CN107957461A - A kind of remaining method of benzene in gas chromatographic detection fluorouracil - Google Patents
A kind of remaining method of benzene in gas chromatographic detection fluorouracil Download PDFInfo
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- CN107957461A CN107957461A CN201711475887.XA CN201711475887A CN107957461A CN 107957461 A CN107957461 A CN 107957461A CN 201711475887 A CN201711475887 A CN 201711475887A CN 107957461 A CN107957461 A CN 107957461A
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- benzene
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- G—PHYSICS
- G01—MEASURING; TESTING
- 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 kind of remaining method of benzene in gas chromatographic detection fluorouracil, the detection method comprises the following steps：The preparation of benzene titer, the preparation of sample test liquid, the chromatographic operating condition of setting, sample detection and result calculate the residual quantity of benzene in measure fluorouracil.It the advantage is that：The present invention by residue that gas chromatograph detects benzene in fluorouracil it is easy, it is quick, accurate, stablize, reliable, can more comprehensive, objective, scientifically evaluate the quality of fluorouracil, important meaning is respectively provided with to the health aspect of patient；Whole technique of the invention has the advantages that detection speed is fast, easy to operate, accuracy is high；By optimizing detection chromatographic condition, substantially reduce analysis time and improve the sensitivity of detection.
Description
Technical field
The invention belongs to benzene in technical field of biochemical industry, more particularly to a kind of detection fluorouracil with gas chromatography is residual
The method stayed.
Background technology
Fluorouracil (Fluorouracil, 5-FU), molecular formula C4H3FN2O2, molecular weight 130.08 are white for white or class
The crystallization of color or crystalline powder.This product is slightly molten in water, in ethanol slightly soluble, almost insoluble in chloroform, in dilute salt
Dissolved in acid or sodium hydroxide solution.Fluorouracil is anti-miazines medicine, clinically for kinds of tumors such as tumor in digestive tract,
The treatment of breast cancer, oophoroma, chorioepithelioma, cervical carcinoma, carcinoma of urinary bladder, liver cancer, cutaneum carcinoma etc. is effective, especially to digestive system cancer
And other solid tumors have good efficacy, can vein or intracavitary administration, oral absorption is incomplete.
At present, industrially the method for production fluorouracil generally use is condensation and cyclization method.This method is mainly with fluoroacetic acid
Methyl esters is raw material, is condensed to obtain fluoro formyl acetic acid ester enol form sodium salt (compound with Ethyl formate under sodium methoxide, toluene catalytically
I), chemical compounds I obtains 2- methoxyl groups -5 FU 5 fluorouracil (compound ii) with O- Methyl Isourea Sulfate cyclizations, and II in dilute hydrochloric acid
It is hydrolyzed to 5 FU 5 fluorouracil.It is 2ppm, therefore, benzene content in fluorouracil according to the residual limit of the requirement benzene of ICH guides
Measure the quality for fluorouracil, the health aspect of patient is respectively provided with important meaning.
The content of the invention
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to the continuity of detection can be realized by now providing a kind of offer,
Improve the remaining method of benzene in the sensitivity of detection and the gas chromatographic detection fluorouracil of repeatability.
In order to solve the above technical problems, the technical solution adopted by the present invention is：In a kind of gas chromatographic detection fluorouracil
The remaining method of benzene, its innovative point are：Comprise the following steps：
The preparation of step 1. benzene titer：A. 0.05g benzene is weighed to be added in 100mL volumetric flasks, with ethanol solution constant volume,
Then the accurate 1.0mL that draws, with ethanol solution constant volume, obtains benzene standard reserving solution in another volumetric flasks of 100mL；B. it is accurate to inhale
1.0mL benzene standard reserving solution is taken in 25mL volumetric flasks, it is fixed molten with ethanol solution, up to benzene titer；
The preparation of step 2. sample test liquid：Precision weighs fluorouracil sample 1.0g, is placed in 10ml volumetric flasks, ethanol
Solution constant volume, up to test liquid；
Step 3. sets chromatographic operating condition：Chromatographic column is HP-5 capillary chromatographic columns, and size is 30m × 0.32mm
× 0.25 μm, injector temperature is 260 DEG C, and detector temperature is 260 DEG C, nitrogen flow rate 30mL/min, and hydrogen flow rate is
40mL/min, air velocity 400mL/min, split ratio 50:1, sample size is 1 μ L；
Step 4. sample detection：Gas of the solution injection equipped with flame ionization ditector that step 1 and step 2 are obtained
Chromatography, by chromatographic data processor, obtains standard items chromatic graph spectrum and sample chromatogram figure, the Loading sequence is with first
Pin blank sample, then continuous five pins titer, then into sample test liquid, finally again into a pin titer Loading sequence successively
Sample detection；
Step 5. result calculates：The content of benzene in fluorouracil is calculated according to reference colour spectrogram and sample chromatogram figure, it is described
Calculation formula is：
In formula：
ASampleThe peak area of benzene in-sample test liquid；
AMarkThe peak area of benzene in-titer；
CSampleThe concentration of fluorouracil, g/mL in-sample test liquid；
CMarkThe concentration of benzene, g/mL in-titer.
Further, column temperature uses temperature programming in the step 3, and 60 DEG C of initial temperature, keeps 2min, with 5 DEG C/min
Heating rate rises to 80 DEG C, keeps 5min, rises to 220 DEG C with 30 DEG C/min heating rates, keeps 2min.
Further, the pin number of continuous sample introduction product must not exceed ten pins in the step 4, then every ten pins of unnecessary ten pin it
Between intersect again into a pin titer.
Beneficial effects of the present invention are as follows：
(1) present invention is easy, quick, accurate, steady by the residue that gas chromatograph detects benzene in fluorouracil
It is fixed, reliable, can it is more comprehensive, objective, scientifically evaluate fluorouracil quality, to patient health aspect be respectively provided with it is important
Meaning；Whole technique of the invention has the advantages that detection speed is fast, easy to operate, accuracy is high；
(2) present invention is by optimizing detection chromatographic condition, and under the premise of it ensure that each peak separating degree is preferable, ethanol retains
Time is 1.78min, and benzene retention time is 3.51min, substantially reduces analysis time；
(3) by optimizing detection chromatographic condition, the detection of benzene is limited to 0.19 μ g/mL, is quantitatively limited to 0.4 μ g/ the present invention
ML, the rate of recovery substantially increase the sensitivity of detection between 99~101%.
Brief description of the drawings
Fig. 1 is the gas chromatogram that blank solvent of the present invention detects；
Fig. 2 is the gas chromatogram that titer of the present invention detects；
Fig. 3 is benzene titer linear relationship chart of the present invention；
The chromatogram of Fig. 4 test limit solution of the present invention；
Fig. 5 is the chromatogram of quantitative limit solution of the present invention；
Fig. 6 is the gas chromatogram that test liquid of the present invention detects.
Embodiment
Embodiments of the present invention are illustrated by particular specific embodiment below, those skilled in the art can be by this explanation
Content disclosed by book understands other advantages and effect of the present invention easily.
The gas chromatograph that following embodiments use：Shimadzu GC-2014, Labsolution work station, chromatographic column HP-5
Capillary column, equipped with flame ionization ditector.
Chromatography lives operating condition：Chromatographic column is HP-5 capillary chromatographic columns, and size is 30m × 0.32mm × 0.25 μm,
Injector temperature is 260 DEG C, and detector temperature is 260 DEG C, and column temperature uses temperature programming, and 60 DEG C of initial temperature, keeps 2min, with
5 DEG C/min heating rates rise to 80 DEG C, keep 5min, rise to 220 DEG C with 30 DEG C/min heating rates, keep 2min, nitrogen stream
Speed is 30mL/min, hydrogen flow rate 40mL/min, air velocity 400mL/min, split ratio 50:1, sample size is 1 μ L.
(1) specificity is tested
Precision weighs benzene 0.05g and adds in the 100mL volumetric flasks of a small amount of ethanol, and with ethanol constant volume, precision draws the solution
1.0mL is in 10mL volumetric flasks, constant volume, obtains benzene standard reserving solution, and precision draws benzene standard reserving solution 1mL in 25mL volumetric flasks
In, ethanol constant volume, is configured to benzene titer.
Precision measures the blank alcohol solvent of 1 μ L, injects gas chromatograph, blank solvent chromatogram is recorded, such as Fig. 1 institutes
Show.Precision measures 1 μ L benzene titers, injects gas chromatograph, records benzene titer chromatogram, as shown in Figure 2.
From Fig. 1 and Fig. 2, blank solvent does not disturb this product to measure, noiseless between each peak.
(2) linear relationship is investigated
Precision measures benzene standard reserving solution and is configured to the solution of five kinds of concentration, be respectively 0.712 μ g/mL, 1.064 μ g/mL,
1.655μg/mL、1.982μg/mL、2.316μg/mL.Precision measures the 1 μ L of solution of each solubility respectively, successively sample introduction, Mei Gerong
3 pin of sample introduction is spent, records peak area；To mark benzene standard reserving solution concentration as abscissa, benzene average peak area draws mark for ordinate
Directrix curve, benzene linear relationship chart, as shown in figure 3, the results are shown in Table 1 for Linear Experiment.
1 linear test result of table
From table 1 and Fig. 3, benzene concentration is more than 0.999 for related coefficient in the range of the μ g/ml of 0.712 μ g/ml~2.316,
It is in good linear relationship between peak area and concentration.
(3) precision test
Precision weighs benzene 0.05g and adds in the 100mL volumetric flasks of a small amount of ethanol, and with ethanol constant volume, precision draws the solution
1.0mL is in 10mL volumetric flasks, constant volume, obtains benzene standard reserving solution.
In 25mL volumetric flasks, ethanol constant volume, matches somebody with somebody accurate benzene the standard reserving solution 0.8mL, 0.9mL, 1mL of drawing respectively respectively
The benzene titer of various concentrations processed, as contrast solution.
Precision weighs fluorouracil standard items 1g, is placed in 25mL volumetric flasks, is separately added into benzene titer 0.8mL,
0.9mL, 1mL add ethanol to dissolve and are diluted to scale, mix, each to prepare 3 parts, as test solution.
Precision measures 1 μ L of contrast solution and each test solution, is injected separately into gas chromatograph, chromatogram is recorded, by outer
Mark method calculates the rate of recovery, the results are shown in Table shown in 2.
2 Precision test result of table
As shown in Table 2, the rate of recovery reaches standard requirement, method is feasible, and precision is good between 99%~101%.
(4) repetitive test
The identical benzene standard solution of six parts of concentration is prepared, precision measures each 1 μ L of standard solution, and sample introduction, is injected separately into successively
Gas chromatograph, records chromatogram, investigates repeatability.The results are shown in Table 3.
3 repetitive test result of table
As shown in Table 3, assay method repeatability is preferable.
(5) test limit is tested with quantitative limit
Precision weighs benzene 0.05g and adds in the 100mL volumetric flasks of a small amount of ethanol, and with ethanol constant volume, precision draws the solution
1.0mL is in 10mL volumetric flasks, constant volume, obtains benzene standard reserving solution.Take benzene standard reserving solution appropriate, add ethanol to dilute step by step,
By signal-to-noise ratio about 3：1 is test limit solution, signal-to-noise ratio about 10：1 is quantitative limit solution, and three times, 1 μ L of sample size, remember continuous sample introduction
Chromatogram is recorded, as shown in Figure 4,5, and is recorded as a result, the results are shown in Table 4.
4 test limit of table, quantitative limit result
As shown in Table 4, the standard of signal-to-noise ratio about 3: 1 is 0.19 μ g/mL of test limit, and the standard of signal-to-noise ratio about 10: 1 is quantitative
Limit 0.4 μ g/mL.
Embodiment 1
A kind of remaining method of benzene in gas chromatographic detection fluorouracil, it is characterised in that：Comprise the following steps：
The preparation of step 1. benzene titer：A. 0.05g benzene is weighed to be added in 100mL volumetric flasks, with ethanol solution constant volume,
Then the accurate 1.0mL that draws, with ethanol solution constant volume, obtains benzene standard reserving solution in another volumetric flasks of 100mL；B. it is accurate to inhale
1.0mL benzene standard reserving solution is taken in 25mL volumetric flasks, it is fixed molten with ethanol solution, up to benzene titer；
The preparation of step 2. sample test liquid：Precision weighs fluorouracil sample 1.0g, is placed in 10ml volumetric flasks, ethanol
Solution constant volume, up to test liquid；
Step 3. sets chromatographic operating condition：Chromatographic column is HP-5 capillary chromatographic columns, and size is 30m × 0.32mm
× 0.25 μm, injector temperature is 260 DEG C, and detector temperature is 260 DEG C, and column temperature uses temperature programming, and 60 DEG C of initial temperature, is protected
2min is held, 80 DEG C is risen to 5 DEG C/min heating rates, keeps 5min, 220 DEG C is risen to 30 DEG C/min heating rates, keeps
2min, nitrogen flow rate 30mL/min, hydrogen flow rate 40mL/min, air velocity 400mL/min, split ratio 50:1,
Sample size is 1 μ L；
Step 4. sample detection：Gas of the solution injection equipped with flame ionization ditector that step 1 and step 2 are obtained
Chromatography, by chromatographic data processor, obtains standard items chromatic graph spectrum and sample chromatogram figure, Loading sequence is empty with the first pin
White sample, then continuous five pins titer, then into sample test liquid, finally again into a pin benzene titer Loading sequence successively into
Sample detects.The pin number of continuous sample introduction product must not exceed ten pins, intersect again between then every ten pins of unnecessary ten pin into a pin benzene standard
Liquid.
Step 5. result calculates：The content of benzene in fluorouracil is calculated according to reference colour spectrogram and sample chromatogram figure, is calculated
Formula is：
In formula：
ASampleThe peak area of benzene in-sample test liquid；
AMarkThe peak area of benzene in-titer；
CSampleThe concentration of fluorouracil, g/mL in-sample test liquid；
CMarkThe concentration of benzene, g/mL in-titer.
From Fig. 1 and Fig. 2, the peak area A of benzene in sample test liquidSample：30810th, in titer benzene peak area AMark：
55114th, in sample test liquid fluorouracil concentration CSample：The concentration C of benzene in 0.103g/mL, titerMark：1.982×10-7g/
mL。
The results show that residual solvent levels are 1.076ppm, meet the requirement of ICH guides.
Above-described embodiment is presently preferred embodiments of the present invention, is not the limitation to technical solution of the present invention, as long as
The technical solution that can be realized without creative work on the basis of above-described embodiment, is regarded as falling into patent of the present invention
Rights protection scope in.
Claims (3)
1. a kind of remaining method of benzene in gas chromatographic detection fluorouracil, it is characterised in that：Comprise the following steps：
The preparation of step 1. benzene titer：A. weigh 0.05g benzene to be added in 100mL volumetric flasks, with ethanol solution constant volume, then
Precision draws 1.0mL in another volumetric flasks of 100mL, with ethanol solution constant volume, obtains benzene standard reserving solution；B. it is accurate to draw
1.0mL benzene standard reserving solution is fixed molten with ethanol solution in 25mL volumetric flasks, up to benzene titer；
The preparation of step 2. sample test liquid：Precision weighs fluorouracil sample 1.0g, is placed in 10ml volumetric flasks, ethanol solution
Constant volume, up to test liquid；
Step 3. sets chromatographic operating condition：Chromatographic column is HP-5 capillary chromatographic columns, size for 30m × 0.32mm ×
0.25 μm, injector temperature is 260 DEG C, and detector temperature is 260 DEG C, nitrogen flow rate 30mL/min, hydrogen flow rate 40mL/
Min, air velocity 400mL/min, split ratio 50:1, sample size is 1 μ L；
Step 4. sample detection：Gas phase color of the solution injection equipped with flame ionization ditector that step 1 and step 2 are obtained
Spectrometer, by chromatographic data processor, obtains standard items chromatic graph spectrum and sample chromatogram figure, the Loading sequence is empty with the first pin
White sample, then continuous five pins titer, then into sample test liquid, finally again into the Loading sequence sample introduction successively of a pin titer
Detection；
Step 5. result calculates：The content of benzene in fluorouracil, the calculating are calculated according to reference colour spectrogram and sample chromatogram figure
Formula is：
In formula：
ASampleThe peak area of benzene in-sample test liquid；
AMarkThe peak area of benzene in-titer；
CSampleThe concentration of fluorouracil, g/mL in-sample test liquid；
CMarkThe concentration of benzene, g/mL in-titer.
2. the remaining method of benzene in a kind of gas chromatographic detection fluorouracil according to claim 1, it is characterised in that：Institute
State column temperature in step 3 and use temperature programming, 60 DEG C of initial temperature, keeps 2min, rises to 80 DEG C with 5 DEG C/min heating rates, protects
5min is held, 220 DEG C is risen to 30 DEG C/min heating rates, keeps 2min.
3. the remaining method of benzene in a kind of gas chromatographic detection fluorouracil according to claim 1, it is characterised in that：Institute
The pin number for stating continuous sample introduction product in step 4 must not exceed ten pins, intersect again between then every ten pins of unnecessary ten pin into a pin standard
Liquid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112763603A (en) * | 2020-12-24 | 2021-05-07 | 四川欣美加生物医药有限公司 | Detection method of benzene content and application |
| CN113325120A (en) * | 2021-06-17 | 2021-08-31 | 湖南农业大学 | Method for detecting content of trifluoro-benzene pyrimidine by GC-MS |
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| CN104165958A (en) * | 2014-08-20 | 2014-11-26 | 云南中烟工业有限责任公司 | Method for measuring content of benzene and benzene series in glycerol triacetate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101261255A (en) * | 2008-04-22 | 2008-09-10 | 天津市产品质量监督检测技术研究院 | Gasoline benzene, oxygen content rapid detection method |
| CN102230918A (en) * | 2011-06-22 | 2011-11-02 | 红云红河烟草(集团)有限责任公司 | Method for measuring contents of benzene and benzene series in tobacco flavor and fragrance |
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| CN104165958A (en) * | 2014-08-20 | 2014-11-26 | 云南中烟工业有限责任公司 | Method for measuring content of benzene and benzene series in glycerol triacetate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112763603A (en) * | 2020-12-24 | 2021-05-07 | 四川欣美加生物医药有限公司 | Detection method of benzene content and application |
| CN113325120A (en) * | 2021-06-17 | 2021-08-31 | 湖南农业大学 | Method for detecting content of trifluoro-benzene pyrimidine by GC-MS |
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