CN112433019A - Method for quantitatively determining carbamazepine in human plasma and application - Google Patents
Method for quantitatively determining carbamazepine in human plasma and application Download PDFInfo
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Abstract
The invention relates to a method for quantitatively determining carbamazepine in human plasma and application thereof, belonging to the technical field of chemical analysis. The method comprises the first step of taking a plasma sample, adding internal standard working solution, carrying out vortex oscillation, then centrifuging, and taking supernate to sample into a liquid chromatograph-mass spectrometer; and secondly, measuring the obtained supernatant according to set chromatographic conditions and mass spectrum conditions respectively to obtain peak areas of a chromatogram, an analyte and an internal standard, and obtaining the content of carbamazepine in the plasma according to a standard curve of carbamazepine. The invention has the advantages of small plasma sample amount, high sensitivity, simple and convenient pretreatment, economy, rapidness, short analysis time, no residue, no matrix interference, good precision, accuracy and extraction recovery rate, is suitable for rapidly detecting the concentration or content of the trace amount of carbamazepine in human plasma with high flux, and provides powerful technical support for the research on the development of novel preparation of carbamazepine, the monitoring of therapeutic drugs of carbamazepine, the interaction between the drugs of carbamazepine and the like.
Description
Technical Field
The invention relates to a method for quantitatively determining carbamazepine in human plasma and application thereof, belonging to the technical field of chemical analysis.
Background
Carbamazepine is a drug for the treatment of epilepsy and neuropathic pain. The individual difference of the blood concentration of the carbamazepine is large, and the carbamazepine is a CYP450 enzyme system inducer and can interact with various medicaments, so that the clinical monitoring of the concentration is very necessary.
In domestic reports on the detection method of carbamazepine in human plasma, the reported method mostly uses a larger sample size, such as 0.5mL, and/or uses gradient elution for longer analysis time, and the sensitivity is mostly above 10 ng/mL (Wei Jiang et al, 2018; Eun kyung Oh et al, 2006).
It is therefore necessary to develop a sensitive, accurate, rapid and validated method for the detection of carbamazepine.
Disclosure of Invention
The invention aims to provide a method for quantitatively determining carbamazepine in human plasma and application thereof, aiming at the defect of detection of carbamazepine in the prior art.
The invention solves the technical problem by the following technical scheme: a method for quantitatively determining carbamazepine in human plasma comprising the steps of:
firstly, pretreating a sample, namely taking a plasma sample, adding an internal standard working solution, carrying out vortex oscillation, then centrifuging for 5-20 min, and taking supernatant to sample into a liquid chromatograph-mass spectrometer;
and secondly, determining the supernatant obtained in the first step according to set chromatographic conditions and mass spectrum conditions respectively to obtain a chromatogram and a mass spectrum, obtaining the content of the carbamazepine in the plasma according to a standard curve of the carbamazepine, wherein the obtaining of the standard curve of the carbamazepine comprises the steps of preparing a sample of a standard curve of the carbamazepine from a working solution of the standard curve of the carbamazepine, injecting a sample according to the first step, recording peak areas of an analyte and an internal standard, calculating the peak area ratio of the analyte and the internal standard, and performing linear regression on the theoretical concentration of the carbamazepine.
In the first step of the method, the internal standard working solution is a carbamazepine D10 acetonitrile solution with the volume 5-20 times that of the sample. The preparation method of the internal standard working solution comprises the steps of dissolving a carbamazepine D10 solid in dimethyl sulfoxide and fixing the volume to obtain an internal standard stock solution; and taking the internal standard stock solution, and diluting the internal standard stock solution step by taking acetonitrile as a solvent to obtain the internal standard working solution.
Further, the chromatographic conditions of the second step comprise 2.1 x 100mm, 3.5 μm Waters Xbridge C18 chromatographic column with the column temperature of 10-40 ℃; the mobile phase A is 0.1 percent formic acid aqueous solution; the mobile phase B is acetonitrile; the isocratic elution ratio is 30-60% B, and the flow rate is 0.1-1.0 mL/min; the automatic sample injection temperature is 0-30 ℃; the sample injection amount is 0.50-20.0 mu L; the analysis time is 1.00-10.0 min.
The mass spectrum conditions of the second step comprise that an ionization mode is electrospray ionization and a positive ion mode; ion pair for carbamazepine is 237.1 → 194.1; ion pair for carbamazepine D10 was 247.2 → 204.1; the ion source parameters are GS1=10~60psig, GS2=10~60psig, CAD =1~20psig, CUR =10~50psig, TEM =100~550 ℃, IS =2000~5500V, EP =1~15V, CXP =1~ 16V.
In the second step, the carbamazepine is weighed, dissolved in dimethyl sulfoxide and subjected to constant volume to prepare a carbamazepine stock solution; diluting the stock solution of carbamazepine step by using methanol as a solvent to obtain a working solution of a standard curve of carbamazepine; taking blank plasma as a blank matrix, preparing standard curve samples of carbamazepine with different concentrations, injecting samples according to the first step, and obtaining the standard curve of carbamazepine through determination.
In the second step, weighing carbamazepine, dissolving with dimethyl sulfoxide, fixing the volume, and preparing a carbamazepine stock solution; diluting the stock solution of carbamazepine step by using methanol as a solvent to obtain a quality control working solution; and (3) preparing quality control samples with different concentrations by taking blank plasma as a blank matrix, and injecting samples according to the first step to ensure the reliability of an analysis batch by quality control.
The invention further provides application of the method for quantitatively determining the carbamazepine in human plasma in preclinical research of the carbamazepine.
The invention further provides an application of the method for quantitatively determining the carbamazepine in human plasma in the development of a carbamazepine preparation.
The invention has the beneficial effects that: the method for quantitatively determining the carbamazepine in the blood plasma and the application thereof provided by the invention have the advantages of small amount of used blood plasma samples (40 mu L), high sensitivity (2ng/mL), simple, convenient, economic and rapid pretreatment, short analysis time (3.2min), no residue, no matrix interference, good precision, accuracy and extraction recovery rate, are suitable for high-flux and rapid detection of the concentration or content of trace carbamazepine in human blood plasma, and provide powerful technical support for development of novel preparation of carbamazepine, monitoring of therapeutic drugs of carbamazepine, research of interaction between drugs of carbamazepine and the like.
Drawings
FIG. 1 is a typical mass spectrum of the present invention carbamazepine excimer ion (top) and product ion (bottom).
Figure 2 is a typical mass spectrum of the carbamazepine D10 excimer ion (top) and product ion (bottom) within the present invention.
FIG. 3 is a typical chromatogram of carbamazepine (top) and carbamazepine D10 (bottom) in plasma from a blank human of the present invention.
FIG. 4 is a typical chromatogram of carbamazepine (top) and carbamazepine D10 (bottom) from a LLOQ sample of the present invention.
Figure 5 is a typical chromatogram of carbamazepine (top) and carbamazepine D10 (bottom) in an authentic sample of the present invention.
Fig. 6 is a typical standard graph of carbamazepine of the present invention.
FIG. 7 shows the results and the certificate of the present invention for determining the passage of real samples through the chamber.
Detailed Description
The technical solutions of the present invention are further described below with reference to specific examples, it should be understood that these examples are only for illustrating the present invention, and the specific numerical values are typical values, and do not limit the scope of the present invention in any way. Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
In the following examples, various procedures, methods and reagents not described in detail are conventional methods and products well known in the art.
The noun explains:
ai: peak area of the internal standard;
as: sample peak area;
b QL: below the lower limit of quantitation;
CAD: air-blast
And (4) CUR: air curtain
CV: coefficient of variation;
CXP: collision cell ejection voltage
DMSO, DMSO: dimethyl sulfoxide;
DP: de-clustering voltage;
dwell: ion residence time;
CE: collision energy;
EP: an injection voltage;
ESI: carrying out electrospray ionization;
GS 1: spraying mist;
GS 2: auxiliary heating gas;
IS: an ionization voltage;
LC-MS/MS (HPLC-MS/MS): high performance liquid chromatography-mass spectrometry;
LLOQ: lower limit of quantitation;
ULOQ: an upper limit of quantitation;
ME: matrix effect;
NA or N/A: not applicable;
r2: determining a coefficient;
RE/Bias: relative Error, Relative Error;
rsd (cv): relative standard deviation, or coefficient of variation;
SD/S.D.: standard deviation;
TEM: the ion source heats up the temperature.
Example 1
As shown in fig. 1-7, a method for quantitatively determining carbamazepine in human plasma comprises the following steps:
s1: sample pretreatment
A40.0 mu L plasma sample is taken, 600 mu L internal standard precipitator (acetonitrile solution containing 5 ng/mL carbamazepine D10) is added, vortex oscillation is carried out for 3min, centrifugation is carried out for 5 min under the conditions of 4 ℃ and 12000 rpm, 40.0 mu L supernatant is taken and added into 200 mu L pure water, and the mixture is injected into a liquid chromatograph-mass spectrometer for measurement and analysis. The plasma sample was used in a constant ratio to the internal standard working fluid. S2: setting parameters
1) The chromatographic conditions were set and the elution parameters are shown in table 1.
TABLE 1
| Time (min) | Flow rate (mL/min) | Mobile phase A% | Mobile phase B% |
| 0.00 | 0.40 | 60 | 40 |
| 3.20 | 0.40 | 60 | 40 |
Mobile phase: phase A: 0.1% aqueous formic acid; phase B: acetonitrile
A chromatographic column: an Agilent ZORBAX Eclipse Plus-C18 column, 2.1X 100mm, 3.5 μm in size.
Protection of the column: phenomenex Security Guard Cartridges C18 with a specification of 4X 2.0 mm.
Column temperature: and (4) room temperature.
Autosampler temperature: 5 ℃ is adopted.
Sample introduction amount: 2.0. mu.L.
Analysis time: 3.2 min.
Needle washing procedure: wash 5s before and after aspiration.
Needle washing liquid: 50% aqueous methanol.
Typical retention time: carbamazepine for about 1.4 min; carbamazepine D10 was about 1.4 min.
2) Setting Mass Spectrometry conditions
Ionization mode: ESI, positive ion mode.
The analyte mass spectral parameters are shown in table 2.
TABLE 2
| Analyte and internal standard | ID | Ion pair | Dwell（ms） | DP（V） | CE（V） |
| Carbamazepine | KMXP | 237.1→194.1 | 200 | 162.14 | 27.65 |
| Carbamazepine D10 | KMXPD10 | 247.2→204.1 | 200 | 180.49 | 30.31 |
The ion source parameters are shown in table 3.
TABLE 3
S3: preparation of stock solutions
Precisely weighing about 10mg of the carbamazepine standard, placing the standard into a 10mL volumetric flask, dissolving the standard with DMSO, fixing the volume, calculating the concentration according to the purity to obtain stock solution with the concentration of about 1mg/mL, subpackaging the stock solution with a 1.5mL centrifuge tube, and storing the stock solution at the temperature of less than or equal to-15 ℃ for later use. At least 2 parts of stock solution is prepared each time, stock solution inspection is carried out, and qualified stock solution is used for preparing the working solution.
S4: preparation of working fluid
Taking a proper amount of carbamazepine stock solution (taking 1mg/mL as an example), taking methanol as a solvent, preparing a carbamazepine standard curve working solution according to a standard curve working solution preparation table in table 4, preparing a carbamazepine quality control working solution according to a quality control working solution preparation table in table 5, and storing at 2-8 ℃ for later use.
TABLE 4
TABLE 5
S5: preparation of internal standard precipitant
Dissolving the solid carbamazepine D10 in methanol, transferring the solid carbamazepine D10 into a 5mL volumetric flask for dissolving and fixing the volume, calculating the concentration according to the purity to obtain an internal standard stock solution with the concentration of 0.1mg/mL, subpackaging the internal standard stock solution with a 0.6mL centrifugal tube, and storing the internal standard stock solution at the temperature of less than or equal to-65 ℃ for later use. The invention adopts the shared stock solution to prepare the internal standard working solution.
Taking a proper amount of stock solution of carbamazepine D10, taking 0.1mg/mL as an example, taking acetonitrile as a solvent, preparing an internal standard working solution according to the internal standard working solution of the table 6, and storing the internal standard working solution at 2-8 ℃ for later use.
TABLE 6
S6: preparation of Standard Curve and quality control sample
Taking working solutions of standard curves of carbamazepine with different concentrations to prepare standard curve samples of carbamazepine with the concentrations of 5.00 (LLOQ), 10.0, 50.0, 100, 200, 500, 900 and 1000ng/mL (ULOQ) according to the table 5-1, taking 40.0 mu L and 2 parts in parallel for each sample, carrying out sample injection analysis according to the step S1, analyzing one part at the beginning of an analysis batch and the other part at the end of the analysis batch, recording the peak areas of the analyte and an internal standard, calculating the peak area ratio of the analyte and the internal standard, and carrying out linear regression on the theoretical concentration (weighted least square method, weight coefficient 1/C)2And C is concentration), the obtained regression equation is a standard curve of the carbamazepine, the linear range is 5.00-1000 ng/mL, the formula of the standard curve is y = a + bx, wherein y is the peak area ratio of the analyte to the internal standard, and x is the concentration of the analyte.
And (3) preparing the carbamazepine quality control samples with the concentrations of 5.00, 12.5, 80.0, 400 and 800ng/mL according to the quality control sample preparation table of the table 8 by using the carbamazepine quality control working solution with different concentrations, taking 40.0 mu L of each sample, paralleling 6 parts, and carrying out sample injection analysis according to the step S1.
TABLE 7
TABLE 8
The present embodiment adopts the following method for result verification:
the methodology verification is carried out on the method according to Chinese pharmacopoeia, the contents comprise selectivity and specificity, a standard curve, precision and accuracy, residue, extraction recovery rate and matrix effect, and the method comprises the following steps:
1) selectivity and specificity
Specificity was examined in blank human plasma from 6 different sources, the blank matrix did not interfere with the determination of carbamazepine and internal standard, the peak areas of carbamazepine and carbamazepine D10 in the blank did not exceed 20% and 5% of LLOQ, respectively.
Table 9 shows the interference rate of blank plasma on carbamazepine and carbamazepine D10.
TABLE 9
Carbamazepine with internal standard and ULOQ concentration was added to the plasma of a blank and the interference between carbamazepine and carbamazepine D10 was examined, indicating that the analyte and internal standard did not interfere with each other.
Table 10 is a mutual interference table of carbamazepine and carbamazepine D10.
2) Standard curve
Taking the theoretical concentration of carbamazepine as the abscissa and the peak area ratio of carbamazepine and an internal standard as the ordinate, and adopting a weighted least square method [ weight coefficient (1/C)2）]And (3) performing weight linear regression to obtain a standard curve of carbamazepine, wherein the result shows that the linearity is good within the range of 5-1000 ng/mL as shown in Table 11.
TABLE 11
3) Residue is remained
A blank sample was analyzed immediately after analysis of the ULOQ sample to investigate the residue, and the results indicated that the peak areas of carbamazepine and carbamazepine D10 were less than 20% and 5% of the LLOQ sample, respectively, for the residual sample. The residue does not interfere with the assay.
4) Precision and accuracy (with sensitivity)
Preparing quality control samples of 5.00, 12.5, 80.0, 400 and 800ng/mL, continuously three batches, each concentration of each batch is 6 parts in parallel, and calculating accuracy, precision between batches and precision within batches. The results show that the accuracy of the 5 concentrations is 85-115%, wherein the LLOQ is between 80-120%; precision CV was less than 15%, with LLOQ less than 20%, as shown in the precision and accuracy table of carbamazepine of table 12.
TABLE 12
Continuing from Table 12:
ultralimit quality control, participating in calculation
5) Extraction recovery rate
Table 13 shows the extraction recovery rates of carbamazepine, table 14 shows the extraction recovery rates of carbamazepine D10, and the results of examining the extraction recovery rates at three concentrations of 12.5, 400 and 800ng/mL indicated that the extraction recovery rates of carbamazepine were 90.0% to 101.8% and the extraction recovery rate of carbamazepine D10 was 94.7%.
Watch 13
TABLE 14
6) Matrix effect
Matrix effects of carbamazepine and carbamazepine D10 were examined in blank human plasma from 6 different sources, Table 15 shows the matrix effect of carbamazepine, Table 16 shows the CV of carbamazepine response after internal standard homogenization in plasma from different sources, and the results show that the matrix effect of carbamazepine is between 101.4% and 115.5% at three concentration levels of 12.5, 400 and 800 ng/mL; the CV% of the internal standard after homogenization is less than 15%. Table 17 shows the matrix effect of carbamazepine D10 and 103.6% for carbamazepine D10.
Watch 15
TABLE 16
TABLE 17
7) Application in real sample determination
The concentration of 5 real samples measured by the method meets the requirement of the truth range provided by the indoor evaluation, which shows that the method is accurate and reliable, and the bias is less than 5 percent. The results and certificates are shown in fig. 7.
From the results of the above examples, the beneficial effects of the present invention are:
1) the method uses a small amount of plasma sample (40 mu L), which means that the amount of test sample is reduced, and the protection of the patient can be enhanced;
2) the sensitivity is appropriate, the quantitative range is 2-1000 ng/mL, the lower limit of the quantitative method is 2ng/mL, and the requirement of conventional analysis can be met;
3) the pretreatment is simple, convenient, economical and rapid, the direct protein precipitation method is the most rapid and efficient method in the pretreatment, the used reagent consumables only comprise low-cost formic acid, water and acetonitrile, and the pretreatment process only comprises two steps of adding an internal standard precipitator and oscillating and centrifuging;
4) the analysis time is short (3.2min), so that the number of samples to be analyzed in unit time is increased, and the time cost and the instrument reagent cost are saved;
5) the method has good specificity, significance, sensitivity, precision, accuracy, matrix effect, extraction recovery rate and residual effect, and the bias is less than 5% as verified by the indoor evaluation, which indicates that the method is stable and reliable.
The parts of the invention not described in detail can be realized by adopting the prior art, and are not described in detail herein.
In addition to the above, other embodiments of the present invention are possible. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.
Claims (9)
1. A method for quantitatively determining carbamazepine in human plasma, which is characterized by comprising the following steps: comprises the following steps of (a) carrying out,
firstly, pretreating a sample, namely taking a plasma sample, adding an internal standard working solution, carrying out vortex oscillation, then centrifuging for 5-20 min, and taking supernatant to sample into a liquid chromatograph-mass spectrometer;
and secondly, determining the supernatant obtained in the first step according to set chromatographic conditions and mass spectrum conditions respectively to obtain a chromatogram and a mass spectrum, obtaining the content of the carbamazepine in the plasma according to a standard curve of the carbamazepine, wherein the obtaining of the standard curve of the carbamazepine comprises the steps of preparing a sample of a standard curve of the carbamazepine from a working solution of the standard curve of the carbamazepine, injecting a sample according to the first step, recording peak areas of an analyte and an internal standard, calculating the peak area ratio of the analyte and the internal standard, and performing linear regression on the theoretical concentration of the carbamazepine.
2. The method for the quantitative determination of carbamazepine in human plasma according to claim 1, characterized in that
The method comprises the following steps: in the first step, the internal standard working solution is a carbamazepine D10 acetonitrile solution with the volume 5-20 times that of the sample.
3. The method for the quantitative determination of carbamazepine in human plasma according to claim 2, characterized in that
The method comprises the following steps: the preparation method of the internal standard working solution comprises the steps of dissolving a carbamazepine D10 solid in dimethyl sulfoxide and fixing the volume to obtain an internal standard stock solution; and taking the internal standard stock solution, and diluting the internal standard stock solution step by taking acetonitrile as a solvent to obtain the internal standard working solution.
4. The method for the quantitative determination of carbamazepine in human plasma according to claim 1, characterized in that
The method comprises the following steps: the chromatographic conditions of the second step comprise a Waters Xbridge C18 chromatographic column with the specification of 2.1 x 100mm and the specification of 3.5 mu m, and the column temperature is 10-40 ℃; the mobile phase A is 0.1 percent formic acid aqueous solution; the mobile phase B is acetonitrile; the isocratic elution ratio is 30-60% B, and the flow rate is 0.1-1.0 mL/min; the automatic sample injection temperature is 0-30 ℃; the sample injection amount is 0.50-20.0 mu L; the analysis time is 1.00-10.0 min.
5. The method for the quantitative determination of carbamazepine in human plasma according to claim 1, characterized in that: the mass spectrum conditions of the second step comprise that an ionization mode is electrospray ionization and a positive ion mode; ion pair for carbamazepine is 237.1 → 194.1; ion pair for carbamazepine D10 was 247.2 → 204.1; the ion source parameters are GS1=10~60psig, GS2=10~60psig, CAD =1~20psig, CUR =10~50psig, TEM =100~550 ℃, IS =2000~5500V, EP =1~15V, CXP =1~ 16V.
6. The method for the quantitative determination of carbamazepine in human plasma according to claim 1, characterized in that: in the second step, the carbamazepine is weighed, dissolved in dimethyl sulfoxide and subjected to constant volume to prepare a carbamazepine stock solution; diluting the stock solution of carbamazepine step by using methanol as a solvent to obtain a working solution of a standard curve of carbamazepine; taking blank plasma as a blank matrix, preparing standard curve samples of carbamazepine with different concentrations, injecting samples according to the first step, and obtaining the standard curve of carbamazepine through determination.
7. The method for the quantitative determination of carbamazepine in human plasma according to claim 1, characterized in that: in the second step, weighing carbamazepine, dissolving with dimethyl sulfoxide, fixing the volume, and preparing a carbamazepine stock solution; diluting the stock solution of carbamazepine step by using methanol as a solvent to obtain a quality control working solution; and (3) preparing quality control samples with different concentrations by taking blank plasma as a blank matrix, and injecting samples according to the first step.
8. Use of a method according to any one of claims 1 to 7 for the quantitative determination of carbamazepine in human plasma, characterized in that: including use in preclinical studies with carbamazepine.
9. Use of a method according to any one of claims 1 to 7 for the quantitative determination of carbamazepine in human plasma, characterized in that: including use in the development of carbamazepine formulations.
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