CN111521706A - Method for rapidly detecting concentration of cefixime in blood plasma - Google Patents
Method for rapidly detecting concentration of cefixime in blood plasma Download PDFInfo
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- CN111521706A CN111521706A CN202010390549.1A CN202010390549A CN111521706A CN 111521706 A CN111521706 A CN 111521706A CN 202010390549 A CN202010390549 A CN 202010390549A CN 111521706 A CN111521706 A CN 111521706A
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The invention discloses a method for rapidly detecting concentration of cefixime in blood plasma, which comprises the following steps: (1) plasma sample pretreatment: adding an internal standard solution and acetonitrile into a plasma sample, carrying out vortex oscillation and centrifugation, taking out a supernatant, transferring the supernatant into a 96-well plate, and carrying out LC-MS/MS analysis; (2) and (3) chromatographic separation: an aqueous solution containing 0.1% formic acid and 5 mM ammonium acetate was used as mobile phase a, acetonitrile containing 0.5% formic acid was used as mobile phase B, mobile phase a: mobile phase B = 50: 50; isocratic elution for 2.4 min; (3) and (4) detecting by mass spectrometry. The detection method has high sensitivity, and the lowest concentration which can be quantified can reach 10.00 ng/mL. The invention is suitable for the research of the bioequivalence of cefixime capsules or human pharmacokinetics.
Description
Technical Field
The invention relates to the technical field of pharmaceutical analysis, in particular to a method for rapidly detecting concentration of cefixime in blood plasma.
Background
Cefixime (Cefixime) is an orally-taken third-generation cephalosporin antibiotic and is clinically applied to pneumonia, bronchitis, urinary tract infection, gonorrhea, cholecystitis, cholangitis, scarlet fever, otitis media, paranasal sinusitis and the like caused by sensitive bacteria. At present, common methods for measuring cefixime mainly comprise an HPLC method, a chemiluminescence method, an ultraviolet spectrum method and the like; however, these methods all have the disadvantages of low sensitivity, poor specificity, tedious and time-consuming operation, etc.
Disclosure of Invention
In view of the above prior art, the present invention aims to provide a method for rapidly detecting the concentration of cefixime in blood plasma.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for rapidly detecting the concentration of cefixime in blood plasma comprises the following steps:
(1) plasma sample pretreatment:
adding an internal standard solution and acetonitrile into a plasma sample, carrying out vortex oscillation and centrifugation, taking out a supernatant, transferring the supernatant into a 96-well plate, and carrying out LC-MS/MS analysis;
(2) and (3) chromatographic separation:
an aqueous solution containing 0.1% formic acid and 5 mM ammonium acetate was used as mobile phase a, acetonitrile containing 0.5% formic acid was used as mobile phase B, mobile phase a: mobile phase B = 50: 50; isocratic elution for 2.4 min;
(3) mass spectrum detection:
an electrospray ionization source; the detection mode is positive ions; injection voltage 5500V; gas1 and Gas2 pressures were 65 and 65psi, respectively; the scan mode is + MRM; for quantitative analysis of ion pairs: CFXm/z454.2®285.2，CE 20 eV，DP 60V，CFX-13C,15N2 m/z457.2 ℃ 288.2, CE 22 eV, DP 60V; the scan time is 200 ms.
Preferably, in step (1), the internal standard solution is 200 ng/mL of CFX-13C,15N2And (3) solution.
Preferably, in step (1), the plasma sample, the internal standard solution and the acetonitrile are added in a volume ratio of 1: 1: 4.
preferably, in the step (1), the vortex oscillation time is 2min, the centrifugal rotation speed is 3900 rpm, and the centrifugal time is 10 min.
Preferably, in the step (1), 100 muL of supernatant is taken out and transferred to a 96-well plate, and 3.0 muL is taken out for LC-MS/MS analysis.
Preferably, in step (2), the chromatographic separation further comprises: a chromatographic column: ZOBAX SB-C8, 5 μm, 4.6 x 150 mm; sample introduction amount: 3.0 mu L; column temperature: 40 ℃; the autosampler temperature was 4 ℃ and the flow rates of the mobile phases were: 0.8 mL/min.
The invention has the beneficial effects that:
(1) compared with a liquid-liquid extraction method and a solid phase extraction method, the protein precipitation method has the characteristics of simple and convenient operation, high recovery rate and the like, and can improve the treatment flux and sensitivity to the greatest extent.
(2) The detection method has high sensitivity, and the lowest concentration which can be quantified can reach 10.00 ng/mL. The invention is suitable for the research of the bioequivalence of cefixime capsules or human pharmacokinetics.
Drawings
FIG. 1: ion scan of cefixime.
FIG. 2: cefixime-13C,15N2A scan of the daughter ion.
FIG. 3: a blank matrix sample map; in the figure, A: cefixime; b: cefixime-13C,15N2。
FIG. 4: a zero concentration sample profile; in the figure, A: cefixime; b: cefixime-13C,15N2。
FIG. 5: a quantitative lower limit map; in the figure, A: cefixime; b: cefixime-13C,15N2。
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
Description of terms:
| abbreviations | Full text | Description of Chinese |
| LLOQ | lower limit of quantification | Lower limit of quantification |
| LQC | low quality control | Low quality control |
| MQC | medium quality control | Medium quality control |
| HQC | high quality control | High quality control |
| RSD | relative standard deviation | Relative Standard Deviation (SD) |
| RE | relative Error | Relative deviation of |
As introduced in the background art, the method for determining cefixime in the prior art has the defects of low sensitivity, poor specificity, complex and time-consuming operation and the like.
Based on this, in one embodiment of the present invention, a method for rapidly detecting the concentration of cefixime in human plasma is provided, which comprises the following steps:
step 1: plasma sample pretreatment;
50.0. mu.L of plasma sample and 50.0. mu.L of internal standard solution (CFX-ion at a concentration of 200 ng/mL) are added into the centrifuge tube13C,15N2Solution), 200.0. mu.L of acetonitrile was added, vortex shaking was performed,centrifuging for 10min, taking out 100 muL of supernatant, transferring the supernatant to a 96-well plate with 100 muL of ultrapure water, carrying out vortex mixing, and carrying out LC-MS/MS analysis;
step 2: carrying out chromatographic separation;
chromatographic conditions, chromatographic column: ZOBAX SB-C8, 5 μm, 4.6 x 150mm, Agilent; sample introduction amount: 3.0 mu L; column temperature: 40 ℃; mobile phase A: aqueous solution containing 0.1% formic acid and 5 mM ammonium acetate, mobile phase B: acetonitrile with 0.5% formic acid, isocratic elution, mobile phase a: mobile phase B = 50: 50; the autosampler temperature was 4 ℃ and the flow rates of the mobile phases were: 0.8 mL/min.
And step 3: detecting mass spectrum;
mass spectrum conditions: an electrospray ionization source; the detection mode is positive ions; injection voltage 5500V; gas1 and Gas2 pressures were 65 and 65psi, respectively; the scan mode is + MRM; for quantitative analysis of ion pairs: CFXm/z454.2®285.2，CE 20 eV，DP60 V，CFX-13C,15N2 m/z457.2 ℃ 288.2, CE 22 eV, DP 60V; the scan time is 200 ms.
Because cefixime has strong water solubility, the cefixime has low solubility in some common organic extracting agents and low extraction rate. In the sample pretreatment method, the invention adopts a plasma precipitation method and inspects an extraction solvent, and finds that the effect of precipitating the protein by using the acetonitrile is better than that of other solvents, the protein precipitation is more complete, the matrix interference is less, the stability is good, and the extraction recovery rate is relatively higher, so that the plasma sample is treated by adopting the method of precipitating the protein by using the acetonitrile.
The invention also carries out optimization investigation on the using amount of acetonitrile, and finds that the acetonitrile with the volume 4 times that of the sample is adopted to precipitate the protein, and then the supernatant is taken for direct sample injection, the process is simple and quick, most of the protein can be precipitated, and the sensitivity of cefixime in blood plasma can be ensured.
In the sample pretreatment condition of the invention, 4 steps of sample adding, vortex, centrifugation and supernatant transferring are carried out. Compared with the existing solid phase extraction or liquid-liquid extraction technology, the operation is greatly simplified, and the pretreatment of 96 samples can be completed within 1 hour.
The chromatographic column selected in the chromatographic conditions is ZOBAX SB-C8, 5 mu m and 4.6 x 150mM, and the object to be detected has better chromatographic retention and chromatographic peak shape, so that the chromatographic peak shape is sharper and the sensitivity is improved.
The isochromatic chromatography elution mode is suitable for rapid detection, and the chromatographic analysis time is only 2.4 min.
The chromatographic condition optimized by the method has excellent separation capability, can effectively reduce the interference of a sample matrix during mass spectrometry detection, has an inhibiting effect on the separation of the components to be detected, and effectively improves the detection sensitivity.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention, which were not specifically described, were all those conventional in the art and commercially available.
Example 1:
1 Material
1.1 instruments
Mass spectrometer (model: AB Sciex Triple Quad)TM5500, Sciex, canada). Liquid chromatograph (Shimadzu Japan)
1.2 Standard substance
1.2.1 reference substance to be tested
| Name: | cefixime (Cefixime) |
| Batch number: | 130503-201706 |
| the molecular formula is as follows: | C16H15N5O7S2·3H2O |
| molecular weight: | 507.50 |
| the content is as follows: | 89.2% (as C)16H15N5O7S2Meter) |
| Conversion coefficient: | 89.2% (as C)16H15N5O7S2Meter) |
| The supplier: | NATIONAL INSTITUTES FOR FOOD AND DRUG CONTROL |
| storage conditions were as follows: | shading preservation at 2-8 deg.C |
| The validity period is as follows: | the standard substance stored according to the specified conditions without specific validity period is effective before the Chinese food and drug verification institute issues the notice of stopping use |
1.2.2 internal Standard reference
| Name: | Cefixime-13C,15N2 |
| batch number: | 24-THT-178-1 |
| the molecular formula is as follows: | C15 13CH15N3 15N2O7S2 |
| molecular weight: | 456.43 |
| purity: | 97% |
| isotopic purity: | 98.8% |
| moisture content: | 2.7% |
| conversion coefficient: | 93.2% |
| the supplier: | TRC |
| storage conditions were as follows: | Store at 2~8℃ |
| the validity period is as follows: | 2023-03-31 (date with mark) |
1.3 blank matrix
| Substrate | Anticoagulant agent | Origin of origin |
| Blood plasma | EDTA-K2 | Healthy subjects |
2 method
2.1 preparation of the solution
Standard Curve sample preparation
Cefixime was weighed as a non-control, dissolved in DMSO and made a constant volume with acetonitrile and stored in a brown glass bottle to obtain a cefixime stock solution with a concentration of about 0.945 mg/mL. Sucking a proper amount of the cefixime stock solution, and gradually diluting with acetonitrile-water (50/50, v/v) to obtain a series of standard solutions with concentration, wherein the concentration of cefixime is respectively 200, 400, 1000, 3000, 10000, 30000, 72000 and 80000 ng/mL. The working solution is diluted by blank plasma to obtain standard curve samples with cefixime concentrations of 10.00, 20.00, 50.0, 150.0, 500, 1500, 3600 and 4000 ng/mL respectively.
Internal standard working fluid
Quantitative transfer of CFX-13C,15N2Control 0.25 mg, dissolved in DMSO and diluted to volume with acetonitrile and stored in a brown glass bottle to obtain a stock solution with a concentration of 0.0466 mg/mL. An appropriate amount of the stock solution was diluted with acetonitrile/water (50: 50, v/v) to obtain an internal standard solution having a concentration of 200 ng/mL.
2.2 plasma sample treatment
Adding 50.0 muL of plasma sample, 50.0 muL of internal standard solution (the concentration is 200 ng/mL) and 200 muL of acetonitrile into a 96-well plate; vortex mixing, centrifuging for 10min (4 ℃, 3900 rpm); adding 100 mu L of ultrapure water into a clean 96-hole plate; transferring 100 muL of supernatant into a 96-well plate with 100 muL of ultrapure water, and carrying out vortex mixing; and taking 3.00 mu L for LC-MS/MS analysis.
2.3 chromatographic and Mass Spectrometry conditions
Chromatographic conditions
Conditions of Mass Spectrometry
2.4 methodological validation
Selectivity is
And respectively taking blank human plasma and LLOQ samples for processing and analysis to obtain corresponding chromatograms. Cefixime and internal standard Cefixime-13C,15N2The retention time of (A) is 1.8 min, and no interference peak exists at the retention time in a blank plasma spectrogram.
Standard curve
Taking the Cefixime theoretical concentration as the abscissa (x), Cefixime and the internal standard Cefixime-13C,15N2Is the ordinate (y), and linear regression calculation is performed (weight factor W = 1/x)2) Typical regression equation for cefixime is y =0.00511x +0.000681, r2= 0.9954, apparently linear in the range of 10.00-4000 ng/mL.
Accuracy, precision and stability
And (3) diluting the cefixime stock solution by using human blank plasma to prepare LQC, MQC and HQC (cefixime concentration is 30.0, 250 and 3200 ng/mL) methods to verify that six samples are respectively tested in each analysis batch and used as quality control samples of various concentrations. The precision within and during LLOQ day is acceptable as the Relative Standard Deviation (RSD) is less than 20%, and the precision (RE) is acceptable between-20% and 20%. The QC samples of the rest concentration levels have within-day and daytime precision (RSD) of less than 15 percent and have accuracy (RE) of-15 percent.
The result shows that the precision and the accuracy of the method for determining cefixime are both acceptable, and the LLOQ of cefixime is 10.00 ng/mL.
And taking LQC and HQC samples, and observing the stability of the LQC and HQC samples after the LQC and HQC samples are placed for 12 hours at room temperature, the treated extract is placed for 48 hours at 4 ℃, and the LQC and HQC samples are repeatedly frozen and thawed for 4 times and placed for 30 days at-80 ℃.
The results show that cefixime is stable under the above conditions, and RE is between 1.2% and 5.3%.
Recovery and matrix effects
Six samples of QC samples were analyzed at low, medium and high concentrations. Meanwhile, taking 50.0 mu L of blank plasma, processing according to plasma samples, adding cefixime control solution and internal standard working solution into supernatant, mixing by vortex, and carrying out sample injection measurement, wherein the average peak area ratio of cefixime in 2 samples is the recovery rate. The results showed that the extraction recovery was 106.4% at the three concentration levels. The recovery of the internal standard was 103.6%.
And (3) taking blank plasma (n = 6) of different sources, processing according to plasma samples (without adding the internal standard), adding a control solution and a mixed internal standard working solution into the supernate, and carrying out sample injection and measurement. Another 50.0 μ L deionized water was treated as above and subjected to sample injection for measurement. And calculating the matrix factor according to the peak area ratio of the cefixime of the two samples. The matrix factors of cefixime at LQC and HQC concentrations were 99.7% and 102.1%, respectively, indicating that under the conditions of this experiment, the influence of matrix effects on cefixime assay can be ignored.
Summary of method verification
The method is verified by methodology, the method is high in sensitivity, good in selectivity, accurate, precise, good in stability and good in linearity, and the lower limit of the quantification of the analysis method is 10.00 ng/mL.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (6)
1. A method for rapidly detecting the concentration of cefixime in blood plasma is characterized by comprising the following steps:
(1) plasma sample pretreatment:
adding an internal standard solution and acetonitrile into a plasma sample, carrying out vortex oscillation and centrifugation, taking out a supernatant, transferring the supernatant into a 96-well plate, and carrying out LC-MS/MS analysis;
(2) and (3) chromatographic separation:
an aqueous solution containing 0.1% formic acid and 5 mM ammonium acetate was used as mobile phase a, acetonitrile containing 0.5% formic acid was used as mobile phase B, mobile phase a: mobile phase B = 50: 50; isocratic elution for 2.4 min;
(3) mass spectrum detection:
an electrospray ionization source; the detection mode is positive ions; injection voltage 5500V; gas1 and Gas2 pressures were 65 and 65psi, respectively; the scan mode is + MRM; for quantitative analysis of ion pairs: CFXm/z454.2®285.2，CE 20 eV，DP 60V，CFX-13C,15N2 m/z457.2 ℃ 288.2, CE 22 eV, DP 60V; the scan time is 200 ms.
2. The method as claimed in claim 1, wherein the internal standard solution in step (1) is CFX-13C,15N2And (3) solution.
3. The method according to claim 2, wherein in step (1), the plasma sample, the internal standard solution and the acetonitrile are added in a volume ratio of 1: 1: 4.
4. the method of claim 2, wherein in step (1), the vortex oscillation time is 2min, the centrifugal rotation speed is 3900 rpm, and the centrifugal time is 10 min.
5. The method according to claim 2, characterized in that in step (1), 100 μ L of the supernatant is taken out and transferred to a 96-well plate, and 3.0 μ L is taken out for LC-MS/MS analysis.
6. The method of claim 1, wherein in step (2), the chromatographic separation further comprises: a chromatographic column: ZOBAX SB-C8, 5 μm, 4.6 x 150 mm; sample introduction amount: 3.0 mu L; column temperature: 40 ℃; the autosampler temperature was 4 ℃ and the flow rates of the mobile phases were: 0.8 mL/min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112903849A (en) * | 2021-01-21 | 2021-06-04 | 山东英盛生物技术有限公司 | Method and kit for detecting eszopiclone content in blood and application of kit |
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| CN103889224A (en) * | 2011-08-29 | 2014-06-25 | Ptc医疗公司 | Antibacterial compounds and methods for use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103889224A (en) * | 2011-08-29 | 2014-06-25 | Ptc医疗公司 | Antibacterial compounds and methods for use |
Non-Patent Citations (4)
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| KRISTIE L. CONNOLLY ET AL: "Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
| 李海霞 等: "LC/MS/MS法测定人血浆中头孢克肟含量", 《中国抗生素杂志》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112903849A (en) * | 2021-01-21 | 2021-06-04 | 山东英盛生物技术有限公司 | Method and kit for detecting eszopiclone content in blood and application of kit |
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