CN114518201A - Method for verifying container tightness by fluorescent agent tracing method - Google Patents
Method for verifying container tightness by fluorescent agent tracing method Download PDFInfo
- Publication number
- CN114518201A CN114518201A CN202011302344.XA CN202011302344A CN114518201A CN 114518201 A CN114518201 A CN 114518201A CN 202011302344 A CN202011302344 A CN 202011302344A CN 114518201 A CN114518201 A CN 114518201A
- Authority
- CN
- China
- Prior art keywords
- container
- detected
- verifying
- pressure
- fluorescence intensity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 57
- 239000003814 drug Substances 0.000 claims abstract description 26
- 239000000126 substance Substances 0.000 claims abstract description 22
- 238000004806 packaging method and process Methods 0.000 claims abstract description 20
- 238000007789 sealing Methods 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 238000003825 pressing Methods 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 26
- 229940043267 rhodamine b Drugs 0.000 claims description 22
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 12
- 239000004033 plastic Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 6
- 229930182555 Penicillin Natural products 0.000 claims description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 6
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical group O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 229940049954 penicillin Drugs 0.000 claims description 6
- 229960002477 riboflavin Drugs 0.000 claims description 6
- 235000019192 riboflavin Nutrition 0.000 claims description 6
- 239000002151 riboflavin Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 claims description 5
- 239000011521 glass Substances 0.000 claims description 5
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003708 ampul Substances 0.000 claims description 4
- 238000001802 infusion Methods 0.000 claims description 4
- 239000003889 eye drop Substances 0.000 claims description 2
- 238000001514 detection method Methods 0.000 abstract description 16
- 230000035945 sensitivity Effects 0.000 abstract description 7
- 230000007547 defect Effects 0.000 abstract description 2
- 239000002552 dosage form Substances 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 238000012795 verification Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000012360 testing method Methods 0.000 description 12
- 239000011148 porous material Substances 0.000 description 9
- 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 description 7
- 229960000907 methylthioninium chloride Drugs 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 238000009512 pharmaceutical packaging Methods 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- 230000005284 excitation Effects 0.000 description 3
- 239000003269 fluorescent indicator Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012611 container material Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000011129 pharmaceutical packaging material Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000002352 surface water Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01M—TESTING STATIC OR DYNAMIC BALANCE OF MACHINES OR STRUCTURES; TESTING OF STRUCTURES OR APPARATUS, NOT OTHERWISE PROVIDED FOR
- G01M3/00—Investigating fluid-tightness of structures
- G01M3/02—Investigating fluid-tightness of structures by using fluid or vacuum
- G01M3/04—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point
- G01M3/20—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point using special tracer materials, e.g. dye, fluorescent material, radioactive material
- G01M3/22—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point using special tracer materials, e.g. dye, fluorescent material, radioactive material for pipes, cables or tubes; for pipe joints or seals; for valves; for welds; for containers, e.g. radiators
- G01M3/226—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point using special tracer materials, e.g. dye, fluorescent material, radioactive material for pipes, cables or tubes; for pipe joints or seals; for valves; for welds; for containers, e.g. radiators for containers, e.g. radiators
Landscapes
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
The invention belongs to the technical field of medicine quality control, and particularly relates to a method for verifying the sealing property of a container by a fluorescent agent tracing method. Aiming at the problem that various container leak detection methods in the prior art have defects, the invention provides a novel detection method, which comprises the following steps: (1) immersing a container to be detected into a solution containing a fluorescent substance; (2) applying pressure to the solution containing the fluorescent substance and keeping the pressure for a certain time; (3) and taking out the container to be detected, detecting the fluorescence intensity of the contents in the packaging container, and judging the sealing property of the container according to the fluorescence intensity. The invention can be applied to a medicine packaging system with wide types, is not limited by dosage forms and packaging appearance sizes, has convenient detection, high sensitivity, low price of verification equipment and strong universality, is taken as one of selectable deterministic methods for checking the tightness of medicine packaging, is popularized and can promote the safety and the effectiveness of the medicine quality.
Description
Technical Field
The invention belongs to the technical field of medicine quality control, and particularly relates to a method for verifying the sealing property of a container by a fluorescent agent tracing method.
Background
The medicine packaging material (medicine packaging material for short) is used for packaging medicines and is divided into an inner package, a secondary package and an outer package material, so that protection is provided for the medicines, and the expected safe and effective application of the medicines is met. The medicine is an article which is related to life safety of people, the quality of the medicine is a topic concerned by society, and the quality of the medicine is a requirement that various manufacturers continuously pursue continuous improvement. The sealability of pharmaceutical packaging materials is an important physical monitoring indicator related to the quality of pharmaceutical products. The seventeenth article in the new GMP appendix 1 proposes in particular: the tightness of the sterile pharmaceutical packaging container should be verified to avoid contamination of the product. The sealed products (e.g., glass or plastic ampoules) should be tested for 100% leak detection, and other packaging containers should be checked for leak tightness on a sample basis according to the operating protocol. "
The method for detecting the leak tightness of the container adopts a colored water method (methylene blue dyeing), a tracer gas detection method, a vacuum attenuation method, high-voltage discharge, laser, pressure attenuation and other methods, and is most commonly used in the colored water method. However, the above method has various problems such as low sensitivity in the color water method; the trace gas detection method has a limited application range; the vacuum attenuation method is expensive in testing instrument, and the solid components of the product can block the leakage hole when the instrument is vacuumized, so that the vacuum attenuation is ineffective. Therefore, there is a need to develop a method for verifying the sealability of a package that is versatile (e.g., suitable for use with containers pre-filled with solid components) and highly sensitive.
Disclosure of Invention
Aiming at the problem that various container tightness leak detection methods in the prior art have defects, the invention provides a method for verifying the container tightness by a fluorescent agent tracing method, which aims to solve the problems that: provides a medicine package material sealing performance detection method which has high sensitivity, simplicity, convenience, wide application range and detection limit level up to 3 level.
A method for verifying the tightness of a container by a fluorescent agent tracing method is characterized by comprising the following steps:
(1) immersing a container to be detected in a solution of a fluorescent substance;
(2) applying pressure to the solution of the fluorescent substance of step (1);
(3) and taking out the container to be detected from the solution of the fluorescent substance, detecting the fluorescence intensity of the content of the container material to be detected, and judging the tightness of the container to be detected according to the fluorescence intensity.
The content may be a pharmaceutical product packaged in a container to be tested, or may be a liquid or solid filled in the container to be tested for leak tightness testing.
Preferably, the container to be detected is a plastic bottle, a glass ampoule, a plastic ampoule, a penicillin bottle, an eye drop bottle, a glass infusion bottle, a plastic infusion soft bag or a pre-filled and sealed syringe.
Preferably, the contents of the container to be detected are a liquid preparation or a solid preparation.
Preferably, the fluorescent substance is selected from fluorescein, rhodamine b, 5(6) -hydroxyfluorescein, 7-hydroxycoumarin or riboflavin; preferably, the fluorescent substance is selected from rhodamine b.
Preferably, the concentration of the solution of the fluorescent substance is 0.1 to 4 g/L.
Preferably, the concentration of the solution of the fluorescent substance is 4 g/L.
Preferably, in the step (2), the pressure for applying the pressure is 20 to 100 Kpa.
Preferably, in the step (2), the pressure for applying the pressure is 80-100 Kpa; preferably, the pressure at which the pressure is applied is 80 Kpa.
Preferably, in the step (2), the pressurizing time for applying the pressure is 10-90 min.
Preferably, in the step (2), the pressurizing time for applying the pressure is 30 min.
Preferably, before performing step (1), a medicine packaging container having a micro-hole is prepared as a positive sample; carrying out the operations of the steps (1) to (3) on the positive sample and the medicine packaging container to be detected; and determining whether the sealing performance of the medicine packaging container to be detected is good or not according to the relative magnitude of the fluorescence intensity of the content of the positive sample and the content of the medicine packaging container to be detected.
Preferably, the diameter of the micropore of the positive sample is 5 μm, and when the fluorescence intensity of the contents of the drug packaging container to be tested is equal to or less than 1/22 of the fluorescence intensity of the contents of the positive sample, the sealability of the drug packaging container to be tested is judged to be good.
The method comprises the steps of immersing a detection sample and a punched positive sample in a fluorescent solution, placing the detection sample and the punched positive sample in a sealed pressure-resistant container, applying a proper positive pressure for a period of time, detecting the fluorescence intensity in the sample by a fluorescence spectrometer, and comparing the fluorescence intensity with the fluorescence intensity of the positive sample, so as to judge the sealing property and the integrity of the detected sample. The invention can be used for various types of medicine packaging containers, is suitable for packaging samples of which the contents are liquid preparations or solid preparations, and has multiple general formulations and strong adaptability. Furthermore, the invention optimizes the hole diameter of the punched hole, the fluorescent substance and the concentration thereof, the pressure of positive pressure and the maintaining time thereof, and makes the testing process simpler and more convenient on the premise of reliable detection result and high sensitivity.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
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.
Drawings
FIG. 1 shows the fluorescence intensity of each fluorescent substance in example 1;
FIG. 2 is the fluorescence intensity of 10 μm positive samples under different pressure conditions in example 3;
FIG. 3 is the fluorescence intensity of 10 μm positive samples in example 3 at different concentrations of the fluorescent solution;
FIG. 4 is the fluorescence intensity of 10 μm positive samples at different pressurizing times in example 3;
FIG. 5 is a graph showing the results of visual observation of positive samples and test samples of 5 μm and 10 μm pore size under a condition of a concentration of methylene blue solution of 4g/L and a pressure of 80Kpa maintained for 30min in example 4.
Detailed Description
The instruments, materials and reagents used in the examples were as follows:
fluorescence spectrometer FluoroMax-4(HORIBA Scientific), ultra pure water instrument (Millipore, USA, Advantage100), positive pressure box, 10mL penicillin bottle, capping machine.
Rhodamine b (Shanghai Michelin Biochemical Co., Ltd.), fluorescein (Shanghai Michelin Biochemical Co., Ltd.), 5(6) -hydroxyfluorescein (Chengdu Runz Ben Co., Ltd.), 7-hydroxycoumarin (Chengdu Runz Ben Co., Ltd.), methylene blue (Shanghai Michelin Biochemical Co., Ltd.) and riboflavin (Chengdu City Cologne chemical Co., Ltd.), standard capillaries (phi 5 μm, 10 μm and 20 μm), and AB glue.
Example 1: selection of fluorescent indicators
This example selects 5 common and readily available fluorescent substances: fluorescein, rhodamine b, 5(6) -hydroxyfluorescein, 7-hydroxycoumarin and riboflavin. At the optimal excitation and emission wavelengths of the respective substances, fluorescence response values were determined at different concentrations. As can be seen from FIG. 1, the fluorescence of fluorescein and 5(6) -hydroxyfluorescein is strongest and the fluorescence of rhodamine b and riboflavin is relatively lower at the same concentration, and considering that fluorescein, 5(6) -hydroxyfluorescein, 7-hydroxycoumarin and riboflavin are all slightly soluble in water, the experimental process needs to be diluted with water after being dissolved in an organic solvent, wherein the organic solvent may bring errors to the experimental result. And the rhodamine b has better water solubility and is bright red which is easy to distinguish, and finally, the rhodamine b is selected for further experiments by comprehensively considering factors such as cost, safety, solubility and the like. If the drug itself has fluorescence interference and overlaps with the excitation and emission wavelengths of rhodamine b, other fluorescent indicators may be substituted as appropriate.
The following examples 2-4 were prepared and tested in the following manner:
(1) sample preparation:
positive sample: taking standard capillaries with the inner diameters of 5 microns, 10 microns and 20 microns, and confirming the diameters of the standard capillaries by using a measuring microscope or an electronic scanning electron microscope and the like to ensure the deviation of +/-0.3 microns. And adding 5mL of water or an empty bottle into each vial of the penicillin bottles in the same batch, and pressing the vial for standby. And packaging the standard capillary tube into the injection needle, and sealing the sleeve opening of the needle tube by using AB glue to ensure that the capillary tube is not blocked and serves as a standard positive leak hole. 5 pieces of standard positive leak holes with the diameter of 5 mu m, 10 mu m and 20 mu m are prepared respectively. And (3) directly puncturing the standard positive leak hole into the rubber plug of the penicillin bottle, and sealing the puncture position of the rubber plug by using AB glue to prevent bypass leakage to obtain a series of positive samples.
Preparing a fluorescent solution: accurately weighing rhodamine b, preparing 0.1-4g/L rhodamine b solution, and filtering with a filter membrane of 0.45 mu m for later use.
(2) Sample testing
The prepared positive sample and the experimental sample of the container to be detected (in the embodiment, a penicillin bottle with a packaged medicine) are immersed in the fluorescent solution, placed in a positive pressure box, pressurized and maintained for a certain time, then the pressure is slowly released to a positive pressure device, the sample is taken out, the surface of the sample is carefully washed for 3 times by using ultrapure water, and the surface water is sucked by filter paper. Shaking the sample to mix the liquid in the bottle. The liquid in each sample was aspirated to 3mL, and the fluorescence intensity of the sample was measured by a fluorescence spectrometer FluoroMax-4 under the conditions of an excitation wavelength λ ex of 540nm and an emission wavelength λ em of 574 nm.
Example 2: demonstration of detection method feasibility
Firstly, the influence of the pricking treatment of the positive sample on the fluorescence intensity of the sample is examined, and whether the fluorescence can be detected by the method and the fluorescence difference occurs between the positive sample with the hole diameter phi of 10 mu m and the positive sample with the hole diameter phi of 20 mu m is preliminarily examined. As can be seen from the data in Table 1, the needle is pulled out after the sample is punctured, the puncture needle opening is sealed by AB glue, so that a good sealing effect can be achieved, and the fluorescence intensity is close to that of empty white water; the needle is directly pulled out after the sample is punctured, the flexibility of the rubber plug can be utilized to achieve a good sealing effect without rubber sealing, and the fluorescence intensity is close to that of the empty white water. Therefore, the pricking treatment of the positive sample has little influence on the fluorescence intensity of the sample.
As is clear from the data in Table 1, the pricking treatment of the positive sample has little influence on the fluorescence intensity of the sample, fluorescence can be detected significantly in the positive sample having a pore diameter of 10 μm or 20 μm under the conditions of a concentration of the fluorescence indicator solution of 350mg/L and a pressurization of 60kPa for 30min, and the fluorescence intensity of the other sealing means and the test sample does not differ greatly from that of ultrapure water. The feasibility of verifying the tightness of the packaging system by a fluorescent agent tracing method is proved.
TABLE 1 fluorescence intensity for different sample treatment regimes
Example 3: optimization of test conditions
After the feasibility of the experiment and the types of the fluorescent substances used are determined, the concentration, the pressurizing strength and the pressurizing time of the rhodamine b are further screened so as to determine an optimal experimental condition. Table 2 and fig. 2 show when the rhodamine b solution concentration: 350mg/L for 30min, and the fluorescence intensity of 10 μm positive sample is increased from 20Kpa to 100Kpa in the course of increasing the different pressing intensities. As the pressurizing intensity was increased, the fluorescence intensity of the positive sample was increased from 60 ten thousand to 130 ten thousand, and the fluorescence intensity increased after 80Kpa was decreased, and 80Kpa was finally determined as the optimum experimental intensity in view of the pressure resistance of the apparatus.
TABLE 2 fluorescence intensity of positive samples of 10 μm pore size positive samples under different compression strength conditions
Table 3 and FIG. 3 show the trend of the fluorescence intensity of 10 μm positive samples maintained at a pressing intensity of 80Kpa for 30min and at a rhodamine b solution concentration of 0.1g/L to 4 g/L. When the concentration of the rhodamine b solution is increased, the fluorescence intensity is linearly increased from 36 ten thousand to more than 2000 ten thousand, and considering that the fluorescence intensity of a positive sample is quite high under the condition of 4g/L of the rhodamine b solution concentration and the solubility of rhodamine b, the concentration of 4g/L of the rhodamine b solution is finally determined to be the optimal concentration.
TABLE 3 fluorescence intensity of 10 μm pore size positive samples at different rhodamine b concentrations
Table 4 and FIG. 4 show the fluorescence intensity trend of 10 μm positive samples with rhodamine b solution concentration of 4g/L, pressurization intensity of 80Kpa, and pressurization time from 10min to 90 min. When the pressurizing time was increased, the fluorescence intensity linearly increased from 580 ten thousand to 6500 or more thousand, and the optimal pressurizing time was finally determined to be 30min in consideration of the simplicity of the experimental procedure.
TABLE 4 fluorescence intensity of 10 μm pore size positive samples at different compression times
Example 4: comparison of fluorescent agent tracing method results with color water method
In the embodiment, a fluorescence tracer method detection experiment of a 5-micron pore-size positive sample and an experiment sample with good sealing property is firstly carried out under the conditions that the concentration of a rhodamine b solution is 4g/L, the pressurizing strength is 80Kpa, and the pressurizing time is 30 min. The results are shown in Table 5:
TABLE 5 fluorescence intensity of 5 μm-pore-size positive samples and well-sealed experimental samples in the fluorescent agent tracing method
As can be seen from Table 5, the fluorescence intensity of the positive sample with a pore size of 5 μm is about 22 times that of the experimental sample, and the positive sample has high separation from the experimental sample. Namely, the fluorescent agent tracing method can well distinguish positive samples from negative samples, and has high sensitivity.
For comparison, tests were conducted using a water-in-color method using a 10g/L aqueous solution of methylene blue for positive samples of 5 μm and 10 μm and test samples having good sealing properties, and the ultraviolet absorbance of methylene blue was measured for each sample at an emission wavelength of 664 nm. The results of absorbance are shown in Table 6, and the results of visual observation of the color of each sample are shown in FIG. 5.
TABLE 6 UV Absorbance at 664nm for 5 μm and 10 μm pore size positive samples and good sealability test samples in the color Water method
As can be seen from the results in Table 6 and FIG. 5, in the 10g/L methylene blue aqueous solution group at the same pressing intensity and pressing time, the positive samples, whether having 5 μm pore size or 10 μm pore size, were free from blue color visible to the naked eye, and no change in absorbance was detected at 664 nm. Under these conditions, the sealing property of the packaging system can be easily and sensitively detected by the fluorescence method. However, the color water method cannot reflect the difference between the positive sample and the test sample of the test sample with good sealing performance. I.e. the sensitivity of the fluorescer tracing method is higher than that of the colour water method.
From the experimental results of examples 1-4, it can be seen that the present invention verifies the seal integrity of pharmaceutical packaging systems by detecting the concentration of a fluorescent indicator that potentially leaks into the pharmaceutical packaging system via a fluorescence spectrometer. Through optimization of the method, the optimal concentration, pressurizing strength and pressurizing time of the fluorescent solution are selected in experimental conditions, the concentration of the fluorescent solution is selected to be 4g/L, the pressurizing strength is selected to be 80Kpa, and the pressurizing time is selected to be 30min finally, the method is verified, the leakage level of a leak with the aperture of 5 mu m can be quantitatively detected, the leakage level is obviously separated from a negative sample, the detection limit level of the method can reach the requirement of level 3, and the method belongs to a deterministic method (according to technical guidelines for research on tightness of a chemical injection packaging system (research on comments), the requirements of 2020-06-02).
From the results of comparative experiments, the sensitivity of the method of the invention is far superior to that of the color water method (methylene blue staining). The packaging system applicable to the fluorescent agent tracing method has the advantages of wide types, no limitation of dosage forms and package appearance sizes, convenient detection, low price of verification equipment, popularization as one of selectable deterministic methods for checking the tightness of medicine packages, and capability of promoting the safety and effectiveness of medicine quality.
Claims (10)
1. A method for verifying the tightness of a container by a fluorescent agent tracing method is characterized by comprising the following steps:
(1) immersing a container to be detected in a solution of a fluorescent substance;
(2) applying pressure to the solution of the fluorescent substance of step (1);
(3) and taking out the container to be detected from the solution of the fluorescent substance, detecting the fluorescence intensity of the content of the container to be detected, and judging the tightness of the container to be detected according to the fluorescence intensity.
2. A method of verifying the hermeticity of a container according to claim 1 wherein: the container to be detected is a medicine packaging container, preferably, the medicine packaging container is a plastic bottle, a glass ampoule, a plastic ampoule, a penicillin bottle, an eye drop bottle, a glass infusion bottle, a plastic infusion soft bag or a pre-filling and sealing syringe.
3. A method of verifying the hermeticity of a container according to claim 1 or claim 2, wherein: the content of the medicine packaging container to be detected is a liquid preparation or a solid preparation.
4. A method of verifying the hermeticity of a container according to claim 1 wherein: the fluorescent substance is selected from fluorescein, rhodamine b, 5(6) -hydroxyfluorescein, 7-hydroxycoumarin or riboflavin; preferably, the fluorescent substance is selected from rhodamine b.
5. A method of verifying the hermeticity of a container according to claim 1 wherein: the concentration of the solution of the fluorescent substance is 0.1-4 g/L; preferably, the concentration of the solution of the fluorescent substance is 4 g/L.
6. A method of verifying the hermeticity of a container according to claim 1 wherein: in the step (2), the pressure of the applied pressure is 20-100 Kpa.
7. A method of verifying the hermeticity of a container according to claim 6 wherein: in the step (2), the pressure of the applied pressure is 80-100 Kpa; preferably, the pressure at which the pressure is applied is 80 Kpa.
8. A method of verifying the hermeticity of a container according to claim 1 wherein: in the step (2), the pressurizing time for applying pressure is 10-90 min; preferably, the pressurization time for applying the pressure is 30 min.
9. A method of verifying the hermeticity of a container according to claim 1 wherein: preparing a container having a micro-well as a positive sample before performing the step (1); carrying out the operations of the steps (1) to (3) on the positive sample and the container to be detected; and determining whether the tightness of the container to be detected is good or not according to the relative magnitude of the fluorescence intensity of the content of the positive sample and the content of the container to be detected.
10. A method of verifying the hermeticity of a container according to claim 9 wherein: the aperture of the micropore of the positive sample is 5 mu m, and when the fluorescence intensity of the content of the container to be detected is less than or equal to 1/22 of the fluorescence intensity of the content of the positive sample, the sealing property of the container to be detected is judged to be good.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011302344.XA CN114518201A (en) | 2020-11-19 | 2020-11-19 | Method for verifying container tightness by fluorescent agent tracing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011302344.XA CN114518201A (en) | 2020-11-19 | 2020-11-19 | Method for verifying container tightness by fluorescent agent tracing method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114518201A true CN114518201A (en) | 2022-05-20 |
Family
ID=81594202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011302344.XA Pending CN114518201A (en) | 2020-11-19 | 2020-11-19 | Method for verifying container tightness by fluorescent agent tracing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114518201A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115046697A (en) * | 2022-06-17 | 2022-09-13 | 西南交通大学 | Method for detecting seal front edge of hydraulic conduit joint |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1344365A (en) * | 1999-03-22 | 2002-04-10 | Apv热交换器公司 | Method for leakage control and localisation of leakages in internal faces of heat exchangers |
| CN1682103A (en) * | 2002-08-30 | 2005-10-12 | 热带产品公司 | Closure integrity test method for hot-fill bottling operation |
| CN202083533U (en) * | 2011-06-17 | 2011-12-21 | 楚天科技股份有限公司 | Device for detecting tightness of container |
| CN106290386A (en) * | 2016-08-25 | 2017-01-04 | 宁夏共享机床辅机有限公司 | A kind of sealing quantitative NDT method based on image procossing |
| CN210037094U (en) * | 2019-07-18 | 2020-02-07 | 开原维科容器有限责任公司 | Leakproofness detection device is used in pressure vessel manufacturing |
| 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 |
| CN111811748A (en) * | 2019-04-11 | 2020-10-23 | 辽宁省水利水电勘测设计研究院有限责任公司（原名称为辽宁省水利水电勘测设计研究院） | Comprehensive leakage detection device and method for reservoir hydropower station |
-
2020
- 2020-11-19 CN CN202011302344.XA patent/CN114518201A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1344365A (en) * | 1999-03-22 | 2002-04-10 | Apv热交换器公司 | Method for leakage control and localisation of leakages in internal faces of heat exchangers |
| CN1682103A (en) * | 2002-08-30 | 2005-10-12 | 热带产品公司 | Closure integrity test method for hot-fill bottling operation |
| CN202083533U (en) * | 2011-06-17 | 2011-12-21 | 楚天科技股份有限公司 | Device for detecting tightness of container |
| CN106290386A (en) * | 2016-08-25 | 2017-01-04 | 宁夏共享机床辅机有限公司 | A kind of sealing quantitative NDT method based on image procossing |
| CN111811748A (en) * | 2019-04-11 | 2020-10-23 | 辽宁省水利水电勘测设计研究院有限责任公司（原名称为辽宁省水利水电勘测设计研究院） | Comprehensive leakage detection device and method for reservoir hydropower station |
| CN210037094U (en) * | 2019-07-18 | 2020-02-07 | 开原维科容器有限责任公司 | Leakproofness detection device is used in pressure vessel manufacturing |
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115046697A (en) * | 2022-06-17 | 2022-09-13 | 西南交通大学 | Method for detecting seal front edge of hydraulic conduit joint |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107810398B (en) | Integrity testing method and device for testing container | |
| CN114518201A (en) | Method for verifying container tightness by fluorescent agent tracing method | |
| US7971470B2 (en) | Method for detecting chemical substances in whole, closed and/or sealed containers | |
| CN111896192B (en) | Test method for measuring packaging tightness by color water method | |
| US20230234066A1 (en) | Container Assembly and System for Detection Thereof | |
| CN110793730A (en) | Method for analyzing package integrity of injection by color water method | |
| WO1999046572A1 (en) | Method and apparatus for detection of leaks in hermetic packages | |
| CN111568759B (en) | Packaging bottle for AST-3424 injection and packaging kit and method | |
| PT88393B (en) | PROCESS FOR INSPECTION OF PLASTIC CONTAINERS | |
| EP2372344B1 (en) | Method for analysing a gaseous component present in a hermetically sealed container | |
| US4187798A (en) | Method of detecting defective portion of sealing | |
| EP3278074A1 (en) | System and method for determining the integrity of containers by optical measurement | |
| EA034400B1 (en) | Device and method for testing integrity of a container filled with a drug | |
| US6479294B1 (en) | Method for determining container leakage | |
| EP0429396B1 (en) | Apparatus for detecting gaseous constituents within the inner space of packages | |
| CN111693655A (en) | Method for detecting headspace residual oxygen of medicine package incapable of being punctured | |
| RU2668018C2 (en) | Method for checking of result of training personnel in quality control | |
| CN105699584B (en) | A kind of detection method of Artemether related substances | |
| JP2001099745A (en) | Sealing performance testing method for sealed container, sealing performance testing apparatus and manufacturing apparatus therefor, and sealed container | |
| CN213822550U (en) | Injection packaging bottle and packaging kit | |
| DE102006047040B3 (en) | Sterile vial package tightness determining apparatus, has spacer provided with different characteristics, thickness and diameter for introducing distance between stopper positions so that leakage is generated to guide test gas to tester | |
| CN112525875A (en) | Method for testing sealing integrity of medicine packaging container by improved color water intrusion method | |
| DE59711778D1 (en) | METHOD AND DEVICE FOR NON-DESTRUCTIVE LEAKAGE TESTING OF CONTAINERS FILLED WITH LIQUID | |
| US7485437B1 (en) | Method for detecting bacterial endospores in a sealed container | |
| EP2530047A1 (en) | A capping device and a method for verifying an airtight seal of a coupling between a container made of a non-conductive material and a closure thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |