CN1609610A - Combined liquid determining method for synchronous detecting several kinds of drugs in urine - Google Patents

Combined liquid determining method for synchronous detecting several kinds of drugs in urine Download PDF

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CN1609610A
CN1609610A CN 200310108134 CN200310108134A CN1609610A CN 1609610 A CN1609610 A CN 1609610A CN 200310108134 CN200310108134 CN 200310108134 CN 200310108134 A CN200310108134 A CN 200310108134A CN 1609610 A CN1609610 A CN 1609610A
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drugs
urine
sample
urine sample
interior mark
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CN100381812C (en
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张玉荣
刘罡一
张润生
余琛
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Criminal Investigation General Team, Shanghai Public Security Bureau
Xuhui District Central Hospital, Shanghai
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XUHUI DISTRICT CENTRAL HOSPITAL SHANGHAI
SHANGHAI MUNICIPAL CRIMINAL SCIENCE AND TECHNOLOGY INST
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Abstract

The present invention is hygroplasm combining detection method for detecting several kinds of drugs in urine. The present invention features that based on practical sample condition and required detection sensitivity, the sample is first pre-treated via solid phase extraction, direct deposition or direct sample feeding, and then gradient eluted in linked chromatographic column with SKF525A as internal reference and water or methanol containing formic acid as flow phase. The method is simple and reliable in the quantitative detection of 19 kinds of drugs and has its methodologic indexes meeting the practical requirement.

Description

Detect the determination method by liquid chromatography-electrospray mass of multiple drugs in the urine simultaneously
Technical field
The present invention relates to a kind of method that detects multiple drugs in the urine simultaneously, more specifically relate to a kind of can be simultaneously to 19 kinds of LC-MS/MS methods that drugs carry out quantitative measurement in the urine.
Background technology
Current drugs and the precursor chemicals case of relating to, its kind and quantity are the trend of being growing on and on, and drugs and easy system are poisoned compound, and particularly the analytical control speed to the newtype drugs can't satisfy the requirement of handling a case.For the analysis of external drugs and precursor chemicals, the main at present analytical approachs such as chemical analysis, vapor-phase chromatography, high performance liquid chromatography, gas chromatography mass spectrometry method that adopt.Document has been reported application (Gu Jingkai, Xia Rong, Zhong Dafang etc., the Acta Pharmaceutica Sinica 2002,37 (2): 138 of LC-MS method in drugs are analyzed in succession in recent years; Moore KA, Sklerov J, Levine B etc., J.Analytical Toxicology 2001,25 (7): 583; Yuan HD, Mester Z, Lord H etc., J.Analytical Toxicology 2000,24 (8): 718; Tatsuno M, Nishikawa M, Katagi M, etc., J.Analytical Toxicology 1996,20 (5): 281).But in above-mentioned LC-MS method, be research, the variety classes drugs are not still had a kind of analytical approach of versatility, so the analysis of unknown drugs is lacked practicality at a certain class drugs or a few drugs potpourri.In addition, the drugs analysis exists tangible impurity interference in the urine sample, thereby has influenced the accuracy and the reliability of check.And the analysis operation step complexity of drugs in the existing urine sample, analytical cycle is long, is difficult to realize the rapid screening analysis of suspicious urine sample.
Summary of the invention
The objective of the invention is to overcome the defective that to measure a kind of or a few drugs in the prior art, a kind of LC-MS method that can detect multiple drugs content in the urine effectively is provided, this method is intended to comprising related various drugs in the existing case substantially, to satisfy the needs of real work.
The LC-MS method that the present invention sets up adopts 19 kinds of drugs in the chromatographic process analysis urine one time, comprises alprazolam, cocaine, codeine, diazepam, estazolam, Flunitrazepam, Flurazepam, heroin, ketamine, MDMA, methadone, meth, methaqualone, midazolam, morphine, nitrazepam, pethidine, pholcodine and triazolam.Quantitative employing internal standard method of the present invention, internal standard compound is SKF 525A
The inventive method may further comprise the steps:
One, sample preparation: actual conditions per sample and to the requirement of detection sensitivity, sample preparation can be selected solid phase extraction, direct precipitation method or direct injected method for use.Wherein solid phase extraction has good clean-up effect, is applicable to the urine sample Treatment Analysis of various turbidity grades; Be urine sample clearly for the turbidity grade, can consider to adopt easy direct precipitation method; And when sample size to be analyzed only be 3-5, and the turbidity grade also can be considered the more easy direct injected method of employing during for urine sample clearly.
1, the operation steps of solid phase extraction is: adopt commercially available solid-phase extraction column, its filler can be bondings such as C18, C8, CN and phenyl sorptive material such as silica gel or macroreticular resin mutually, its loading amount specification can be the 0.01-1 gram, by solid-phase extraction column operation instructions method pillar is activated, common available methyl alcohol, each 1mL of water cross the post activation, get 1mL then and contain an amount of interior target urine sample upper prop, contain 0.1-10% (V/V) methanol in water drip washing pillar with 1mL again, the pillar vacuum is drained back 1mL methanol-eluted fractions.
The sample that is higher than detectability for drugs concentration wherein can be with the meoh eluate direct injected, and the sample that is lower than detectability for drugs concentration wherein can dry up meoh eluate nitrogen the back contains 0.02～0.2% (V/V) formic acid with 0.1mL aqueous solution dissolving back sample introduction.
2, the operation steps of direct precipitation method is: get urine sample 100 μ L and add an amount of inner mark solution, add 2 times of amount acetonitrile solutions after vortex mix, with 12000 rev/mins speed high speed centrifugations sample introduction after 2 minutes.
3, the operation steps of direct injected method is: get urine sample 100 μ L, add that vortex mixes behind an amount of inner mark solution, with 12000 rev/mins speed high speed centrifugations sample introduction after 2 minutes.
Inner mark solution can adopt and contain SKF in the above-mentioned preprocess method 525A0.01-0.001mgmL -1Methanol solution, consumption is generally about 5 μ L-10 μ L; Target concentration can be controlled in 50ngmL in the urine sample -1About.
Two, liquid phase separation:
Liquid-phase condition is:
1, moving phase: for containing the water/methanol solution of 0.02～0.2% (V/V) formic acid, flow velocity is 0.25mL/min.
2, chromatographic column: can adopt bonded-phase chromatography posts such as C18, C8, CN (50,100 * 2mm, 5 μ m etc.)
3, gradient elution: design and adjust according to different bonded-phase chromatography posts, can carry out with reference to method shown in the according to the form below for C18 bonded-phase chromatography post:
Time (minute) Flow velocity (ml/min) Water (V/V) % Methyl alcohol (V/V) %
????0 ????0.25 ????97 ????3
????0.5 ????0.25 ????97 ????3
????3 ????0.25 ????5 ????95
????3.1 ????0.25 ????97 ????3
????11 ????0.25 ????97 ????3
Three, Mass Spectrometer Method:
The mass spectrum condition is: adopt electric spray ion source, positive ion MRM scanning, nozzle position: 3: 7; Atomization gas flow velocity: 10L/min, gas curtain gas velocity: 10L/min, collision gas velocity: 8L/min, ion gun voltage: 2500V, ion source temperature: 400 ℃; The MRM scanning analysis, the ion selector channel is respectively m/z: alprazolam 309.6/281.3, cocaine 304.5/181.9, codeine 300.6/183.2, diazepam 285.5/154.1, estazolam 295.5/267.0, Flunitrazepam 314.3/268.2, Flurazepam 388.7/315.1, heroin 370.5/328.0, ketamine 238.3/125.1, MDMA194.7/105.1, methadone 310.5/264.9, meth 150.5/91.0, methaqualone 251.5/132.1, midazolam 326.8/291.3, morphine 286.5/165.4, nitrazepam 282.3/235.7, pethidine 248.4/220.1, pholcodine 399.5/114.3, triazolam 343.2/308.3, SKF 525A(354.6/167.3 interior mark).More than each compound ions channel range can be ± 0.5amu.
Each component appearance time is under the above condition: alprazolam 6.25min, cocaine 5.50min, codeine 5.08min, diazepam 6.60min, estazolam 6.18min, Flunitrazepam 6.11min, Flurazepam 5.81min, heroin 5.39min, ketamine 5.43min, MDMA5.35min, methadone 5.15min, meth 5.37min, methaqualone 6.24min, midazolam 5.91min, morphine 4.77min, nitrazepam 6.13min, pethidine 5.58min, pholcodine 1.12min, triazolam 6.16min, SKF 525A(interior mark) 6.20min.
Four, density calculating method and detectability:
Calculate the concentration of these 19 kinds of drugs in the urine with peak area or peak height method by internal standard method.
The detection of the inventive method is limited to 0.02～21.2ng/ml (signal to noise ratio (S/N ratio) 〉=3).Each concrete composition detection limit is as follows: alprazolam 0.8ngmL -1, cocaine 0.12ngmL -1, codeine 11ngmL -1, diazepam 0.88ngmL -1, estazolam 0.52ngmL -1, Flunitrazepam 0.84ngmL -1, Flurazepam 0.16ngmL -1, heroin 7.6ngmL -1, ketamine 0.24ngmL -1, MDMA2.75ngmL -1, methadone 0.05ngmL -1, meth 3.8ngmL -1, methaqualone 0.02ngmL -1, midazolam 21.2ngmL -1, morphine 8.25ngmL -1, nitrazepam 1.8ngmL -1, pethidine 0.35ngmL -1, pholcodine 6.5ngmL -1, triazolam 0.27ngmL -12～3 orders of magnitude of the range of linearity, correlation coefficient r is more than 0.9958; In a few days reach day to day precision≤13%; Absolute recovery is more than 78.08%, relative recovery 91.8～115.1%.
Beneficial effect:
1, the inventive method sample treatment is easy and simple to handle, and urine sample impurity is noiseless to the detection by quantitative of drugs.
2, the inventive method the drugs measured simultaneously comprised kind related in the existing case substantially, strong, highly sensitive to the detection selectivity of sample, every methodology index all can satisfy the needs of actual inspection case easy, reliably.
Description of drawings
Fig. 1 is 19 kinds of drugs and interior mark chromatogram
Fig. 2 is head-shaking pill person urine sample (undiluted) chromatogram
Fig. 3 is head-shaking pill person urine sample (diluting) chromatogram
Fig. 4 is a neuroleptanesthesia person urine sample chromatogram
Embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
Embodiment 1
1 material
1.1 instrument and material
The API3000 of American AB I company tandem mass spectrometer, the HP1100 chromatograph; The oasis HLB post (1mL/30mg) of waters company; Unimicro Kromasil C available from the logical little company in Shanghai 18Post (5 μ m, 100 * 2mm).
1.2 medicine and reagent
Reference substance: alprazolam (alprazolam), cocaine (cocaine), codeine (codeine), diazepam (diazepam), estazolam (estazolam), Flunitrazepam (flunitrazepam), Flurazepam (flurazepam), heroin (heroin), ketamine (ketamine), MDMA, methadone (methadone), meth (methamphetamine), methaqualone (methaqualone), midazolam (midazolam), morphine (morphine), nitrazepam (nitrazepam), pethidine (pethidine), pholcodine (pholcodine), triazolam (triazolam) provides by Nat'l Pharmaceutical ﹠ Biological Products Control Institute, interior mark SKF 525AProvide by Material Evidence Identification Center, Ministry of Public Security.
Methyl alcohol: chromatographically pure (MERCK company); Formic acid: chromatographically pure (SIGMA company); Distilled water: self-control.Blank urine sample: healthy volunteers keep sample.
1.3 storing solution
1.3.1 reference substance storing solution
19 kinds of medicines are made into earlier 1mgmL respectively -1Methanol solution, be mixed into the following mixing storing solution of each drug concentration again: alprazolam 8ng μ L -1, cocaine 1.2ng μ L -1, codeine 110ng μ L -1, diazepam 8.8ng μ L -1, estazolam 5.2ng μ L -1, Flunitrazepam 8.4ng μ L -1, Flurazepam 1.6ng μ L -1, heroin 76ng μ L -1, ketamine 2.4ng μ L -1, MDMA 27.5ng μ L -1, methadone 0.5ng μ L -1, meth 38ng μ L -1, methaqualone 0.2ng μ L -1, midazolam 212ng μ L -1, morphine 82.5ng μ L -1, nitrazepam 18ng μ L -1, pethidine 3.5ng μ L -1, pholcodine 65ng μ L -1, triazolam 2.7ng μ L -1
1.3.2 interior mark liquid
Get an amount of interior mark (SKF 525A) with dissolve with methanol and the dilution be 0.2mgmL -1Storing solution, being diluted to content again is 0.01mgmL -1Interior mark liquid.
2 methods
2.1 instrument condition
2.1.1 liquid phase chromatogram condition
Moving phase: A. water (containing 0.02%V/V formic acid) B, methyl alcohol (containing 0.02%V/V formic acid); Flow velocity: 0.25mLmin -1
Gradient (in percent by volume): 0～0.5min, A:97%, B:3%; 0.5～3min, A:97～5%, B:3～95%; 3～3.1min, A:5～97%, B:95～3%; 3.1～11min, A:97%, B:3%.
Chromatographic column: Unimicro Kromasil C 18, 5 μ m, 100 * 2mm; Sample size: 3 μ L.
2.1.2 mass spectrum condition
Adopt electric spray ion source, positive ion MRM scanning, nozzle position: 3: 7; Atomization gas flow velocity: 10L/min, gas curtain gas velocity: 10L/min, collision gas velocity: 8L/min, ion gun voltage: 2500V, ion source temperature: 400 ℃; The parent ion and the daughter ion of each medicine are as follows:
Alprazolam 309.6/281.3, cocaine 304.5/181.9, codeine 300.6/183.2, diazepam 285.5/154.1, estazolam 295.5/267.0, Flunitrazepam 314.3/268.2, Flurazepam 388.7/315.1, heroin 370.5/328.0, ketamine 238.3/125.1, MDMA 194.7/105.1, methadone 310.5/264.9, meth 150.5/91.0, methaqualone 251.5/132.1, midazolam 326.8/291.3, morphine 286.5/165.4, nitrazepam 282.3/235.7, pethidine 248.4/220.1, pholcodine 399.5/114.3, triazolam 343.2/308.3, interior mark SKF 525A354.6/167.3.
2.2 sample pretreating method
Respectively earlier with 1mL methyl alcohol and 1mL water activation oasis post; Mark liquid 10 μ L join in the urine sample of 2ml in getting, and get the urine sample 1.0mL upper prop behind the mark in adding, and contain the water wash pillar of 5% methyl alcohol with 1mL; The pillar vacuum is drained the back essence and is got the 1.0mL methanol-eluted fractions, gets eluent 3 μ L sample introductions.
2.3 working curve
The smart respectively interior mark liquid of getting mixing storing solution 0.3,0.5,1,2,5,10,20,50,100 μ L and 5 μ L is in test tube at the bottom of the tool plug tip, and nitrogen dries up the blank 1.0mL of urine of each adding of back, presses down and measures after sample pretreating method is handled; Ratio (Y) with the peak area of each medicine and interior mark peak area carries out linear regression to the concentration (X) of each medicine in the urine sample respectively, obtains the linear equation of each medicine.
2.4 the precision and the recovery
The interior mark liquid of getting mixing storing solution 0.3,1.0,5.0,20 μ L and 5 μ L respectively is in test tube at the bottom of the tool plug tip, and each adds the blank 1.0mL of urine to dry up the back, presses the sample pretreating method operation down.Each concentration re-treatment in a few days mensuration gets withinday precision 6 times, handles mensuration continuously and gets day to day precision in three days.With the peak area of each medicine and interior mark peak area than substitution linear equation, calculate relative recovery.In addition reference substance is made into the methanol solution of respective concentration, direct injected as standard, compares the ratio of two groups of peak areas with interior mark peak area, calculates absolute recovery.
3 results
3.1 separating resulting
This law analysis speed is fast, and finishing once to analyze only needs 11min.Under this experiment condition, blank urine sample is all noiseless to 19 kinds of medicines and interior target analysis.The chromatogram that blank urine sample is added medicine is seen accompanying drawing 1.
3.2 testing result
Concrete testing result is seen Fig. 1 and table 1
Table 1
Nomenclature of drug Detectability (ngmL -1) The range of linearity Related coefficient γ Withinday precision (%) Day to day precision (%) Relative recovery (%) Absolute recovery (%, n=6)
Alprazolam ????0.8 ????2.4～800 ????0.9985 ????4.0～8.1 ????5.4～8.1 ????93.6～99.6 ????95.1～98.2
Cocaine ????0.12 ????0.36～120 ????0.9997 ????2.8～11.5 ????2.8～11.5 ????95.1～107.3 ????95.9～98.7
Codeine ????11 ????33～11000 ????0.9991 ????2.3～7.3 ????2.3～7.3 ????93.6～108.3 ????94.5～98.0
Diazepam ????0.88 ????2.64～880 ????0.9995 ????2.1～7.9 ????2.1～7.9 ????94.9～105.3 ????91.1～99.9
Estazolam ????0.52 ????1.56～520 ????0.9990 ????1.9～9.0 ????1.9～9.0 ????104.9～107.5 ????91.9～97.1
Flunitrazepam ????0.84 ????2.52～840 ????0.9996 ????1.8～8.4 ????1.8～8.4 ????105.7～114.6 ????87.9～99.3
Flurazepam ????0.16 ????0.48～160 ????0.9986 ????3.9～6.9 ????3.9～6.9 ????96.7～107.5 ????93.6～97.3
Heroin ????7.6 ????22.8～7600 ????0.9987 ????1.4～5.4 ????1.4～5.4 ????102.8～112.1 ????80.3～98.6
Ketamine ????0.24 ????0.72～240 ????0.9985 ????1.6～7.3 ????1.8～5.2 ????94.5～107.7 ????88.7～96.5
??MDMA ????2.75 ????8.25～2750 ????0.9997 ????1.6～5.4 ????1.6～5.4 ????96.2～103.0 ????97.1～106.2
Methadone ????0.05 ????0.15～50 ????0.9975 ????1.1～5.5 ????1.1～5.5 ????94.4～104.3 ????95.5～97.1
Meth ????3.8 ????11.4～3800 ????0.9966 ????3.7～6.5 ????3.7～6.5 ????91.8～98.5 ????96.6～100.1
Methaqualone ????0.02 ????0.06～20 ????0.9994 ????3.8～6.7 ????3.8～6.7 ????94.5～104.9 ????90.2～97.3
Midazolam ????21.2 ????63.6～21200 ????0.9958 ????3.9～5.1 ????3.9～5.1 ????93.3～104.5 ????97.9～100.3
Morphine ????8.25 ????24.75～8250 ????0.9963 ????2.4～9.5 ????2.4～9.5 ????99.5～107.3 ????84.8～96.6
Nitrazepam ????1.8 ????5.41～800 ????0.9979 ????5.0～6.9 ????5.0～6.9 ????105.6～110.5 ????93.8～96.1
Pethidine ????0.35 ????1.05～350 ????0.9997 ????1.5～4.4 ????1.5～4.4 ????92.6～107.2 ????92.9～98.4
Pholcodine ????6.5 ????19.5～6500 ????0.9972 ????1.4～6.5 ????1.4～8.3 ????96.5～109.2 ????78.8～94.1
Triazolam ????0.27 ????0.81～270 ????0.9993 ????2.0～10.5 ????2.0～10.5 ????99.4～106.3 ????90.2～99.6
The analysis of drugs in person's urine sample that embodiment 2 takes the head-shaking pill
The urine sample source: drug testing center, Shanghai City, outward appearance is clear and bright.Blank urine sample and other medicines, reagent and used instrument material are with embodiment 1.
Working curve: smartly respectively get mixing storing solution 0.3,0.5,1,2,5,10,20,50,100 μ L with the preparation of 1 method of enforcement in test tube at the bottom of the tool plug tip, mix the standard urine sample that obtains containing various criterion concentration after after nitrogen dries up, respectively adding blank urine sample 1.0mL; Respectively get 100 μ L and add 0.001mgmL -1Interior mark methanol solution 5 μ L, add that vortex mixes behind the 200 μ L acetonitrile solutions, with 12000 rev/mins speed high speed centrifugations after 2 minutes sample introduction measure.Ratio (Y) with the peak area of each medicine and interior mark peak area carries out linear regression to the concentration (X) of each medicine in the urine sample respectively, obtains the linear equation of each medicine.
Sample pretreating method (employing direct precipitation method): its operation steps is: get urine sample 100 μ L and add 0.001mgmL -1Interior mark methanol solution 5 μ L, add that vortex mixes behind the 200 μ L acetonitrile solutions, get the supernatant sample introduction after 2 minutes with 12000 rev/mins speed high speed centrifugations and measure.Instrument detecting condition and method: with embodiment 1, sample size changes 9 μ L into.
The result shows MDMA in this urine sample, ketamine and the meth content curve ranges (its detect chromatogram see accompanying drawing 2) that all is above standard.For obtain correct quantitatively, get and get 100 μ L behind 10 times of this urine sample dilute with waters (100 μ L urine sample adding distil waters are to 1mL) and operate as stated above once more and measure.Urine examination chromatogram after the dilution is seen accompanying drawing 3, after measured, contains MDMA, ketamine and meth in this urine sample, and its content is respectively 3121ngmL -1, 1205ngmL -1, 2117ngmL -1
The analysis of drugs in the embodiment 3 usefulness neuroleptanesthesia person urine samples
Urine sample source: drug testing center, Shanghai City; Outward appearance is clear and bright.Blank urine sample and other medicines, reagent and used instrument material are with embodiment 1.
Working curve: smartly respectively get mixing storing solution 0.3,0.5,1,2,5,10,20,50,100 μ L with the preparation of 1 method of enforcement in test tube at the bottom of the tool plug tip, mix the standard urine sample that obtains containing various criterion concentration after after nitrogen dries up, respectively adding blank urine sample 1.0mL; Respectively get 100 μ L and add 0.001mgmL -1Interior mark methanol solution 5 μ L, after vortex mixes, with 12000 rev/mins speed high speed centrifugations after 2 minutes the supernatant sample introduction measure.Ratio (Y) with the peak area of each medicine and interior mark peak area carries out linear regression to the concentration (X) of each medicine in the urine sample respectively, obtains the linear equation of each medicine.
Sample pretreating method (adopting the direct injected method): its operation steps is: get urine sample 100 μ L and add 0.001mgmL -1Interior mark methanol solution 5 μ L, after vortex mixes, get the supernatant sample introduction after 2 minutes with 12000 rev/mins speed high speed centrifugations and measure.
Instrument detecting condition and method: with embodiment 1.
The urine examination chromatogram is seen accompanying drawing 4, after measured, contains diazepam in this urine sample, and its content is 8.83ngmL -1

Claims (3)

1. a LC-MS/MS assay method that detects multiple drugs in the urine simultaneously comprises sample preparation, liquid phase separation, three steps of Mass Spectrometer Method, it is characterized in that this method carries out positive ion MRM scanning to 19 kinds of drugs in the urine, with SKF 525ABeing interior mark, adopting the bonded-phase chromatography post to separate, is that moving phase is made gradient elution with water, the methyl alcohol that contains formic acid.
2. the LC-MS/MS assay method that detects multiple drugs in the urine simultaneously according to claim 1, when it is characterized in that positive ion MRM scanning analysis, the ion selector channel of each drugs is respectively m/z: alprazolam 309.6/281.3, cocaine 304.5/181.9, codeine 300.6/183.2, diazepam 285.5/154.1, estazolam 295.5/267.0, Flunitrazepam 314.3/268.2, Flurazepam 388.7/315.1, heroin 370.5/328.0, ketamine 238.3/125.1, MDMA194.7/105.1, methadone 310.5/264.9, meth 150.5/91.0, methaqualone 251.5/132.1, midazolam 326.8/291.3, morphine 286.5/165.4, nitrazepam 282.3/235.7, pethidine 248.4/220.1, pholcodine 399.5/114.3, triazolam 343.2/308.3, SKF 525A(354.6/167.3 interior mark), wherein each compound ions channel range can be ± 0.5amu.
3. the LC-MS/MS assay method that detects multiple drugs in the urine simultaneously according to claim 1 is characterized in that sample preparation can adopt solid phase extraction, direct precipitation method or direct injected method.
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