A system and method for detecting intermediates in the production of a chemical drug substance

Abstract

The application discloses a chemical raw material production process intermediate detection system and method, which comprises a sampling device, a quantitative device and a gas chromatography detection device.The sampling device is used to obtain the intermediate of the chemical raw material in an intermediate storage tank, form a to-be-detected solution from the obtained intermediate, and send the to-be-detected solution into the quantitative device.The quantitative device is used to take a set amount of sample from the input to-be-detected solution and send the sample into the gas chromatography detection device.The gas chromatography detection device is used to perform gas chromatography analysis on the input sample and obtain a gas chromatography analysis result.An analysis control system is used to determine whether the intermediate is qualified according to the gas chromatography analysis result.The timely, accurate and safe intermediate detection is ensured, and production process control can be performed according to the detection result of the intermediate.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an intermediate detection system and method for the production process of chemical raw materials. Background Technology

[0002] The statements in this section are merely background information related to the present invention and do not necessarily constitute prior art.

[0003] The production process of chemical active pharmaceutical ingredients (APIs) in the pharmaceutical industry consists of a series of chemical reactions or purification steps. Each step produces intermediates that require corresponding quality control, such as purity and impurities. The purity of each intermediate directly affects the yield of the next process step, while impurities affect the distribution and limits of impurities in the final product, thereby impacting the efficacy and safety of the drug. Therefore, it is essential to test the intermediates used in each process step to control their quality.

[0004] To ensure that the quality of active pharmaceutical ingredients (APIs) meets the requirements, it is necessary to conduct quality testing and control on each intermediate in the API production process. Currently, the main method is to manually sample each intermediate and perform gas chromatography testing to determine the quality of the intermediate.

[0005] Because a large amount of organic solvents are generally used in the production of active pharmaceutical ingredients (APIs), and these solvents are toxic, flammable and explosive, manual sampling of intermediates makes personnel susceptible to toxicity and increases safety risks. In addition, manual sampling is time-consuming, difficult, and limited in the number of samples taken per day, which makes it impossible to obtain test results in a timely manner and affects the production efficiency of APIs.

[0006] Currently, gas chromatograph (GC) injection systems exist that can automatically transport liquid samples to the GC for GC detection. However, these systems are not used in the production of pharmaceutical raw materials (APIs), and they lack a diluent delivery system, making them unsuitable for intermediates in API production processes that require dilution before GC detection. Furthermore, these GC injection systems only provide injection and detection functions and cannot be integrated with the API production cycle to optimize the detection cycle of intermediates, thus failing to effectively improve API production efficiency. Summary of the Invention

[0007] To address the aforementioned problems, this invention proposes an intermediate detection system and method for the production of chemical raw materials, enabling fully automated detection of intermediates during the production process and improving the production efficiency of raw materials.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] In the first aspect, a detection system for intermediates in the production process of chemical raw materials is proposed, including an analysis and control system, a sampling device, a quantitative device, and a gas chromatography detection device;

[0010] The sampling device is used to obtain intermediates of chemical raw materials in intermediate storage tanks, form the obtained intermediates into a test solution, and send the test solution into a quantitative device.

[0011] A quantitative device is used to take a set amount of sample from the input liquid to be tested and send it into a gas chromatograph for detection.

[0012] A gas chromatography detection device is used to perform gas chromatography analysis on input samples and obtain gas chromatography analysis results;

[0013] An analytical control system is used to determine whether an intermediate is qualified based on the results of gas chromatography analysis.

[0014] Furthermore, the sampling device is also used to obtain diluent from the diluent storage tank, and to mix the obtained intermediate with the diluent to form a solution to be tested.

[0015] Furthermore, the sampling device is connected to multiple intermediate storage tanks, and the sampling device obtains intermediates from one intermediate storage tank at a time.

[0016] or,

[0017] Each intermediate storage tank is connected to a separate sampling device, each sampling device is connected to a separate quantification device, and all quantification devices are connected to a gas chromatograph detection device.

[0018] Furthermore, the intermediate storage tank is connected to multiple sampling devices, each sampling device is connected to a separate quantitative device, and each quantitative device is connected to a separate gas chromatographic detection device.

[0019] or,

[0020] The intermediate storage tank is connected to a separate sampling device, which is connected to multiple quantitative devices, each of which is connected to a separate gas chromatographic detection device.

[0021] Furthermore, the metering device is also connected to the recovery device.

[0022] Secondly, a detection method for an intermediate detection system in the production process of chemical raw materials pharmaceuticals, as proposed in the first aspect, is presented, including:

[0023] The intermediates of the chemical raw material drug in the intermediate storage tank are obtained by sampling device, and the obtained intermediates are formed into a solution to be tested.

[0024] The solution to be tested enters the quantitative device, and the set amount of sample is taken out by the quantitative device and sent to the gas chromatography detection device;

[0025] The sample is analyzed by gas chromatography using a gas chromatography detection device to obtain the gas chromatography analysis results.

[0026] Based on the gas chromatography analysis results, determine whether the intermediate is qualified.

[0027] Furthermore, when an intermediate storage tank is connected to multiple sampling devices, multiple samples of the intermediate are obtained from the intermediate storage tank through the multiple sampling devices, forming multiple test solutions; a set amount of sample is taken from each test solution; each sample is analyzed by gas chromatography using a separate gas chromatography detection device to obtain the gas chromatography analysis results of each sample; when the gas chromatography analysis results of all samples are qualified, the intermediate is determined to be qualified.

[0028] Furthermore, qualified intermediates are stored in qualified product containers.

[0029] For intermediates that are deemed unqualified, they are either stored in non-conforming product containers or reprocessed in the production process that produced the intermediate.

[0030] Furthermore, for a sampling device connected to multiple intermediate storage tanks, the sampling device obtains an intermediate of the chemical raw material drug from one intermediate storage tank. After the intermediate is analyzed by gas chromatography using a gas chromatography detection device, the intermediate of the chemical raw material drug from another intermediate storage tank is obtained.

[0031] Furthermore, after the gas chromatography detection device completes the gas chromatography analysis of the sample, the diluent in the diluent storage tank is obtained through the sampling device and sent to the quantitative device. The diluent from the quantitative device enters the gas chromatography detection device to clean the sampling device, the quantitative device, and the gas chromatography detection device.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0033] 1. This invention can automatically sample, dilute, measure, and perform gas chromatography detection and analysis of intermediates in the production process of chemical raw materials and pharmaceuticals, and automatically judge the results, thereby realizing timely and effective detection of each intermediate and improving the production efficiency of chemical raw materials and pharmaceuticals.

[0034] 2. After the intermediate sample is analyzed by gas chromatography, the present invention can also rinse the sampling device, the quantitative device and the gas chromatography detection device with a diluent to ensure the accuracy of the next gas chromatography analysis of the intermediate sample.

[0035] 3. This invention performs multiple gas chromatographic analyses on the same intermediate. Only when all multiple gas chromatographic analyses are qualified is the intermediate put into the next process, thus ensuring the quality of the chemical raw material.

[0036] 4. Based on the production cycle, this invention rationally arranges the sequential detection of multiple intermediates using the same gas chromatography analysis device, thereby reducing production costs and improving production efficiency while achieving timely and effective detection of each intermediate.

[0037] 5. This invention can control the production process based on the detection results of intermediates; for intermediates that fail the gas chromatography analysis, they are returned to the corresponding production process for reprocessing, ensuring that all intermediates flowing into the next process are qualified by gas chromatography analysis, and ultimately guaranteeing the quality of the produced chemical raw materials.

[0038] Advantages of additional aspects of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0039] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments of this application and their descriptions are used to explain this application and do not constitute an undue limitation of this application.

[0040] Figure 1 This is a schematic diagram of the overall structure of an intermediate detection system in the production process of a chemical raw material drug, as disclosed in the embodiment.

[0041] Figure 2 This is a flowchart of a detection method for an intermediate detection system in the production process of a chemical raw material drug, as disclosed in an embodiment.

[0042] The components are: 1. Vacuum pump, 2. Shut-off valve, 3. Shut-off valve, 4. Shut-off valve, 5. Diluent storage tank, 6. Intermediate storage tank, 7. Shut-off valve, 8. Sampling tank, 9. Shut-off valve, 10. Filter, 11. Metering cup, 12. Solvent recovery device, 13. Injector, 14. Shut-off valve, 15. Flow restrictor, 16. Sample recovery device. Detailed Implementation

[0043] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0044] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0045] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments according to this application. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0046] In this invention, terms such as "fixed connection," "connected," and "linked" should be interpreted broadly, indicating a fixed connection, an integral connection, or a detachable connection; a direct connection or an indirect connection through an intermediate medium. Those skilled in the art can determine the specific meaning of these terms in this invention based on the specific circumstances, and they should not be construed as limitations on the invention.

[0047] Where there is no conflict, the embodiments and features in the embodiments of the present invention can be combined with each other.

[0048] Example 1

[0049] In this embodiment, an intermediate detection system for the production process of chemical active pharmaceutical ingredients is disclosed, such as... Figure 1 As shown, it includes an analysis and control system, a sampling device, a quantitative device, and a gas chromatography detection device;

[0050] The sampling device is used to obtain intermediates of chemical raw materials in intermediate storage tank 6, form the obtained intermediates into a test solution, and send the test solution into a quantitative device.

[0051] A quantitative device is used to take a set amount of sample from the input liquid to be tested and send it into a gas chromatograph for detection.

[0052] A gas chromatography detection device is used to perform gas chromatography analysis on input samples and obtain gas chromatography analysis results;

[0053] An analytical control system is used to determine whether an intermediate is qualified based on the results of gas chromatography analysis.

[0054] Since some intermediates need to be diluted before gas chromatography analysis, this embodiment limits the sampling device to also obtain the diluent in the diluent storage tank 5, and mixes the obtained intermediates and diluent to form the solution to be tested.

[0055] Intermediate storage tank 6 contains intermediates used in the production of chemical raw materials, and diluent storage tank 5 contains diluent.

[0056] Specifically, the sampling device includes a sampling tank 8, which is equipped with an outlet, an inlet, a sample inlet, a diluent inlet, and a mixed liquid outlet. The outlet is connected to a vacuum pump 1, the inlet is connected to a gas source, the sample inlet is connected to an intermediate storage tank 6, the diluent inlet is connected to a diluent storage tank 5, and the mixed liquid outlet is connected to a metering device. Shut-off valves are installed on the pipelines connecting the vacuum pump 1, the gas source, the intermediate storage tank 6, and the diluent storage tank 5 to the sampling tank 8. Specifically, a shut-off valve 2 is installed on the pipeline connecting the vacuum pump 1 to the sampling tank 8, a shut-off valve 3 is installed on the pipeline connecting the gas source to the sampling tank 8, a shut-off valve 7 is installed on the pipeline connecting the intermediate storage tank 6 to the sampling tank 8, and a shut-off valve 4 is installed on the pipeline connecting the diluent storage tank 5 to the sampling tank 8.

[0057] Open shut-off valve 2 and close the other valves. Vacuum pump 1 is used to evacuate sampling tank 8. Then, shut-off valves 4 and 7 are opened to allow the intermediate in intermediate storage tank 6 and the diluent in diluent storage tank 5 to enter sampling tank 8. After sampling tank 8 has obtained a sufficient amount of intermediate and diluent, shut-off valve 2 and vacuum pump 1 are closed. The intermediate and diluent are mixed in sampling tank 8 and diluted with the diluent. After dilution is completed, the solution to be tested is obtained. Shut-off valves 3 and 9 are opened, and compressed air is introduced into sampling tank 8 through the air source to fill the quantitative device with the solution to be tested.

[0058] In addition, the diluent in diluent storage tank 5 can be used not only to dilute intermediates to obtain the solution to be tested, but also to rinse the sampling device, the quantitative device and the gas chromatography detection device.

[0059] Preferably, the air outlet, air inlet, sample inlet, and diluent inlet are located at the upper end of the sampling tank 8, and the mixed liquid outlet is located at the lower end of the sampling tank 8.

[0060] Sampling container 8 uses a 50ml quantitative container.

[0061] The shut-off valve 2 is connected to the sampling tank 8 via a pipeline that is connected to a pressure gauge. The pressure gauge is used to display the pressure status in the sampling tank 8. When the pressure in the sampling tank 8 is lower than 0 MPa, it indicates that the sampling tank 8 is in a vacuum state, and the vacuum pump 1 stops evacuating the sampling tank 8.

[0062] When the pressure in sampling tank 8 is greater than the set value, it indicates that there is a sufficient amount of liquid in sampling tank 8. Close shut-off valve 4 and shut-off valve 7, and sampling tank 8 completes sampling. At this time, the liquid volume in sampling tank 8 is 50ml.

[0063] The quantitative device includes a filter 10 and a metering cup 11. The inlet of the filter 10 is connected to the sampling device, the outlet of the filter 10 is connected to the inlet of the metering cup 11, and the outlet of the metering cup 11 is connected to the gas chromatography detection device.

[0064] The quantitative device is also connected to the recovery device. After the quantitative device takes out a set amount of sample from the solution to be tested, it passes the remaining solution into the recovery device for recovery.

[0065] The recovery device includes a sample recovery device 16 and a solvent recovery device 12. The quantitative device is connected to the sample recovery device 16 and the solvent recovery device 12 respectively. The quantitative device discharges the remaining test solution, except for the sample entering the gas chromatography detection device, into the sample recovery device 16. When the sampling device, the quantitative device and the gas chromatography detection device are cleaned with diluent, the excess diluent after passing through the quantitative device enters the solvent recovery device 12 for temporary storage.

[0066] Preferably, the metering cup 11 is connected to the sample recovery device 16 and the solvent recovery device 12 respectively; the solution to be tested is filtered by the filter 10, and the filtered liquid enters the metering cup 11. The metering cup 11 takes a set amount of sample from the solution to be tested and sends it to the gas chromatography detection device, and sends the remaining solution to be tested to the sample recovery device 16.

[0067] The gas chromatography detection device includes an injector 13, a chromatographic column, and a flame ionization detector connected in sequence. The injector 13 vaporizes the incoming sample, and the vaporized sample is separated by the chromatographic column. The separated components enter the flame ionization detector for gas chromatography analysis and detection to obtain the gas chromatography analysis results of the sample.

[0068] The metering cup 11 includes a six-way valve and a metering tube disposed within the six-way valve. The metering tube is rotatably connected to the six-way valve. The six-way valve includes three sets of valve ports, which are evenly distributed circumferentially on the six-way valve. Each set of valve ports includes two adjacent valve ports. The three sets of valve ports are the feed valve port, the discharge valve port, and the standby valve port. The feed valve port includes valve port w and valve port s, and the discharge valve port includes valve port p and valve port c. Valve port p is connected to the carrier gas. The metering tube can be connected to any set of valve ports by rotation. When the metering tube is connected to any set of valve ports, each end of the metering tube is connected to two corresponding valve ports in that set.

[0069] Valve port s is connected to filter 10, valve port w is connected to liquid three-way selector valve, and the other two valve ports of liquid three-way selector valve are connected to the test solution delivery pipeline and the diluent delivery pipeline, respectively; the test solution delivery pipeline is connected to sample recovery device 16, and the diluent delivery pipeline is connected to solvent recovery device 12. A flow limiter 15 is installed in the test solution delivery pipeline, and a shut-off valve 14 is installed in the diluent delivery pipeline.

[0070] Valve port c is connected to the inlet of injector 13, and the outlet of injector 13 is connected to the chromatographic column.

[0071] The injector 13 uses an injection needle and has a temperature of 250°C, which allows the incoming gas to be completely vaporized before the sample enters the chromatographic column.

[0072] A pressure sensor is installed on the pipeline for delivering the solution to be tested. The pressure sensor is located between the liquid three-way selector valve and the flow restrictor 15. The pressure sensor displays the liquid pressure in the pipeline connecting the liquid three-way selector valve and the flow restrictor 15.

[0073] The process of inputting liquid from sampling vessel 8 into metering cup 11 is as follows: rotate the metering tube to connect with valve port w and valve port s; open shut-off valve 3 and shut-off valve 9; adjust the liquid three-way selector valve to connect the valve port w of the six-way valve, the pressure sensor, and the flow limiter 15; fill the sampling vessel 8 with compressed air through the air source, with the gas on top and the liquid on the bottom in the sampling vessel 8; the compressed air will push the liquid out of the sampling vessel 8 and flow through shut-off valve 9, filter 10, valve port s of the six-way valve, metering tube, valve port w of the six-way valve, liquid three-way selector valve, pressure sensor, and flow limiter 15 in sequence, and finally flow into the sample recovery device 16, completing the sample injection into metering cup 11.

[0074] The flow restrictor 15 has a flow rate of 10 ml / min, and the pressure sensor displays a flow liquid pressure of 0.1 MPa.

[0075] The process of introducing liquid from the metering cup 11 into the injector 13 includes: when the liquid pressure and flow rate in the solution delivery line remain stable, it indicates that the metering tube is full and stable; rotating the metering tube until it connects with valve port p and valve port c, the carrier gas is introduced into the metering tube through valve port p, pushing the liquid in the metering tube through valve port c into the injector 13. The injector 13 has a temperature of 250℃, which can completely vaporize the incoming liquid, and the vaporized gas is introduced into the chromatographic column for separation. The separated sample enters the flame ionization detector from the chromatographic column for detection. After the detection is completed, the six-way valve is closed, that is, valve port w, valve port p, valve port s, and valve port c are restored to their default states, completing the entire process of liquid injection, vaporization, and analysis.

[0076] After the sample analysis is completed, the sample is recovered. The sample recovery process includes: rotating the quantitative tube to connect with valve port w and valve port s; opening shut-off valves 3 and 9; adjusting the liquid three-way selector valve to connect the valve port w of the six-way valve, the pressure sensor, and the flow restrictor 15; filling the sampling tank 8 with compressed air through the air source, with the gas on top and the liquid at the bottom in the sampling tank 8; the compressed air will push the liquid out of the sampling tank 8 and flow sequentially through shut-off valve 9, filter 10, valve port s of the six-way valve, quantitative tube, valve port w of the six-way valve, liquid three-way selector valve, pressure sensor, and flow restrictor 15; at this time, the flow restrictor 15 will not restrict the flow and will be fully open, allowing the liquid to enter the sample recovery device 16 for recovery, until the liquid in the sampling tank 8 is completely discharged into the sample recovery device 16; closing shut-off valves 3 and 9, completing the entire sample recovery process.

[0077] After sample recovery is complete, the entire detection system is flushed. The flushing process includes: opening shut-off valve 2 and closing the other valves; evacuating the sampling tank 8 using vacuum pump 1; then closing vacuum pump 1 and shut-off valve 2; opening shut-off valve 4 to allow diluent from diluent storage tank 5 to enter the sampling tank 8 until it is full; rotating the metering tube to connect it with valve port w and valve port s; opening shut-off valves 3, 9, and 14; adjusting the liquid three-way selector valve to connect the six-way valve's valve port w, pressure sensor, and flow limiter 15; and then using a gas source. Compressed air is introduced into sampling vessel 8, with the gas at the top and the liquid at the bottom. The compressed air pushes the liquid out of sampling vessel 8 and sequentially through shut-off valve 9, filter 10, valve port S of the six-way valve, metering tube, valve port W of the six-way valve, liquid three-way selector valve, shut-off valve 14, and solvent recovery device 12. At this time, flow restrictor 15 is not restricting the flow and will be fully open, allowing the liquid to enter the sample recovery device 16 for recovery. This process continues until all the liquid in sampling vessel 8 is discharged into the sample recovery device 16. Then, shut-off valves 3 and 9 are closed, completing the entire sample recovery process. This process also includes solvent cleaning and gas flushing of the flow path to ensure that the next sample analysis is free from interference from other components, reducing data errors.

[0078] In this embodiment, the switching of each valve and vacuum pump is controlled by a PLC control board. The connecting pipes between each device in this embodiment are all made of 1 / 16 stainless steel pipe.

[0079] The analytical control system determines the quality of intermediates based on gas chromatography analysis results. Based on this, it controls the discharge valve of intermediate storage tank 6. Specifically, when an intermediate is deemed qualified, the discharge valve opens, allowing the intermediate to enter the qualified product tank for storage. When an intermediate is deemed unqualified, it is either placed in the unqualified product tank or returned to the production process that obtained it for reprocessing. This ensures the quality of intermediates entering the next process.

[0080] To ensure that the previous gas chromatographic detection of the intermediate does not affect the detection of the next intermediate, in this embodiment, after each gas chromatographic detection of the intermediate, the sampling device is controlled to obtain diluent from the diluent storage tank 5 and pressurize the diluent into the metering device. The set amount of diluent from the metering device enters the gas chromatographic detection device, and the remaining diluent enters the solvent recovery device 12, thereby achieving the rinsing of the sampling device, metering device and gas chromatographic detection device by the diluent.

[0081] To ensure rinsing quality, this embodiment specifies that the sampling device, quantitative device, and gas chromatography detection device are rinsed repeatedly with a diluent, and the diluent is tested after each rinse. When the diluent test results after rinsing meet the predetermined standards, it indicates that the sampling device, quantitative device, and gas chromatography detection device are clean, and rinsing of the sampling device, quantitative device, and gas chromatography detection device is stopped.

[0082] Since various intermediates are generated during the production of chemical raw materials, each intermediate is stored in a corresponding intermediate storage tank 6. In order to achieve full-process monitoring of chemical raw material production, this embodiment also connects the sampling device to multiple intermediate storage tanks 6. The sampling device obtains an intermediate from one intermediate storage tank 6 at a time; or, each intermediate storage tank is connected to a separate sampling device, and each sampling device is connected to a separate quantitative device. All quantitative devices are connected to a gas chromatography detection device. After the intermediate in one intermediate storage tank 6 has been tested and rinsed clean, the intermediate in another intermediate storage tank 6 is obtained for testing. This reduces the testing cost while ensuring the accuracy of the test.

[0083] To ensure the accuracy of the detection, this embodiment connects the intermediate storage tank 6 to multiple sampling devices, each sampling device to a separate quantitative device, and each quantitative device to a separate gas chromatography detection device; or, the intermediate storage tank is connected to a separate sampling device, which is connected to multiple quantitative devices, each quantitative device to a separate gas chromatography detection device; all gas chromatography detection devices are communicatively connected to the analysis and control system; for the intermediate in the same intermediate storage tank 6, the intermediate is analyzed by gas chromatography using multiple gas chromatography detection devices. Only when all gas chromatography analysis results for the intermediate are qualified is the intermediate finally determined to be qualified, and the intermediate storage tank 6 is controlled to send the intermediate to the qualified product tank for storage; when one or more gas chromatography analysis results are unqualified, the intermediate is determined to be unqualified, and the intermediate storage tank 6 is controlled to re-enter the intermediate into the production process for processing, or to send the intermediate to the unqualified product tank for storage.

[0084] The process of intermediate detection using an intermediate detection system in the production process of a chemical raw material drug disclosed in this embodiment is described with reference to examples.

[0085] When the intermediate is recycled solvent A, recycled solvent A contains two main components: recycled solvent A and B. The detection of recycled solvent A includes two items: whether there are other impurities in recycled solvent A and the concentration of B in recycled solvent A; both items are detected using gas chromatography. Since three batches of product are produced simultaneously during the production of recycled solvent A, and these three batches are stored in tanks A, B, and C respectively, the concentration of B in the three batches is different. Therefore, two gas chromatographs (GCs) are used for the detection of recovered solvent A. Each GC is connected to a separate quantitative device, and each quantitative device is connected to a separate sampling device. Each sampling device is connected to tanks A, B, and C, or each quantitative device is connected to three sampling devices, with tanks A, B, and C each connected to two sampling devices. The sampling devices connected to tanks A, B, and C are all different. One GC is used to detect whether there are other impurities in recovered solvent A in tanks A, B, and C. The other GC is used to detect the concentration of ethyl acetate in the recovered solvent heptane in tanks A, B, and C. The two GCs can perform analysis simultaneously. When detecting recovered solvent A, dilution is not required; therefore, the sampling device only needs to obtain recovered solvent A as the solution to be tested. The process for detecting recovered solvent A in tanks A, B, and C is as follows:

[0086] The recovered solvent A in tank A is obtained using one or two sampling devices and used as the test solution. Quantitative samples are taken from this test solution using two quantitative devices and sent to two gas chromatographs (GCs). The GCs obtain the results of whether there are other impurities in the sample and the concentration of solvent B in the sample. To improve the accuracy of the test, the recovered solvent A in tank A is sampled twice and tested twice by GC. After the two tests, the average of the two results is taken to obtain the final results of whether there are other impurities in the sample and the concentration of solvent B in the sample. When both the final results of whether there are other impurities in the sample and the concentration of solvent B in the sample are qualified, the recovered solvent A in tank A is deemed qualified. The qualified recovered solvent A is then transferred to a qualified storage tank. When one or both of the final results of whether there are other impurities in the sample and the concentration of solvent B in the sample are unqualified, the recovered solvent A in tank A is deemed unqualified, and the unqualified recovered solvent A in tank A is transferred to a pre-distillation tank for redistribution.

[0087] After the recovered solvent A in tank A is tested, the recovered solvent A in tank B is sampled and tested using a sampling device, a quantitative device, and a gas chromatography detection device. After the recovered solvent A in tank B is tested, the recovered solvent A in tank C is sampled and tested using a sampling device, a quantitative device, and a gas chromatography detection device.

[0088] After each test, the sampling device, quantitative device, and gas chromatography detection device are cleaned. The remaining sample in the sampling device after each test, as well as the cleaning solution after cleaning the sampling device, quantitative device, and gas chromatography detection device, are sent to the corresponding tanks A, B, and C through pipelines.

[0089] When the intermediate is a chromatographically purified product, the chromatographically separated product is collected into six product containers. The product content in each of the six containers is analyzed using a gas chromatography (GC) device, without dilution. A sampling device is connected to every three product containers, and each sampling device is connected to a quantification device. Each quantification device is connected to a separate GC device. During analysis, the products in two product containers are simultaneously analyzed using two GC devices. Then, the products in the next two product containers are analyzed simultaneously. Finally, the products in the last two product containers are analyzed simultaneously. To ensure accuracy, each product container is analyzed twice, and the average of the two results is taken as the final result.

[0090] Qualified products in the product tank are transferred to qualified product tanks; unqualified products in the product tanks are transferred to unqualified product tanks.

[0091] After each test, the sampling device, quantitative device, and gas chromatography detection device are cleaned. The remaining sample in the sampling device after each test, as well as the cleaning solution after cleaning the sampling device, quantitative device, and gas chromatography detection device, are sent to the waste liquid receiving tank through pipelines.

[0092] When the intermediate is the mobile phase required for the chromatography process, there are two mobile phase preparation tanks. The concentration of the mobile phase in both tanks needs to be tested to ensure it meets requirements. The mobile phase components in the two tanks are the same, but their concentrations differ. During production, the two tanks are not used simultaneously; therefore, they are connected to a sampling device, which in turn is connected to a quantitative device, which is then connected to a separate gas chromatographic detection device. The gas chromatographic detection device performs gas chromatographic analysis on the mobile phase in one of the tanks at a time. During detection, the mobile phase sample does not need to be diluted. To ensure accurate results, the mobile phase in each tank is analyzed twice in parallel, and the average value is taken as the final result.

[0093] Upon completion of the test, if the mobile phase passes the test, it is stored in the preparation tank for normal use. If the mobile phase fails the test, the mobile phase preparation ratio is adjusted according to the test results, and the solution is tested again until the concentration meets the requirements. After each test, the sampling device, quantitative device, and gas chromatography detection device are cleaned. The remaining sample in the sampling device after each test, as well as the cleaning solution used to clean the sampling device, quantitative device, and gas chromatography detection device, are sent to the waste liquid receiving tank through pipelines.

[0094] When the intermediate is recovered solvent B, the main component is B. Recovered solvent B contains two components, B and A. It is stored in two sample containers, and the concentration of B in the recovered solvent B needs to be detected using a gas chromatography (GC) device. The concentration of B in the two sample containers differs. Each sample container is connected to a separate sampling device, which in turn is connected to a separate quantitative device, and finally, a separate GC device. The concentration of B in the recovered solvent B in both sample containers is detected using two GC devices. During detection, the concentration of B does not require dilution. To ensure accuracy, the recovered solvent B in each sample container is detected in parallel three times, and the average value is taken as the final result. The final result obtained from one of the GC devices is used to determine whether the recovered solvent B is qualified. Qualified recovered solvent B is transferred to a qualified storage tank, while unqualified recovered solvent B is transferred to a pre-distillation tank for re-distillation. The final result obtained from the other GC device serves as the data basis for the next configuration operation.

[0095] Intermediate products that require dilution before gas chromatography analysis are designated as Intermediate Product 1 and Intermediate Product 2. Both intermediate products require analysis for product and impurity content. Intermediate Product 1 and Intermediate Product 2 are stored in separate product containers, each containing different products and requiring different analysis methods. To prevent cross-contamination, each container is connected to a separate gas chromatography analyzer. Specifically, each product container is connected to a separate sampling device, which in turn is connected to a separate quantitative device, and finally, a separate gas chromatography analyzer. The intermediate products in both product containers are analyzed one-to-one using the two gas chromatography analyzers. When the sampling devices obtain the intermediate products, they also need to obtain the diluent according to the pre-set dilution ratio. The diluent is then mixed with the intermediate products according to the dilution ratio to obtain the solution to be analyzed. To ensure accuracy, each product container's intermediate products are analyzed in triplicate, and the average value is taken as the final result. Intermediate products that pass the test in the product tank are transferred to qualified storage tanks, while intermediate products that fail the test in the product tank are transferred to unqualified tanks. Regardless of whether they pass or fail, the remaining samples after each test in the sampling device, as well as the cleaning solution after cleaning the sampling device, quantitative device, and gas chromatography detection device, are sent to the pre-distillation tanks of their respective products through pipelines.

[0096] This embodiment discloses an intermediate detection system for the production process of chemical raw materials, which can automatically sample, dilute, measure, and perform gas chromatography detection and analysis of intermediates in the production process of chemical raw materials. It realizes timely and effective detection of each intermediate and can control the production process based on the detection results of the intermediates.

[0097] This embodiment discloses an intermediate detection system for the production process of chemical active pharmaceutical ingredients (APIs). Based on the production cycle of the API, the system sets the number of sampling devices, quantitative devices, and gas chromatography detection devices. While ensuring accurate quality detection of each intermediate, it uses as few gas chromatography detection devices as possible to perform quality detection of each intermediate, thereby improving the production efficiency of the API.

[0098] Example 2

[0099] In this embodiment, such as Figure 2 As shown, Example 1 discloses a detection method for an intermediate detection system in the production process of a chemical raw material drug, comprising:

[0100] The intermediate of the chemical raw material drug is obtained from the intermediate storage tank through a sampling device, and the obtained intermediate is used to form a solution to be tested;

[0101] The solution to be tested enters the quantitative device, and the set amount of sample is taken out by the quantitative device and sent to the gas chromatography detection device;

[0102] The sample is analyzed by gas chromatography using a gas chromatography detection device to obtain the gas chromatography analysis results.

[0103] Based on the gas chromatography analysis results, determine whether the intermediate is qualified.

[0104] When an intermediate storage tank is connected to multiple sampling devices, multiple samples of the intermediate are obtained from the intermediate storage tank through the multiple sampling devices, forming multiple test solutions; a set amount of sample is taken from each test solution; each sample is analyzed by gas chromatography using a separate gas chromatography detection device to obtain the gas chromatography analysis results of each sample; when the gas chromatography analysis results of all samples are qualified, the intermediate is determined to be qualified.

[0105] For a sampling device connected to multiple intermediate storage tanks, the sampling device obtains an intermediate of the chemical raw material drug from one intermediate storage tank. After the intermediate is analyzed by gas chromatography using a gas chromatography detection device, the intermediate of the chemical raw material drug from another intermediate storage tank is obtained.

[0106] Each gas chromatographic detection device connected to the intermediate storage tank performs gas chromatographic analysis on the intermediate in the intermediate storage tank; when all gas chromatographic analysis results of the sample are qualified, the analysis control system controls the intermediate in the intermediate storage tank to enter the qualified product tank.

[0107] Furthermore, after the gas chromatography detection device completes the gas chromatography analysis of the sample, the diluent in the diluent storage tank is obtained through the sampling device and sent to the quantitative device. The diluent from the quantitative device then enters the gas chromatography detection device to clean the sampling device, quantitative device, and gas chromatography detection device. By cleaning the device after each gas chromatography analysis, it is ensured that each gas chromatography analysis is not affected by the previous liquid, thus guaranteeing the accuracy of each gas chromatography analysis.

[0108] While the specific embodiments of the present invention have been described above in conjunction with the accompanying drawings, this is not intended to limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art without creative effort based on the technical solutions of the present invention are still within the scope of protection of the present invention.

Claims

1. A detection method for an intermediate detection system in the production process of chemical raw materials pharmaceuticals, characterized in that, The detection system includes: an analysis and control system, a sampling device, a quantitative device, and a gas chromatography detection device; the quantitative device includes a filter and a metering cup, the metering cup being housed within a six-way valve; the sampling device includes a sampling vessel, on which the outlet is connected to a vacuum pump, the inlet is connected to a gas source, the sample inlet is connected to an intermediate storage tank, the diluent inlet is connected to a diluent storage tank, the mixed liquid outlet is connected to the filter inlet, the filter outlet is connected to the metering cup inlet, and the metering cup outlet is connected to the gas chromatography detection device; shut-off valves are respectively installed on the pipelines connecting the vacuum pump, gas source, intermediate storage tank, and diluent storage tank to the sampling vessel; the quantitative device is also connected to a recovery device via the six-way valve, the recovery device including a sample recovery device and a solvent recovery device; Each intermediate storage tank is connected to a separate sampling device, each sampling device is connected to a separate quantification device, and all quantification devices are connected to a gas chromatograph detection device; or the intermediate storage tank is connected to multiple sampling devices, each sampling device is connected to a separate quantification device, and each quantification device is connected to a separate gas chromatograph detection device; or the intermediate storage tank is connected to a separate sampling device, the sampling device is connected to multiple quantification devices, and each quantification device is connected to a separate gas chromatograph detection device. The detection method includes: The sampling tank is evacuated by a vacuum pump, allowing the intermediates in the intermediate storage tank and the diluent in the diluent storage tank to enter the sampling tank. The intermediates and diluent are mixed in the sampling tank to obtain the solution to be tested. Compressed air is introduced into the sampling tank through a gas source, and the solution to be tested is introduced into the quantitative device. The set amount of sample is taken out through the quantitative device and sent to the gas chromatography detection device. The sample is analyzed by gas chromatography using a gas chromatography detection device to obtain the gas chromatography analysis results. The analysis and control system determines whether the intermediate is qualified based on the gas chromatography analysis results; qualified intermediates are stored in qualified product tanks; unqualified intermediates are stored in unqualified product tanks or reprocessed in the production process that obtained the intermediate. After each gas chromatography analysis of a sample, the sampling tank is evacuated by a vacuum pump, allowing diluent from the diluent storage tank to enter the sampling tank until it is full. Compressed air is then introduced into the sampling tank through a gas source, with the gas on top and the liquid at the bottom. The compressed air pushes the liquid out of the sampling tank, performing solvent cleaning and gas flushing of the sampling device, quantitative device, and gas chromatography detection device.

2. The detection method of the intermediate detection system in the production process of chemical raw materials pharmaceuticals as described in claim 1, characterized in that, When an intermediate storage tank is connected to multiple sampling devices, multiple samples of the intermediate are obtained from the intermediate storage tank through the multiple sampling devices, forming multiple test solutions; a set amount of sample is taken from each test solution. Each sample is analyzed by gas chromatography using a separate gas chromatography detection device to obtain the gas chromatography analysis results for each sample; when the gas chromatography analysis results of all samples are qualified, the intermediate is deemed qualified.

3. The detection method of the intermediate detection system in the production process of chemical raw materials pharmaceuticals as described in claim 1, characterized in that, For a sampling device connected to multiple intermediate storage tanks, the sampling device obtains an intermediate of the chemical raw material drug from one intermediate storage tank. After the intermediate is analyzed by gas chromatography using a gas chromatography detection device, the intermediate of the chemical raw material drug from another intermediate storage tank is obtained.

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