CN103226142A - Method for detecting leucogen concentration in blood plasma - Google Patents
Method for detecting leucogen concentration in blood plasma Download PDFInfo
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- CN103226142A CN103226142A CN2011104050114A CN201110405011A CN103226142A CN 103226142 A CN103226142 A CN 103226142A CN 2011104050114 A CN2011104050114 A CN 2011104050114A CN 201110405011 A CN201110405011 A CN 201110405011A CN 103226142 A CN103226142 A CN 103226142A
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- tinidazole
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Abstract
The invention provides a method for detecting leucogen concentration in blood plasma, which is characterized in that leucogen in blood plasma and tinidazole are subjected to protein precipitation through perchloric acid, a LC-MS method is used for separating and detecting. The detecting method is accurate and realizable through methodology validation, and can be used for detecting leucogen concentration in blood plasma.
Description
Technical field
But the present invention relates to the detection method of profit monarch concentration in a kind of blood plasma, but particularly a kind of method that adopts liquid chromatograph mass spectrography technical Analysis profit monarch concentration.
Background technology
But profit monarch is a drug for increasing white cells, is used to leukopenia, alpastic anemia and thrombopenia etc. of preventing and treating a variety of causes to cause, chemistry is by name: thiazolidine-4-carboxylic acid 2-(α-phenyl-α-carbethoxyl group-methyl).
But existing many to profit monarch's pharmacology activity research, but but in the biological sample profit monarch's concentration determination and pharmacokinetic report thereof but do not have.
In addition, but there are 3 chiral centers in the profit monarch, and a plurality of chiral centers are arranged, and therefore, provides a kind of method that can detect all these isomeride reliably just to become the thing of positive difficulty.
Summary of the invention
The present invention wants the technical solution problem to be, overcomes the defective of prior art, but the method for profit monarch blood concentration in a kind of simple, quick, sensitive mensuration blood plasma is provided.
But the invention provides the detection method of profit monarch concentration in a kind of blood plasma, comprise following steps:
(a) plasma sample is carried out pre-treatment: get testing sample, mark and perchloric acid carry out albumen precipitation in adding, and get supernatant, be designated as Tinidazole in described, to contain Tinidazole concentration in the sample be 100ng-1mg/ml to its consumption in order to make, and the consumption of described perchloric acid solution is that to add perchloric acid weight in every 1ml sample be 10-100mg.
(b) adopt liquid chromatography-mass spectrography (LC-MS) but combined instrument is measured the concentration of profit monarch in the above-mentioned supernatant, wherein, the chromatographic condition of LC-MS coupling is: chromatographic column is to be filling agent with octadecylsilane chemically bonded silica; Internal standard method, with Tinidazole as interior mark; Moving phase is the mixed liquor of acetonitrile-water-glacial acetic acid, and its volume ratio scope is 20 ± 1:80 ± 5:0.3 ± 0.03); The mass spectrum condition of LC-MS coupling is: ion gun is the ESI ion gun, and positive ion detects.
Perchloric acid can be pre-configured to aqueous solution in the described step (a), and concentration is 1-10%, is preferably 3-7%, most preferably is 4%.
Tinidazole can be pre-configured to aqueous solution in the described step (a), and concentration is 1.0-1.5 μ g/ml.
But the detection method of the side of profit monarch content in the described analysed for plasma, chromatographic condition moving phase is made up of acetonitrile-water-glacial acetic acid, and its proportioning is acetonitrile-water-glacial acetic acid=20:80:0.3.
Described detection method is characterized in that, in the step LC-MS coupling mass spectrum condition, scan mode is the selectivity ion detection.
Above-mentioned chromatographic condition is a representative condition, according to the different characteristics of institute's use instrument, can make suitable adjustment to each parameter in the practical application, in the hope of obtaining best effect.That the present invention has set up is simple, sensitive, but the LC-MS method is measured the concentration of profit monarch in the blood plasma fast, but make its high sensitivity, less sample demand and relatively short analysis time the inventive method be applicable to before profit monarch clinical and clinical medicine dynamics research from generation to generation, utilize this method, but can well separation detection profit monarch and diastereo-isomerism thereof.
Description of drawings
But Fig. 1 is profit monarch's a structural formula.
But Fig. 2 A is profit monarch's mass spectrum full scan figure.
Fig. 2 B is the mass spectrum full scan figure of Tinidazole.
But Fig. 3 A-3C is the total ions chromatogram of profit monarch and Tinidazole among the embodiment one, and I is represented the chromatographic peak of Tinidazole, but II, III, IV and V are represented four kinds of diastereo-isomerisms of profit monarch respectively; Wherein: Fig. 3 A represents blank plasma; But Fig. 3 B represents and adds profit monarch and Nei mark Tinidazole in the blank plasma; Fig. 3 C represents plasma sample.
But Fig. 4 A-4C is the total ions chromatogram of profit monarch and Tinidazole among another embodiment, and I is represented the chromatographic peak of Tinidazole, but II, III, IV and V are represented four kinds of diastereo-isomerisms of profit monarch respectively; Wherein: Fig. 4 A represents blank plasma; But Fig. 4 B represents and adds profit monarch and Nei mark Tinidazole in the blank plasma; Fig. 4 C represents plasma sample.
Embodiment
Embodiment one
1 instrument, material and reagent
1.1 instrument LC-MS combined instrument (Tianjin, island LC-MS2020)
But 1.2 sample and reagent profit monarch (purity is＞99.5%); Tinidazole (purity＞99.8%) is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute; It is pure that other chemical reagent are analysis.
2 experimental sections
2.1 the plasma sample pre-treatment is got the rat plasma sample 100 μ L that gather behind the intravenous administration and is placed 1.5mL plastics Ep pipe, add 30 μ L inner mark solutions (1140ng/mL), vortex mixed 30s, add 100 μ L4% perchloric acid solutions again, vortex mixed 3min, the centrifugal 10min twice of 20000rpm under 4 ℃ of conditions gets supernatant 10 μ L and carries out the LC-MS analysis.
2.2 LC-MS analysis condition
2.2.1 chromatographic condition chromatographic column: Agilent ZORBAX Eclipse Plus C18 (2.1*150mm, 5-Micro); Moving phase: acetonitrile: water: glacial acetic acid=20; 80; 0.3; Column temperature: 30 ℃; Flow velocity: 0-4min is 0.3mL/min, and 4-5min rises to 0.6mL/min by the 0.3mL/min linearity, keeps 0.6mL/min and finishes to analysis time; Sample size: 10 μ L.
2.2.2 mass spectrum condition ESI ion gun, positive ion detects; Scan mode: selectivity ion detection; The ion of quantitative test is respectively: but m/z 296.2(profit monarch) and m/z 248.1(Tinidazole, interior mark).
2.3 LC-MS analysis result
But sample profit monarch and Nei are marked the scanning of the mass spectrum figure of Tinidazole referring to Fig. 2 A and Fig. 2 B.
3 methods conclusive evidence
3.1 determinand and interior target specificity compare with the blank plasma of operating with method with concentration point in the typical curve and estimate in specificity this method.
But the chromatogram that adds profit monarch and Nei mark Tinidazole, plasma sample in blank plasma, the blank plasma is seen Fig. 3 A, 3B and 3C respectively, as can be seen from the figure, but the endogenous material in the blank plasma does not disturb profit monarch and Nei target to measure, the retention time of interior mark Tinidazole is 3.2min, but the retention time of four diastereo-isomerisms of profit monarch is respectively 9.5min, 10.6min, 11.9min and 13.2min.
3.2 but linear and sensitivity profit monarch's standard series working fluid is prepared by acetonitrile.Get blank plasma 100 μ L, add inner mark solution 30 μ L, but add profit monarch standard series working fluid designated volume more successively, be mixed with that to be equivalent to plasma concentration be 50,100,200,400,1000,2000,5000 and the plasma sample of 10000ng/mL, by 2.1 operations down, carry out LC-MS and analyze, try to achieve linear regression equation, be working curve.It is measured and analysis result sees Table 1.
But table 1 profit monarch's typical curve
| Concentration (ng/mL) | 50 | 100 | 200 | 400 | 1000 | 2000 | 5000 | 10000 |
| Analog value (in A sample/A) | 0.2413 | 0.2696 | 0.7651 | 0.9645 | 1.6370 | 4.9575 | 16.8421 | 35.3485 |
The range of linearity of this method is 50 ~ 10000ng/mL, and the equation of typical curve is: y=0.003556x-0.70697 (r
2=0.994999), y represents the ratio of determinand and interior target peak area, and x represents the concentration of determinand.This method lowest detectable limit and minimum quantitative limit are respectively 10ng/mL (S/N=3) and 50ng/mL (S/N=10).
3.3 extraction recovery is got blank plasma 100 μ L, by 3.2 operations down, the sample for preparing basic, normal, high three concentration is analyzed, the record chromatographic peak.Simultaneously, other gets pure water and replaces blank plasma, and by 3.2 operations down, the sample for preparing basic, normal, high three concentration is analyzed, and obtains the respective peaks area, with the ratio of the peak area of the two chromatogram, investigates the extraction recovery of sample.Mensuration and analysis result see Table 2.
But table 2 profit monarch's extraction recovery
It is as shown in the table, but three concentration profit monarchs' extraction recovery is respectively 77.38 ± 6.14%, 81.45 ± 5.35%, 97.44 ± 3.78%.
3.4 precision and accuracy are by 3.2 operations down, but the quality control sample of basic, normal, high three concentration of preparation profit monarch, each concentration is carried out 6 sample analyses, METHOD FOR CONTINUOUS DETERMINATION three days, method precision by try to achieve in a few days, RSD(% in the daytime) estimate, accuracy gets deviation evaluation by actual measured value and theoretical value, and analysis result is as shown in table 3.
But the accuracy and the precision of profit monarch LC-MS assay method in table 3 plasma sample
As shown in table 3, in a few days, in 5.69% and 7.71%, accuracy range is 86.4 ~ 112.5% to day to day precision respectively, shows that this method has good precision and accuracy.
But 3.5 stability with-20 ℃ freezing 10 days and freezing-dissolve the stability of investigating the profit monarch for three times, stablize if the deviation of measured value and theoretical value in ± 15%, then shows sample, the stability result of this experimental technique sees Table 4.
Table 4 stability result
As shown in table 4, but the deviation of the measured value of profit monarch concentration and theoretical value shows that this method has good stable in ± 15%.
Embodiment two
1 instrument, material and reagent
1.1 instrument LC-MS combined instrument
But 1.2 sample and reagent profit monarch (purity is＞99.5%); Tinidazole (purity＞99.8%) is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute; It is pure that other chemical reagent are analysis.
2 experimental sections
2.1 the plasma sample pre-treatment is got the rat plasma sample 100 μ L that gather behind the gastric infusion and is placed 1.5mL plastics Ep pipe, add 30 μ L inner mark solutions (1100ng/mL), vortex mixed 30s, add 100 μ L6.2% perchloric acid solutions again, vortex mixed 5min, the centrifugal 150min twice of 20000rpm under 4 ℃ of conditions gets supernatant 10 μ L and carries out the LC-MS analysis.
2.2 LC-MS analysis condition
2.2.1 chromatographic condition chromatographic column: octadecylsilane chemically bonded silica is a filling agent; Moving phase: acetonitrile: water: glacial acetic acid=21; 85; 0.33; Column temperature: 30 ℃; Flow velocity: 0-4min is 0.35mL/min, and 4-5min rises to 0.7mL/min by the 0.35mL/min linearity, keeps 0.7mL/min and finishes to analysis time; Sample size: 10 μ L.
2.2.2 mass spectrum condition ESI ion gun, positive ion detects; Scan mode: selectivity ion detection; The ion of quantitative test is respectively: but m/z 296.2(profit monarch) and m/z 248.1(Tinidazole, interior mark).
2.3 LC-MS analysis result
But sample profit monarch and Nei are marked the scanning of the mass spectrum figure of Tinidazole referring to Fig. 2 A and Fig. 2 B.
3 methods conclusive evidence
3.1 determinand and interior target specificity compare with the blank plasma of operating with method with concentration point in the typical curve and estimate in specificity this method.
But the chromatogram that adds profit monarch and Nei mark Tinidazole, plasma sample in blank plasma, the blank plasma is seen Fig. 3 A, 3B and 3C respectively, as can be seen from the figure, but the endogenous material in the blank plasma does not disturb profit monarch and Nei target to measure, the retention time of interior mark Tinidazole is 3.2min, but the retention time of four diastereo-isomerisms of profit monarch is respectively 9.5min, 10.6min, 11.9min and 13.2min.
3.2 but linear and sensitivity profit monarch's standard series working fluid is prepared by acetonitrile.Get blank plasma 100 μ L, add inner mark solution 30 μ L, but add profit monarch standard series working fluid designated volume more successively, be mixed with that to be equivalent to plasma concentration be 50,100,200,400,1000,2000,5000 and the plasma sample of 10000ng/mL, by 2.1 operations down, carry out LC-MS and analyze, try to achieve linear regression equation, be working curve.It is measured and analysis result sees Table 5.
But table 5 profit monarch's typical curve
| Concentration (ng/mL) | 50 | 100 | 200 | 400 | 1000 | 2000 | 5000 | 10000 |
| Analog value (in A sample/A) | 0.0399 | 0.0849 | 0.1895 | 0.3161 | 1.4369 | 2.8029 | 9.1374 | 20.3577 |
The range of linearity of this method is 50 ~ 10000ng/mL, and the equation of typical curve is: y=0.002039x-0.48431 (r
2=0.995685), y represents the ratio of determinand and interior target peak area, and x represents the concentration of determinand.This method minimum detectability and lowest detectable limit are respectively 10ng/mL (S/N=3) and 50ng/mL (S/N=10).
3.3 extraction recovery is got blank plasma 100 μ L, by 3.2 operations down, the sample for preparing basic, normal, high three concentration is analyzed, the record chromatographic peak.Simultaneously, other gets pure water and replaces blank plasma, and by 3.2 operations down, the sample for preparing basic, normal, high three concentration is analyzed, and obtains the respective peaks area, with the ratio of the peak area of the two chromatogram, investigates the extraction recovery of sample.Mensuration and analysis result see Table 6.
But table 6 profit monarch's extraction recovery
It is as shown in the table, but three concentration profit monarchs' extraction recovery is respectively 77.38 ± 6.14%, 81.45 ± 5.35%, 97.44 ± 3.78%.
3.4 precision and accuracy are by 3.2 operations down, but the quality control sample of basic, normal, high three concentration of preparation profit monarch, each concentration is carried out 6 sample analyses, METHOD FOR CONTINUOUS DETERMINATION three days, method precision by try to achieve in a few days, RSD(% in the daytime) estimate, accuracy gets deviation evaluation by actual measured value and theoretical value, and analysis result is as shown in table 7.
But the accuracy and the precision of profit monarch LC-MS assay method in table 7 plasma sample
As shown in table 3, in a few days, in 6.43% and 7.82%, accuracy range is 85.9 ~ 114.1% to day to day precision respectively, shows that this method has good precision and accuracy.
But 3.5 stability with-20 ℃ freezing 10 days and freezing-dissolve the stability of investigating the profit monarch for three times, stablize if the deviation of measured value and theoretical value in ± 15%, then shows sample, the stability result of this experimental technique sees Table 4.
Table 8 stability result
As shown in table 8, but the deviation of the measured value of profit monarch concentration and theoretical value shows that this method has good stable in ± 15%.
Claims (6)
1. but the detection method of profit monarch concentration in the blood plasma is characterized in that comprising following steps:
(a) plasma sample is carried out pre-treatment: get testing sample, mark and perchloric acid carry out albumen precipitation in adding, and get supernatant, be designated as Tinidazole in described, to contain Tinidazole concentration in the sample be 100ng-1mg/ml to its consumption in order to make, and the consumption of described perchloric acid solution is that to add perchloric acid weight in every 1ml sample be 10-100mg.
(b) but adopt the LC-MS combined instrument to measure the concentration of profit monarch in the above-mentioned supernatant, wherein, the chromatographic condition of LC-MS coupling is: chromatographic column is to be filling agent with octadecylsilane chemically bonded silica; Internal standard method, with Tinidazole as interior mark; Moving phase is the mixed liquor of acetonitrile-water-glacial acetic acid, and its proportional range is 20 ± 1:80 ± 5:0.3 ± 0.03); The mass spectrum condition of LC-MS coupling is: ion gun is the ESI ion gun, and positive ion detects.
3. detection method according to claim 1 is characterized in that, perchloric acid can be pre-configured to aqueous solution in the step (a), and concentration is 1-10%, is preferably 3-7%, most preferably is 4%.
4. detection method according to claim 1 is characterized in that, Tinidazole can be pre-configured to aqueous solution in the step (a), and concentration is 1.0-1.5 μ g/ml.
5. but the detection method of the side of profit monarch content is characterized in that in the analysed for plasma according to claim 1, and described chromatographic condition moving phase is made up of acetonitrile-water-glacial acetic acid, and its volume ratio is acetonitrile-water-glacial acetic acid=20:80:0.3.
6. detection method according to claim 1 is characterized in that, in the LC-MS coupling mass spectrum condition, scan mode is the selectivity ion detection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107389807A (en) * | 2017-06-09 | 2017-11-24 | 江苏泰洁检测技术有限公司 | A kind of assay method of the carboxylic acid concentration of L thiazolidines 4 |
| CN107478477A (en) * | 2017-08-04 | 2017-12-15 | 福州新北生化工业有限公司 | A kind of jaundice, haemolysis, the serum processing method of piarhemia |
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| CN1865251A (en) * | 2005-12-23 | 2006-11-22 | 张宏业 | Leucogen diastereoisomeride structural confirmation and determination method |
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Patent Citations (4)
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| RU2029466C1 (en) * | 1992-01-22 | 1995-02-27 | Юрий Юрьевич Ивницкий | Agent for increase of body mass, thymus, spleen and red marrow bone in animals |
| CN1746670A (en) * | 2005-07-15 | 2006-03-15 | 张宏业 | Quality inspection of Ricosi preparation |
| CN1865251A (en) * | 2005-12-23 | 2006-11-22 | 张宏业 | Leucogen diastereoisomeride structural confirmation and determination method |
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| 吴悦 等: "利可君的高效液相色谱测定条件的优化", 《海峡药学》, vol. 19, no. 12, 31 December 2007 (2007-12-31), pages 37 - 38 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107389807A (en) * | 2017-06-09 | 2017-11-24 | 江苏泰洁检测技术有限公司 | A kind of assay method of the carboxylic acid concentration of L thiazolidines 4 |
| CN107478477A (en) * | 2017-08-04 | 2017-12-15 | 福州新北生化工业有限公司 | A kind of jaundice, haemolysis, the serum processing method of piarhemia |
| CN107478477B (en) * | 2017-08-04 | 2020-07-10 | 福州新北生化工业有限公司 | Serum treatment method for jaundice, hemolysis and lipemia |
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