CN106872627B - 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 fields, are related to a kind of LC-MS detection method of protopanoxadiol.C18 chromatographic column is used using high performance liquid chromatography in the present invention, aqueous formic acid, methanol, acetonitrile are eluent gradient elution；Mass Spectrometry Conditions are 121 DEG C of ion source temperature, source injection electric 5500V, and 461.6 → 425.4 are used as quota ion pair.The qualitative analysis that protopanoxadiol is carried out according to the retention time of sample, Information in Mass Spectra carries out quantitative analysis according to its peak area and internal standard peak area ratio.The method has many advantages, such as that high speed, sensitive, favorable reproducibility, the rate of recovery are high.
Description
Technical field
The invention belongs to Pharmaceutical Analysis fields, are related to a kind of LC-MS detection method, in particular to a kind of blood plasma sample
The LC-MS detection method of protopanoxadiol in product.
Background technique
According to research reports, protopanoxadiol is the extracorporeal hydrolysis product of protopanaxadiol-type's ginsenoside, and living in vivo
Property metabolite.Structurally, it belongs to dammarane type four-ring triterpenoid class ginsengenin compound, molecular formula is
C30H52O3, molecular weight 460.70,197.5-198.5 degrees Celsius of fusing point.Protopanoxadiol has extensive pharmacological activity, packet
Include antitumor action, inhibit epileptic attack, antidepressant effect etc..Currently, protopanoxadiol is as a kind of antidepressant a kind of new
Medicine comes into clinical experimental stage, therefore, measures it in the intracorporal blood concentration of people for evaluation efficacy of new drug, guarantee medication
Safety is particularly important.
Protopanoxadiol ultraviolet detection method based on efficient liquid phase it has been reported that however, since its sensitivity is lower, and
Usual human administration's dosage is smaller, and endogenous interfering substance is more in blood plasma, therefore is not possible in the prior art to the intracorporal protoplast of people
Ginseng glycol blood concentration is measured.LC-MS technology is using high performance liquid chromatography as separation means, is inspection with second order ms
Quantitative technique is analyzed in a kind of separation for surveying device, has both had the separating capacity of high performance liquid chromatography, but also with mass spectrographic highly sensitive
The detection feature of degree and high specificity；Therefore, the proposed vertical a kind of protopanoxadiol based on LC-MS of present inventor
Detection method, this method can be used for monitoring the intracorporal protopanoxadiol blood concentration of people, provide reliable analysis for clinical research
Means.
Summary of the invention
The purpose of the present invention is to provide a kind of LC-MS detections of quick, accurate, highly sensitive protopanoxadiol
Method.
The invention discloses a kind of LC-MS detection methods of protopanoxadiol, wherein high performance liquid chromatography uses C18
Chromatographic column, aqueous formic acid, methanol, acetonitrile are eluent gradient elution；Mass Spectrometry Conditions are 121 DEG C of ion source temperature, source injection
Voltage 5500V, 461.6 → 425.4 are used as quota ion pair；Protoplast's ginseng two is carried out according to the retention time of sample, Information in Mass Spectra
The qualitative analysis of alcohol carries out quantitative analysis according to its peak area and internal standard peak area ratio.This method has high speed, sensitive, again
Existing the advantages that property is good, the rate of recovery is high.
Specifically, a kind of LC-MS detection method of protopanoxadiol of the invention comprising:
1) the plasma sample pretreatment containing protopanoxadiol；
2) chromatographic separation condition is set；
3) Mass Spectrometer Method condition is set；
4) standard curve is established,
Wherein, plasma standard curvilinear equation are as follows: 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 measurement 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 filled out using chromatographic column for C18
Material, 5 μm of partial sizes, 2.1 × 150mm specification；Mobile phase is 0.2% aqueous formic acid (A), methanol (B), acetonitrile (C), and gradient is washed
It is de-, flow velocity 0.3ml/min, 30 DEG C of column temperature；Chromatography 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+ by 95%B+5%C linear transformation
80%B+5%C；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
For 20L/min；Ion pair 461.6 → 425.4 and 461.6 → 443.4 pair protopanoxadiol is selected to carry out qualitative, wherein 461.6
→ 425.4 are used as quota ion pair.
In the present invention, gradient elution can make the method have high sensitivity and separating degree.
Further, the mass spectrograph is second order ms instrument.Second order ms may be selected parent ion further ionize be crushed after
Detection, compared to for first mass spectrometric, second order ms have higher specificity.
Further, the method is internal standard method, and internal standard compound is dexamethasone.Internal standard method can reduce sample pretreatment
Operating error caused by journey, measurement result are more accurate.Dexamethasone is similar with protopanoxadiol structure, has similar reason
Change property, guarantees 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 be determined
Amount has high specificity and high sensitivity.
Further, determinand is blood plasma.Blood plasma is the most common clinical sample of clinical test, is easily obtained, and can be accurate
The case where ground reflects drug in vivo.
Further, the determinand pre-treating method is liquid-liquid extraction method.Liquid-liquid extraction method can effective and rapidly from
Protopanoxadiol is extracted in plasma sample.
This method has carried out withinday precision and the rate of recovery investigates experiment, acquires phase by the ratio of measured amount and additional amount
To the rate of recovery；The present invention has carried out day to day precision and the rate of recovery and has investigated experiment, with 15 parts of measured values calculate day to day precision and
As a result relative recovery shows respectively, relative recovery and RSD value within the specified scope, illustrate this detection method it is accurate, can
It leans on；This method has carried out the stability experiment of analysis sample, the results showed that, this method has better stability.
The beneficial effects of the method for the present invention is:
LC-MS has both the high score dynamics and mass spectrographic high specificity, highly sensitive feature of chromatography, and then realizes fast
Speed accurately studies protopanoxadiol quantitative test in sample；The application of internal standard compound dexamethasone can be reduced operating error pair
The influence of measurement result further increases the accuracy and precision of detection method；Liquid-liquid extraction can quick, efficient, low cost
Ground extracts concentration to the protopanoxadiol in plasma sample, improves detection sensitivity.
The present invention is described in further detail below in conjunction with drawings and examples.Following embodiment is only to illustrate this hair
Bright technical idea, this does not limit the scope of protection of the present invention, it is all according to the technical idea provided by the invention, in technology
Any change done on the basis of scheme, falls within the scope of the present invention.
Detailed description of the invention
Fig. 1 is that protopanoxadiol LC-MS measures 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 is 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 is to 393.2 → 355.2 chromatograms；C-1. actual measurement plasma sample intermediate ion is to 461.6 → 425.4 chromatograms；C-2 actual measurement
Plasma sample intermediate ion is to 393.2 → 355.2 chromatograms.
Fig. 2 is protopanoxadiol standard curve.
Specific embodiment
Embodiment 1
1. instrument and reagent
1) analysis instrument
The triple quadrupole tandem mass spectrometers of API 4000Q type, match ESI electric spray ion source, and analysis software is Analyst
1.6 data processing systems are purchased from Applied Biosystem company, the U.S.；1200 high performance liquid chromatograph of Agilent, takes
1200 autosampler of Agilent is carried, U.S. Agilent company is purchased from；Chromatographic column be Ultimate XB-C18,5 μm, 2.1x
150mm is purchased from Shanghai Welch company.
2) test drug
Protopanoxadiol standard items (CAS:30636-90-9, content 99.00%), by the limited public affairs of Dalian U.S. logical sequence technology
Department provides.
Methanol, the chromatography pure reagent that acetonitrile is the production of U.S. Merck company, ether, methylene chloride are Chinese Medicine (collection
Group) Solution on Chemical Reagents in Shanghai company production analytical reagents, pure water be Millipore deionized water.
2. test method and result
1) the plasma sample pretreatment containing protopanoxadiol
Venous samples are placed in 10ml glass centrifuge tube and (add anticoagulant heparin), and 3500r/min is centrifuged 5min separated plasma, take
500 μ l of blood plasma is sub-packed in cryopreservation tube, -80 DEG C of cryopreservations.Melt 500 μ l blood plasma when detection again, 50 μ l internal standards are added, is vortexed
0.5ml buffer is added after mixing, and is transferred in 10ml glass tool plug conical centrifuge tube；4ml ether-dichloromethane is then added
Alkane (3:1, V/V), vortex 90s are mixed, and continue to shake 10min, are centrifuged 10min then at 3000r/min；Divide and take organic layer 4.0ml,
It is heated on 40 DEG C of heat blocks, logical nitrogen volatilizes, and 60 μ l methanol is added to dissolve, and 15000r/min high speed centrifugation 10min takes supernatant
50 μ l sample introductions, 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% aqueous formic acid (A), methanol
(B), acetonitrile (C) gradient elution, flow velocity 0.3ml/min, 30 DEG C of column temperature.Chromatography condition of gradient elution is as follows: 0-2min 15%A+
80%B+5%C；2.01-6min 5%B+95%C；6.01-15min 95%B+5%C；15-20min is become by 95%B+5%C
For 15%A+80%B+5%；
3) Mass Spectrometer Method condition
Ion source is electrospray ionisation source (ESI), and the detection of cation scan pattern, dry gas stream flow velocity is 20L/min, from
Source temperature is 121 DEG C, and source injection electric is 5500V, and GAS 1 is 25L/min, and GAS 2 is 20L/min.Select ion pair
461.6 → 425.4 and 461.6 → 443.4 pairs of protopanoxadiols progress are qualitative, wherein 461.6 → 425.4 are used as quota ion
It is right.Internal standard compound dexamethasone selection ion pair 393.2 → 355.2 is quantified；
4) foundation of standard curve
Precision weighs protopanoxadiol standard reference material 10.00mg, is placed in 10.00ml volumetric flask, adds methanol dissolution simultaneously
It is diluted to scale, shakes up the Standard Reserving Solution to get 1.000mg/ml.Precision absorption Standard Reserving Solution is a certain amount of, dilutes respectively
It is settled in 4 10.0ml measuring bottles, being made into concentration is 100.0 μ g/ml, 10.00 μ g/ml, 1.000 μ g/ml and 100.0ng/ml
Standard solution；
Accurate draw is equivalent to 1.00,2.00,5.00,10.00,20.00,50.00 from protopanoxadiol standard solution
It is placed in 7 10.0ml measuring bottles with the protopanoxadiol solution of 100.0ng, wherein liquid leads to nitrogen in 40 DEG C of water-baths and volatilizes,
Blank plasma is added and dilutes constant volume, is configured to 0.100,0.200,0.500,1.000,2.000,5.000 He containing protopanoxadiol
10.00ng/ml Standard plasma samples；It is operated by above-mentioned plasma sample pre-treatment step, and carries out LC-MS analysis.With original
The peak area (A, Y) of panoxadiol standard reference material is weighted (1/X2) linear regression to corresponding concentration (C, ng/ml), obtains
Plasma standard curvilinear equation are as follows: Y=0.117C+0.133, R2=0.9923, range of linearity 0.10-10ng/ml；Protopanoxadiol
Plasma standard curve it is as shown in Figure 2；
The minimum of protopanoxadiol is quantitatively limited to 0.100ng/ml in this method measurement blood plasma；
5) withinday precision and the rate of recovery are investigated
Prepare the protopanoxadiol of the basic, normal, high three kinds of various concentrations of 0.200ng/ml, 1.000ng/ml, 5.000ng/ml
Standard plasma samples are operated by above-mentioned plasma sample pre-treatment step, and protopanoxadiol chromatographic peak area substitutes into plasma sample
Plasma standard curve acquires relative recovery by the ratio of measured amount and additional amount, and as a result basic, normal, high concentration samples measure
Amount is respectively 0.22 ± 0.02ng/mL, 1.08 ± 0.16ng/mL, 5.23 ± 0.74ng/mL, relative recovery 109.67%
± 8.81%, 108.03% ± 15.56%, 104.67% ± 14.72%, RSD value be 8.03%, 14.41%, 14.06%；Phase
Within the specified scope to the rate of recovery and RSD value, illustrate that the detection method is accurate, reliable；
6) day to day precision and the rate of recovery are investigated
By plasma sample standard curve determination method prepare 0.200ng/ml, 1.000ng/ml, 5.000ng/ml it is low, in,
Each 5 parts of the protopanoxadiol plasma sample of high three kinds of various concentrations is operated by above-mentioned biological sample pre-treatment step with method, continuously
Measurement 3 days calculates day to day precision and relative recovery 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 is 11.79%, 14.67%, 11.42%.Relative recovery
Within the specified scope with RSD value, illustrate that the detection method is accurate, reliable.
7) stability of sample is analyzed
Centrifugation point takes blood plasma immediately after venous blood sampling, and it is to be measured to be placed in -20 DEG C of refrigerators preservations.This experiment investigation protoplast ginseng two
The stability of alcohol Standard Reserving Solution and plasma standard sample.1000.00 μ g/ml protopanoxadiol Standard Reserving Solutions be protected from light, it is close
Under envelope and cryo-conservation (- 20 DEG C) experiment condition, protopanoxadiol content, which has no, in 90 days is decreased obviously.
Sample introduction solution (sealing) after 1.000ng/ml protopanoxadiol plasma standard sample pretreatment is placed at room temperature for
Stability, as a result the protopanoxadiol in 8h in sample introduction solution has good stability；1.000ng/ml protopanoxadiol plasma standard
The decentralization of sample room temperature postpones (in 2h), then carries out biological sample pretreatment and analysis is used in conjunction with liquid matter, analyzes protoplast's ginseng in sample
Glycol reproducibility is good；1.000ng/ml protopanoxadiol plasma standard sample carries out 3 freeze-thaw cyclic tests, as a result
It has good stability through the protopanoxadiol in 3 freeze-thaw test post analysis samples；1.000ng/ml protopanoxadiol blood
Standard sample is starched under cryo-conservation (- 20 DEG C) experiment condition, the protopanoxadiol analyzed in sample has good stability, and 40 days
Interior content, which has no, to be decreased obviously, and illustrates that the method has better stability.
Claims (2)
1. a kind of LC-MS detection method of protopanoxadiol, characterized in that it comprises:
1) the determinand sample pretreatment containing protopanoxadiol, wherein take ether-dichloro of the plasma sample with volume ratio for 3:1
Methane extraction, nitrogen volatilize rear methanol dissolution, and centrifuging and taking supernatant is test sample；
2) chromatographic separation condition is set,
The chromatographic column used is C18 filler, 5 μm of partial sizes, 2.1 × 150 mm specifications；Mobile phase be 0.2% aqueous formic acid A,
Methanol B, acetonitrile C, gradient elution, flow velocity be 0.3 ml/min, 30 DEG C of column temperature；Chromatography condition of gradient elution is 0-2 min 15%A
+ 80%B+5%C, 2.01-6 min 5%B+95%C, 6.01-15 min 95%B+5%C, 15-20 min by 95%B+
5%C linear transformation is 15%A+80%B+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 5500 V, and GAS 1 is 25 L/min, and GAS 2 is 20
L/min；Ion pair 461.6 → 425.4 and 461.6 → 443.4 pair protopanoxadiol is selected to carry out qualitative,
Wherein 461.6 → 425.4 it is used as quota ion pair；
4) standard curve is established,
Wherein, plasma standard curvilinear equation are as follows: Y=0.117C+0.133, R2=0.9923,0.10-10 ng/ml of the range of linearity；
The minimum of protopanoxadiol is quantitatively limited to 0.100 ng/ml in measurement 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；
In the method, used mass spectrograph is second order ms instrument；
The method is internal standard method, and the internal standard compound used is dexamethasone.
2. the LC-MS detection method of protopanoxadiol according to claim 1, which is characterized in that the internal standard compound choosing
Ion pair 393.2 → 355.2 is selected to be quantified.
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| CN109342586A (en) * | 2018-10-10 | 2019-02-15 | 泓博元生命科技（深圳）有限公司 | Protopanoxadiol determination method |
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| CN1885032A (en) * | 2005-06-20 | 2006-12-27 | 中国医学科学院药用植物研究所 | Detection method for dammarane type four-ring triterpenoid saponin |
| CN104316604A (en) * | 2014-08-28 | 2015-01-28 | 曲阜师范大学 | Derivation-based detection analysis method for ginsenoside and aglycone thereof |
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| CN1885032A (en) * | 2005-06-20 | 2006-12-27 | 中国医学科学院药用植物研究所 | Detection method for dammarane type four-ring triterpenoid saponin |
| CN104316604A (en) * | 2014-08-28 | 2015-01-28 | 曲阜师范大学 | Derivation-based detection analysis method for ginsenoside and aglycone thereof |
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