CN106872627A - A kind of LC-MS detection method of protopanoxadiol - Google Patents
A kind of LC-MS detection method of protopanoxadiol Download PDFInfo
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Abstract
The invention belongs to Pharmaceutical Analysis field, it is related to a kind of LC-MS detection method of protopanoxadiol.C18 chromatographic columns are used using high performance liquid chromatography in the present invention, aqueous formic acid, methyl alcohol, acetonitrile are eluted for eluent gradient；Mass Spectrometry Conditions be 121 DEG C of ion source temperature, source injection electric 5500V, 461.6 → 425.4 used as quota ion pair.Retention time, Information in Mass Spectra according to sample carry out the qualitative analysis of protopanoxadiol, and quantitative analysis is carried out according to its peak area and internal standard peak area ratio.Methods described has the advantages that high speed, sensitive, favorable reproducibility, the rate of recovery are high.
Description
Technical field
The invention belongs to Pharmaceutical Analysis field, it is related to a kind of LC-MS detection method, more particularly to a kind of blood
The LC-MS detection method of protopanoxadiol in slurry samples.
Background technology
According to research reports, protopanoxadiol is the extracorporeal hydrolysis product of protopanaxadiol-type's ginsenoside, is also body
Interior active metabolite.From structure, it belongs to dammarane type four-ring triterpenoid class ginsengenin compound,
Molecular formula is C30H52O3, molecular weight is 460.70,197.5-198.5 degrees Celsius of fusing point.Protopanoxadiol has
There is extensive pharmacological activity, including antitumor action, suppress epileptic attack, antidepressant effect etc..At present,
Protopanoxadiol comes into clinical experimental stage as the antidepressant kind new medicine of one kind, therefore, determine its
Blood concentration in human body is for evaluating efficacy of new drug, ensureing that drug safety is particularly important.
Protopanoxadiol ultraviolet detection method based on efficient liquid phase it has been reported that however, due to its sensitivity compared with
It is low, and generally human administration's dosage is smaller, endogenous interfering material is more in blood plasma, therefore there is no method in the prior art
Protopanoxadiol blood concentration in human body is measured.LC-MS technology be with high performance liquid chromatography as point
From means, a kind of separation with second order mses as detector analyzes quantitative technique, and it both has high performance liquid chromatography
Separating power, but also with mass spectrographic high sensitivity and the detection feature of specificity high；Therefore, the hair of the application
A person of good sense is proposed to found a kind of protopanoxadiol detection method based on LC-MS, and the method can be used for monitoring human body
Interior protopanoxadiol blood concentration, for clinical research provides reliable analysis means.
The content of the invention
It is an object of the invention to provide a kind of quick, accurate, highly sensitive protopanoxadiol LC-MS
Detection method.
The invention discloses a kind of LC-MS detection method of protopanoxadiol, wherein, high performance liquid chromatography is adopted
C18 chromatographic columns are used, aqueous formic acid, methyl alcohol, acetonitrile are eluted for eluent gradient；Mass Spectrometry Conditions are ion gun
121 DEG C of temperature, source injection electric 5500V, 461.6 → 425.4 used as quota ion pair；According to sample
Retention time, Information in Mass Spectra carry out the qualitative analysis of protopanoxadiol, according to its peak area and internal standard peak area ratio
Value carries out quantitative analysis.This method has the advantages that high speed, sensitive, favorable reproducibility, the rate of recovery are high.
Specifically, a kind of LC-MS detection method of protopanoxadiol of the invention, it includes：
1) the plasma sample pretreatment containing protopanoxadiol；
2) chromatographic separation condition is set；
3) Mass Spectrometer Method condition is set；
4) standard curve is set up,
Wherein, plasma standard curvilinear equation is：Y=0.117C+0.133, R2=0.9923, range of linearity 0.10-
10ng/ml；The minimum of protopanoxadiol is quantitatively limited to 0.100ng/ml in determining blood plasma；
5) withinday precision and the rate of recovery are investigated,
6) day to day precision and the rate of recovery are investigated, and,
7) stability of sample is analyzed.
It is furthermore preferred that a kind of LC-MS detection method of protopanoxadiol of the invention, is using chromatographic column
C18 fillers, 5 μm of particle diameters, 2.1 × 150mm specifications；Mobile phase is 0.2% aqueous formic acid (A), first
Alcohol (B), acetonitrile (C), gradient elution, flow velocity is 0.3ml/min, 30 DEG C of column temperature；Chromatogram gradient elution bar
Part is 0-2min 15%A+80%B+5%C, 2.01-6min 5%B+95%C, 6.01-15min 95%B
+ 5%C, 15-20min are 15%A+80%B+5%C by 95%B+5%C linear transformations；Mass Spectrometry Conditions are
Ion source temperature is 121 DEG C, and source injection electric is 5500V, and GAS 1 is 25L/min, and GAS 2 is 20L/min；
Selection ion pair 461.6 → 425.4 and 461.6 → 443.4 pairs of protopanoxadiols carry out it is qualitative, wherein 461.6
→ 425.4 used as quota ion pair.
In the present invention, gradient elution can make the methods described have high sensitivity and separating degree.
Further, the mass spectrograph is second order mses instrument.Second order mses may be selected parent ion, and further ionization is broken
Detection after broken, for first mass spectrometric, second order mses have specificity higher.
Further, methods described is internal standard method, and internal standard compound is dexamethasone.It is pre- that internal standard method can reduce sample
The operating error caused in processing procedure, measurement result is more accurate.Dexamethasone and protopanoxadiol structure class
Seemingly, with similar physicochemical property, it is ensured that the accuracy of internal standard method.
Further, the Selection of internal standard ion pair 393.2 → 355.2 is quantified.The ion pair is selected to enter
Row is quantitative, with specificity high and high sensitivity.
Further, determinand is blood plasma.Blood plasma is the most frequently used clinical sample of clinical test, is easily obtained, and
Medicine situation in vivo can exactly be reflected.
Further, the determinand pre-treating method is liquid-liquid extraction method.Liquid-liquid extraction method can be with effective and rapid
Ground extracts protopanoxadiol from plasma sample.
This method has carried out withinday precision and the rate of recovery investigates experiment, is asked with the ratio of addition by measured amount
Obtain relative recovery；The present invention has carried out day to day precision and the rate of recovery investigates experiment, in terms of 15 parts of measured values
Day to day precision and relative recovery are calculated, is as a result shown respectively, relative recovery and RSD values are in prescribed limit
It is interior, illustrate that this detection method is accurate, reliable；This method analyze the stability experiment of sample, as a result table
Bright, this method has better stability.
The beneficial effects of the method for the present invention is：
The characteristics of LC-MS has the high score dynamics and mass spectrographic specificity high, high sensitivity of chromatogram concurrently, Jin Ershi
Now quickly and accurately protopanoxadiol quantitative test in sample is studied；The application of internal standard compound dexamethasone can subtract
Few influence of the operating error to measurement result, further improves the degree of accuracy and the precision of detection method；Liquid liquid extracts
Take can it is quick, extraction concentration is carried out to the protopanoxadiol in plasma sample efficiently at low cost, improve detection
Sensitivity.
The present invention is described in further detail below in conjunction with drawings and Examples.Following examples are only explanation
Technological thought of the invention, it is impossible to which protection scope of the present invention is limited with this, it is every according to skill proposed by the present invention
Art thought, any change done on the basis of technical scheme, each falls within the scope of the present invention.
Brief description of the drawings
Fig. 1 is protopanoxadiol LC-MS measure chromatogram in blood plasma,
In figure：A-1. blank plasma intermediate ion is to 461.6 → 425.4 chromatograms；A-2. blank plasma intermediate ion
To 393.2 → 355.2 chromatograms；B-1. blood plasma adds standard items intermediate ion to 461.6 → 425.4 chromatograms；
B-2. blood plasma adds standard items intermediate ion to 393.2 → 355.2 chromatograms；C-1. plasma sample intermediate ion is surveyed
To 461.6 → 425.4 chromatograms；C-2 surveys plasma sample intermediate ion to 393.2 → 355.2 chromatograms.
Fig. 2 is protopanoxadiol standard curve.
Specific embodiment
Embodiment 1
1. instrument and reagent
1) analytical instrument
The triple quadrupole rods tandem mass spectrometry instrument of API 4000Q types, with ESI electric spray ion sources, analysis software is
The data handling systems of Analyst 1.6, are purchased from Applied Biosystem companies of the U.S.；Agilent 1200
High performance liquid chromatograph, carries the automatic samplers of Agilent 1200, purchased from Agilent companies of the U.S.；Color
Spectrum post is Ultimate XB-C18,5 μm, 2.1x 150mm, purchased from Shanghai Welch companies.
2) test drug
Protopanoxadiol standard items (CAS：30636-90-9, content 99.00%), by Dalian U.S. logical sequence technology
Co., Ltd provides.
Methyl alcohol, acetonitrile are the chromatogram pure reagent of Merck companies of U.S. production, and ether, dichloromethane are middle traditional Chinese medical science
The AR of medicine (group) Solution on Chemical Reagents in Shanghai company production, pure water is Millipore deionized waters.
2. test method and result
1) the plasma sample pretreatment containing protopanoxadiol
Venous samples are placed in 10ml glass centrifuge tubes (plus anticoagulant heparin), 3500r/min centrifugations 5min
Separated plasma, takes the μ l of blood plasma 500 and is sub-packed in cryopreservation tube, -80 DEG C of Excised Embryos.Melt 500 during detection again
μ l blood plasma, adds 50 μ l internal standards, is vortexed and 0.5ml buffer solutions are added after mixing, and be transferred to 10ml
In glass tool plug conical centrifuge tube；It is subsequently added 4ml ether-dichloromethane (3:1, V/V), vortex 90s
Mix, continue to shake 10min, 10min is centrifuged then at 3000r/min；Divide and take organic layer 4.0ml,
Heated on 40 DEG C of heat blocks, logical nitrogen volatilizes, plus the dissolving of 60 μ l methyl alcohol, 15000r/min at a high speed from
Heart 10min, takes the μ l sample introductions of supernatant 50, the analysis of peak area inner mark method ration；
2) chromatographic separation condition
Chromatographic column：WelchTM (moon rising sun) C185 μm of 2.1 × 150mm；Mobile phase：0.2% formic acid is water-soluble
Liquid (A), methyl alcohol (B), acetonitrile (C) gradient elution, flow velocity 0.3ml/min, 30 DEG C of column temperature.Chromatogram gradient
Elution requirement is as follows：0-2min 15%A+80%B+5%C；2.01-6min 5%B+95%C；6.01-15
Min 95%B+5%C；15-20min is changed into 15%A+80%B+5% from 95%B+5%C；
3) Mass Spectrometer Method condition
Ion gun is electron spray ionisation source (ESI), and cation scan pattern detection, dry gas stream flow velocity is 20
L/min, ion source temperature is 121 DEG C, and source injection electric is 5500V, and GAS 1 is 25L/min, GAS 2
It is 20L/min.Selection ion pair 461.6 → 425.4 and 461.6 → 443.4 pairs of protopanoxadiols are determined
Property, wherein 461.6 → 425.4 used as quota ion pair.Internal standard compound dexamethasone selection ion pair 393.2 →
355.2 are quantified；
4) foundation of standard curve
Precision weighs protopanoxadiol standard reference material 10.00mg, is placed in 10.00ml volumetric flasks, plus first
Alcohol dissolves and is diluted to scale, shakes up, and obtains final product the Standard Reserving Solution of 1.000mg/ml.Accurate absorption standard storage
Standby liquid is a certain amount of, and dilution respectively is settled in 4 10.0ml measuring bottles, be made into concentration for 100.0 μ g/ml,
The standard liquid of 10.00 μ g/ml, 1.000 μ g/ml and 100.0ng/ml；
It is accurate from protopanoxadiol standard liquid to draw equivalent to 1.00,2.00,5.00,10.00,20.00,
The protopanoxadiol solution of 50.00 and 100.0ng is placed in 7 10.0ml measuring bottles, and wherein liquid is at 40 DEG C
Lead to nitrogen in water-bath to volatilize, add blank plasma dilution constant volume, be configured to containing protopanoxadiol 0.100,0.200,
The Standard plasma samples of 0.500,1.000,2.000,5.000 and 10.00ng/ml；By above-mentioned blood plasma sample
Product pre-treatment step is operated, and carries out LC-MS analysis.With the peak area of protopanoxadiol standard reference material
(A, Y) is weighted (1/X2) linear regression to corresponding concentration (C, ng/ml), obtains plasma standard curve
Equation is：Y=0.117C+0.133, R2=0.9923, range of linearity 0.10-10ng/ml；Protoplast's ginseng two
The plasma standard curve of alcohol is as shown in Figure 2；
The minimum of protopanoxadiol is quantitatively limited to 0.100ng/ml during this method determines blood plasma；
5) withinday precision and the rate of recovery are investigated
Prepare the basic, normal, high three kinds of various concentrations of 0.200ng/ml, 1.000ng/ml, 5.000ng/ml
Protopanoxadiol Standard plasma samples, are operated, plasma sample Central Plains ginseng by above-mentioned plasma sample pre-treatment step
Glycol chromatographic peak area substitutes into plasma standard curve, and relative recovery is tried to achieve by measured amount and the ratio of addition
Rate, as a result basic, normal, high concentration samples measured amount be respectively 0.22 ± 0.02ng/mL, 1.08 ± 0.16ng/mL,
5.23 ± 0.74ng/mL, relative recovery is 109.67% ± 8.81%, 108.03% ± 15.56%, 104.67%
± 14.72%, RSD value are 8.03%, 14.41%, 14.06%；Relative recovery and RSD values are in regulation model
In enclosing, illustrate that the detection method is accurate, reliable；
6) day to day precision and the rate of recovery are investigated
0.200ng/ml, 1.000ng/ml, 5.000ng/ml are prepared by plasma sample standard curve determination method
Each 5 parts of the protopanoxadiol plasma sample of basic, normal, high three kinds of various concentrations, is pre-processed by above-mentioned biological sample
Step is operated with method, METHOD FOR CONTINUOUS DETERMINATION 3 days, and day to day precision and relative recovery are calculated with 15 parts of values.As a result
Basic, normal, high concentration samples measured amount is respectively 0.23 ± 0.03ng/mL, 0.90 ± 0.13ng/mL, 5.41
± 0.62ng/mL, relative recovery be 113.18% ± 1.34%, 89.50% ± 13.13%, 108.15% ±
12.34%, RSD value are 11.79%, 14.67%, 11.42%.Relative recovery and RSD values are in prescribed limit
It is interior, illustrate that the detection method is accurate, reliable.
7) stability of sample is analyzed
Centrifugation point takes blood plasma immediately after venous blood sampling, is placed in -20 DEG C of Refrigerator stores to be measured.This experiment investigation
The stability of protopanoxadiol Standard Reserving Solution and plasma standard sample.1000.00 μ g/ml protopanoxadiol marks
Quasi- stock solution lucifuge, sealing and Cord blood (- 20 DEG C) experiment condition under, protopanoxadiol in 90 days
Content has no and is decreased obviously.
Sample introduction solution (sealing) room temperature after 1.000ng/ml protopanoxadiol plasma standard sample pretreatments
The stability of placement, as a result the protopanoxadiol in 8h in sample introduction solution have good stability；1.000ng/ml is former
The decentralization of panoxadiol plasma standard sample room temperature is postponed (in 2h), then carries out biological sample pretreatment with liquid matter company
With analysis, the protopanoxadiol reappearance in analysis sample is good；1.000ng/ml protopanoxadiol blood plasma marks
Quasi- sample carries out 3 freeze-thaw cyclic tests, as a result through in 3 freeze-thaws experiment post analysis samples
Protopanoxadiol have good stability；1.000ng/ml protopanoxadiol plasma standard samples are in Cord blood
Under (- 20 DEG C) experiment condition, the protopanoxadiol in analysis sample has good stability, and content is not in 40 days
See and be decreased obviously, illustrate that methods described has better stability.
Claims (6)
1. the LC-MS detection method of a kind of protopanoxadiol, it is characterised in that it includes：
1) the determinand sample pretreatment containing protopanoxadiol；
2) chromatographic separation condition is set,
The chromatographic column for using is C18 fillers, 5 μm of particle diameters, 2.1 × 150mm specifications；Mobile phase is 0.2%
Aqueous formic acid (A), methyl alcohol (B), acetonitrile (C), gradient elution, flow velocity is 0.3ml/min, column temperature 30
℃；Chromatogram condition of gradient elution is 0-2min 15%A+80%B+5%C, 2.01-6min 5%B+95%C,
6.01-15min 95%B+5%C, 15-20min are 15%A+80%B+ by 95%B+5%C linear transformations
5%C；
3) Mass Spectrometer Method condition is set,
Mass Spectrometry Conditions are that ion source temperature is 121 DEG C, and source injection electric is 5500V, and GAS 1 is 25L/min,
GAS 2 is 20L/min；Selection ion pair 461.6 → 425.4 and 461.6 → 443.4 pairs of protopanoxadiols enter
Row is qualitative,
Wherein 461.6 → 425.4 used as quota ion pair；
4) standard curve is set up,
Wherein, plasma standard curvilinear equation is：Y=0.117C+0.133, R2=0.9923, range of linearity 0.10-
10ng/ml；The minimum of protopanoxadiol is quantitatively limited to 0.100ng/ml in determining blood plasma；
5) withinday precision and the rate of recovery are investigated,
6) day to day precision and the rate of recovery are investigated, and,
7) stability of sample is analyzed.
2. the LC-MS detection method of protopanoxadiol according to claim 1, it is characterised in that
The mass spectrograph for wherein using is second order mses instrument.
3. the LC-MS detection method of protopanoxadiol according to claim 1, it is characterised in that
Described method is internal standard method, and the internal standard compound for using is dexamethasone.
4. the LC-MS detection method of protopanoxadiol according to claim 3, it is characterised in that
The Selection of internal standard ion pair 393.2 → 355.2 is quantified.
5. the LC-MS detection method of protopanoxadiol according to claim 4, it is characterised in that
Determinand is blood plasma.
6. the LC-MS detection method of protopanoxadiol according to claim 1 or 5, its feature exists
In the determinand preprocess method is liquid-liquid extraction method.
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| CN110907542A (en) * | 2018-09-17 | 2020-03-24 | 复旦大学 | Method for detecting selegiline and metabolite thereof in saliva by liquid chromatography-mass spectrometry |
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