Online detection device and method for ultramicro precipitates of medicine packaging film

Abstract

The invention discloses an online detection device and method for ultramicro precipitates of a medicine packaging film. The device comprises a sampling cabin, a microfluidic gas circuit and pretreatment unit, a miniature mass spectrometer and a central control system. The sampling cabin is used for heating the penetrating thin film and collecting separated gas; the micro-fluidic unit is used for pretreating and concentrating a gas sample through adsorption enrichment and thermal desorption; carrying out rapid qualitative and quantitative analysis on a target object by using a miniature mass spectrometer; and the central control system processes data and is linked with the production line to realize feedback control. According to the invention, ppb-level online, real-time and automatic monitoring of the film precipitates is realized, the product quality can be controlled from the source, the production of batch unqualified products is avoided, and the production intelligence level and the product quality safety are obviously improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of detection methods for biological medicine packaging films, and in particular to an online detection device and method for ultra-micro precipitates of medicine packaging films. BACKGROUND

[0002] In the production process of high-barrier films (such as aluminum-plastic composite films and high-barrier transparent films) for medicine packaging, low-molecular-weight volatile or sublimable organic substances may be produced from the high-molecular materials, inks, adhesives and additives (such as antioxidants, plasticizers and slip agents) in the production process. These substances may migrate into the medicine during use, affecting the safety, effectiveness and stability of the medicine (i.e. E&L problem). The current industry practice is to take samples from the parent roll after production is completed and send them to the laboratory for time-consuming offline analysis (such as GC-MS and LC-MS), which usually takes several days or even weeks to obtain results. This lag prevents real-time feedback control of the production process, and once unqualified products are found, the entire batch of products is scrapped, resulting in significant economic losses.

[0003] Therefore, there is an urgent need for a technical solution that can be integrated into the production line to achieve real-time, online and ultra-micro monitoring of E&L, thereby achieving closed-loop quality control of the production process. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the deficiencies in the prior art and provide an online detection device and method for ultra-micro precipitates of medicine packaging films.

[0005] The technical solution adopted by the present application to solve the technical problem is an online detection device for ultra-micro precipitates of medicine packaging films, comprising: a sampling cabin configured to allow the film on the production line to pass through and be sealed to form a closed sampling space, the sampling cabin being provided with a heating unit for heating the film and a pressure sensor for detecting the pressure in the cabin; a microfluidic gas circuit and a pretreatment unit connected to the gas outlet of the sampling cabin through a heating transmission pipeline, the microfluidic gas circuit and the pretreatment unit comprising a multi-way switching valve, an enrichment trap for adsorbing and enriching precipitates, and a micro thermal desorber for rapid heating and desorption of the enrichment trap; a carrier gas source connected to the multi-way switching valve through a gas circuit; a micro mass spectrometer with a sampling inlet connected to the outlet of the micro thermal desorber through a heating pipeline; a vacuum pump set connected to the sampling cabin and the micro mass spectrometer respectively for providing pumping power for the sampling cabin and the required vacuum for the mass spectrometer; A central control system is electrically connected with the heating unit and pressure sensor of the sampling cabin, the multi-way switching valve and micro thermal desorber of the microfluidic gas path and pretreatment unit, the carrier gas source, the micro mass spectrometer, and the vacuum pump group, respectively; The central control system is also in communication connection with a production line control center through an industrial communication interface.

[0006] Further, the inner wall surface of the sampling cabin is inertized and provided with one or more automatically openable and closable sealed cabin doors.

[0007] Further, the enrichment trap is a metal or glass tube filled with a porous adsorbent.

[0008] Further, the micro thermal desorber is tightly integrated with the enrichment trap, and can accurately heat the enrichment trap to any set temperature between 50℃ and 350℃ within milliseconds by electric current, so as to instantaneously desorb the adsorbed organic matter.

[0009] Further, the micro mass spectrometer is a linear ion trap mass spectrometer or a quadrupole mass spectrometer, and its working modes include full scan mode and selected ion monitoring mode.

[0010] Further, the central control system is configured to: control the sampling cabin, the heating transmission pipeline, and the gas path of the microfluidic gas path and pretreatment unit to be maintained at a set temperature higher than the ambient temperature, so as to prevent sample condensation; receive analysis data of the micro mass spectrometer, and compare the concentration of the analyte with a preset threshold value; when the concentration exceeds the preset threshold value, generate an alarm signal and / or send a control instruction to the production line control center to adjust the production process parameters.

[0011] A detection method of an online detection device for ultra-micro analyte of a medical packaging film, comprising the following steps: S1: online sampling: control the film to enter the sampling cabin and be sealed, start the heating unit to heat the film, and at the same time, use the vacuum pump group to blow the gas containing the analyte in the sampling cabin through the heating transmission pipeline and adsorb it into the micro adsorption enrichment trap for enrichment; S2: sample desorption and sampling: after the enrichment is completed, the gas path is switched by the multi-way switching valve to connect the carrier gas source (high-purity helium) with the micro adsorption enrichment trap, and the micro thermal desorber is started to instantaneously heat the enrichment trap at high temperature, so that the enriched analyte is desorbed and all of them are brought into the sampling port of the micro mass spectrometer by high-speed carrier gas in a “pulse” manner; S3: real-time analysis: use the micro mass spectrometer to perform mass spectrometric analysis on the analyte, and qualitatively or quantitatively detect the type and concentration of specific analyte S4: Feedback control: the central control system receives the analysis results, if the concentration of a specific precipitate exceeds the preset threshold, sends a signal to the production line control center, triggering automatic adjustment of production parameters or alarm.

[0012] Further, in step S3, the micro mass spectrometer adopts a selected ion monitoring mode to monitor the characteristic ions of the target precipitate.

[0013] Further, in step S1, the heating temperature is 40-150℃, and the enrichment time is 1-15 minutes; in step S2, the analysis temperature is 200-300℃.

[0014] The beneficial effects of the present application are: 1. Real-time online: change the quality detection from offline lag to online real-time, realize "early warning" and "in-process control" of the production process.

[0015] 2. Ultra-high sensitivity: through the "adsorption enrichment + thermal desorption" technology, combined with the SIM mode of the micro mass spectrometer, the detection limit can reach ppb level, meeting the stringent requirements of pharmaceutical packaging materials.

[0016] 3. Automation and intelligence: full-process automatic operation, and can be integrated with the production line to realize closed-loop feedback control, improve production quality and efficiency, and is a typical application of Industry 4.0.

[0017] 4. Non-destructive testing: only collect extremely small amount of gas released from the surface of the film, and has no effect on the film body and continuous production process. BRIEF DESCRIPTION OF DRAWINGS

[0018] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiment or prior art description. Obviously, the drawings in the following description are only some embodiments described in the present application, and those skilled in the art can obtain other drawings according to these drawings without creative labor.

[0019] Figure 1 is a structural connection schematic diagram of the present application; Figure 2 is a working process principle block diagram of the present application. DETAILED DESCRIPTION

[0020] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0021] As shown in Figure 1 and Figure 2 An on-line detection device for ultra-micro release of a medical packaging film, comprising: A sampling cabin configured to allow the film on the production line to pass through and to be sealed to form a closed sampling space, wherein a heating unit for heating the film and a pressure sensor for detecting the pressure in the cabin are arranged inside the sampling cabin; The heating unit is integrated with a high-precision temperature controller (for heating the sample to a set temperature, such as 40-150℃, which can be adjusted, to simulate accelerated release); A microfluidic gas circuit and a pretreatment unit connected to the gas outlet of the sampling cabin through a heated transmission pipeline, wherein the microfluidic gas circuit and the pretreatment unit comprise a multi-way switching valve, an enrichment trap for adsorbing and enriching the release, and a micro thermal desorber for rapid heating and desorption of the enrichment trap; The heating transmission pipeline is a heated inert transmission pipeline (to prevent sample condensation and adsorption) connected to the inlet of the multi-way switching valve of the downstream microfluidic gas circuit. The internal vacuum is maintained by an independent vacuum pump set to ensure that the gas in the cabin can be effectively extracted to the analysis unit; The multi-way switching valve is used to realize automatic switching of multiple gas circuit modes such as sampling / desorption / cleaning; A carrier gas source is a device for providing high-purity inert gas, commonly high-purity helium or high-purity nitrogen, which is connected to the multi-way switching valve through a gas circuit; A micro mass spectrometer, wherein the sampling inlet of the micro mass spectrometer is connected to the outlet of the micro thermal desorber through a heating pipeline; A vacuum pump set connected to the sampling cabin and the micro mass spectrometer, respectively, for providing pumping power for the sampling cabin and providing the required vacuum for the mass spectrometer; A central control system electrically connected to the heating unit and the pressure sensor of the sampling cabin, the multi-way switching valve and the micro thermal desorber of the microfluidic gas circuit and the pretreatment unit, the carrier gas source, the micro mass spectrometer, and the vacuum pump set. The central control system is also communicatively connected to the production line control center through an industrial communication interface.

[0022] The inner wall surface of the sampling cabin is inertized and provided with one or more automatically openable and closable sealing cabin doors.

[0023] The enrichment trap is a metal or glass tube filled with porous adsorbent inside, which adsorbs and enriches trace organic matter from the sampling cabin, and realizes the concentration from "large volume gas" to "small volume high concentration sample".

[0024] The micro thermal desorber is tightly integrated with the enrichment trap, and can accurately heat the enrichment trap to any set temperature between 50℃ and 350℃ within milliseconds by electric current, so that the adsorbed organic matter is instantaneously desorbed.

[0025] The micro mass spectrometer is a linear ion trap mass spectrometer or a quadrupole mass spectrometer, and its working modes include full scan mode and selected ion monitoring mode.

[0026] The central control system is configured to: control the sampling cabin, the heating transmission pipeline, and the gas path of the microfluidic gas path and the pretreatment unit to maintain a set temperature higher than the ambient temperature to prevent sample condensation; receive analysis data of the micro mass spectrometer, and compare the concentration of the analyte with a preset threshold; when the concentration exceeds the preset threshold, generate an alarm signal and / or send a control instruction to the production line control center to adjust the production process parameters.

[0027] A detection method of an online detection device for ultra-trace analyte of a pharmaceutical packaging film, comprising the following steps: S1: online sampling: control the film to enter the sampling cabin and seal, start the heating unit to heat the film, and at the same time use the vacuum pump set to blow the gas containing the analyte in the sampling cabin through the heating transmission pipeline and adsorb it into the micro adsorption enrichment trap for enrichment; S2: sample desorption and injection: after enrichment, switch the gas path by the multi-way switching valve to connect the carrier gas source (high-purity helium) with the micro adsorption enrichment trap, start the micro thermal desorber to instantaneously heat the enrichment trap at high temperature, so that the enriched analyte is desorbed and all brought into the injection port of the micro mass spectrometer by high-speed carrier gas in "pulse" mode; S3: real-time analysis: use the micro mass spectrometer to perform mass spectrometric analysis on the analyte, and qualitatively or quantitatively detect the type and concentration of the specific analyte; S4: feedback control: the central control system receives the analysis result, and if the concentration of the specific analyte exceeds the preset threshold, sends a signal to the production line control center to trigger automatic adjustment of the production parameters or alarm.

[0028] In step S3, the micro mass spectrometer uses selected ion monitoring mode to monitor the characteristic ions of the target analyte. The heating temperature in step S1 is 40℃ to 150℃, and the enrichment time is 1 to 15 minutes; the desorption temperature in step S2 is 200℃ to 300℃. Embodiment

[0029] Take monitoring of antioxidant BHT (2,6-di-tert-butyl-p-cresol) in a certain type of PVC / PVDC high-barrier pharmaceutical composite film as an example.

[0030] Device parameter settings: sampling chamber heating temperature: 80℃; enrichment time: 10 minutes; transfer line temperature: 180℃; thermal desorption temperature: 280℃ (for 0.5 minutes); carrier gas: high-purity helium, flow rate 50 mL / min; mass spectrometer mode: selected ion monitoring (SIM), monitoring BHT characteristic ions m / z 205, 220.

[0031] Experimental process and results: The online detection device is installed before the composite film winding station. The system automatically samples and analyzes at a frequency of every 15 minutes. When the production line is in stable production, the monitored BHT signal is stable at a low level (concentration of about ~0.8 μg / m²). Subsequently, we simulate an abnormal condition: artificially increase the temperature of the third zone of the extruder by 15℃. This operation will exacerbate polymer degradation, resulting in an increase in the precipitation of antioxidant BHT. After adjusting the temperature for about 45 minutes (i.e. 3 analysis cycles), the monitoring system clearly captures the significant upward trend of the BHT signal, and in the fourth cycle, its concentration value (2.5 μg / m²) exceeds the threshold value (2.0 μg / m²) preset in the central control system.

[0032] System response: the central control system immediately triggers a secondary alarm and executes the preset control strategy: through the production line control center, automatically adjusts the temperature of the third zone of the extruder to the original set value. After the process parameters are corrected, the BHT precipitation signal begins to gradually decrease, and after about 2 hours, it falls within the safe threshold, successfully avoiding the production of a batch of substandard products.

[0033] Comparative example (traditional offline detection): Sample from the same roll of film during the signal exceeding period, send to the laboratory for offline GC-MS analysis according to the standard of “USP <1663\”. The report issued by the laboratory after 2 days of time-consuming shows that the BHT precipitation amount of the sample is 2.48 μg / m², which is highly consistent with the result of 2.5 μg / m² monitored by the online system of the application, verifying the accuracy of the device. However, at this time, thousands of meters of film have been produced and wound, and if the offline result is determined, the entire roll of film will be scrapped.

[0034] Experimental data table: Table 1: Comparison of online monitoring system and offline GC-MS method

[0035] Table 2: Response data of the system under simulated abnormal conditions

[0036] In summary, the application effectively solves the industry pain point that the E&L risk cannot be monitored in real time in the production of medical packaging film, realizes the change from "after-inspection" to "pre-warning and middle-control", and has high industrial application value.

[0037] The above merely describes the preferred embodiments of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can make equivalent replacements or changes to the technical solutions and the inventive concept of the present application within the technical range disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. An online detection device for ultra-trace leaching substances from pharmaceutical packaging films, characterized in that, include: The sampling chamber is configured to allow a film to pass through on the production line and to be sealed to form a closed sampling space. The sampling chamber is equipped with a heating unit for heating the film and a pressure sensor for detecting the pressure inside the chamber. The microfluidic gas path and pretreatment unit is connected to the gas outlet of the sampling chamber via a heated transmission line. The microfluidic gas path and pretreatment unit includes a multi-way switching valve, an enrichment trap for adsorbing and enriching precipitates, and a micro thermal desorption device for rapidly heating and desorbing the enrichment trap. A carrier gas source, a device that provides high-purity inert gas, is connected to the multi-way switching valve via a gas path; The sample inlet of the miniature mass spectrometer is connected to the outlet of the miniature thermal desorber via a heating line. A vacuum pump assembly, which is connected to the sampling chamber and the miniature mass spectrometer respectively, is used to provide pumping power to the sampling chamber and to provide the required vacuum for the mass spectrometer; The central control system is electrically connected to the heating unit and pressure sensor of the sampling chamber, the multi-way switching valve and micro thermal desorber of the microfluidic gas path and pretreatment unit, the carrier gas source, the micro mass spectrometer, and the vacuum pump group, respectively. The central control system is configured to: maintain the sampling chamber, the heating transmission pipeline, and the gas path of the microfluidic gas path and the pretreatment unit at a set temperature higher than the ambient temperature to prevent sample condensation; receive the analytical data from the micro mass spectrometer and compare the concentration of the precipitate with a preset threshold; when the concentration exceeds the preset threshold, generate an alarm signal and / or send a control command to the production line control center to adjust the production process parameters; The central control system is also connected to the production line control center via an industrial communication interface, thereby enabling online, real-time closed-loop feedback control of the production process.

2. The online detection device for ultra-trace leaching substances from pharmaceutical packaging films as described in claim 1, characterized in that: The inner wall surface of the sampling chamber is inertized and equipped with one or more automatically opening and closing sealed doors.

3. The online detection device for ultra-trace leaching substances from pharmaceutical packaging films as described in claim 1, characterized in that: The enrichment trap is a metal or glass tube filled with a porous adsorbent.

4. The online detection device for ultra-trace leaching substances from pharmaceutical packaging films as described in claim 1, characterized in that: The micro thermal desorber is tightly integrated with the enrichment trap and can precisely heat the enrichment trap to any set temperature between 50°C and 350°C within milliseconds using an electric current, causing the adsorbed organic matter to desorb instantly.

5. The online detection device for ultra-trace leaching substances from pharmaceutical packaging films as described in claim 1, characterized in that: The miniature mass spectrometer is a linear ion trap mass spectrometer or a quadrupole mass spectrometer, and its operating modes include full scan mode and selected ion monitoring mode.

6. A detection method using an online detection device for ultra-trace leaching from pharmaceutical packaging films as described in any one of claims 1-5, characterized in that, Includes the following steps: S1: Online sampling: Control the film to enter the sampling chamber and seal it, start the heating unit to heat the film, and at the same time use the vacuum pump group to purge the gas containing the precipitate in the sampling chamber through the heating transmission pipeline and adsorb it into the micro adsorption enrichment trap for enrichment. S2: Sample analysis and injection: After enrichment, the gas path is switched through the multi-port switching valve to connect the carrier gas source with the micro adsorption enrichment trap. The micro thermal desorber is started to heat the enrichment trap at high temperature for a moment, so that the enriched precipitate is desorbed and carried into the injection port of the micro mass spectrometer in a "pulse" manner by the high-speed carrier gas. S3: Real-time analysis: Using a miniature mass spectrometer to perform mass spectrometry analysis on the precipitates, qualitatively or quantitatively detecting the type and concentration of specific precipitates; S4: Feedback Control: The central control system receives the analysis results. If the concentration of a specific precipitate exceeds the preset threshold, it sends a signal to the production line control center to trigger automatic adjustment of production parameters or an alarm.

7. The detection method as described in claim 6, characterized in that: In step S3, the micro mass spectrometer adopts a selected ion monitoring mode to monitor the characteristic ions of the target precipitate.

8. The detection method as described in claim 6, characterized in that: The heating temperature in step S1 is 40°C to 150°C, and the enrichment time is 1 to 15 minutes; the desorption temperature in step S2 is 200°C to 300°C.

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