CN110208450A - A kind of method of Aripiprazole and dehydroaripiprazole in detection blood - Google Patents
A kind of method of Aripiprazole and dehydroaripiprazole in detection blood Download PDFInfo
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Abstract
The present invention provides a kind of methods of Aripiprazole and dehydroaripiprazole in detection blood, it include: that at least three kinds of standard solution are detected under preset testing conditions using liquid chromatograph-mass spectrometer, obtain corresponding first testing result of each standard solution, wherein, the internal standard compound of at least three kinds of standard solution Aripiprazole containing various concentration, dehydroaripiprazole and same concentrations；Based on the concentration of the first testing result, Aripiprazole, dehydroaripiprazole and internal standard compound, fitting obtains calibration curve equation；It is added a certain amount of internal standard compound and protein precipitation reagent into blood sample to be measured, carries out centrifugal treating, the supernatant that takes that treated；Supernatant is detected under the conditions of same detection using liquid chromatograph-mass spectrometer, obtains the second testing result；Based on calibration curve equation and the second testing result, the concentration of the concentration and dehydroaripiprazole of Aripiprazole in blood sample to be measured is obtained.This programme can be improved the detection efficiency of blood sample.
Description
Technical field
The present invention relates to technical field of biological, in particular to Aripiprazole and dehydrogenation A Li piperazine in a kind of detection blood
The method of azoles.
Background technique
Aripiprazole chemical structural formula and pharmacological action are unique, belong to third generation antipsychotic drug, belong to carbostyril derivative,
Clinic is widely used in the treatment of various acute and chronic schizophrenia and schizoaffective disorder.It is positive to schizophrenia and negative
Symptom and depression and anxiety, cognitive function etc. have apparent curative effect.Dehydroaripiprazole is the chief active generation of Aripiprazole
Thank to product, vivo system exposure value about can reach the 40% of raw medicine, therefore to the prison of Aripiprazole and its active metabolite
Measuring tool has important clinical meaning.
Currently, generalling use high phase liquid chromatography when the blood sample for the patient that Aripiprazole is taken in detection and being surveyed
Examination.
But the Aripiprazole in blood sample is detected by the above method and is contained with its active metabolite dehydroaripiprazole
It when amount, needs to carry out pre-treatment to blood sample, for example, extraction.Since the time of extraction processing is usually longer, so that inspection
The survey time is long, causes the detection efficiency of blood sample low.
Summary of the invention
The embodiment of the invention provides a kind of methods of Aripiprazole and dehydroaripiprazole in detection blood, can be improved
The detection efficiency of blood sample.
The embodiment of the invention provides a kind of methods of Aripiprazole and dehydroaripiprazole in detection blood, comprising:
Prepare at least three kinds of standard solution, wherein at least three kinds of standard solution contain different known concentrations Ah
Vertical piperazine azoles, the different dehydroaripiprazole of known concentration and the internal standard compound of identical known concentration；
Using liquid chromatograph-mass spectrometer under preset testing conditions, each described standard solution is detected respectively,
Obtain corresponding first testing result of each standard solution；
Based on the concentration of Aripiprazole and the concentration of internal standard compound in each first testing result, the standard solution,
Fitting obtains the calibration curve equation of Aripiprazole and the calibration curve equation of dehydroaripiprazole respectively；
Into blood sample to be measured, addition and same amount of internal standard compound and protein precipitation reagent in the standard solution, go forward side by side
The processing of row high speed centrifugation, the supernatant after taking centrifugal treating；
The supernatant is detected under the testing conditions using liquid chromatograph-mass spectrometer, obtains the supernatant
Corresponding second testing result；
The calibration curve equation of calibration curve equation and the dehydroaripiprazole based on the Aripiprazole and described
Second testing result obtains the concentration of Aripiprazole and the concentration of dehydroaripiprazole in the blood sample to be measured.
Preferably,
The chromatographic condition of the testing conditions, comprising:
C18 reverse chromatograms column；Column temperature is 20~40 DEG C；
Mobile phase are as follows: the aqueous solution containing 0.1% formic acid, and the methanol solution containing 0.1% formic acid and 1mM ammonium formate,
In, the volume ratio of the aqueous solution and the methanol solution is 1:9, when the isocratic elution of the aqueous solution and the methanol solution
Between be not less than 2.5min；
The flow velocity of the mobile phase is 0.5~0.8ml/min.
Preferably,
The Mass Spectrometry Conditions of the testing conditions, comprising:
The mass detector of liquid chromatograph-mass spectrometer is ESI (+) mode；
The source parameters, comprising: throughput is 8~50L/min, and spray amount is 20~50L/min, and gas temperature is
300~400 DEG C, capillary voltage is 3000~5000V.
Preferably,
The C18 reverse chromatograms column, comprising: Agilent Eclipse plus C18.
Preferably,
The internal standard compound, comprising: Aripiprazole-d8.
Preferably,
Two variables of the calibration curve equation of the Aripiprazole are respectively as follows:
The ratio of the chromatographic peak peak area of the chromatographic peak peak area and internal standard compound of Aripiprazole and the concentration of Aripiprazole
With the ratio of the concentration of internal standard compound；
Two variables of the calibration curve equation of the dehydroaripiprazole are respectively as follows:
The ratio of the chromatographic peak peak area of the chromatographic peak peak area and internal standard compound of dehydroaripiprazole and Aripiprazole
The ratio of concentration and the concentration of internal standard compound.
Preferably,
Preparation at least three kinds of standard solution, comprising:
Prepare Aripiprazole standard reserving solution: the methanol solution for being 0%~30% for water content dissolves Aripiprazole mark
Quasi- product obtain Aripiprazole standard reserving solution, and save under the conditions of -80 DEG C；
The bent mixing intermediate fluid of preparation mark: with diluted and Aripiprazole standard reserving solution and dehydroaripiprazole are mixed
Standard reserving solution obtains mixing intermediate fluid with the mark song of dehydroaripiprazole containing 20~2560ng/mL Aripiprazole, and-
It is saved under the conditions of 80 DEG C；
Preparation internal standard working solution: with diluted and internal standard compound stock solution is mixed, is obtained containing 50~250ng/mL's
Internal standard working solution, and saved under the conditions of -80 DEG C；
Prepare standard solution: the mobile at least mark song of three kinds of same volumes and various concentration mixing intermediate fluid, to what is pipetted
The mark song of each concentration mixes the described of the internal standard working solution and same volume that same volume is added in intermediate fluid
Protein precipitation reagent, and be vortexed in the case where revolving speed is 1000~2000rpm and mix 30s~1min, at least three kinds of various concentrations are made
Standard solution.
Preferably,
It is tried in described be added into blood sample to be measured with same amount of internal standard compound in the standard solution and protein precipitation
Agent, and before carrying out high speed centrifugation processing, further comprise:
The blood to be detected of at least 2ml is centrifuged 8~15min at 3000~4000RPM of centrifugal speed, and after taking centrifugation
Supernatant as blood sample to be measured, saved under the conditions of -20 DEG C；
The addition into blood sample to be measured and same amount of internal standard compound and protein precipitation reagent in the standard solution,
And carry out high speed centrifugation processing, comprising:
Pipette with the internal standard working solution same amount of in the standard solution, into the internal standard working solution pipetted plus
Enter the blood sample to be measured, be vortexed concussion mixing 30s~1min under the revolving speed of 1500~2500RPM, and it is described heavy to add
Shallow lake protein reagent is vortexed after 2~4min of concussion mixing under the revolving speed of 1200~2000RPM, then 10000~15000RPM's
5~10min of high speed centrifugation under revolving speed.
Preferably,
The dilution is 10%~80% acetonitrile solution of water content.
Preferably,
The protein precipitation reagent, comprising: methanol, wherein the volume ratio of the blood sample to be measured and methanol be 1:3~
1:10.
The embodiment of the invention provides a kind of methods of Aripiprazole and dehydroaripiprazole in detection blood, utilize liquid phase
Chromatograph-mas spectrometer detects the standard solution of at least three kinds concentration respectively, wherein standard solution is the A Li with internal standard compound
The standard solution of piperazine azoles and dehydroaripiprazole, and internal standard compound concentration is consistent at least three kinds of concentration standard solution；According at least
The testing result of three kinds of concentration standard solution is fitted the calibration curve equation of Aripiprazole and the mark of dehydroaripiprazole respectively
Directrix curve equation；High speed centrifugation processing is carried out to blood to be detected, and into the supernatant after centrifugation in addition and standard solution
Same amount of internal standard compound working solution, vortex oscillation mixes at high speed, adds protein precipitation reagent, and carries out high speed again
Vortex oscillation mixing and high speed centrifugation processing, so that solution is uniformly mixed the supernatant after obtaining removal chaff interferent.Utilize liquid
Phase chromatograph-mas spectrometer detects the supernatant, the first testing result and A Li based on Aripiprazole and dehydroaripiprazole
The calibration curve equation of piperazine azoles and the calibration curve equation of dehydroaripiprazole, obtain in blood sample to be measured Aripiprazole and
The concentration of dehydroaripiprazole realizes while detecting the Aripiprazole in blood and dehydroaripiprazole, is effectively shortened
Detection time.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is the present invention
Some embodiments for those of ordinary skill in the art without creative efforts, can also basis
These attached drawings obtain other attached drawings.
Fig. 1 is the method for Aripiprazole and dehydroaripiprazole in a kind of detection blood of one embodiment of the invention offer
Flow chart；
Fig. 2 is the chemical structural formula of the Aripiprazole ARPZ that one embodiment of the invention provides and dehydroaripiprazole DPZ；
Fig. 3 is Aripiprazole, dehydroaripiprazole and Aripiprazole-d8 in the standard solution of one embodiment of the invention offer
Chromatogram；
Fig. 4 is Aripiprazole, dehydroaripiprazole and Aripiprazole-d8 in the standard solution of one embodiment of the invention offer
Mass spectrogram；
Fig. 5 is Aripiprazole, dehydroaripiprazole and the A Li in the blood sample to be measured that one embodiment of the invention provides
The chromatogram of piperazine azoles-d8；
Fig. 6 is Aripiprazole, dehydroaripiprazole and the A Li in the blood sample to be measured that one embodiment of the invention provides
The mass spectrogram of piperazine azoles-d8.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In attached drawing, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is
A part of the embodiment of the present invention, instead of all the embodiments, based on the embodiments of the present invention, those of ordinary skill in the art
Every other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.
As shown in Figure 1, the embodiment of the invention provides the sides of Aripiprazole and dehydroaripiprazole in a kind of detection blood
Method, comprising:
Step 101: preparation at least three kinds of standard solution, wherein at least three kinds of standard solution contain known to difference
The Aripiprazole of concentration, the different dehydroaripiprazole of known concentration and the internal standard compound of identical known concentration；
Step 102: using liquid chromatograph-mass spectrometer under preset testing conditions, detected described in each respectively
Standard solution obtains corresponding first testing result of each standard solution；
Step 103: concentration and internal standard compound based on Aripiprazole in each first testing result, the standard solution
Concentration, respectively fitting obtain the calibration curve equation of Aripiprazole and the calibration curve equation of dehydroaripiprazole；
Step 104: being added into blood sample to be measured and same amount of internal standard compound and protein precipitation in the standard solution
Reagent, and carry out high speed centrifugation processing, the supernatant after taking centrifugal treating；
Step 105: detecting the supernatant under the testing conditions using liquid chromatograph-mass spectrometer, obtain institute
State corresponding second testing result of supernatant；
Step 106: the standard curve side of calibration curve equation and the dehydroaripiprazole based on the Aripiprazole
Journey and second testing result obtain the dense of the concentration and dehydroaripiprazole of Aripiprazole in the blood sample to be measured
Degree.
Liquid chromatograph-mass spectrometer detection process used in detection method provided in an embodiment of the present invention can be, can
Chromatographic peak peak area based on the standard target object in standard solution and the relationship between the concentration of standard target object construct, mark
Calibration curve equation between the chromatographic peak peak area of quasi- object and the concentration of standard target object, then will be in blood sample to be measured
The chromatographic peak peak area of object substitutes into the concentration that object in blood sample to be measured can be calculated in calibration curve equation.
Due to blood sample treatment process to be measured and detection error, so that the above-mentioned chromatographic peak peak based on standard target object
There are certain deviations for the calibration curve equation that the concentration of area and standard target object constructs, then, it is based on the standard curve
The concentration for the object in blood sample to be measured that equation calculation goes out can also have deviation.Preferably, it is used in detection method
Liquid chromatograph-mass spectrometer detection process can also be, by the corresponding internal standard compound of addition object, with the color of object
The ratio of the chromatographic peak peak area of spectral peak peak area and internal standard compound is the first independent variable, the concentration of object and the concentration of internal standard compound
Ratio be the second independent variable, pass through at least three groups (the first independent variable and the second independent variable) progresss linear regression fit standards songs
Line equation, then by the ratio of the chromatographic peak peak area of the object in blood sample to be measured and the chromatographic peak peak area of internal standard compound,
It substitutes into above-mentioned standard curvilinear equation, in available blood sample to be measured
The chromatographic peak peak area of the object of blood sample to be measured and the concentration of internal standard compound, are calculated blood sample to be measured
The ratio of the concentration of the concentration and internal standard compound of middle object, since the concentration of internal standard compound is known, it is possible thereby to calculate to
Survey the concentration of object in blood sample.
Preferably, two variables in Aripiprazole calibration curve equation are respectively as follows: the chromatographic peak peak area of Aripiprazole
With the ratio of chromatographic peak peak area of internal standard compound and the ratio of the concentration of Aripiprazole and the concentration of internal standard compound；
Two variables of the calibration curve equation of the dehydroaripiprazole are respectively as follows:
The ratio of the chromatographic peak peak area of the chromatographic peak peak area and internal standard compound of dehydroaripiprazole and Aripiprazole
The ratio of concentration and the concentration of internal standard compound.
For the embodiment of the present invention, the object in above-mentioned standard object and blood sample to be measured is A Li piperazine
Azoles and dehydroaripiprazole；Above-mentioned internal standard compound can be Aripiprazole-d8.
The processing mode of known volume blood sample to be measured also will affect final testing result, the embodiment of the present invention above
By the addition into blood sample to be measured and same amount of internal standard compound and protein precipitation reagent in the standard solution, and carry out height
Fast centrifugal treating, the supernatant after taking centrifugal treating, can retain to the greatest extent Aripiprazole in blood sample to be measured and
Dehydroaripiprazole, while chaff interferent is removed, since the time of centrifugal treating is short, blood sample pre-treatment can be shortened
Time, and then shorten detection duration, improve the detection efficiency of blood sample.
It is understood that above-mentioned testing result refers in the map of the standard solution of each concentration, Aripiprazole
The chromatographic peak peak area of chromatographic peak peak area, dehydroaripiprazole chromatographic peak peak area and internal standard compound.
For liquid chromatograph-mass spectrometer used in Aripiprazole in detection blood to be detected and dehydroaripiprazole
For, the chromatographic condition of efficient liquid phase includes: C18 reverse chromatograms column；Column temperature is 20~40 DEG C；Mobile phase are as follows: contain 0.1% formic acid
Aqueous solution, and the methanol solution containing 0.1% formic acid and 1mM ammonium formate, wherein the aqueous solution and the methanol solution
Volume ratio is 1:9, and the isocratic elution time of the aqueous solution and the methanol solution is not less than 2.5min；The stream of the mobile phase
Speed is 0.5~0.8ml/min；Wherein, the C18 reverse chromatograms column, comprising: Agilent Eclipse plus C18.
It is understood that sample volume can be any volume within the scope of 0.1 μ L to 30 μ L, for example, 0.1 μ L, 0.2 μ
L, 0.5 μ L, 1 μ L, 5 μ L, 10 μ L, 15 μ L, 20 μ L, 25 μ L and 30 μ L.
For column temperature, 20~40 DEG C of any temperature referred at 20 DEG C to 40 DEG C, for example, 20 DEG C, 21 DEG C, 22.5
DEG C, 23 DEG C, 24 DEG C, 25 DEG C, 27.5 DEG C, 29 DEG C, 30.5 DEG C, 33 DEG C, 34 DEG C, 35 DEG C, 37 DEG C, 38.5 DEG C, 39 DEG C and 40 DEG C
Deng in the range at any temperature, the result that detected is unanimous on the whole.
For liquid chromatograph-mass spectrometer used in Aripiprazole and dehydroaripiprazole in detection detection blood come
It says, Mass Spectrometry Conditions, comprising: the mass detector of liquid chromatograph-mass spectrometer is ESI (+) mode；The source parameters,
It include: throughput for 8~50L/min, spray amount is 20~50L/min, and gas temperature is 300~400 DEG C, and capillary voltage is
3000~5000V.
For throughput, 8~50L/min refers to any flow velocity in 8L/min to 50L/min, for example, 8L/min,
8.5L/min, 9L/min, 11L/min, 14L/min, 19L/min, 24L/min, 28.5L/min, 35L/min, 38.5L/min,
42L/min, 44L/min, 47.5L/min, 49L/min and 50L/min etc..
For spray amount, 20~50L/min refers to any flow velocity in 20L/min to 50L/min, for example, 20L/
Min, 22.5L/min, 26L/min, 30L/min, 32L/min, 35.5L/min, 36L/min, 40L/min, 43L/min,
46.5L/min and 50L/min etc..
For gas temperature, 300~400 DEG C refer to 300 DEG C to 400 DEG C of any temperature, for example, 300 DEG C, 320
DEG C, 350 DEG C, 380 DEG C, 400 DEG C, 420 DEG C, 430 DEG C, 440 DEG C, 460 DEG C, 480 DEG C and 500 DEG C etc..
For capillary voltage, 3000~5000V refers to any voltage of 3000V to 5000V, for example, 3000V,
3100V, 3300V, 3500V, 3900V, 4000V, 4200V, 4300V, 4500V, 4700V, 4900V and 5000V etc..
Further, the mass spectrometry parameters of liquid chromatograph-mass spectrometer can be further as shown in table 1 below:
Table 1
| Substance title | Parent ion | Daughter ion | Dwell | Fragmentor | CE | CAV |
| Aripiprazole | 448.1 | 285.0 | 30 | 120 | 28 | 4 |
| Dehydroaripiprazole | 446.1 | 285.0 | 50 | 150 | 20 | 4 |
| Aripiprazole-d8 | 456.0 | 293.1 | 30 | 120 | 28 | 4 |
In above-mentioned table, Dwell characterizes sweep time, Fragmentor characterization cracking voltage, and CE characterizes collision voltage, CAV
Characterize collision cell acceleration voltage.
In general, the manner of formulation of mixed standard solution will directly affect the accuracy of detection, institute of the embodiment of the present invention
The preparation method of the standard solution of selection can guarantee the accuracy of testing result.The preparation method of the standard solution includes: system
Standby Aripiprazole standard reserving solution, preparation mark are bent to be mixed intermediate fluid, preparation internal standard working solution and prepares standard solution, wherein
Prepare Aripiprazole standard reserving solution: the methanol solution for being 0%~30% for water content dissolves Aripiprazole mark
Quasi- product obtain Aripiprazole standard reserving solution, and save under the conditions of -80 DEG C；
The bent mixing intermediate fluid of preparation mark: with diluted and Aripiprazole standard reserving solution and dehydroaripiprazole are mixed
Standard reserving solution obtains mixing intermediate fluid with the mark song of dehydroaripiprazole containing 20~2560ng/mL Aripiprazole, and-
It is saved under the conditions of 80 DEG C；
Preparation internal standard working solution: with diluted and internal standard compound stock solution is mixed, is obtained containing 50~250ng/mL's
Internal standard working solution, and saved under the conditions of -80 DEG C；
Prepare standard solution: the mobile at least mark song of three kinds of same volumes and various concentration mixing intermediate fluid, to what is pipetted
The mark song of each concentration mixes the described of the internal standard working solution and same volume that same volume is added in intermediate fluid
Protein precipitation reagent, and be vortexed in the case where revolving speed is 1000~2000rpm and mix 30s~1min, at least three kinds of various concentrations are made
Standard solution.
In general, the pre-treatment of blood sample to be measured will directly affect the accuracy of detection, selected by the embodiment of the present invention
The pre-treatment of blood sample to be measured can guarantee the accuracy of testing result.The pretreatment mode includes:
The blood to be detected of at least 2ml is centrifuged 8~15min at 3000~4000RPM of centrifugal speed, and after taking centrifugation
Supernatant as blood sample to be measured, saved under the conditions of -20 DEG C；
Pipette with the internal standard working solution same amount of in the standard solution, into the internal standard working solution pipetted plus
Enter the blood sample to be measured, be vortexed concussion mixing 30s~1min under the revolving speed of 1500~2500RPM, and it is described heavy to add
Shallow lake protein reagent is vortexed after 2~4min of concussion mixing under the revolving speed of 1200~2000RPM, then 10000~15000RPM's
5~10min of high speed centrifugation under revolving speed.It enables to internal standard working solution to be uniformly mixed with blood sample to be measured, while removing interference
Object.
Above-mentioned dilution is 10%~80% acetonitrile solution of water content.
Protein precipitation reagent described above, comprising: methanol, wherein the volume ratio of the blood sample to be measured and methanol is
1:3~1:10.Volume ratio is any proportion of the volume in 1:3 to 1:10 that 1:3~1:10 refers to blood sample and methanol to be measured,
For example, 1:3,1:4.5,1:5,1:6.5,1:7.5,1:8,1:9 and 1:10 etc..
The chemical structural formula of Aripiprazole ARPZ and dehydroaripiprazole DPZ that the present invention detects are as shown in Figure 2.
Blood mentioned by the embodiment of the present invention can be blood itself, or the associated sample of blood such as whole blood,
Serum, blood plasma etc..
The method of Aripiprazole and dehydroaripiprazole in detection blood is described in detail with several embodiments below.
Embodiment 1: the standard solution of series of concentrations is prepared
It prepares Aripiprazole standard reserving solution: accurately weighing Aripiprazole standard items 1.56mg and be placed in 2ml volumetric flask, with containing
Water is that the methanol solution of 0%-30% is dissolved, and constant volume saves under the conditions of -80 DEG C in 2ml.
The bent mixing intermediate fluid of preparation mark: it is diluted with water content for 10%~80% acetonitrile solution and mixes Aripiprazole standard
The mark song mixing intermediate fluid of eight kinds of various concentrations is made in stock solution and dehydroaripiprazole standard reserving solution, and in -80 DEG C of conditions
Lower preservation, the mixing intermediate fluid of eight kinds of various concentrations are respectively as follows: the Aripiprazole and 20ng/ml dehydrogenation that concentration is 20ng/ml
The mark song of Aripiprazole mixes intermediate fluid, and concentration is the mark song of the Aripiprazole of 40ng/ml and the dehydroaripiprazole of 40ng/ml
Intermediate fluid is mixed, the Aripiprazole of 80ng/ml and the mark song of 80ng/ml dehydroaripiprazole mix intermediate fluid, 160ng/ml's
Aripiprazole and the mark song of 160ng/ml dehydroaripiprazole mix intermediate fluid, and the Aripiprazole and 320ng/ml of 320ng/ml is gone
The mark song of hydrogen Aripiprazole mixes intermediate fluid, the Aripiprazole of 640ng/ml and the mark song mixing of 640ng/ml dehydroaripiprazole
Intermediate fluid, the Aripiprazole of 1280ng/ml and the mark song of 1280ng/ml dehydroaripiprazole mix intermediate fluid, 2560ng/ml's
Aripiprazole and the mark song of 2560ng/ml dehydroaripiprazole mix intermediate fluid.
Preparation internal standard working solution: being diluted with water content for 10%~80% acetonitrile solution and mixes Aripiprazole-d8 deposit
Liquid obtains the internal standard working solution containing 50~250ng/mL, and saves under the conditions of -80 DEG C.
It prepares series standard solution: pipetting 10 μ L respectively without the mark song mixing intermediate fluid of concentration, to each pipetted
Be added the internal standard working solution of 10 μ L and the methanol of 100 μ L in the bent mixing intermediate fluid of the mark of concentration, and revolving speed be 1000~
It is vortexed under 2000rpm and mixes 30s~1min, the standard solution of eight kinds of various concentrations is made, wherein the standard of each concentration is molten
The concentration for the internal standard compound for including in liquid is identical.
Embodiment 2: fit standard curvilinear equation
The standard solution that each concentration that above-described embodiment 1 obtains is detected using liquid chromatograph-mass spectrometer, is obtained
The map of the Aripiprazole of the standard solution of eight kinds of various concentrations, dehydroaripiprazole and Aripiprazole-d8.
Aripiprazole, dehydroaripiprazole and A Li piperazine are respectively obtained from the map of the standard solution of above-mentioned every kind of concentration
The chromatographic peak peak area of azoles-d8, respectively with the chromatographic peak peak face of the Aripiprazole in the standard solution of above-mentioned eight kinds of various concentrations
The long-pending ordinate y1 with the ratio of the chromatographic peak peak area of Aripiprazole-d8 as calibration curve equation, dehydroaripiprazole
Ordinate y2 of the ratio of the chromatographic peak peak area of chromatographic peak peak area and Aripiprazole-d8 as calibration curve equation, it is above
The ratio of the concentration of the concentration and Aripiprazole-d8 of Aripiprazole in the standard solution of eight kinds of various concentrations is as standard curve
Abscissa x1, abscissa x2 of the ratio of the concentration of the concentration and Aripiprazole-d8 of dehydroaripiprazole as standard curve,
The data of the resulting eight kinds of various concentrations of above-mentioned detection are subjected to linear regression, fitting obtains the corresponding standard curve of Aripiprazole
Equation are as follows: y1=a*x1+b, the corresponding calibration curve equation of dehydroaripiprazole are as follows: y2=c*x2+d, and obtain weight system
Number a, b, c, d；The calibration curve equation and coefficient a, b, c, d need to redeterminate before detection every time.I.e. the embodiment 2 is
The step of Aripiprazole and dehydroaripiprazole have to carry out in detection blood in a period of time.It is usually to mark in a period of time
In the effective period of time of quasi- solution.
In above-mentioned liquid chromatograph-mass spectrometer,
The chromatographic condition of efficient liquid phase includes:
Agilent Eclipse plus C18 chromatographic column；Column temperature is 40 DEG C；
Mobile phase are as follows: the aqueous solution containing 0.1% formic acid, and the methanol solution containing 0.1% formic acid and 1mM ammonium formate,
In, the volume ratio of aqueous solution and methanol solution is 1:9, and the isocratic elution time of aqueous solution and methanol solution is 2.5min；Flowing
The flow velocity of phase is 0.5ml/min.
Mass spectrometric Mass Spectrometry Conditions include:
Mass detector is ESI (+) mode；
The source parameters, comprising: throughput 10L/min, spray amount 30L/min, gas temperature are 350 DEG C,
Capillary voltage is 4500V.Detailed parameter is as shown in Table 1 above.
Aripiprazole, dehydroaripiprazole and Aripiprazole-d8 in the standard solution of one of above-described embodiment concentration
Chromatogram as shown in figure 3, mass spectrogram is as shown in Figure 4.Wherein, the number mark 1 in Fig. 3 is Aripiprazole in standard solution
Chromatogram, number mark 2 are the chromatogram of Aripiprazole-d8 in standard solution, and number mark 3 is dehydrogenation A Li in standard solution
The chromatogram of piperazine azoles；Number mark 1 in Fig. 4 is the mass spectrogram of Aripiprazole in standard solution, and number mark 2 is standard solution
The mass spectrogram of middle Aripiprazole-d8, number mark 3 are the mass spectrogram of dehydroaripiprazole in standard solution.In standard solution
The retention time of Aripiprazole, dehydroaripiprazole and Aripiprazole-d8 is 1.91min.
Further, pot strainer used in liquid chromatograph-mass spectrometer are as follows:
SSI COL PRE-FILTER WATER 1/16 0.5M。
Embodiment 3, blood sample processing to be measured
Detection blood at least 2ml is taken, is centrifuged 10min at centrifugal speed 3500rpm, supernatant is taken to obtain serum, and by blood
It is used as blood sample to be measured clearly, and is saved under the conditions of -20 DEG C；
It pipettes in 10 μ L of Aripiprazole-d8 and 1.5ml centrifuge tube, adds the blood sample to be measured in above-described embodiment 2
10 μ L, be vortexed concussion mixing 1min under the revolving speed of 2500RPM, and 100 μ L of methanol is then added in above-mentioned centrifuge tube again,
It is vortexed after concussion mixing 3min under the revolving speed of 2000rpm, then the high speed centrifugation 10min under the revolving speed of 14000rpm, obtains supernatant
Liquid.
The supernatant that embodiment 4, the calibration curve equation provided based on embodiment 2 and embodiment 3 are obtained, detects blood to be measured
Aripiprazole and dehydroaripiprazole in liquid sample
The supernatant obtained using liquid chromatograph-mass spectrometer detection embodiment 3, obtains the figure of blood sample to be measured
Spectrum.
From chromatographic peak peak area, the dehydrogenation of the Aripiprazole obtained in the map of blood sample to be measured in blood sample to be measured
The chromatographic peak peak area of Aripiprazole and the chromatographic peak peak area of Aripiprazole-d8；
By the chromatographic peak peak area of the chromatographic peak peak area of the Aripiprazole in blood sample to be measured and Aripiprazole-d8
Ratio substitutes into y1=a*x1+b as y1, obtains the concentration of the Aripiprazole in blood sample to be measured with Aripiprazole-d8's
The ratio x1 of concentration, since the concentration of Aripiprazole-d8 is it is known that it is possible thereby to calculating Aripiprazole in blood sample to be measured
Concentration.
Similarly, by the color of the chromatographic peak peak area of the dehydroaripiprazole in blood sample to be measured and Aripiprazole-d8
The ratio of spectral peak peak area substitutes into y2=c*x2+d as y2, obtains the dense of the dehydroaripiprazole in blood sample to be measured
The ratio x2 of degree and the concentration of Aripiprazole-d8, since the concentration of Aripiprazole-d8 is it is known that it is possible thereby to calculating to be measured
The concentration of dehydroaripiprazole in blood sample.
In this embodiment, the chromatographic condition of the efficient liquid phase of liquid chromatograph-mass spectrometer and mass spectrometric mass spectrum item
Part provides consistent with above-described embodiment 2, and details are not described herein.
The color of the Aripiprazole in blood sample to be measured, dehydroaripiprazole and Aripiprazole-d8 in above-described embodiment
Spectrogram is as shown in figure 5, mass spectrogram is as shown in Figure 6；Wherein, the number mark 1 in Fig. 3 is Aripiprazole in blood sample to be measured
Chromatogram, number mark 2 are the chromatogram of Aripiprazole-d8 in blood sample to be measured, and number mark 3 is in blood sample to be measured
The chromatogram of dehydroaripiprazole；Mass spectrogram of the number mark 1 for Aripiprazole in blood sample to be measured in Fig. 4, number mark
2 are known for the mass spectrogram of Aripiprazole-d8 in blood sample to be measured, and number mark 3 is dehydroaripiprazole in blood sample to be measured
Mass spectrogram.The retention time of Aripiprazole, dehydroaripiprazole and Aripiprazole-d8 in blood sample to be measured is
1.91min。
By Fig. 3, Fig. 4, Fig. 5 and Fig. 6 comparison as it can be seen that the guarantor of Aripiprazole and dehydroaripiprazole in blood sample to be measured
It stays the time and marks the retention time of the Aripiprazole in solution and dehydroaripiprazole it is known that using Aripiprazole-d8 as internal standard
Object, so that the identification of Aripiprazole and dehydroaripiprazole is more accurate, analysis time is short, interference is small, and interior scalar quantity is suitable for spy
Anisotropic strong, accuracy and high sensitivity.
It should be noted that the abscissa of Fig. 3 and Fig. 5 is acquisition time, ordinate is electrical signal intensity.Fig. 4 and
The abscissa of Fig. 6 is the mass-to-charge ratio of ion, and ordinate is the intensity of ion stream.
Embodiment 5: the linear relationship and quantitative limit of the method for Aripiprazole and dehydroaripiprazole in detection blood
The Aripiprazole for each concentration that above-described embodiment 1 is prepared and the standard working solution of dehydroaripiprazole are added
10 μ L internal standard working solutions, and 100 μ L of methanol is added and mixes sample introduction, it is detected by the processing and testing conditions of embodiment 2, with fixed
It measures ion chromatography peak peak area and concentration is mapped, obtain standard curve, the results showed that the line of Aripiprazole and dehydroaripiprazole
Property range and quantitative limit are as follows:
Aripiprazole
(1) detection line (LOD): 1.080ng/mL.
(2) quantitative limit (LOQ): 3.851ng/mL.
(3) range of linearity: linear good in 20ng/mL to 2560ng/mL range, 2 ﹥ 0.999 of coefficient R.
Dehydroaripiprazole
(1) detection line (LOD): 0.769ng/mL.
(2) quantitative limit (LOQ): 3.819ng/mL.
(3) range of linearity: linear good in 20ng/mL to 2560ng/mL range, 2 ﹥ 0.999 of coefficient R.
Embodiment 6: the rate of recovery and precision of the method for Aripiprazole and dehydroaripiprazole in detection blood
Take respectively mixed containing Aripiprazole with the mark song of dehydroaripiprazole intermediate fluid be configured to high, medium and low 3 kinds of concentration into
The experiment of row sample recovery rate and Precision Experiment, are detected by the processing mode and testing conditions of embodiment 2, and replicate analysis is surveyed
Fixed 3 batches, the rate of recovery and precision of Aripiprazole are as shown in table 2 below, and the rate of recovery and precision of dehydroaripiprazole are as follows
Shown in table 3:
Table 2
| Scalar quantity | 40ng/mL | 320ng/mL | 1280ng/mL |
| Average recovery rate | 98.03% | 98.29% | 96.74% |
| Precision RSD | 1.52% | 2.05% | 2.02% |
As shown in Table 2, average recovery rate of the Aripiprazole within the scope of 3 basic, normal, high pitch-based spheres is 96.74%
~98.29%, relative standard deviation is 1.52%~2.05%.
Table 3
As shown in Table 3, average recovery rate of the dehydroaripiprazole within the scope of 3 basic, normal, high pitch-based spheres is
98.87%~101.75%, relative standard deviation is 1.86%~3.49%.
In summary verification test, all technicals such as the detection limit, the rate of recovery and precision of the present embodiment meet
It is required that Aripiprazole and dehydroaripiprazole concentration in method detection blood, reproducibility is good, and sample recovery rate is high, improves
The accuracy of testing result.
The each embodiment of the present invention at least has the following beneficial effects:
1, the mark of at least three kinds concentration in an embodiment of the present invention, is detected respectively using liquid chromatograph-mass spectrometer
Quasi- solution, wherein standard solution is the standard solution of the Aripiprazole with internal standard compound and dehydroaripiprazole, and at least three kinds
Internal standard compound concentration is consistent in concentration standard solution；According to the testing result of at least three kinds concentration standard solution, it is fitted A Li respectively
The calibration curve equation of piperazine azoles and the calibration curve equation of dehydroaripiprazole；Blood to be detected is carried out at high speed centrifugation
Reason, and be added and same amount of internal standard compound working solution in standard solution, at high speed vortex vibration into the supernatant after centrifugation
Mixing is swung, protein precipitation reagent is added, and carries out the mixing of high speed vortex oscillation and high speed centrifugation processing again, so that solution
The supernatant being uniformly mixed after obtaining removal chaff interferent.The supernatant is detected using liquid chromatograph-mass spectrometer, is based on A Li
The calibration curve equation of the first testing result and Aripiprazole of piperazine azoles and dehydroaripiprazole and the mark of dehydroaripiprazole
Directrix curve equation obtains the concentration of Aripiprazole and dehydroaripiprazole in blood sample to be measured, realizes while detecting blood
In Aripiprazole and dehydroaripiprazole, be effectively shortened detection time.
2, in an embodiment of the present invention, the selection of the processing method to blood sample to be measured and internal standard compound so that Ah
The identification of vertical piperazine azoles and dehydroaripiprazole is more accurate, and analysis time is short, interference is small, and interior scalar quantity appropriate specificity is strong, clever
Sensitivity is high, meanwhile, the rate of recovery, all technicals such as detection limit and precision meet the requirements, meanwhile, in the detection blood Ah
The method of vertical piperazine azoles and dehydroaripiprazole, reproducibility is good, and sample recovery rate is good, to improve the accurate of testing result
Degree eliminates systematic error.
It should be noted that, in this document, such as first and second etc relational terms are used merely to an entity
Or operation is distinguished with another entity or operation, is existed without necessarily requiring or implying between these entities or operation
Any actual relationship or order.Moreover, the terms "include", "comprise" or its any other variant be intended to it is non-
It is exclusive to include, so that the process, method, article or equipment for including a series of elements not only includes those elements,
It but also including other elements that are not explicitly listed, or further include solid by this process, method, article or equipment
Some elements.In the absence of more restrictions, the element limited by sentence " including a 〃 〃 ", it is not excluded that
There is also other identical factors in the process, method, article or apparatus that includes the element.
Finally, it should be noted that the foregoing is merely presently preferred embodiments of the present invention, it is merely to illustrate skill of the invention
Art scheme, is not intended to limit the scope of the present invention.Any modification for being made all within the spirits and principles of the present invention,
Equivalent replacement, improvement etc., are included within the scope of protection of the present invention.
Claims (10)
1. a kind of method of Aripiprazole and dehydroaripiprazole in detection blood characterized by comprising
Prepare at least three kinds of standard solution, wherein at least three kinds of standard solution contain the A Li piperazine of different known concentrations
Azoles, the different dehydroaripiprazole of known concentration and the internal standard compound of identical known concentration；
Using liquid chromatograph-mass spectrometer under preset testing conditions, each described standard solution is detected respectively, is obtained
Corresponding first testing result of each standard solution；
Based on the concentration of Aripiprazole and the concentration of internal standard compound in each first testing result, the standard solution, respectively
Fitting obtains the calibration curve equation of Aripiprazole and the calibration curve equation of dehydroaripiprazole；
Addition and same amount of internal standard compound and protein precipitation reagent in the standard solution into blood sample to be measured, and carry out height
Fast centrifugal treating, the supernatant after taking centrifugal treating；
The supernatant is detected under the testing conditions using liquid chromatograph-mass spectrometer, and it is corresponding to obtain the supernatant
The second testing result；
The calibration curve equation and described second of calibration curve equation and the dehydroaripiprazole based on the Aripiprazole
Testing result obtains the concentration of Aripiprazole and the concentration of dehydroaripiprazole in the blood sample to be measured.
2. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 1, which is characterized in that
The chromatographic condition of the testing conditions, comprising:
C18 reverse chromatograms column；Column temperature is 20~40 DEG C；
Mobile phase are as follows: the aqueous solution containing 0.1% formic acid, and the methanol solution containing 0.1% formic acid and 1mM ammonium formate, wherein institute
The volume ratio of aqueous solution and the methanol solution is stated as 1:9, the isocratic elution time of the aqueous solution and the methanol solution is not
Less than 2.5min；
The flow velocity of the mobile phase is 0.5~0.8ml/min.
3. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 2, which is characterized in that
The Mass Spectrometry Conditions of the testing conditions, comprising:
The mass detector of liquid chromatograph-mass spectrometer is ESI (+) mode；
The source parameters, comprising: throughput is 8~50L/min, and spray amount is 20~50L/min, gas temperature 300
~400 DEG C, capillary voltage is 3000~5000V.
4. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 2, which is characterized in that
The C18 reverse chromatograms column, comprising: Agilent Eclipse plus C18.
5. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 1, which is characterized in that
The internal standard compound, comprising: Aripiprazole-d8.
6. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 1, which is characterized in that
Two variables of the calibration curve equation of the Aripiprazole are respectively as follows:
The concentration of the ratio of the chromatographic peak peak area of the chromatographic peak peak area and internal standard compound of Aripiprazole and Aripiprazole with it is interior
Mark the ratio of the concentration of object；
Two variables of the calibration curve equation of the dehydroaripiprazole are respectively as follows:
The ratio of the chromatographic peak peak area of the chromatographic peak peak area and internal standard compound of dehydroaripiprazole and the concentration of Aripiprazole
With the ratio of the concentration of internal standard compound.
7. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 1, which is characterized in that
Preparation at least three kinds of standard solution, comprising:
Prepare Aripiprazole standard reserving solution: the methanol solution for being 0%~30% for water content dissolves Aripiprazole standard items,
Aripiprazole standard reserving solution is obtained, and is saved under the conditions of -80 DEG C；
The bent mixing intermediate fluid of preparation mark: with diluted and Aripiprazole standard reserving solution and dehydroaripiprazole standard are mixed
Stock solution obtains mixing intermediate fluid with the mark song of dehydroaripiprazole containing 20~2560ng/mL Aripiprazole, and at -80 DEG C
Under the conditions of save；
Preparation internal standard working solution: with diluted and internal standard compound stock solution is mixed, obtains the internal standard containing 50~250ng/mL
Working solution, and saved under the conditions of -80 DEG C；
Prepare standard solution: the mobile at least mark song of three kinds of same volumes and various concentration mixing intermediate fluid, it is each to what is pipetted
The internal standard working solution of same volume and the precipitating of same volume is added in the mark song mixing intermediate fluid of kind concentration
Protein reagent, and be vortexed in the case where revolving speed is 1000~2000rpm and mix 30s~1min, the mark of at least three kinds various concentrations is made
Quasi- solution.
8. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 7, which is characterized in that
In the addition into blood sample to be measured and same amount of internal standard compound and protein precipitation reagent in the standard solution, and
Before carrying out high speed centrifugation processing, further comprise:
The blood to be detected of at least 2ml is centrifuged 8~15min at 3000~4000RPM of centrifugal speed, and is taken upper after centrifugation
Clear liquid saves under the conditions of -20 DEG C as blood sample to be measured；
The addition into blood sample to be measured and same amount of internal standard compound and protein precipitation reagent in the standard solution, go forward side by side
The processing of row high speed centrifugation, comprising:
Pipette with the internal standard working solution same amount of in the standard solution, institute is added into the internal standard working solution pipetted
Blood sample to be measured is stated, be vortexed concussion mixing 30s~1min under the revolving speed of 1500~2500RPM, adds the precipitating egg
White reagent is vortexed after 2~4min of concussion mixing under the revolving speed of 1200~2000RPM, then in the revolving speed of 10000~15000RPM
5~10min of lower high speed centrifugation.
9. the method for Aripiprazole and dehydroaripiprazole in detection blood according to claim 7, which is characterized in that
The dilution is 10%~80% acetonitrile solution of water content.
10. according to claim 1 into the detection blood any in 9 Aripiprazole and dehydroaripiprazole method,
It is characterized in that,
The protein precipitation reagent, comprising: methanol, wherein the volume ratio of the blood sample to be measured and methanol is 1:3~1:
10。
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