CN107478747B - The liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood - Google Patents
The liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood Download PDFInfo
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- CN107478747B CN107478747B CN201710700674.6A CN201710700674A CN107478747B CN 107478747 B CN107478747 B CN 107478747B CN 201710700674 A CN201710700674 A CN 201710700674A CN 107478747 B CN107478747 B CN 107478747B
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- mobile phase
- target detection
- drugs
- detection thing
- formic acid
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- 239000008280 blood Substances 0.000 title claims abstract description 46
- 231100000614 poison Toxicity 0.000 title claims abstract description 42
- 239000000126 substance Substances 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 32
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- 238000012216 screening Methods 0.000 title claims abstract description 19
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- SHXWCVYOXRDMCX-UHFFFAOYSA-N 3,4-methylenedioxymethamphetamine Chemical compound CNC(C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-UHFFFAOYSA-N 0.000 description 1
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- 230000015556 catabolic process Effects 0.000 description 1
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- 230000009852 coagulant defect Effects 0.000 description 1
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- 239000013078 crystal Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229960004192 diphenoxylate Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 239000011487 hemp Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- HOQADATXFBOEGG-UHFFFAOYSA-N isofenphos Chemical compound CCOP(=S)(NC(C)C)OC1=CC=CC=C1C(=O)OC(C)C HOQADATXFBOEGG-UHFFFAOYSA-N 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960002221 methylephedrine Drugs 0.000 description 1
- 229960001952 metrifonate Drugs 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- HKOIXWVRNLGFOR-KOFBORESSA-N norcodeine Chemical compound O[C@H]([C@@H]1O2)C=C[C@H]3[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4 HKOIXWVRNLGFOR-KOFBORESSA-N 0.000 description 1
- 229950004392 norcodeine Drugs 0.000 description 1
- HKOIXWVRNLGFOR-UHFFFAOYSA-N norcodeine Natural products O1C2C(O)C=CC3C4CC5=CC=C(OC)C1=C5C23CCN4 HKOIXWVRNLGFOR-UHFFFAOYSA-N 0.000 description 1
- 229950006134 normorphine Drugs 0.000 description 1
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- 231100000572 poisoning Toxicity 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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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
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention discloses a kind of liquid chromatography-mass spectrography screening methods of unknown poisonous substance in blood: taking blood sample to be detected, acetonitrile precipitation albumen is added, oscillation, centrifugation, take supernatant, then 0.22 μm of organic membrane filtration of micropore carries out LC-MS/MS analysis, judges whether contain toxins in blood sample to be detected based on the analysis results；Instrument is selected from 3200 QTRAP triplex tandem quadrupole mass spectrometer of AB company ultraLC 100-XL-4000Q TRAP LC-MS instrument or 1100 liquid chromatogram-AB of Agilent.The present invention establishes the detection method of different classes of poisonous substance, detection is quickly, accurately, give the detection limit of common poisons, ensure highly sensitive effective inspection of all kinds of objects, the data supporting of science is provided for negative test result, strong scientific basis is then provided for relevant clinical diagnosis, rescue and criminal investigation, lawsuit.
Description
Technical field
The present invention relates to the liquid chromatography-mass spectrography screening methods of poisonous substance unknown in blood, belong to chemical substance detection technique
Field.
Background technique
Common poisons screening occupies sizable specific gravity in forensic science physical and chemical inspection.Applicant passes through investigation Shandong
Case of being involved in drug traffic in the past 10 years is saved, finds to have the following problems in such case examination of material evidence:
(1) case-involving poison type increased significantly, investigate and prosecute it is certain whether be poisoned in indefinite case, need screening
Poisonous substance is not limited solely to that certain is several or certain is a kind of, i.e., Objective is not strong.In such cases, several if still continuing to use out-of-date methods only
The most common poisonous substance of kind carries out screening, it is most likely that causes missing inspection.
(2) currently, gas chromatography mass spectrometry method is the instrument analytical method that prefectures and cities, the whole province generally grasp and use, the method phase
The sample-pretreating method answered is lack of standardization, also examines or check without optimization.
(3) gas chromatography mass spectrometry method cannot carry out highly sensitive effective inspection to certain poisonous substances by being limited by instrument self performance
It tests.Though prefectures and cities introduce LC-MS equipment successively, it not can be carried out the method exploitation of system, liquid matter cannot be made full use of to join
Poisonous substance detection sensitivity is improved with technology.
(4) though application of the LC-MS in poisonous substance screening appears in the newspapers, pre-treatment step is excessively complicated, and all points
Analysis object is analyzed under unified liquid-phase condition, and the effect is unsatisfactory.Simultaneously as instrument brand, model difference, related
Conditions and data can not be directly as this province forensic science poisonous substance screening foundation.
(5) systematicness examination is carried out using detection limit of the LC-MS technology to case-involving poisonous substance still belong to blank, negative findings
Evaluation lacks the data supporting of science.
In view of the above circumstances, to meet the needs of public security work under the new situation, it is necessary to provide it is a kind of it is with versatility,
Screening method easy to operate.
Summary of the invention
For the above-mentioned prior art, the present invention provides a kind of liquid chromatography-mass spectrography screening sides of unknown poisonous substance in blood
Method.The application system has carried out pesticide (including organic phosphates, carbamates, pyrethroids class, organochlorine class), herbicide (packet
Include amides, heterocyclic oxy group phenoxy group fatty acid), hypnotic sedative activity (including the miscellaneous nitrogen Zhuo class of benzo, phenothiazines, barbital
Other common hypnotic and sedatives such as class and zopiclone), the inspection of raticide, amphetamine, the poisonous substances such as m orphine and other drugs
Proved recipe jurisprudential study obtains their detection limit in optimal conditions, provides data supporting for negative findings evaluation, is then phase
Clinical diagnosis, rescue and criminal investigation, the lawsuit of pass provide strong scientific basis.
The present invention is achieved by the following technical solutions:
The liquid chromatography-mass spectrography screening method of unknown poisonous substance in a kind of blood: taking blood sample 1.0mL to be detected, is added
2.0mL acetonitrile precipitation albumen vibrates 10min, is centrifuged (12000r/min, 5min), takes supernatant, 0.22 μm of organic filter membrane of micropore
Then filtering carries out LC-MS/MS analysis, judges whether contain toxins in blood sample to be detected based on the analysis results；Institute
1100 liquid chromatogram-AB of AB company ultraLC 100-XL-4000Q TRAP LC-MS instrument or Agilent is selected from instrument
3200 QTRAP triplex tandem quadrupole mass spectrometers.
When using AB company ultraLC 100-XL-4000Q TRAP LC-MS instrument, Mass Spectrometry Conditions are as follows: a) ion
Source: electrospray ionisation (ESI)；B) scanning mode: multiple-reaction monitoring pattern (MRM)；C) gas curtain gas (CUR): 20psi；D) it collides
Gas (CAD): Medium；E) spray voltage (IS): 5500 (- 4500) V；F) temperature (TEM): 500 DEG C；G) spraying gas (GS1):
50psi；H) auxiliary heating gas (GS2): 50psi；I) interface heats (ihe): on；J) collision cell entrance potential (EP): 10V；k)
Collision cell exit potential (CXP): 6V；L) it goes cluster voltage (DP), collision energy (CE) parameter sees attached list A.
Liquid-phase chromatographic analysis condition is as follows:
A) when target detection thing is organic phosphorus 1 and carbamates drug: chromatographic column: 1.7 μm of Waters BEH C18
2.1 × 50mm Column, flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are 0.1% formic acid (mass percent), 5mM
Ammonium acetate solution, Mobile phase B are methanol；Eluent gradient elution program is shown in Table 1.
Table 1: eluent gradient elution program
B) when target detection thing is organic phosphorus 2: chromatographic column: 1.7 μm of 2.1 × 50mm Column of Waters BEH C18,
Flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are 5mM ammonium acetate solution, and Mobile phase B is methanol；Eluent gradient is washed
De- program is shown in Table 2.
Table 2: eluent gradient elution program
C) when target detection thing is the miscellaneous nitrogen Zhuo class of benzo, phenothiazines and other cation analytical model drugs: chromatographic column:
1.7 μm of 2.1 × 50mm Column of Waters BEH C18, flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are
0.1% formic acid, 5mM ammonium acetate solution, Mobile phase B are methanol；Eluent gradient elution program is shown in Table 3.
Table 3: eluent gradient elution program
D) when target detection thing is barbiturates and other anion analytical model drugs: chromatographic column: Waters BEH
1.7 μm of 2.1 × 50mm Column of C18, flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are water, and Mobile phase B is first
Alcohol；Eluent gradient elution program is shown in Table 4.
Table 4: eluent gradient elution program
E) when target detection thing is raticide: chromatographic column: 1.7 μm of 2.1 × 50mm Column of Waters BEH C18, stream
Speed: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are 0.1% aqueous formic acid, and Mobile phase B is methanol；Eluent gradient elution
Program is shown in Table 5.
Table 5: eluent gradient elution program
F) when target detection thing is quaternary ammonium salt: chromatographic column: 2.7 μm of 2.1 × 50mm Column of HILIC, flow velocity:
1.0mL/min；Sample volume: 5 μ L, mobile phase A are 0.1% formic acid, 5mM ammonium acetate solution, and Mobile phase B is acetonitrile；Mobile phase
Gradient elution program is shown in Table 6.
Table 6: eluent gradient elution program
G) when target detection thing is drugs class: chromatographic column: 1.7 μm of 2.1 × 50mm Column of Waters BEH C18,
Flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are 0.1% aqueous formic acid, and Mobile phase B is acetonitrile；Eluent gradient is washed
De- program is shown in Table 7.
Table 7: eluent gradient elution program
When using 1100 liquid chromatogram-AB of Agilent, 3200 QTRAP triplex tandem quadrupole mass spectrometer, mass spectrum item
Part are as follows: a) spray voltage (IS): 5500V/-4500V；B) gas curtain gas (CUR): 25psi；C) atomization gas (GS1): 65psi；d)
Auxiliary heating gas (GS2): 55psi；E) temperature degree (TEM) is assisted: 650 DEG C；F) ion residence time: 70ms；G) scan pattern:
MRM；H) retention time of malicious (medicine) object and fragments characteristic ion see attached list B.
Liquid phase chromatogram condition is as follows: chromatographic column: Eclipse XDB-C18 (4.6mm × 150mm, 5 μm)；Sample volume: 10 μ
L；
Liquid chromatogram elution requirement:
A) target detection thing be the miscellaneous nitrogen Zhuo class of benzo, phenothiazines, carbamates, organic phosphates 1 and it is other just from
When sub- analytical model drug: mobile phase: A: methanol；B:5mM NH4AC aqueous solution；C:0.1% aqueous formic acid；Eluent gradient
Setting is shown in Table 8.
The setting of 8 eluent gradient of table
B) when target detection thing is organic phosphates 2: mobile phase: A: methanol；B:5mM NH4AC aqueous solution；Eluent gradient
Setting is shown in Table 9.
The setting of 9 eluent gradient of table
C) when target detection thing is barbiturates and other anion analytical model drugs: mobile phase: A: methanol；B: water；
Eluent gradient setting is shown in Table 9.
D) when target detection thing is raticide class: mobile phase: A: methanol；B:0.1% aqueous formic acid；Eluent gradient setting
It is shown in Table 9.
E) when target detection thing is drugs 1: analysis condition is same a) shown in item.
F) when target detection thing is drugs 2: mobile phase: A: acetonitrile；B:5mM NH4AC aqueous solution；C:0.1% formic acid is water-soluble
Liquid；Eluent gradient setting is shown in Table 8.
G) when target detection thing is drugs 3: mobile phase: A: acetonitrile；B:0.1% aqueous formic acid；Eluent gradient setting
It is shown in Table 9.
Target detection thing referred to above is classified as follows:
(1) organic phosphorus 1 (13 kinds): methidathion, Azodrin, flolimat, parathion-methyl, orthene, chlopyrifos,
Phosalone, sulfotep, malathion, Isofenphos methyl, DDVP, acephatemet, Rogor.
(2) organic phosphorus 2 (4 kinds): thimet, parathion, Terbufos, phoxim.
(3) carbamates drug (8 kinds): Aphox, carbofuran, Methomyl, MTMC, Mobucin, Aldicarb, tears
Wire of going out sulfone, Aldicarb sulfone.
(4) the miscellaneous nitrogen Zhuo class drug of benzo (12 kinds): stable, alprazolam, Lorazepam, estazolam, triazolam, chlorine nitrogen
Flat, librium, carbamazepine, midazolam maleate, Oxazepam, clonazepam, 7- amino clonazepam.
(5) barbiturate (5 kinds): barbital, phenobarbital, amytal, allyl isopropyl barbital, speed can
It sleeps.
(6) phenothiazines (5 kinds): chlorpromazine, promethazine hydrochloride, imipramine, triperazine, perphenazine.
(7) quaternary ammonium salt drug (a kind): paraquat.
(8) raticide (2 kinds): Bromadiolone, Brodifacoum.
(9) drugs (22 kinds):
Drugs 1: cannabidiol, tetrahydrocannabinol；
Drugs 2: methcathinone, cocaine, morphine and codeine and their derivative；
Drugs 3: Cathinone, common amphetamine and other drugs；
(10) other drugs:
A: cation analytical model drug (17 kinds): aminopyrine, zopiclone, doxepin, amitriptyline, miltown,
Pethidine hydrochloride, antipyrine, caffeine, chlorpheniramine, Tai Erdeng, prednisone acetate, fentanyl citrate, Triamcinolone acetonide, salt
Sour diphenoxylate, brufen, Halcinonide, SKF525。
B: anion analytical model drug (2 kinds): phenytoinum naticum, analgin.
Further, with the target detection thing from the addition detection limit concentration to blank blood sample or internal standard compound (cation of
Mode internal standard compound is SKF525A, negative ion mode internal standard compound is allyl isopropyl barbital) and it is used as negative control, with to blank blood
2~5 times of amount target detection things of detection limit concentration are added in liquid sample as positive control；It is evaluated according to testing result:
Under identical experiment condition, the chromatographic peak retention time and addition target detection that occur in blood sample to be detected
The chromatographic peak retention time of the control sample of object compares, and relative deviation is in ± 5%, and fragments characteristic ion occurs, institute
The ion relative abundance of selection is no more than model as defined in table 10 than the relative error of the ion relative abundance ratio with addition reference substance
It encloses, then can determine whether that there are this compounds in sample.
The maximum allowable relative error (%) of 10 relative ion abundance ratio of table
Positive findings evaluation: if detecting Appendix B/appendix C toxicity ingredient in blood sample to be detected, and blank blood
Sample is noiseless, then positive findings are reliable；If detecting toxins in blood sample to be detected and blank blood sample being also in
The positive, then positive findings are unreliable.
Negative findings evaluation: blank, which is added, detects respective objects object or internal standard compound in sample, and in blood sample to be detected
Related poisonous substance is not detected, then negative findings are reliable；If respective objects object or internal standard compound is not detected in blank addition sample, yin
Property result is unreliable.
The liquid chromatography-mass spectrography screening method of unknown poisonous substance, establishes the inspection of different classes of poisonous substance in blood of the invention
Survey method, detection quickly, accurately, optimize liquid phase chromatogram condition, Mass Spectrometry Conditions, give common poisons and (cover method substantially
The common poisons that front yard scientific domain is related to) detection limit (seeing attached list C), it is ensured that highly sensitive effective inspection of all kinds of objects is
Negative test result provides the data supporting of science, then provides for relevant clinical diagnosis, rescue and criminal investigation, lawsuit
Strong scientific basis.In project research process, project team constantly summarizes each stage research achievement, and in time with reality
Border, which is handled a case, to be combined, and is run reason case more than 100 jointly and is risen, obtains accurate, reliable qualification result, played project research achievement
It acts under battle conditions.
Detailed description of the invention
Fig. 1: the miscellaneous nitrogen Zhuo class of benzo and phenothiazines (methanol) spectrogram.Fig. 2: the miscellaneous nitrogen Zhuo class of benzo and phenothiazines medicine
Object (acetonitrile) spectrogram.Fig. 3: organic phosphorus 1 (methanol) spectrogram.Fig. 4: organic phosphorus 1 (acetonitrile) spectrogram.Fig. 5: raticide (methanol) spectrogram.
Fig. 6: raticide (acetonitrile) spectrogram.Fig. 7: drugs (acetonitrile) spectrogram.Fig. 8: drugs (methanol) spectrogram.Fig. 9: organic phosphorus 1 and amino first
Esters of gallic acid drug (5mM NH4- 0.1% aqueous formic acid of AC aqueous solution) spectrogram.Figure 10: organic phosphorus 1 and carbamates medicine
Object (0.1% formic acid) spectrogram.Figure 11: organic phosphorus 1 and carbamates drug (5mM NH4AC) spectrogram.Figure 12: organic phosphorus 2
(5mM NH4AC) spectrogram.Figure 13: organic phosphorus 2 (5mM NH4- 0.1% aqueous formic acid of AC aqueous solution) spectrogram.Figure 14: organic phosphorus 2
(0.1% formic acid) spectrogram.Figure 15: barbiturate (pure water) spectrogram.Figure 16: barbiturate (0.1% formic acid) spectrogram.
Figure 17: barbiturate (5mM NH4AC) spectrogram.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.
Instrument involved in following embodiments, reagent, material etc. are unless otherwise noted existing in the prior art
Conventional instrument, reagent, material etc., can be obtained by regular commercial sources.Experimental method involved in following embodiments, inspection
Survey method etc. is unless otherwise noted existing routine experiment method in the prior art, detection method etc..
Test 1 liquid phase chromatogram condition optimization (AB Sciex ultraLC 100-XL-4000Q TRAP LC-MS system
Liquid-phase condition optimization)
The property of reagent selected by liquid chromatogram mobile phase has larger shadow to the reservation of analyte, peak shape and sensitivity
It rings.In this research, we select common agents methanol or acetonitrile respectively to examine or check analysis of organic phase constituent to inhomogeneity poisonous substance
Effect.On this basis, to the poisonous substance for being suitable for cation analytical model, respectively in 0.1% aqueous formic acid, 5mM NH4AC
Aqueous solution or 5mM NH4Water-phase component is examined or check under the conditions of AC aqueous solution and 0.1% aqueous formic acid mix reagent to the shadow of analysis
It rings, to the poisonous substance for being suitable for anion analytical model, respectively in pure water, 5mM NH4AC aqueous solution or 0.1% aqueous formic acid item
Influence of the water-phase component to analysis is examined or check under part.
(1) selection of organic phase: from experimental conditions as can be seen that the miscellaneous nitrogen Zhuo class of benzo and phenothiazines are with methanol
Or acetonitrile as organic solvent when, can appearance, the peak width of most analytes within 0.1min, but use acetonitrile
When, miltown peak shape is bad, and Oxazepam and clonazepam sensitivity are very poor (referring to Fig. 1, Fig. 2).Organic phosphates, barbital
Class, paraquat and other medicines when using methanol or acetonitrile as organic solvent, can appearance, and peak width is in 0.1-0.2min
Left and right (referring to Fig. 3~Fig. 4).Raticide class under the conditions of two kinds of organic phases can appearance, but utilize acetonitrile be organic phase when, mesh
It is poor to mark object peak shape, peak width is in 0.3min or so, and when with methanol, and peak shape and sensitivity have very big improvement, and peak width exists
0.15min or so (referring to Fig. 5, Fig. 6).To sum up, the peak shape and detection sensitivity of all kinds of all drugs are taken into account, selecting methanol to be used as has
Machine phase reagent.
When drugs class drug uses methanol or acetonitrile as organic solvent, can appearance, but in peak shape methanol not as good as acetonitrile effect
Fruit is good, and when using acetonitrile being organic phase, peak width in 0.15min or so, and when with methanol, (join between 0.2-0.3min by peak width
See Fig. 7, Fig. 8), therefore drugs class uses acetonitrile as organic phase.
(2) optimization of water phase composition: can be seen that various drugs equal energy appearance under the conditions of different water phases by experiment, but
There are the difference of peak shape and response, the miscellaneous nitrogen Zhuo of benzo, phenothiazines, organic phosphorus 1, carbamates poisonous substance and paraquat exist
Under the conditions of three kinds of water phases, peak width is within 0.1-0.2min, in contrast, uses 5mM NH4AC aqueous solution and 0.1%
When aqueous formic acid mix reagent, peak shape and response are better than other two kinds (referring to Fig. 9~Figure 11), therefore use 5mM
NH4AC aqueous solution and 0.1% aqueous formic acid mix reagent are as water phase.Organic phosphorus 2 under the conditions of three kinds of water phases, peak shape compared with
Good, peak width is using 5mM NH between 0.1-0.2min4When AC aqueous solution is as water phase, 4 kinds of object response highests
(referring to Figure 12~Figure 14), so selecting 5mM NH4AC aqueous solution is as water phase reagent.Barbiturates and suitable for anion point
Peak width is between 0.1-0.2min in three kinds of water phases for the other medicines of analysis mode, when using pure water, response highest (referring to
Figure 15~Figure 17)；And drugs and raticide are best using 0.1% aqueous formic acid analytical effect.
Test the liquid-phase condition optimization of 3200 QTRAP LC-MS system of 2Agilent 1100-AB Sciex
(1) selection of organic phase
From experimental conditions as can be seen that the miscellaneous nitrogen Zhuo class drug of benzo is when using methanol or acetonitrile as organic solvent, equal energy
Appearance, and signal strength no significant difference.Under relatively low flow conditions, the peak width of most analytes is in 0.5-
Between 0.75min, but when using acetonitrile, Clozapine spectral peak is broadened to 3min or so.Different organic solvents are to phenothiazines medicine
The influence of object analysis clearly, such analyte not appearance when using acetonitrile, and good detection can be obtained in methanol when.
Barbiturate and carbamate chemicals for agriculture when using methanol or acetonitrile as organic solvent, can appearance, and peak width is equal
In 0.5min or so.In contrast, the signal strength differences of Aphox and Aldicarb under two kinds of reagent conditions are little, and other
Detection sensitivity of several analytes under the conditions of methanol is substantially better than acetonitrile.When being analyzed with methanol organic phosphates, mesh
Mark object can obtain good detection, and when with acetonitrile, parathion-methyl in 20min do not mix by appearance, metrifonate, DDVP, first
Phosphorus, parathion, Terbufos response are very low, and the signal strength of other several analytes is also markedly less than methanol.Raticide class is at two kinds
Under the conditions of organic phase can appearance, but utilize acetonitrile be organic phase when, object peak shape is very poor, and sensitivity is low, and uses methanol
When, peak shape and sensitivity have very big improvement.Analysis to other Common drugs, if using acetonitrile as organic phase, amitriptyline
Appearance, caffeine do not trail seriously with doxepin, and peak shape is very poor.Aminopyrine, zopiclone, pethidine hydrochloride, caffeine, peace
Though can be detected for substances more several than woods etc., when signal intensity ratio methanol, is much lower.In drugs substance, cannabidiol is removed
Signal strength is substantially better than outside acetonitrile under the conditions of methanol with tetrahydrocannabinol, and other analytes are had more under the conditions of acetonitrile
High detection sensitivity.To sum up, the peak shape and detection sensitivity of all kinds of cytotoxic drugs are taken into account, common poisons class, which selects methanol to be used as, to be had
Machine phase reagent；In drugs in addition to cannabidiol and tetrahydrocannabinol select methanol, it is organic phase that other analytes, which select acetonitrile,.
(2) optimization of water phase composition
Pass through experiment, it has been found that the cannabidiol and tetrahydro suitable for the common poisons of positive ion mode and drugs are big
Numb phenol, when using 0.1% aqueous formic acid as water phase, signal strength is substantially reduced, but partial target object peak shape makes moderate progress,
Comprehensively consider detection sensitivity and peak shape, we are emphatically to 5mM NH4AC and 5mM NH4- 0.1% aqueous formic acid of AC aqueous solution
The analysis situation of mix reagent compares；Other drugs in addition to cannabidiol and tetrahydrocannabinol, use 5mM NH4AC
When for water phase, even there is broadening and forms to 4min or so in generally existing trailing phenomenon, cannabinol spectral peak corresponding with methadone
The case where to wrap greatly, and the detection sensitivity of analyte is not high.In consideration of it, we focus on to 0.1% formic acid to these drugs
Aqueous solution and 5mM NH4The analysis situation of -0.1% aqueous formic acid mix reagent of AC aqueous solution is compared.
The miscellaneous nitrogen Zhuo class 5mM NH of benzo4When AC is as water phase, alprazolam, Lorazepam, estazolam, triazolam,
Clozapine, librium, carbamazepine, midazolam peak shape are bad, and with 5mM NH4AC-0.1% formic acid mix reagent conduct
When water phase, all analytes can not only obtain good peak shape, but also the signal response of most objects has obviously
Enhancing.
Phenothiazines 5mM NH4When AC is as water phase, object peak trails and most of chromatographic peak has bifurcated tendency,
Peak width is between 0.75min-1min.With 5mM NH4When AC-0.1% formic acid mix reagent is as water phase, all analyte peak shapes
Well, peak width is in 0.25min or so.In addition to triperazine, the signal response of other analytes is remarkably reinforced.
Carbamates 5mM NH4When AC is as water phase, there is bifurcated tendency at object peak, and peak width is in 0.4min-
Between 0.6min.With 5mM NH4When AC-0.1% formic acid mix reagent is as water phase, the peak width of all analytes narrows, and
Peak shape is improved.Wherein, the signal response difference of Methomyl and Aldicarb under two kinds of reagent conditions is little, other analytes
When with mixing water phase reagent, sensitivity is improved.
Organic phosphates 5mM NH4When AC-0.1% formic acid mix reagent is as water phase, object peak shape is improved, but
It is four kinds of thimet, parathion, phoxim, Terbufos analytes when using mix reagent, signal strength decline is more apparent.
Other medicines 5mM NH4When AC is as water phase, doxepin, amitriptyline, pethidine hydrochloride hangover are serious, peak width
Between 0.8min to 1min.When using mix reagent as water phase, peak shape is greatly improved, response signal enhancing.
When barbiturates use pure water as water phase, signal is most strong, uses 5mM NH instead4AC or when 0.1% formic acid, signal has
Different degrees of reduction.
Raticide class: under the conditions of three kinds of water phases, pure water signal is most strong, and 0.1% formic acid takes second place, 5mM NH4AC is worst.But make
When with pure water, Bromadiolone appearance is bimodal, and Brodifacoum spectral peak obviously divides.
Cannabidiol and tetrahydrocannabinol 5mM NH4AC or 5mM NH4AC-0.1% formic acid mix reagent is as water phase
When, peak shape is preferable, and sensitivity is close.
In other drugs, amphetamine, crystal methamphetamine, MDA, Cathinone, methadone are better than with 0.1% aqueous formic acid
5mM NH4AC-0.1% formic acid mix reagent；Methcathinone, morphine, Norcodeine, normorphine, cocaine 5mM
NH4AC-0.1% formic acid mix reagent effect is more preferable；MDMA, MDEA, 6- acetylmorphine, codeine, 6- codeine, hemp
Phenol, ephedrine, methylephedrine, ketamine effect under the conditions of two kinds of water phases are close.
Comprehensively consider various kinds of drug analysis situation, the miscellaneous nitrogen Zhuo class of benzo, phenothiazines, carbamate in common poisons
Class, organic phosphates 1 (methidathion, Azodrin, flolimat, parathion-methyl, orthene, sulfotep, malathion, first
Base isofenphos, DDVP, acephatemet, Rogor) and suitable for positive ion mode other common poisons select 5mM NH4AC-
The mix reagent of 0.1% formic acid is as water phase；Thimet, parathion, phoxim and Terbufos are because of signal in acid condition
It is substantially reduced, so selecting 5mM NH4AC is as water phase；Barbiturates and suitable for anion analytical model other medicines select
Use pure water；Raticide class selects 0.1% formic acid as water phase.In common drugs, cannabidiol, tetrahydrocannabinol, cocaine, first card
Western ketone, morphine and codeine and their derivative select 5mM NH4The mix reagent of AC-0.1% formic acid is as water phase；Cassie
Ketone, amphetamine and other drugs select 0.1% aqueous formic acid as water phase.
Test the influence of 3 flow rate of mobile phase
The influence that we choose carbamates respectively and raticide class examines flow velocity to analysis.When flow velocity is 0.7mL/
When min, most of carbamates analyte spectral peaks have bifurcation, and raticide class spectral peak is wider；Flow velocity is promoted to
After 1.0mL/min, analyte retention time shortens, and peak shape is improved.Below in experiment, flow rate of mobile phase is disposed as
1.0mL/min。
Test 4 matrix interferences
Precision draws 12 parts of blank whole bloods and each 1mL of blank water, is divided into 3 groups.Every group is added standard substance, concentration point respectively
Not Wei 20,50,100ng/mL, by 1.5 whole blood sample processing item methods handle measure, from experimental result as can be seen that each drug
It is close with signal strength in water in blood, it was demonstrated that directly to can be very good the base in removal blood with acetonitrile precipitation albumen
Matter interference, this sample-pretreating method are simple and effective.Specific data are shown in Table 11.
The blood matrix of 11 barbiturate of table influences examination
Test 5 method stability tests
Precision draws 12 parts of each 1mL of blank whole blood, adds standard substance solution amytal (20ng/mL), department respectively
It can barbital (20ng/mL), stable (1ng/mL), chlorpromazine (5ng/mL), Bromadiolone (1ng/mL), flolimat (2ng/
ML), carbofuran (1ng/mL), Azodrin (1ng/mL), phoxim (20ng/mL), Terbufos (20ng/mL), phenytoinum naticum
(20ng/mL), chlorpheniramine (2ng/mL), fentanyl (20ng/mL), cannabinol (20ng/mL), ephedrine (20ng/mL), chloramines
Ketone (20ng/mL) is handled by whole blood sample processing item method and is measured, and relative standard deviation is 2.8%-9.8% (n=12), is seen
Table 12, table 14.
The stability of 12 barbiturate of table
Case on December 18th, 1: 2015,19 days, Zibo high and new technology industrial development zone Liu Zhi successively occur with girl friend Sun Qi plum by force abdominal pain,
The symptoms such as hematuria, and gradually aggravate, hospital checks display coagulation disorders.To find out cause of disease symptomatic treatment, December 28, mention
Liu Zhiqiang, Sun Qimei venous blood and Liu Zhi Qiang Jiazhong soy cruet inspection are taken, is analyzed through LC-MS instrument, detection raticide Bromadiolone
Ingredient, patient are given treatment in time.Conclusion accordingly has further investigated thoroughly that suspect Chen Lin says good-bye therewith because being discontented with Liu Zhiqiang, steathily
Liu Zhiqiang dwelling is slipped into steathily and launches the crime fact that Bromadiolone causes it to be poisoned in soy cruet, this plays revenge and poisons case water falling rocks
Out.
When case on June 17th, 2: 2016, shop Zhu Hui and male's client meetings, the drink that the client provides is drunk
It goes into a coma after material.Next day is suspected by fan traitor, after reporting a case to the security authorities, extracts the blood sample of Zhu Hui, though by tens hours catabolism, liquid matter connection
Hypnotic sedative class drug clonazepam, aminopyrine ingredient are still therefrom detected with instrument.
Case on July 1st, 3: 2016, the new alarm of the neat member of the high valley villager in Yiyuan County Shandong villages and small towns claim: he is from June, 2016
Start saliva morning on the 26th, discovery has blood in the mouth, and leg also aches, and symptom is increasingly severe within several later days, on the face, in nose, tooth
Oulorrhagia；It is blue on leg, swollen；It dare not walk, foot aches once the leg that lands.On June 30th, 2016 goes to Yiyuan County hospital to be examined
It looks into, doctor does not give definite diagnosis to its illness, only suspects that poisoning causes.After my physical and chemical room accepts this case, set about being aligned immediately
Member newly eats used soy sauce, vinegar, barreled peanut oil, white wine, salt, white sugar, little cake and Qi Yuanxin blood and tests, neat from sending
Raticide Brodifacoum ingredient is detected in first new blood.
Case on August 16th, 4: 2016, wife Qi Yuanxin Liu Tonglan alarm claims: she went to Linzhou City on June 8th, 2016
There is that leg back is blue, bleeding in the mouth the day before yesterday of daughter man, area, after going to Linzhou City to build hospital admission, when one section of traumatism treatment
Time restores normal.And occurs bleeding in the mouth second day since after the family that on July 23rd, 2016 returns to Yiyuan Lu Cun, has a pain in the leg
Deng similar symptom, without specific diagnostic result after going to Yiyuan County Yiyuan medical.After the merit is learnt in my physical and chemical room, it is desirable that the Yihe River
As long as the edible sample that source county telephone central office policeman in charge of the case Liu Tonglan August contacts after going home for 16th all extracts inspection, and from sent metal
Vegetable oil in bucket and detection raticide Brodifacoum ingredient in the blood of Liu Tonglan provide key evidence for the qualitative of case.
Subordinate list A
Instrument (AB ultraLC 100-XL-4000Q TRAP) is to the analysis parameter of 89 kinds of poison (medicine) objects and 2 kinds of internal standard compounds
Subordinate list B
Analysis of the instrument (Agilent 1100-AB Sciex 3200Q TRAP) to 84 kinds of poison (medicine) objects and a kind of internal standard compound
Parameter
Detection limit of the subordinate list C drug on AB Sciex ultraLC 100-XL-4000QTRAP
Claims (8)
1. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in a kind of blood, it is characterised in that: blood sample to be detected is taken,
Acetonitrile precipitation albumen is added, vibrates, centrifugation takes supernatant, then 0.22 μm of organic membrane filtration of micropore carries out LC-MS/MS points
Analysis, judges whether contain toxins in blood sample to be detected based on the analysis results；Instrument is selected from AB company ultraLC
3200 QTRAP triplex tandem quadrupole of 100-XL-4000Q TRAP LC-MS instrument or 1100 liquid chromatogram-AB of Agilent
Bar mass spectrograph；
When using AB company ultraLC 100-XL-4000Q TRAP LC-MS instrument, Mass Spectrometry Conditions are as follows: a) ion source: electricity
Spraying ionization；B) scanning mode: multiple-reaction monitoring pattern；C) gas curtain gas: 20psi；D) collision gas: Medium；E) spray voltage:
5500/-4500V；F) temperature: 500 DEG C；G) spraying gas: 50psi；H) auxiliary heating gas: 50psi；I) interface heats: on；J) it touches
Hit chamber inlet voltage: 10V；K) collision cell exit potential: 6V；L) cluster voltage is removed；
Liquid-phase chromatographic analysis condition is as follows:
A) when target detection thing is organic phosphorus 1 and carbamates drug: chromatographic column: 1.7 μm 2.1 of Waters BEH C18
× 50mm Column, flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are 0.1% formic acid, 5mM ammonium acetate solution, stream
Dynamic phase B is methanol；
B) when target detection thing is organic phosphorus 2: chromatographic column: 1.7 μm of 2.1 × 50mm Column of Waters BEH C18, stream
Speed: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are 5mM ammonium acetate solution, and Mobile phase B is methanol；
C) when target detection thing is the miscellaneous nitrogen Zhuo class of benzo, phenothiazines and other cation analytical model drugs: chromatographic column:
1.7 μm of 2.1 × 50mm Column of Waters BEH C18, flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are
0.1% formic acid, 5mM ammonium acetate solution, Mobile phase B are methanol；
D) when target detection thing is barbiturates and other anion analytical model drugs: chromatographic column: Waters BEH C18
1.7 μm of 2.1 × 50mm Column, flow velocity: 0.3mL/min；Sample volume: 2 μ L, mobile phase A are water, and Mobile phase B is methanol；
E) when target detection thing is raticide: chromatographic column: 1.7 μm of 2.1 × 50mm Column of Waters BEH C18, flow velocity:
0.3mL/min；Sample volume: 2 μ L, mobile phase A are 0.1% aqueous formic acid, and Mobile phase B is methanol；
F) when target detection thing is quaternary ammonium salt: chromatographic column: 2.7 μm of 2.1 × 50mm Column of HILIC, flow velocity: 1.0mL/
min；Sample volume: 5 μ L, mobile phase A are 0.1% formic acid, 5mM ammonium acetate solution, and Mobile phase B is acetonitrile；
G) when target detection thing is drugs class: chromatographic column: 1.7 μm of 2.1 × 50mm Column of Waters BEH C18, flow velocity:
0.3mL/min；Sample volume: 2 μ L, mobile phase A are 0.1% aqueous formic acid, and Mobile phase B is acetonitrile；
When using 1100 liquid chromatogram-AB of Agilent, 3200 QTRAP triplex tandem quadrupole mass spectrometer, Mass Spectrometry Conditions
Are as follows: a) spray voltage: 5500V/-4500V；B) gas curtain gas: 25psi；C) atomization gas: 65psi；D) auxiliary heating gas: 55psi；
E) auxiliary temperature degree: 650 DEG C；F) ion residence time: 70ms；G) scan pattern: MRM；
Liquid phase chromatogram condition is as follows: chromatographic column: Eclipse XDB-C18,4.6mm × 150mm, 5 μm, flow rate of mobile phase is set as
1.0mL/min；
Liquid chromatogram elution requirement:
A) target detection thing is the miscellaneous nitrogen Zhuo class of benzo, phenothiazines, carbamates, organic phosphates 1 and other cations point
When analysing model drug: mobile phase: A: methanol；B:5mM NH4AC aqueous solution；C:0.1% aqueous formic acid；
B) when target detection thing is organic phosphates 2: mobile phase: A: methanol；B:5mM NH4AC aqueous solution；
C) when target detection thing is barbiturates and other anion analytical model drugs: mobile phase: A: methanol；B: water；
D) when target detection thing is raticide class: mobile phase: A: methanol；B:0.1% aqueous formic acid；
E) when target detection thing is drugs 1: analysis condition is same a) shown in item；
F) when target detection thing is drugs 2: mobile phase: A: acetonitrile；B:5mM NH4AC aqueous solution；C:0.1% aqueous formic acid；
G) when target detection thing is drugs 3: mobile phase: A: acetonitrile；B:0.1% aqueous formic acid；
Target detection thing referred to above is classified as follows:
(1) organic phosphorus 1: methidathion, Azodrin, flolimat, parathion-methyl, orthene, chlopyrifos, Phosalone,
Sulfotep, malathion, Isofenphos methyl, DDVP, acephatemet, Rogor；
(2) organic phosphorus 2: thimet, parathion, Terbufos, phoxim；
(3) carbamates drug: Aphox, carbofuran, Methomyl, MTMC, Mobucin, Aldicarb, Tinidazole glucose injection,
Aldicarb sulfone；
(4) the miscellaneous nitrogen Zhuo class drug of benzo: stable, alprazolam, Lorazepam, estazolam, triazolam, Clozapine, librium,
Carbamazepine, midazolam maleate, Oxazepam, clonazepam, 7- amino clonazepam；
(5) barbiturate: barbital, phenobarbital, amytal, allyl isopropyl barbital, secobarbital sodium；
(6) phenothiazines: chlorpromazine, promethazine hydrochloride, imipramine, triperazine, perphenazine；
(7) quaternary ammonium salt drug: paraquat；
(8) raticide: Bromadiolone, Brodifacoum；
(9) drugs:
Drugs 1: cannabidiol, tetrahydrocannabinol；
Drugs 2: methcathinone, cocaine, morphine and codeine and their derivative；
Drugs 3: Cathinone, amphetamine；
(10) other drugs:
A: cation analytical model drug: aminopyrine, zopiclone, doxepin, amitriptyline, miltown, pethidine hydrochloride,
Antipyrine, caffeine, chlorpheniramine, Tai Erdeng, prednisone acetate, fentanyl citrate, Triamcinolone acetonide, diphenoxylate hydrochloride,
Brufen, Halcinonide, SKF525；
B: anion analytical model drug: phenytoinum naticum, analgin.
2. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood according to claim 1, it is characterised in that: with
The target detection thing or internal standard compound for adding detection limit concentration into blank blood sample are as negative control, positive ion mode internal standard
Object is SKF525A, negative ion mode internal standard compound is allyl isopropyl barbital；It is dense to add detection limit into blank blood sample
2~5 times of amount target detection things of degree are as positive control；It is evaluated according to testing result:
Under identical experiment condition, the chromatographic peak retention time and the addition target detection thing that occur in blood sample to be detected
The chromatographic peak retention time of control sample compares, and relative deviation is in ± 5%, and fragments characteristic ion occurs, selected
Ion relative abundance than with addition reference substance ion relative abundance ratio relative error be no more than table 10 as defined in range, then
It can determine whether that there are this compounds in sample；
The maximum allowable relative error (%) of 10 relative ion abundance ratio of table
3. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood according to claim 1, it is characterised in that: when
When using AB company ultraLC 100-XL-4000Q TRAP LC-MS instrument, a)~g) in eluent gradient elution program according to
It is secondary as shown in 1~table of table 7:
Table 1: eluent gradient elution program
Table 2: eluent gradient elution program
Table 3: eluent gradient elution program
Table 4: eluent gradient elution program
Table 5: eluent gradient elution program
Table 6: eluent gradient elution program
Table 7: eluent gradient elution program
4. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood according to claim 1, it is characterised in that: when
When using 1100 liquid chromatogram-AB of Agilent, 3200 QTRAP triplex tandem quadrupole mass spectrometer, a)~g) in mobile phase ladder
Degree elution program is successively as shown in table 8, table 9, table 9, table 9, table 8, table 8, table 9:
The setting of 8 eluent gradient of table
The setting of 9 eluent gradient of table
5. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood according to claim 1, it is characterised in that: when
When using AB company ultraLC 100-XL-4000Q TRAP LC-MS instrument, cluster voltage is removed, collision energy parameter sees attached list A.
6. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood according to claim 1, it is characterised in that: when
When using 1100 liquid chromatogram-AB of Agilent, 3200 QTRAP triplex tandem quadrupole mass spectrometer, the retention time of object
B is seen attached list with fragments characteristic ion.
7. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood according to claim 1, it is characterised in that: when
When using AB company ultraLC 100-XL-4000Q TRAP LC-MS instrument, the detection limit of object is referring to subordinate list C.
8. the liquid chromatography-mass spectrography screening method of unknown poisonous substance in blood according to claim 1, it is characterised in that: take
2.0mL acetonitrile precipitation albumen is added in blood sample 1.0mL to be detected, vibrates 10min, centrifugation, 12000r/min, 5min take
Then clear liquid, 0.22 μm of organic membrane filtration of micropore carry out LC-MS/MS analysis, judge blood sample to be detected based on the analysis results
Whether contain Toxic in product.
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| CN107991420A (en) * | 2018-01-25 | 2018-05-04 | 北京和合医学诊断技术股份有限公司 | The liquid phase chromatography analytical method of carbamazepine content in a kind of detection blood |
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| CN113109491A (en) * | 2020-01-13 | 2021-07-13 | 四川基因格司法鉴定中心 | Universal method for detecting toxic drugs from biological samples |
| CN114646711B (en) * | 2020-12-21 | 2023-06-23 | 四川科瑞德制药股份有限公司 | Method for detecting hydroxymethyl phenytoin related impurities |
| CN112903849B (en) * | 2021-01-21 | 2021-11-30 | 山东英盛生物技术有限公司 | Method and kit for detecting eszopiclone content in blood and application of kit |
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