linearity of the intermediate precision fraction in an embodiment of the present application;
FIG. 5 is a hollow white group chromatogram of an embodiment of the application;
FIG. 6 is a chromatogram of a control solution of 25ng/ml in an embodiment of the application;
fig. 7 is a chromatogram of a sample solution of irbesartan in an embodiment of the present application;
fig. 8 is a chromatogram of a sample solution of irbesartan intermediate in an embodiment of the present application.
Detailed Description
The present application will be described in further detail with reference to examples. The specific description is: the following examples were conducted under conventional conditions or conditions recommended by the manufacturer, without specifying the specific conditions. The instruments and materials used in the examples below were all commercially available except for the specific descriptions.
The application provides a detection method of bromoalkane genotoxic impurities in irbesartan and an intermediate thereof, wherein irbesartan is an angiotensin II receptor antagonist with high efficiency and selectivity and is used for treating hypertension and heart failure. Brominated alkanes genotoxic impurities may be present in irbesartan and intermediates thereof, and these impurities may be potentially harmful to human health.
Brominated alkanes are a class of organic bromine compounds that may decompose under certain conditions to produce deleterious brominated alkanes genotoxic materials. These substances may damage biomolecules such as DNA, RNA, and proteins of the human body, and thus cause abnormal cell functions, mutations, and cancer. If the bromoalkane genotoxic impurities in the irbesartan and the intermediate thereof can be accurately detected, the quality and the safety of the medicine can be guaranteed. By detecting brominated alkane impurities in the medicine, the purity and the non-toxicity of the medicine can be ensured, and the potential health risk is reduced.
2-cyano-4 '-bromomethyl biphenyl (monobromo for short) and 2-cyano-4' -dibromomethyl biphenyl (dibromo) are main brominated alkane genotoxic impurities in the synthesis of irbesartan, wherein monobromo is an important starting material of irbesartan, and a byproduct, namely dibromo, is generated in the synthesis reaction of the monobromo. More than about 1% of the dibromo in the starting monobromide is present and is carried over to the irbesartan production process. However, at present, only a method for detecting monobromide or dibromo in irbesartan exists in the prior art, the detection precision of the method is limited, and a method capable of accurately detecting two brominated alkanes genotoxic impurities simultaneously is lacked. Because of the relatively low content of bromoalkane impurities in irbesartan, only trace amounts may exist, which makes it difficult to accurately detect and quantify the bromoalkane impurities. In addition to this, other detection difficulties exist, such as the structural similarity of monobromide and dibromo, differing only in the fact that the same carbon atom is mono-or dibromo-substituted, and therefore, the partition coefficients of both are similar to those of the C18 packing on the chromatographic column, resulting in very close retention times of both on the chromatographic column, difficult to achieve effective separation, and in other words, accurate detection.
Based on the above, the inventor discovers that monobromo and dibromo impurities exist in the irbesartan intermediate, and the probability of detecting monobromo and dibromo in the irbesartan intermediate is greater than that of irbesartan, so that the detection method of brominated alkane genotoxic impurities in the irbesartan and the irbesartan intermediate can detect two impurities simultaneously, and has the characteristics of wide range, strong specificity, high sensitivity, good precision, high accuracy and the like.
The detection method comprises the following steps:
step S1: taking 25mg of each of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl reference substances, precisely weighing, placing into a 50ml measuring flask, adding acetonitrile for dissolving and diluting to a scale, shaking uniformly, and quantitatively diluting with methanol to prepare reference substance solutions with standard curves of 2.5ng, 6.25ng, 12.5ng, 25ng, 37.5 ng, 50ng and 125ng in each 1 ml;
step S2: respectively taking 100mg of irbesartan and irbesartan intermediates, precisely weighing, adding methanol for dissolving and quantitatively diluting to prepare a sample to-be-detected liquid containing about 5mg of each 1 ml;
step S3: and respectively carrying out liquid chromatography-mass spectrometry detection on the standard curve reference substance solution and the liquid to be detected, recording chromatograms, establishing a standard curve by taking the liquid chromatogram peak areas of the 2-cyano-4 '-bromomethylbiphenyl and the 2-cyano-4' -dibromomethylbiphenyl as the ordinate and the concentration as the abscissa, calculating the content of the 2-cyano-4 '-bromomethylbiphenyl and the 2-cyano-4' -dibromomethylbiphenyl according to the standard curve, and judging whether the content of the 2-cyano-4 '-bromomethylbiphenyl and the 2-cyano-4' -dibromomethylbiphenyl is within the standard limit range.
The standard limit ranges are as follows:
2-cyano-4' -bromomethylbiphenyl content omega in irbesartan 1 2-cyano-4' -dibromomethylbiphenyl content omega in irbesartan less than or equal to 5ppm 2 ≤5ppm；
2-cyano-4' -bromomethylbiphenyl content omega in irbesartan intermediates 11 2-cyano-4' -dibromomethylbiphenyl content omega in irbesartan intermediate less than or equal to 20ppm 22 ≤20ppm。
Wherein, the chromatographic conditions are as follows:
an Agilent120PFP (3.0X100 mm,2.7 μm) column was used; gradient elution was carried out with 0.01mol/L ammonium acetate solution as mobile phase A and methanol as mobile phase B according to Table 1 below; the flow rate is 0.4ml per minute; the column temperature is 30 ℃; the sample injection temperature is 4 ℃; the sample volume was 5. Mu.l.
TABLE 1 liquid phase gradient elution procedure
| Time (min) | Mobile phase A% | Mobile phase B% |
| 0 | 40 | 60 |
| 10 | 30 | 70 |
| 12 | 0 | 100 |
| 22 | 0 | 100 |
| 22.01 | 40 | 60 |
| 30 | 40 | 60 |
The mass spectrum conditions are as follows:
detection was performed with a triple quadrupole tandem mass spectrometer using electrospray ionization source (ajsis) using a positive ion scan mode, the monitoring mode being multi-reaction monitoring (MRM), the monitoring ion pairs of the compounds being shown in table 2 below.
TABLE 2 monitoring ion pairs
The above-described ajsis ion source parameters are shown in table 3 below:
table 3. Ajsis ion source parameters
System applicability requirements: taking a reference substance solution with the concentration of 25ng/ml, repeatedly sampling for 6 times, wherein the relative standard deviation of the peak areas of all impurities is not more than 10.0%; and (3) respectively taking reference substance solutions of the standard curves for sample injection, drawing the standard curves according to the peak areas corresponding to the concentrations, and calculating a linear regression equation, wherein the correlation coefficient (r) is not lower than 0.995.
Methodological validation results
Methodological validation and acceptance criteria are shown in table 4 below:
TABLE 4 methodological validation and acceptance criteria
1. Specificity and solution stability
1. Solution preparation
(1) Monobromo impurity stock solution (0.5 mg/ml): 25mg of monobromo reference substance is taken, precisely weighed, placed in a 50ml measuring flask, dissolved and diluted to a scale by acetonitrile, and shaken well.
(2) Dibromoimpurity stock solution (0.5 mg/ml): 25mg of dibromo reference substance is taken, precisely weighed, placed in a 50ml measuring flask, dissolved and diluted to a scale by acetonitrile, and shaken well.
(3) Control stock solution (0.5. Mu.g/ml): accurately measuring 1ml of monobromine and dibromo impurity stock solutions respectively, placing the stock solutions into the same 50ml measuring flask, diluting to a scale with methanol, shaking uniformly, accurately measuring 2.5ml, placing the stock solutions into the 50ml measuring flask, diluting to the scale with methanol, and shaking uniformly.
(4) Control solution (25 ng/ml): precisely measuring 1ml of control stock solution, placing into a 20ml measuring flask, diluting to scale with methanol, and shaking.
(5) Test solution: taking 100mg of irbesartan intermediate (hereinafter referred to as intermediate DPI-5), 100mg of irbesartan crude product and 100mg of irbesartan sample respectively, precisely weighing, putting into different 20ml measuring flasks, adding methanol for dissolving and diluting to a scale, and shaking uniformly.
(6) Adding a standard solution to a test sample: 100mg of intermediate DPI-5, crude irbesartan and irbesartan samples are respectively precisely weighed and placed into different 20ml measuring flasks, 1ml of reference substance stock solution is precisely added, methanol is added for dissolution and dilution to a scale, and shaking is carried out uniformly.
2. Test procedure and results
Precisely measuring 5 μl of each of the reference solution, the test solution and the test addition solution according to the chromatographic conditions, the mass spectrum conditions and the method in the step S1-3, respectively injecting into a liquid chromatograph, and recording the chromatograms. Wherein the reference substance solution is repeatedly sampled for 6 times, and the RSD of the impurity peak area is inspected; the test sample is added with the standard solution and is prepared and immediately injected into the liquid chromatograph, at the moment, the solution is placed at a low temperature (about 4 ℃) according to the time of 0 hour, the liquid chromatograph is respectively injected in different time periods, the stability of the solution is inspected, the specific results are shown in the following tables 1-1, and the stability results are shown in the following tables 1-2.
TABLE 1-1 specificity results
TABLE 1-2 solution stability results
3. Conclusion(s)
The method has the advantages that the shapes of monobromo and dibromo peaks are good, the response is large, the RSD of the 6-needle peak area is 1.39% and 2.02% respectively, the method meets the acceptance standard, and the blank solvent, each sample and other impurities in the blank solvent do not interfere the determination of the monobromo and dibromo peaks, so that the detection method has strong specificity; adding monobromide and dibromo into irbesartan, crude products thereof and intermediate test solution, wherein the measured recovery rate is within 75-120%, and meets the acceptance standard; the standard solution is added and placed for 20 hours, the peak areas of monobromide and dibromo are unchanged, and the RSD of the peak areas in each time period is less than 10.0%, so that the solution stability is proved to be good.
2. Quantitative limit and detection limit
1. Solution preparation
(1) Quantitative limiting solution: precisely measuring 2ml of the reference substance solution under item one, placing into a 20ml measuring flask, diluting to scale with methanol, and shaking.
(2) Detection limit solution: precisely measuring 0.8ml of the reference substance solution under item one, placing into a 20ml measuring flask, diluting to scale with methanol, and shaking.
2. Test procedure and results
According to the chromatographic conditions, mass spectrum conditions and methods in the step S1-3, 5 μl of each of the quantitative limit solution and the detection limit solution is precisely measured, and the mixture is injected into a liquid chromatograph to record the chromatograms. The signal measured by the impurity on the chromatograph is compared with the baseline of the nearby blank, and the selected blank baseline segment is not less than 1 minute. Continuously injecting the quantitative limit solution and the detection limit solution into a liquid chromatograph for 6 times, recording a chromatogram, and examining RSD and signal-to-noise ratio of the impurity peak area under the quantitative limit concentration; the signal to noise ratio of the impurity peak under the detection limit concentration is examined, and the quantitative limit and the detection limit result are shown in the following table 2-1.
TABLE 2-1 quantitative limit and detection limit
3. Conclusion(s)
The quantitative limits of monobromide and dibromo are 2.53ng/ml and 2.47ng/ml respectively, which are about 0.5ppm of the concentration of the test sample solution; the signal-to-noise ratio under the quantitative limit and the detection limit is respectively more than 10 and the RSD of the peak area under the 3, 6-needle quantitative limit is less than 5.0%, and the test results meet the acceptance standard, so that the method has high sensitivity and good precision.
3. Linear relationship and accuracy
1. Solution preparation
(1) Control stock solution: namely the control stock solution under item "one" above.
(2) Linear series of solutions: precisely measuring 0.5ml, 1ml, 1.5ml, 2ml and 5ml of reference substance stock solution respectively, placing into 5 20ml measuring flasks, diluting to scale with methanol, and shaking to obtain linear solution with relative concentration of 50%, 100%, 150%, 200% and 500%; respectively precisely measuring 1ml and 2.5ml of 200% linear solution, placing into 2 20ml measuring flasks, diluting to scale with methanol, and shaking to obtain linear solution with relative concentration of 10% and 25%.
(3) Background solution: taking 100mg of the product, placing the product into a 20ml measuring flask, adding methanol for dissolution, diluting to a scale, and shaking uniformly.
(4) 25% recovery solution: 100mg of the product is taken and placed in a 20ml measuring flask, 1ml of 500% linear solution is precisely added, methanol is added for dissolution and dilution to scale, and 3 parts of the product are prepared in parallel by shaking.
(5) 50% recovery solution: 100mg of the product is taken and placed in a 20ml measuring flask, 0.5ml of reference substance stock solution is precisely added, methanol is added for dissolution and dilution to scale, and 3 parts of the product are prepared in parallel by shaking.
(6) 100% recovery solution: 100mg of the product is taken and placed in a 20ml measuring flask, 1ml of reference substance stock solution is precisely added, methanol is added for dissolution and dilution to scale, and 3 parts of the product are prepared in parallel by shaking.
(7) 150% recovery solution: 100mg of the product is taken and placed in a 20ml measuring flask, 1.5ml of reference substance stock solution is precisely added, methanol is added for dissolution and dilution to scale, and 3 parts of the product are prepared in parallel by shaking.
Remarks: the product can be as follows: DPI-5, irbesartan and crude products, DPI-5, irbesartan and crude products background solution and recovery rate solution preparation methods are consistent.
2. Test procedure and results
Precisely measuring 5 mu l of each of the linear solution, the background solution and the recovery solution according to the chromatographic conditions, the mass spectrometry conditions and the method in the step S1-3, respectively injecting into a liquid chromatograph, and recording the chromatograms. Wherein, 100% linear solution is repeatedly injected for 6 times, and other linear solutions with other concentrations are repeatedly injected for 2 times. Taking the sample injection concentration C (ng/ml) as an abscissa, taking the average peak area A as an ordinate, adopting a least square method and a regression analysis tool to perform data analysis, calculating the ratio of the intercept to the peak area of the solution with the relative concentration of 100%, and calculating the recovery rate according to a standard curve method. Wherein, the monobromo linear result is shown in the following table 3-1, the dibromo linear result is shown in the following table 3-2, the monobromo linear relation diagram is shown in figure 1, and the dibromo linear relation diagram is shown in figure 2.
TABLE 3-1 monobromolinear results
TABLE 3-2 dibromo Linear results
The test results were summarized for the linear results of monobromide and dibromo, see tables 3-3 below.
TABLE 3 summary of test results for linear relationship
Conclusion: the linearity of monobromide and dibromo is good in the range of quantitative limit to 25ppm, and the correlation coefficient r is about 1.0, which accords with the acceptance standard.
The recovery rate of monobromo and dibromo in irbesartan and monobromo and dibromo in crude irbesartan and DPI-5 is shown in the following table 3- (4-9).
Tables 3-4. Results of recovery of monobromo in irbesartan by sample addition
Tables 3-5. Results of recovery of dibromo in irbesartan
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Tables 3-6. Results of recovery of monobromo from crude Irbesartan
Tables 3-7. Recovery results of dibromo-loaded samples from crude Irbesartan
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Table 3-8. Results of recovery of monobromide loading in DPI-5
Table 3-9. Recovery results for dibromo-loading in DPI-5
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3. Conclusion(s)
Sample adding recovery rates of monobromine and dibromo measured in DPI-5, irbesartan and crude products thereof are all in a range of 75% -120%, and RSD of 12 parts of results is less than 10.0%, which proves that the detection method provided by the application is high in accuracy.
4. Intermediate precision
1. Solution preparation
(1) Monobromo stock solution (0.5 mg/ml): 25mg of monobromo reference substance is taken, precisely weighed, placed in a 50ml measuring flask, dissolved and diluted to a scale by acetonitrile, and shaken well.
(2) Dibromo stock solution (0.5 mg/ml): 25mg of dibromo reference substance is taken, precisely weighed, placed in a 50ml measuring flask, dissolved and diluted to a scale by acetonitrile, and shaken well.
(3) Control stock solution (0.5. Mu.g/ml): accurately measuring 1ml of monobromine and dibromo stock solution respectively, placing into a same 50ml measuring flask, diluting to a scale with methanol, shaking uniformly, accurately measuring 2.5ml, placing into a 50ml measuring flask, diluting to a scale with methanol, and shaking uniformly.
(4) Linear series of solutions: precisely measuring 0.5ml, 1ml, 1.5ml, 2ml and 5ml of reference substance stock solution respectively, placing into 5 20ml measuring flasks, diluting to scale with methanol, and shaking to obtain linear solution with relative concentration of 50%, 100%, 150%, 200% and 500%; respectively precisely measuring 1ml of 200% and 500% of linear solution, sequentially placing into 2 20ml measuring flasks, diluting to scale with methanol, and shaking to obtain linear solution with relative concentration of 10% and 25%.
(5) Background solution: 100mg of irbesartan sample is taken, placed in a 20ml measuring flask, dissolved and diluted to the scale by adding methanol, and shaken well.
(6) 25% recovery solution: 100mg of irbesartan sample is taken, placed in a 20ml measuring flask, 1ml of 500% linear solution is precisely added, methanol is added for dissolution and dilution to a scale, and 3 parts are prepared in parallel by shaking.
(7) 50% recovery solution: 100mg of irbesartan sample is taken, placed in a 20ml measuring flask, 0.5ml of control stock solution is precisely added, methanol is added for dissolution and dilution to scale, shaking is carried out, and 3 parts of irbesartan sample are prepared in parallel.
(8) 100% recovery solution: 100mg of irbesartan sample is taken, placed in a 20ml measuring flask, 1ml of control stock solution is precisely added, methanol is added for dissolution and dilution to scale, shaking is carried out, and 3 parts of irbesartan sample are prepared in parallel.
(9) 150% recovery solution: 100mg of irbesartan sample is taken, placed in a 20ml measuring flask, 1.5ml of control stock solution is precisely added, methanol is added for dissolution and dilution to scale, shaking is carried out, and 3 parts of irbesartan sample are prepared in parallel.
3. Test procedure and results
Precisely measuring 5 mu l of each of the linear solution, the background solution and the recovery solution according to the chromatographic conditions, the mass spectrometry conditions and the method in the step S1-3, respectively injecting into a liquid chromatograph, and recording the chromatograms. Wherein, 100% linear solution is repeatedly injected for 6 times, and other linear solutions with other concentrations are repeatedly injected for 2 times. Data analysis is carried out by using sample injection concentration C (ng/ml) as an abscissa and average peak area A as an ordinate, using a least square method and a regression analysis tool, calculating the ratio of the intercept to the peak area of the solution with the relative concentration of 100%, and calculating the recovery rate according to a standard curve method, wherein the detection results are shown in tables 4-1, 4-2, 4-3, 4-4 and figures 3 and 4.
TABLE 4-1 monobromo Linear results
TABLE 4-2 dibromo Linear results
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TABLE 4-3 results of recovery of monobromo in irbesartan
Tables 4-4. Results of recovery of dibromo in Irbesartan
3. Conclusion(s)
The detection result under the 'four' item is consistent with the detection result under the 'three' item, the correlation coefficient r of monobromine and dibromo is about 1.0, the sample recovery rate in irbesartan is within the range of 75% -120%, and the RSD of 12 parts of results is less than 10.0%, so that the detection method is proved to have high precision.
5. Sample determination (detection of monobromide and dibromo content in irbesartan and its intermediates)
According to the analysis of the content of monobromide and dibromo in irbesartan and intermediates thereof in the figures 5-8, wherein, the figure 5 is a blank chromatogram, the figure 6 is a control solution (a (4) control solution (25 ng/ml) under one item), the figure 7 is an irbesartan sample solution (sample to be tested liquid) chromatogram, and the figure 8 is an irbesartan intermediate sample solution (sample to be tested liquid) chromatogram, so that monobromide is not detected in the intermediates DPI-5, irbesartan crude product and irbesartan; dibromo was detected in intermediate DPI-5, at maximum about 11ppm, meeting the limit, and not in both crude and irbesartan.
The above embodiments are not intended to limit the scope of the present application, so: all equivalent changes in structure, shape and principle of the application should be covered in the scope of protection of the application.
Claims (10)
1. A method for detecting bromoalkane genotoxic impurities in irbesartan and intermediates thereof, which is characterized by comprising the following steps:
selecting reference substances of 2-cyano-4 '-bromomethyl biphenyl and 2-cyano-4' -dibromomethyl biphenyl, and preparing a reference substance solution;
respectively selecting an irbesartan sample and an irbesartan intermediate sample, and preparing a sample to-be-detected liquid;
and respectively carrying out liquid chromatography-mass spectrometry detection on the reference substance solution and the liquid to be detected, recording chromatograms, establishing a standard curve by taking the liquid chromatogram peak areas of the 2-cyano-4 '-bromomethyl biphenyl and the 2-cyano-4' -dibromomethyl biphenyl as the ordinate and the concentration as the abscissa, calculating the contents of the 2-cyano-4 '-bromomethyl biphenyl and the 2-cyano-4' -dibromomethyl biphenyl according to the standard curve, and judging whether the contents of the 2-cyano-4 '-bromomethyl biphenyl and the 2-cyano-4' -dibromomethyl biphenyl are within a standard limit range.
2. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 1, wherein the standard limit range is:
content omega of the 2-cyano-4' -bromomethylbiphenyl in the irbesartan 1 Less than or equal to 5ppm, and the content omega of the 2-cyano-4' -dibromomethyl biphenyl in the irbesartan 2 Less than or equal to 5ppm and omega 1 +ω 2 ≤5ppm；
Content omega of the 2-cyano-4' -bromomethyl biphenyl in the irbesartan intermediate 11 The content omega of the 2-cyano-4' -dibromomethylbiphenyl in the irbesartan intermediate is less than or equal to 20ppm 22 Less than or equal to 20ppm and omega 11 +ω 22 ≤20ppm。
3. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 1, wherein the method comprises the following steps: the quantitative limit LOQ of the 2-cyano-4' -bromomethyl biphenyl 1 2.5ng/ml, limit of detection LOD 1 1.0ng/ml;
the quantitative limit LOQ of the 2-cyano-4' -dibromomethyl biphenyl 2 2.5ng/ml, limit of detection LOD 2 1.0ng/ml.
4. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 1, wherein the liquid chromatography conditions in the liquid chromatography-mass spectrometry detection process comprise:
chromatographic column: a C18 chromatographic column;
mobile phase: the phase A is ammonium acetate solution with the concentration of 0.01mol/L, and the phase B is methanol solution;
flow rate: 0.3-0.5ml/min;
sample injection amount: 4-6 μl, sample injection temperature: 2-8 ℃;
column temperature: 28-32 ℃.
5. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 4, wherein the elution procedure of the liquid phase is as follows:
0min, 40% by volume of phase A and 60% by volume of phase B;
0-10min, the volume of the A phase is changed from 40% to 30%, and the volume of the B phase is changed from 60% to 70%;
10-12min, the volume of the A phase is changed from 30% to 0%, and the volume of the B phase is changed from 70% to 100%;
12-22min, wherein the volume of the phase A is 0% and the volume of the phase B is 100%;
22-22.01min, the volume of the A phase is changed from 0% to 40%, and the volume of the B phase is changed from 100% to 60%;
01-30min, the volume of the A phase is 40% and the volume of the B phase is 60%.
6. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 1, wherein mass spectrometry conditions in the liquid chromatography-mass spectrometry detection process comprise:
ion source: an electrospray ionization source; scanning mode: a positive ion scanning mode; monitoring mode: monitoring multiple reactions;
parameters of the electrospray ionization source include: a sprayer: 55-65psi; capillary voltage: 5500-6500V; nozzle voltage: 450-550V.
7. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 6, wherein parameters of the electrospray ionization source further comprise:
drying gas temperature: 350 ℃; gas flow rate: 13L/min; sheath temperature: 100 ℃; sheath air flow rate: 12L/min.
8. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 1, wherein the preparation step of the reference solution comprises the following steps:
and respectively taking 20-30mg of the 2-cyano-4 '-bromomethyl biphenyl and the 2-cyano-4' -dibromomethyl biphenyl, adding acetonitrile for dissolution, and diluting with methanol to obtain a series of concentrations to obtain a reference substance solution for preparing the standard curve.
9. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 8, wherein the method comprises the following steps: the concentration of the reference substance in the reference substance solution is 2.5% -125%.
10. The method for detecting brominated alkanes genotoxic impurities in irbesartan and intermediates thereof according to claim 9, wherein the step of preparing a sample test solution comprises:
respectively taking 80-120mg of irbesartan and irbesartan intermediate, adding the methanol for dissolution, and preparing a sample to-be-detected liquid;
and diluting the concentration of the sample to be tested to 3-8% by using the methanol.
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