CN113588812A - Detection method of methylene blue in Tirofiban hydrochloride injection package tightness experiment - Google Patents
Detection method of methylene blue in Tirofiban hydrochloride injection package tightness experiment Download PDFInfo
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- CN113588812A CN113588812A CN202110758124.6A CN202110758124A CN113588812A CN 113588812 A CN113588812 A CN 113588812A CN 202110758124 A CN202110758124 A CN 202110758124A CN 113588812 A CN113588812 A CN 113588812A
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- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960000907 methylthioninium chloride Drugs 0.000 title claims abstract description 49
- 238000001514 detection method Methods 0.000 title claims abstract description 48
- 229960004929 tirofiban hydrochloride Drugs 0.000 title claims abstract description 38
- HWAAPJPFZPHHBC-FGJQBABTSA-N tirofiban hydrochloride Chemical compound O.Cl.C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 HWAAPJPFZPHHBC-FGJQBABTSA-N 0.000 title claims abstract description 38
- 238000002347 injection Methods 0.000 title claims abstract description 34
- 239000007924 injection Substances 0.000 title claims abstract description 34
- 238000002474 experimental method Methods 0.000 title abstract description 7
- 239000000243 solution Substances 0.000 claims abstract description 43
- 239000012488 sample solution Substances 0.000 claims abstract description 32
- 239000013558 reference substance Substances 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 52
- 238000004806 packaging method and process Methods 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- 238000012360 testing method Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 238000004140 cleaning Methods 0.000 claims description 6
- -1 octadecyl silicagel Chemical compound 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 229960001866 silicon dioxide Drugs 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 2
- 239000012085 test solution Substances 0.000 claims description 2
- 238000003556 assay Methods 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 6
- 239000012088 reference solution Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 9
- 239000012490 blank solution Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000003570 air Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Images
Classifications
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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
- G01N30/02—Column chromatography
-
- 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
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
-
- 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
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
Abstract
The invention relates to a detection method of methylene blue in a Tirofiban hydrochloride injection package tightness experiment, which adopts a high performance liquid chromatography for detection and comprises the following operation steps: 1) preparing a reference substance solution; 2) preparing a sample solution; 3) injecting the reference solution and the sample solution into a liquid chromatograph, and measuring. The detection method for the methylene blue in the package tightness detection of the tirofiban hydrochloride injection provided by the invention has high sensitivity, other substances in the tirofiban hydrochloride injection cannot interfere with the detection of the methylene blue, the immersed methylene blue can be detected more accurately, and the package tightness of the tirofiban hydrochloride injection can be accurately reflected, so that the product quality of the tirofiban hydrochloride injection can be better controlled.
Description
The technical field is as follows:
the invention relates to the field of chemical inspection and the technical field of drug analysis, in particular to a detection method of methylene blue in a Tirofiban hydrochloride injection package tightness test.
Background art:
the sealability of a packaging system, also called the integrity of the seal of a container, refers to the ability of the packaging system to prevent the loss of contents, the invasion of microorganisms, and the entry of gases (oxygen, air, water vapor, etc.) or other substances, and to ensure that the pharmaceutical product continuously meets the safety and quality requirements. The tightness of a packaging system is a key concern of injection research and evaluation, and must be verified, so that the medicine can meet the corresponding physicochemical and microbiological quality requirements in the shelf life and the using process.
The method for checking the tightness of the packaging system is divided into two main types, namely a deterministic method and a probabilistic method, wherein the water-color method belongs to the probabilistic method, and when the water-color method is adopted, a methylene blue solution can be adopted as an immersion liquid, and the methylene blue immersed in the tirofiban hydrochloride injection is detected, so that the tightness of the packaging system of the tirofiban hydrochloride injection is judged.
In the product packaging tightness checking process, the immersion amount of methylene blue is possibly less, the operation is relatively simple and the consumed time is short by adopting an ultraviolet spectrophotometry, but the sensitivity of the ultraviolet spectrophotometry is not high, and trace methylene blue immersed in the product cannot be detected, so that the condition judgment of the product packaging system tightness is not accurate, and the quality risk of the product during the storage period is increased.
The invention adopts the high performance liquid chromatography to detect the methylene blue in the Tirofiban hydrochloride injection package tightness test, and the detection method is simple and feasible, has accurate determination index, high sensitivity and strong specificity.
The invention content is as follows:
the invention provides a detection method of methylene blue in a Tirofiban hydrochloride injection package tightness test, which has high sensitivity, simple operation and strong specificity and adopts a high performance liquid chromatography for detection. The technical scheme adopted by the invention is as follows:
the operation steps of the detection method of methylene blue in the Tirofiban hydrochloride injection package tightness test are as follows:
(1) establishment of chromatographic conditions and system adaptability: using octadecyl silicagel column, and mixing the raw materials in a volume ratio of 0.3% phosphoric acid solution: and (3) acetonitrile 62-58: 38-42 is a mobile phase, and the detection wavelength, the flow velocity and the column temperature are set;
(2) preparation of control solutions: dissolving methylene blue control in 50% acetonitrile to obtain control solution containing 0.1 μ g of methylene blue per 1 ml;
(3) preparation of positive sample solution: completely packaging and inversely immersing the tirofiban hydrochloride injection into a methylene blue solution to prepare a test solution containing 0.05mg of tirofiban hydrochloride per 1ml, standing for 27-33 minutes at the temperature of 22-28 ℃ and under the pressure of vacuumizing to 48-52 kpa, taking out, and cleaning to obtain a positive sample solution;
(4) and respectively injecting 30 mu l of the reference substance solution and 30 mu l of the positive sample solution into a liquid chromatograph, and recording the chromatogram.
The sealing experiment of the tirofiban hydrochloride injection package adopts a color water method and methylene blue as a coloring agent.
The step (1) is to mix the phosphoric acid solution with the volume ratio of 0.3 percent: acetonitrile 60:40 is a mobile phase.
The detection wavelength in the step (1) is 664 nm.
The flow rate in the step (1) is 0.8 ml/min-1.5 ml/min.
Preferably, the flow rate in the step (1) is 1.0 ml/min.
The column temperature in the step (1) is 25-40 ℃.
Preferably, the column temperature in the step (1) is 30 ℃.
The octadecyl silica gel column in the step 3) has the specification of 4.6mm by 250mm and 5 mu m.
The temperature in the step (3) is 25 ℃, and the pressure is between vacuum pumping and 50 kpa.
Preferably, the standing time in the step (3) is 30 minutes.
Has the advantages that:
1. the detection method for testing the tightness of the packaging of the tirofiban hydrochloride injection provided by the invention has the advantages of high sensitivity, strong specificity and good durability.
2. The detection of methylene blue cannot be interfered by other substances in the tirofiban hydrochloride injection, the immersed methylene blue can be detected more accurately, and the packaging tightness of the tirofiban hydrochloride injection can be accurately reflected, so that the product quality of the tirofiban hydrochloride injection can be better controlled.
Description of the drawings:
FIG. 1 chromatogram of control solution
FIG. 2 chromatogram of positive sample solution
FIG. 3 chromatogram of positive sample solution
FIG. 4 quantitative limiting solution chromatogram
FIG. 5 detection limit solution chromatogram
Fig. 6 mobile ratio phase a: chromatogram of positive sample solution of B phase (58:42)
Fig. 7 mobile ratio phase a: chromatogram of positive sample solution of phase B (62:38)
FIG. 8 chromatogram of positive sample solution at column temperature of 32 ℃
FIG. 9 chromatogram of positive sample solution at column temperature 28 ℃
FIG. 10 chromatogram of positive sample solution with flow rate of 0.9ml/min
FIG. 11 chromatogram of positive sample solution with flow rate of 1.1ml/min
Detailed Description
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1 detection method
(1) Chromatographic condition establishment and system adaptability steps:
using a C18 column, and mixing the following components in a volume ratio of 0.3% phosphoric acid solution: acetonitrile 60:40 is a mobile phase, and the detection wavelength is 664nm, the flow rate is 1.0ml/min and the column temperature is 30 ℃;
(2) preparation of control solutions: dissolving methylene blue control in 50% acetonitrile to obtain control solution containing 0.1 μ g of methylene blue per 1 ml;
(3) preparation of positive sample solution: completely packaging and inversely immersing the tirofiban hydrochloride injection into a methylene blue solution to prepare a test sample solution containing 0.05mg of tirofiban hydrochloride per 1ml, standing for 30 minutes at the temperature of 25 ℃ and under the pressure of vacuumizing to 50kpa, taking out, and cleaning to obtain a positive sample solution;
(4) and respectively injecting 30 mu l of the reference substance solution and 30 mu l of the positive sample solution into a liquid chromatograph, and recording the chromatogram.
Example 2 detection method
(1) Chromatographic condition establishment and system adaptability steps:
using a C18 column, and mixing the following components in a volume ratio of 0.3% phosphoric acid solution: acetonitrile 62:38 is a mobile phase, and the detection wavelength is 664nm, the flow rate is 0.8ml/min and the column temperature is 25 ℃;
(2) preparation of control solutions: dissolving methylene blue control in 50% acetonitrile to obtain control solution containing 0.1 μ g of methylene blue in 1ml of 50% acetonitrile;
(3) preparation of positive sample solution: completely packaging and inversely immersing the tirofiban hydrochloride injection into a methylene blue solution to prepare a test sample solution containing 0.05mg of tirofiban hydrochloride per 1ml, standing for 27 minutes at the temperature of 22 ℃ and under the pressure of vacuumizing to 48kpa, taking out, and cleaning to obtain a positive sample solution;
(4) and respectively injecting 30 mu l of the reference substance solution and 30 mu l of the positive sample solution into a liquid chromatograph, and recording the chromatogram.
Example 3 detection method
(1) Chromatographic condition establishment and system adaptability steps:
using a C18 column, and mixing the following components in a volume ratio of 0.3% phosphoric acid solution: acetonitrile 58:42 is a mobile phase, and the detection wavelength is 664nm, the flow rate is 1.5ml/min and the column temperature is 40 ℃;
(2) preparation of control solutions: dissolving methylene blue control in 50% acetonitrile to obtain control solution containing 0.1 μ g of methylene blue in 1ml of 50% acetonitrile;
(3) preparation of positive sample solution: completely packaging and inversely immersing the tirofiban hydrochloride injection into a methylene blue solution to prepare a test sample solution containing 0.05mg of tirofiban hydrochloride per 1ml, standing for 33 minutes at the temperature of 28 ℃ and under the pressure of vacuumizing to 52kpa, taking out, and cleaning to obtain a positive sample solution;
(4) and respectively injecting 30 mu l of the reference substance solution and 30 mu l of the positive sample solution into a liquid chromatograph, and recording the chromatogram.
To further verify the effectiveness of the present invention, the inventors performed a series of tests, specifically as follows:
experimental example 1: specificity experiments
Control solution: taking a proper amount of methylene blue reference substances, and dissolving and diluting the reference substances by using 50% acetonitrile to obtain a solution with the concentration of 0.1 mu g/ml.
Positive sample solution: completely packaging and inversely soaking the tirofiban hydrochloride injection in the jack into a methylene blue solution, standing for a period of time at a specific temperature and pressure, taking out, cleaning, shaking up, and taking the solution in the bottle as a positive sample solution.
Blank solution: tirofiban hydrochloride injection.
Chromatographic conditions are as follows:
a chromatographic column: philomen Titank C185 μm 4.6mm 250mm
Mobile phase: 0.3% phosphoric acid solution-acetonitrile (60:40)
And (3) an elution mode: isocratic elution
Detection wavelength: 664nm
Column temperature: 30 deg.C
Flow rate: 1.0ml/min
Sample introduction amount: 30 μ l
Injecting the reference substance solution, the positive sample solution and the blank solution into a chromatographic system respectively, wherein the detection spectra are shown in figures 1-3.
The chromatogram shows that other substances in the tirofiban hydrochloride injection have no peak, the detection of methylene blue cannot be interfered, and the detection method has strong specificity.
Experimental example 2: sensitivity test
Quantitative limiting solution: the methylene blue control solution was diluted 10-fold with 50% acetonitrile.
Detection limiting solution: the quantitation limiting solution was diluted 3-fold with 50% acetonitrile.
The quantitative limiting solution and the detection limiting solution are taken and injected into the chromatographic system of the example 1, the result is shown in the table 1, and typical maps are shown in the figures 4 and 5.
TABLE 1 sensitivity profiles of methylene blue
When the concentration of the methylene blue is 3.05ng/ml, the methylene blue can be detected; at 10.2ng/ml, the quantitative detection of methylene blue can be realized, which shows that the detection method has high sensitivity and completely meets the detection of methylene blue in a sealing experiment of packaging in a tirofiban hydrochloride injection.
Experimental example 3: durability test
Mixing mobile phase A phase: the proportion of the phase B is slightly changed from 58:42 to 62: 38; the column temperature slightly varies from 28 ℃ to 32 ℃; the flow rate was varied slightly from 0.9ml/min to 1.1ml/min, and the change in the amount of methylene blue detected was examined.
The above conditions were slightly varied based on the chromatography system of example 1, and the positive sample solution was taken into the chromatography system, and the results are shown in Table 2, and representative spectra are shown in FIGS. 6 to 11.
TABLE 2 methylene blue test method durability
The chromatographic condition is slightly changed, the detection amount of the methylene blue is slightly changed, and the detection of the methylene blue in the packaging tightness test of the tirofiban hydrochloride injection is met.
In conclusion, the detection method for the methylene blue in the test of the packaging tightness of the tirofiban hydrochloride injection provided by the invention has high sensitivity, other substances in the tirofiban hydrochloride injection do not interfere with the detection of the methylene blue, the immersed methylene blue can be detected more accurately, the packaging tightness of the tirofiban hydrochloride injection can be accurately reflected, and the product quality of the tirofiban hydrochloride injection can be better controlled.
While the invention has been described in detail in the foregoing by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that certain changes and modifications may be made therein based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A detection method of methylene blue in a Tirofiban hydrochloride injection package tightness test is characterized in that high performance liquid chromatography is adopted for detection, and the operation steps are as follows:
(1) establishment of chromatographic conditions and system adaptability: using octadecyl silicagel column, and mixing the raw materials in a volume ratio of 0.3% phosphoric acid solution: and (3) acetonitrile 62-58: 38-42 is a mobile phase, and the detection wavelength, the flow velocity and the column temperature are set;
(2) preparation of control solutions: dissolving methylene blue control in 50% acetonitrile to obtain control solution containing 0.1 μ g of methylene blue per 1 ml;
(3) preparation of positive sample solution: completely packaging and inversely immersing the tirofiban hydrochloride injection into a methylene blue solution to prepare a test solution containing 0.05mg of tirofiban hydrochloride per 1ml, standing for 27-33 minutes at the temperature of 22-28 ℃ and under the pressure of vacuumizing to 48-52 kpa, taking out, and cleaning to obtain a positive sample solution;
(4) and respectively injecting 30 mu l of the reference substance solution and 30 mu l of the positive sample solution into a liquid chromatograph, and recording the chromatogram.
2. The detection method according to claim 1, wherein the step (1) is performed by mixing the following components in a 0.3% phosphoric acid solution by volume: acetonitrile 60:40 is a mobile phase.
3. The detection method according to claim 1, wherein the detection wavelength in step (1) is 664 nm.
4. The detection method according to claim 1, wherein the flow rate in the step (1) is 0.8ml/min to 1.5 ml/min.
5. The detection method according to claim 4, wherein the flow rate in the step (1) is 1.0 ml/min.
6. The detection method according to claim 1, wherein the column temperature in the step (1) is 25 to 40 ℃.
7. The detection method according to claim 6, wherein the column temperature in the step (1) is 30 ℃.
8. The detection method according to claim 1, characterized in that: and 3) the octadecyl silica gel column with the specification of 4.6mm by 250mm and 5 μm.
9. The detection method according to claim 1, wherein the temperature in the step (3) is 25 ℃ and the pressure is between 50 kpa.
10. The assay of claim 1, wherein the standing time of step (3) is 30 minutes.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990002742A1 (en) * | 1988-09-14 | 1990-03-22 | Tropix, Inc. | Purification of stable water-soluble dioxetanes |
| CN110793730A (en) * | 2019-11-21 | 2020-02-14 | 浙江华海药业股份有限公司 | Method for analyzing package integrity of injection by color water method |
| CN111896192A (en) * | 2020-08-12 | 2020-11-06 | 重庆华邦制药有限公司 | Test method for measuring packaging tightness by color water method |
-
2021
- 2021-07-05 CN CN202110758124.6A patent/CN113588812A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990002742A1 (en) * | 1988-09-14 | 1990-03-22 | Tropix, Inc. | Purification of stable water-soluble dioxetanes |
| CN110793730A (en) * | 2019-11-21 | 2020-02-14 | 浙江华海药业股份有限公司 | Method for analyzing package integrity of injection by color water method |
| CN111896192A (en) * | 2020-08-12 | 2020-11-06 | 重庆华邦制药有限公司 | Test method for measuring packaging tightness by color water method |
Non-Patent Citations (2)
| Title |
|---|
| 仲淑贤等: "石墨烯复合材料固相萃取环境水样中的亚甲基蓝", 《浙江师范大学学报( 自然科学版)》 * |
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