Intermediate detection system and method in production process of chemical raw material medicine

Abstract

The invention discloses a system and method for detecting intermediates in the production process of chemical bulk drugs, and the system comprises a sampling device which is used for obtaining the intermediates of the chemical bulk drugs in an intermediate storage tank, forming a to-be-detected solution from the obtained intermediates, and feeding the to-be-detected solution into a quantifying device; the quantifying device is used for taking a set amount of sample from the input to-be-detected liquid and feeding the sample into the gas chromatography detection device; the gas chromatography detection device is used for carrying out gas chromatography analysis on the input sample to obtain a gas chromatography analysis result; and the analysis control system is used for judging whether the intermediate is qualified or not according to a gas chromatographic analysis result. And the timeliness, accuracy and safety of intermediate detection are ensured. And the production process can be controlled according to the detection result of the intermediate.

Description

Technical Field

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

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

[0003] The production process of chemical APIs in the pharmaceutical field consists of a series of chemical reactions or purification steps. The intermediates produced in each step must have corresponding quality control, such as the purity and impurities of the intermediates. The purity of the intermediates in each step will directly affect the yield of the next process step, and the impurities will affect the distribution and limit of impurities in the final product, and then affect the effectiveness and safety of the drug. Therefore, the intermediates that have completed the process steps must be tested to control their quality.

[0004] In order to ensure that the quality of raw materials meets the requirements, it is necessary to carry out quality inspection and control on each intermediate in the production process of raw materials. Currently, the quality of intermediates is mainly judged by manually sampling each intermediate and performing gas chromatography on the intermediates.

[0005] Since a large amount of organic solvents are generally used in the production process of raw materials, and organic solvents are toxic, flammable and explosive, the manual sampling of intermediates makes personnel vulnerable to toxic injuries, increasing safety risks. In addition, the manual sampling method takes a long time and is difficult to sample. The number of samplings per day is limited, and the test results cannot be obtained in a timely manner, affecting the production efficiency of raw materials.

[0006] Currently, there is a gas chromatograph sampling system that can automatically transport liquid samples to the gas chromatograph for gas chromatography detection; however, the gas chromatograph sampling system has not been applied to the production of chemical raw materials, and the system lacks a diluent delivery part, and is not suitable for intermediates in the production process of raw materials that need to be diluted before gas chromatography detection; in addition, the gas chromatograph sampling system can only realize the sampling and detection functions separately, and cannot reasonably arrange the detection rhythm of the intermediates in combination with the production rhythm of the raw materials, so it cannot effectively improve the production efficiency of the raw materials. Summary of the invention

[0007] In order to solve the above problems, the present invention proposes a system and method for detecting intermediates in the production process of chemical raw materials, which can realize full-automatic detection of intermediates in the production process of chemical raw materials and improve the production efficiency of raw materials.

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

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

[0010] A sampling device, used to obtain the intermediate of the chemical raw material drug in the intermediate storage tank, form the obtained intermediate into a solution to be tested, and send the solution to be tested into the quantitative device;

[0011] A quantitative device, used to take a set amount of sample from the input liquid to be tested and send it to the gas chromatography detection device;

[0012] A gas chromatography detection device, used for performing gas chromatography analysis on the input sample to obtain gas chromatography analysis results;

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

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

[0015] Furthermore, the sampling device is connected to a plurality of intermediate storage tanks, and the sampling device obtains the intermediate in 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 quantitative device, and all quantitative devices are connected to a gas chromatography detection device.

[0018] Furthermore, the intermediate storage tank is connected to a plurality of sampling devices, each sampling device is connected to a separate quantitative device, and each quantitative device is connected to a separate gas chromatography detection device;

[0019] or,

[0020] The intermediate storage tank is connected to a separate sampling device, the sampling device is connected to a plurality of quantitative devices, and each quantitative device is connected to a separate gas chromatography detection device.

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

[0022] In the second aspect, a detection method for an intermediate detection system in the production process of a chemical raw material drug proposed in the first aspect is proposed, comprising:

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

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

[0025] Performing gas chromatography analysis on the sample through a gas chromatography detection device to obtain a gas chromatography analysis result;

[0026] Determine whether the intermediate is qualified based on the gas chromatography analysis results.

[0027] Furthermore, when an intermediate storage tank is connected to multiple sampling devices, multiple intermediates in the intermediate storage tank are obtained through the multiple sampling devices, and multiple solutions to be tested are formed; a set amount of sample is taken out from each solution to be tested; each sample is subjected to gas chromatography analysis by a separate gas chromatography detection device to obtain a gas chromatography analysis result of each sample; when the gas chromatography analysis results of all samples are qualified, the intermediate is judged to be qualified.

[0028] Furthermore, the qualified intermediates are put into qualified product tanks for storage;

[0029] The intermediates judged as unqualified are placed in a defective product tank for storage, or are placed in the production process from which the intermediates were obtained for reprocessing.

[0030] Furthermore, for a sampling device connected to a plurality of intermediate storage tanks, the sampling device obtains an intermediate of a chemical raw material drug in an intermediate storage tank, and after completing a gas chromatography analysis of the intermediate by a gas chromatography detection device, obtains an intermediate of a chemical raw material drug in another intermediate storage tank.

[0031] Furthermore, when 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 the diluent is sent to the quantitative device. The diluent coming out of the quantitative device enters the gas chromatography detection device, and the sampling device, the quantitative device and the gas chromatography detection device are cleaned.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] 1. The present invention can complete the automatic sampling, dilution, metering and gas chromatography detection and analysis of intermediates in the production process of chemical raw materials, automatically judge the results, realize timely and effective detection of various intermediates, and thus improve the production efficiency of chemical raw materials.

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

[0035] 3. The present invention performs multiple gas chromatography analyses on the same intermediate. Only when multiple gas chromatography analyses are qualified, the intermediate is placed in the next process, thereby ensuring the quality of the chemical raw material medicine.

[0036] 4. The present invention reasonably arranges the detection of multiple intermediates in sequence through the same gas chromatography analysis device according to the production rhythm, thereby reducing production costs and improving production efficiency on the basis of realizing timely and effective detection of each intermediate.

[0037] 5. The present invention can control the production process according to the detection results of the intermediates; the intermediates that fail the gas chromatography analysis are returned to the corresponding production process for reprocessing to ensure that the intermediates flowing into the next process are all qualified intermediates detected by gas chromatography analysis, ultimately ensuring the quality of the produced chemical raw materials.

[0038] Advantages of additional aspects of the present invention will be given in part in the following description, and in part will become obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The drawings in the specification, which constitute a part of the present application, are used to provide further understanding of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

[0040] Figure 1 The overall structural diagram of an intermediate detection system in the production process of a chemical raw material drug disclosed in the embodiment;

[0041] Figure 2 The present invention is a flow chart of a detection method of an intermediate detection system in a chemical raw material drug production process disclosed in an embodiment.

[0042] Among them: 1. Vacuum pump, 2. Stop valve, 3. Stop valve, 4. Stop valve, 5. Diluent storage tank, 6. Intermediate storage tank, 7. Stop valve, 8. Sampling tank, 9. Stop valve, 10. Filter, 11. Quantitative cup, 12. Solvent recovery device, 13. Sampler, 14. Stop valve, 15. Flow restrictor, 16. Sample recovery device. DETAILED DESCRIPTION

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

[0044] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0045] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0046] In the present invention, terms such as "fixed connection", "connected", "connection", etc. should be understood in a broad sense, indicating that it can be fixedly connected, integrally connected or detachably connected; it can be directly connected or indirectly connected through an intermediate medium. Relevant scientific research or technical personnel in this field can determine the specific meanings of the above terms in the present invention according to specific circumstances, and they should not be understood as limiting the present invention.

[0047] In the absence of conflict, the embodiments of the present invention and the features of the embodiments may be combined with each other.

[0048] Example 1

[0049] In this embodiment, a system for detecting intermediates in the production process of chemical raw materials is disclosed, such as Figure 1 As shown, it includes an analysis control system, a sampling device, a quantitative device and a gas chromatography detection device;

[0050] A sampling device, used to obtain the intermediate of the chemical raw material drug in the intermediate storage tank 6, form the obtained intermediate into a solution to be tested, and send the solution to be tested into the quantitative device;

[0051] A quantitative device, used to take a set amount of sample from the input liquid to be tested and send it to the gas chromatography detection device;

[0052] A gas chromatography detection device, used for performing gas chromatography analysis on the input sample to obtain gas chromatography analysis results;

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

[0054] Since some intermediates need to be diluted before gas chromatography analysis, the sampling device defined in this embodiment is also used to obtain the diluent in the diluent storage tank 5, and mix the obtained intermediate and the diluent to form a solution to be detected.

[0055] The intermediate storage tank 6 is filled with intermediates used in the production process of chemical raw materials, and the diluent storage tank 5 is filled with diluents.

[0056] Specifically, the sampling device includes a sampling tank 8, on which an air outlet, an air inlet, a sample inlet, a diluent inlet and a mixed liquid outlet are arranged, the air outlet is connected to the vacuum pump 1, the air inlet is connected to the air source, the sample inlet is connected to the intermediate storage tank 6, the diluent inlet is connected to the diluent storage tank 5, the mixed liquid outlet is connected to the quantitative device, and stop valves are respectively arranged on the pipelines connecting the vacuum pump 1, the air source, the intermediate storage tank 6 and the diluent storage tank 5 with the sampling tank 8, wherein a stop valve 2 is arranged on the pipeline connecting the vacuum pump 1 with the sampling tank 8, a stop valve 3 is arranged on the pipeline connecting the air source with the sampling tank 8, a stop valve 7 is arranged on the pipeline connecting the intermediate storage tank 6 with the sampling tank 8, and a stop valve 4 is arranged on the pipeline connecting the diluent storage tank 5 with the sampling tank 8.

[0057] Open the stop valve 2 and close the other valves, and evacuate the sampling tank 8 by means of the vacuum pump 1. After that, open the stop valve 4 and the stop valve 7 to allow the intermediate in the intermediate storage tank 6 and the diluent in the diluent storage tank 5 to enter the sampling tank 8. When the sampling tank 8 obtains a sufficient amount of the intermediate and the diluent, close the stop valve 2 and the vacuum pump 1, and the intermediate and the diluent are mixed in the sampling tank 8. The intermediate is diluted by the diluent. After the dilution is completed, the solution to be detected is obtained. Open the stop valve 3 and the stop valve 9, and fill the sampling tank 8 with compressed air through the air source, and fill the solution to be detected into the quantitative device.

[0058] In addition, the diluent in the diluent storage tank 5 is used not only to dilute the intermediate to obtain the solution to be detected, but also to flush the sampling device, the quantitative device and the gas chromatography detection device.

[0059] Preferably, the air outlet, the air inlet, the sample inlet and the 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] The sampling tank 8 adopts a 50ml quantitative barrel.

[0061] The stop valve 2 is connected to the sampling tank 8 through a pipeline connected to a pressure gauge, which is used to display the pressure status in the sampling tank 8. When the pressure in the sampling tank 8 is lower than 0Mpa, 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 the sampling tank 8 is greater than the set value, it indicates that there is a sufficient amount of liquid in the sampling tank 8, and the stop valve 4 and the stop valve 7 are closed, and the sampling tank 8 completes sampling. At this time, the amount of liquid in the sampling tank 8 is 50 ml.

[0063] The quantitative device comprises a filter 10 and a quantitative 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 quantitative cup 11, and the outlet of the quantitative 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 detected, the remaining solution is passed into the recovery device for recovery.

[0065] Among them, 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, and the quantitative device discharges the remaining solution to be detected except 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 by the diluent, the excess diluent after passing through the quantitative device enters the solvent recovery device 12 for temporary storage.

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

[0067] The gas chromatography detection device includes an injector 13, a chromatographic column and a hydrogen flame detector which are connected in sequence. The injector 13 gasifies the incoming sample, and the gasified sample is separated into components by the chromatographic column. The separated components enter the hydrogen flame detector for gas chromatography analysis and detection to obtain the gas chromatography analysis result of the sample.

[0068] The quantitative cup 11 includes a six-way valve and a quantitative tube arranged in the six-way valve, the quantitative tube is rotatably connected to the six-way valve, the six-way valve includes three groups of valve ports, the three groups of valve ports are evenly distributed on the six-way valve in a circumferential manner, and each group of valve ports includes two adjacent valve ports; the three groups of valve ports are respectively a feed group valve port, a discharge port valve port, and a spare valve port; the feed group valve port includes valve port w and valve port s, the discharge port valve port includes valve port p and valve port c, and valve port p is connected to the carrier gas. The quantitative tube can be connected to any group of valve ports by rotating. When the quantitative tube is connected to any group of valve ports, the two ends of the quantitative tube are connected to the two valve ports in the group of valve ports in a one-to-one correspondence.

[0069] The valve port s is connected to the filter 10, the valve port w is connected to the liquid three-way selection valve, and the other two valve ports of the liquid three-way selection valve are respectively connected to the detection solution delivery pipeline and the diluent delivery pipeline; the detection solution delivery pipeline is connected to the sample recovery device 16, and the diluent delivery pipeline is connected to the solvent recovery device 12, wherein a flow limiter 15 is arranged in the detection solution delivery pipeline, and a stop valve 14 is arranged in the diluent delivery pipeline.

[0070] The valve port c is communicated with the inlet of the sample injector 13, and the outlet of the sample injector 13 is communicated with the chromatographic column.

[0071] The injector 13 uses an injection needle, and the temperature of the injector 13 is 250° C., which can completely gasify the incoming gas, and the gasified sample enters the chromatographic column.

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

[0073] The process of inputting the liquid in the sampling tank 8 into the quantitative cup 11 is as follows: rotate the quantitative tube to, and connect it with the valve port w and the valve port s; open the stop valve 3 and the stop valve 9, adjust the liquid three-way selection valve, so that the valve port w of the six-way valve, the pressure sensor and the flow restrictor 15 are in a connected state, and fill the sampling tank 8 with compressed air through the air source. The gas in the sampling tank 8 is at the top and the liquid is at the bottom. The compressed air will push the liquid to flow out of the sampling tank 8, and flow through the stop valve 9, the filter 10, the valve port s of the six-way valve, the quantitative tube, the valve port w of the six-way valve, the liquid three-way selection valve, the pressure sensor and the flow restrictor 15 in sequence, and finally flow into the sample recovery device 16 to complete the sample injection of the quantitative cup 11.

[0074] The limiting flow rate of the flow restrictor 15 is 10 ml / min, and the pressure sensor shows that the pressure of the flowing liquid is 0.1 MPa.

[0075] The process of inputting the liquid in the quantitative cup 11 into the sample injector 13 includes: when the liquid pressure and flow rate in the delivery pipeline of the solution to be detected remain stable, it indicates that the quantitative tube is full of liquid and stable; rotating the quantitative tube until the quantitative tube is connected with the valve port p and the valve port c, inputting the carrier gas into the quantitative tube through the valve port p, and pushing the liquid in the quantitative tube into the sample injector 13 through the valve port c. The temperature of the sample injector 13 is 250°C, which can completely vaporize the incoming liquid, and input the vaporized gas into the chromatographic column for separation. The separated sample enters the hydrogen flame detector from the chromatographic column for detection. After the detection is completed, the six-way valve is closed, and the valve ports w, valve port p, valve port s, and valve port c are restored to the default state, completing the entire process of liquid injection, vaporization and analysis.

[0076] After the sample analysis is completed, the sample is recovered. The process of sample recovery includes: rotating the quantitative tube to, connected with valve port w and valve port s; opening the stop valve 3 and the stop valve 9, adjusting the liquid three-way selection valve, so that the valve port w of the six-way valve, the pressure sensor and the flow limiter 15 are in a connected state, and compressed air is filled into the sampling tank 8 through the air source. The gas in the sampling tank 8 is on the top and the liquid is on the bottom. The compressed air will push the liquid out of the sampling tank 8 and flow through the stop valve 9, the filter 10, the valve port s of the six-way valve, the quantitative tube, the valve port w of the six-way valve, the liquid three-way selection valve, the pressure sensor and the flow limiter 15 in sequence. At this time, the flow limiter 15 does not limit the flow and will be fully opened. The sample enters the sample recovery device 16 from the flow limiter 15 for recovery until the liquid in the sampling tank 8 is completely discharged into the sample recovery device 16, and the stop valve 3 and the stop valve 9 are closed to complete the entire sample recovery process.

[0077] After the sample recovery is completed, the entire detection system is flushed. The flushing process includes: opening the stop valve 2, closing the other valves, and evacuating the sampling tank 8 by the vacuum pump 1. After that, closing the vacuum pump 1 and the stop valve 2, opening the stop valve 4, allowing the diluent in the diluent storage tank 5 to enter the sampling tank 8 until the sampling tank 8 is full, rotating the quantitative tube to, and connecting with the valve port w and the valve port s; opening the stop valve 3, the stop valve 9 and the stop valve 14, adjusting the liquid three-way selection valve, so that the valve port w of the six-way valve, the pressure sensor and the flow restrictor 15 are in a connected state, and passing the gas source Compressed air is filled into the sampling tank 8, where the gas is on the top and the liquid is on the bottom. The compressed air will push the liquid out of the sampling tank 8 and flow through the stop valve 9, the filter 10, the valve port s of the six-way valve, the quantitative tube, the valve port w of the six-way valve, the liquid three-way selection valve, the stop valve 14 and the solvent recovery device 12 in sequence. At this time, the flow restrictor 15 does not limit the flow and will be fully opened. The sample recovery device 16 is recovered from the flow restrictor 15 until the liquid in the sampling tank 8 is completely discharged into the sample recovery device 16, and the stop valve 3 and the stop valve 9 are closed to complete the entire sample recovery process. And the solvent cleaning and gas flushing of the flow path ensure that there is no interference from other components when analyzing the sample next time, reducing data errors.

[0078] In this embodiment, the switches of the valves and the vacuum pump are controlled by a PLC control panel. The connecting pipes between the components in this embodiment are all made of 1 / 16 stainless steel pipes.

[0079] The analysis control system determines whether the intermediate is qualified according to the gas chromatography analysis results, and then controls the discharge valve of the intermediate storage tank 6 according to whether the intermediate is qualified. Specifically, when the intermediate is determined to be qualified, the discharge valve of the intermediate storage tank 6 is controlled to open, so that the intermediate in the intermediate storage tank 6 enters the qualified product tank for storage; when the intermediate is determined to be unqualified, the intermediate in the intermediate storage tank 6 is placed in the unqualified product tank for storage, or the intermediate is re-injected to the production process where the intermediate is obtained for reprocessing. The quality of the intermediate entering the next process is guaranteed.

[0080] In order to ensure that the gas chromatography detection of the previous intermediate does not affect the detection of the next intermediate, in this embodiment, after each gas chromatography detection of the intermediate is completed, the sampling device is controlled to obtain the diluent from the diluent storage tank 5 and press the diluent into the quantitative device. The set amount of diluent coming out of the quantitative device enters the gas chromatography detection device, and the remaining diluent enters the solvent recovery device 12, so that the sampling device, the quantitative device and the gas chromatography detection device are flushed by the diluent.

[0081] In order to ensure the flushing quality, this embodiment stipulates that the sampling device, the quantitative device and the gas chromatography detection device are repeatedly flushed with a diluent, and the diluent after each flushing is tested. When the diluent test after flushing meets the established standards, it means that the sampling device, the quantitative device and the gas chromatography detection device are flushed clean, and the flushing of the sampling device, the quantitative device and the gas chromatography detection device is stopped.

[0082] Since a variety of intermediates are produced during the production process of chemical raw materials, each intermediate is stored in a corresponding intermediate storage tank 6. In order to realize the whole process monitoring of the production of chemical raw materials, the present embodiment also connects the sampling device with multiple intermediate storage tanks 6, and the sampling device obtains the intermediate in one intermediate storage tank 6 each time; or, each intermediate storage tank is connected to a separate sampling device, each sampling device is connected to a separate quantitative device, and all quantitative devices are connected to a gas chromatography detection device. When the intermediate in one intermediate storage tank 6 is detected and rinsed, the intermediate in another intermediate storage tank 6 is obtained for detection, thereby reducing the detection cost while ensuring the detection accuracy.

[0083] In order to ensure the accuracy of detection, the present embodiment also connects the intermediate storage tank 6 with a plurality of sampling devices, each sampling device is connected with a separate quantitative device, each quantitative device is connected with a separate gas chromatography detection device; or, the intermediate storage tank is connected with a separate sampling device, the sampling device is connected with a plurality of quantitative devices, each quantitative device is connected with a separate gas chromatography detection device; all gas chromatography detection devices are connected in communication with the analysis and control system; for the intermediates in the same intermediate storage tank 6, gas chromatography analysis is performed on the intermediates through a plurality of gas chromatography detection devices, and when all gas chromatography analysis results of the intermediates are qualified, the intermediates are finally judged to be qualified, and the intermediate storage tank 6 is controlled to send the intermediates therein to the qualified product tank for storage; when one or more gas chromatography analysis results are unqualified, the intermediate is judged to be unqualified, and the intermediate storage tank 6 is controlled to send the intermediates therein back to the production process for processing, or to send the intermediates to the unqualified product tank for storage.

[0084] The process of performing intermediate detection by an intermediate detection system in the production process of a chemical raw material drug disclosed in this embodiment is explained with reference to an example.

[0085] When the intermediate is recycled solvent A, the 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; and both items are detected by gas chromatography analysis method; because three batches of products are produced simultaneously when recycled solvent A is produced, the three batches of products are respectively stored in tank A, tank B and tank C. The concentration of B in the three batches of products is different. To this end, two gas chromatography detection devices are set up for the detection of recovered solvent A, each gas chromatography detection device is connected to a separate quantitative device, each quantitative device is connected to a separate sampling device, each sampling device is connected to tank A, tank B and tank C, or each quantitative device is connected to three sampling devices, tank A, tank B and tank C are connected to two sampling devices respectively; the sampling devices connected to tank A, tank B and tank C are all different; one of the gas chromatography detection devices is used to detect whether there are other impurities in the recovered solvent A in tank A, tank B and tank C; the other gas chromatography detection device is used to detect the concentration of B in the recovered solvent A heptane in tank A, tank B and tank C, and the two gas chromatography detection devices can perform analysis and detection at the same time; when the recovered solvent A is detected, it is not necessary to dilute the recovered solvent A, so the sampling device only obtains the recovered solvent A as the solution to be detected; the process of detecting the recovered solvent A in tank A, tank B and tank C is:

[0086] The recovered solvent A in tank A is obtained by one or two sampling devices as the solution to be tested; quantitative samples are taken from the solution to be tested by two quantitative devices respectively, and sent to two gas chromatography detection devices, and the two gas chromatography detection devices obtain the detection results of whether there are other impurities in the sample and the concentration results of B in the sample; in order to improve the accuracy of the detection, the recovered solvent A in tank A is sampled twice and gas chromatography detection is performed twice; after the two detections are completed, the average of the two detection results is taken to obtain the final detection results of whether there are other impurities in the sample and the concentration results of B in the sample; when the final detection results of whether there are other impurities in the sample and the concentration results of B in the sample are qualified, the recovered solvent A in tank A is judged to be qualified; the qualified recovered solvent A is transported to a qualified storage tank; when one or both of the final detection results of whether there are other impurities in the sample and the concentration results of B in the sample are unqualified, the recovered solvent A in tank A is judged to be unqualified, and the unqualified recovered solvent A in tank A is transferred to the front fraction tank for re-fractionation.

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

[0088] After each test is completed, the sampling device, quantitative device and gas chromatography detection device are cleaned; the remaining sample after each test in the sampling device and the cleaning liquid after cleaning the sampling device, quantitative device and gas chromatography detection device are sent to the corresponding tank A, tank B and tank C through pipelines.

[0089] When the intermediate is a chromatographic purification product, the product after chromatographic separation is collected in 6 product tanks. The products in the 6 product tanks need to be tested for product content by gas chromatography detection device, and no dilution is required during the detection. Every three product tanks are connected to a sampling device, and each sampling device is connected to a quantitative device; each quantitative device is connected to a separate gas chromatography detection device; during the detection, the products in two product tanks are simultaneously tested by gas chromatography through two gas chromatography detection devices; then the products in the other two product tanks are tested simultaneously; finally, the products in the last two product tanks are tested simultaneously; to ensure the accuracy of the detection, the product in each product tank is tested twice, and the average of the two test results is taken as the final test result.

[0090] The qualified products in the product tank are transported to the qualified product tank; the unqualified products in the product tank are transported to the unqualified product tank.

[0091] After each test is completed, the sampling device, quantitative device and gas chromatography detection device are cleaned; the remaining sample after each test in the sampling device and the cleaning liquid after cleaning the sampling device, quantitative device and gas chromatography detection device are sent to the waste liquid receiving tank through the pipeline.

[0092] When the intermediate is the mobile phase required for the chromatography process, there are two mobile phase preparation tanks, and the mobile phases in the two mobile phase preparation tanks need to be tested to see if the concentration of the prepared mobile phase meets the requirements. The mobile phase components in the two preparation tanks are the same, but the concentrations are different. During production, the two preparation tanks will not be used at the same time, so the two preparation tanks are connected to a sampling device, and the sampling device is connected to a quantitative device, which is connected to a separate gas chromatography detection device; the gas chromatography detection device performs gas chromatography detection and analysis on the mobile phase in one of the preparation tanks each time; during detection, the mobile phase sample does not need to be diluted. To ensure the accuracy of the results, the mobile phase in each preparation tank is tested twice in parallel, and the average value is taken as the final result.

[0093] After the test is completed, if the mobile phase is qualified, the mobile phase will be stored in the preparation tank and wait for normal use. If the mobile phase is unqualified, the mobile phase preparation ratio will be adjusted according to the test results, and the mobile phase will be tested again after preparation until the concentration meets the requirements. After each test is completed, the sampling device, quantitative device and gas chromatography detection device are cleaned; the remaining samples after each test in the sampling device and the cleaning liquid after cleaning the sampling device, quantitative device and gas chromatography detection device are sent to the waste liquid receiving tank through the pipeline.

[0094] When the intermediate is recovered solvent B, the main component is B, and the recovered solvent B contains two components, B and A. The recovered solvent B is stored in two sample tanks, and the concentration of B in the recovered solvent B needs to be detected by a gas chromatography detection device. The concentration of B in the two sample tanks is different. Each sample tank is connected to a sampling device separately, each sampling device is connected to a separate quantitative device, and each quantitative device is connected to a separate gas chromatography detection device; the concentration of B in the recovered solvent B in the two sample tanks is detected by two gas chromatography detection devices; during the detection, the concentration of B does not need to be diluted. To ensure the accuracy of the results, the recovered solvent B in each sample tank is detected three times in parallel, and the average value is taken as the final detection result; the final detection result obtained by one of the gas chromatography detection devices is used to determine whether the recovered solvent B is qualified; for qualified recovered solvent B, it is transported to a qualified storage tank, and for unqualified recovered solvent B, it is transferred to the front fraction tank for re-fractionation; for the final detection result obtained by the other gas chromatography detection device, it is used as the data basis for the next configuration operation.

[0095] For intermediates that need to be diluted with diluents before gas chromatography detection, they are called intermediate products one and intermediate products two. The products and impurity content of these two intermediate products need to be detected. Intermediate products one and two are stored in separate product tanks, and the two tanks have different products and different detection methods. In order to prevent cross contamination, it is selected to connect a gas chromatography detection device for each test. Specifically, the two product tanks are each connected to a sampling device, each sampling device is connected to a separate quantitative device, and each quantitative device is connected to a separate gas chromatography detection device; the intermediate products in the two product tanks are analyzed one by one by two gas chromatography detection devices, and when the two sampling devices obtain the intermediate products, they also need to obtain the diluent according to the set dilution ratio, mix the diluent with the intermediate product according to the dilution ratio, and obtain the solution to be tested. In order to ensure the accuracy of the results, the intermediate products in each product tank are tested three times in parallel, and the average value is taken as the final result. The qualified intermediate products in the product tank are transported to the qualified storage tank, and the unqualified intermediate products in the product tank are transported to the unqualified tank. Regardless of whether they are qualified or not, the remaining samples after each test in the sampling device and the cleaning liquid after cleaning the sampling device, quantitative device and gas chromatography detection device are sent to the front fraction tank of each product through pipelines.

[0096] The present embodiment discloses an intermediate detection system for the production process of chemical raw materials, which can complete the automatic sampling, dilution, metering and gas chromatography detection and analysis of intermediates in the production process of chemical raw materials, realize timely and effective detection of each intermediate, and can control the production process according to the detection results of the intermediates.

[0097] The present embodiment discloses an intermediate detection system in the production process of a chemical raw material drug. The number of sampling devices, quantitative devices and gas chromatography detection devices is set according to the production rhythm of the raw material drug. On the basis of ensuring the accurate quality detection of each intermediate, as few gas chromatography detection devices as possible are used to perform quality detection of each intermediate, thereby improving the production efficiency of the raw material drug.

[0098] Example 2

[0099] In this embodiment, if Figure 2 As shown, a detection method for an intermediate detection system in a chemical raw material drug production process disclosed in Example 1 is disclosed, comprising:

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

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

[0102] Performing gas chromatography analysis on the sample through a gas chromatography detection device to obtain a gas chromatography analysis result;

[0103] Determine whether the intermediate is qualified based on the gas chromatography analysis results.

[0104] Among them, when an intermediate storage tank is connected to multiple sampling devices, multiple intermediates in the intermediate storage tank are obtained through the multiple sampling devices, and multiple solutions to be tested are formed; a set amount of sample is taken out from each solution to be tested; each sample is subjected to gas chromatography analysis by a separate gas chromatography detection device to obtain the gas chromatography analysis result of each sample; when the gas chromatography analysis results of all samples are qualified, the intermediate is judged to be qualified.

[0105] For a sampling device connected to multiple intermediate storage tanks, the sampling device obtains an intermediate of a chemical raw material drug in an intermediate storage tank, and after completing a gas chromatography analysis of the intermediate by a gas chromatography detection device, the sampling device obtains an intermediate of a chemical raw material drug in another intermediate storage tank.

[0106] Each gas chromatography detection device connected to the intermediate storage tank performs gas chromatography analysis on the intermediate in the intermediate storage tank; when all gas chromatography 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] In addition, when 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 the diluent is sent to the quantitative device. The diluent from the quantitative device enters the gas chromatography detection device, and the sampling device, the quantitative device and the gas chromatography detection device are cleaned. By cleaning the device after each gas chromatography analysis, it is ensured that each gas chromatography analysis is not affected by the last liquid, and the accuracy of each gas chromatography analysis is guaranteed.

[0108] Although the above describes the specific implementation mode of the present invention in conjunction with the accompanying drawings, it 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 on the basis of the technical solution of the present invention without creative work are still within the scope of protection of the present invention.

Claims

1. A system for detecting intermediates in the production process of chemical raw materials, characterized in that: It includes analysis and control system, sampling device, quantitative device and gas chromatography detection device; A sampling device, used to obtain the intermediate of the chemical raw material drug in the intermediate storage tank, form the obtained intermediate into a solution to be tested, and send the solution to be tested into the quantitative device; A quantitative device, used to take a set amount of sample from the input liquid to be tested and send it to the gas chromatography detection device; A gas chromatography detection device, used for performing gas chromatography analysis on the input sample to obtain gas chromatography analysis results; The analysis control system is used to determine whether the intermediate is qualified based on the gas chromatography analysis results.

2. A chemical raw material drug production process intermediate detection system as claimed in claim 1, characterized in that: The sampling device is also used to obtain the diluent in the diluent storage tank, and mix the obtained intermediate and the diluent to form a solution to be tested.

3. The intermediate detection system in the production process of chemical raw materials as claimed in claim 1, characterized in that: The sampling device is connected to the plurality of intermediate storage tanks, and the sampling device obtains the intermediate in one intermediate storage tank each time; or, Each intermediate storage tank is connected to a separate sampling device, each sampling device is connected to a separate quantitative device, and all quantitative devices are connected to a gas chromatography detection device.

4. The intermediate detection system in the production process of chemical raw materials as claimed in claim 1, characterized in that: The intermediate storage tank is connected to a plurality of sampling devices, each sampling device is connected to a separate quantitative device, and each lightweight device is connected to a separate gas chromatography detection device; or, The intermediate storage tank is connected to a separate sampling device, the sampling device is connected to a plurality of quantitative devices, and each quantitative device is connected to a separate gas chromatography detection device.

5. The intermediate detection system in the production process of chemical raw materials as claimed in claim 1, characterized in that: The dosing device is also connected to the recovery device.

6. A detection method for an intermediate detection system in a chemical raw material drug production process according to any one of claims 1 to 5, characterized in that: include: The intermediate of the chemical raw material drug in the intermediate storage tank is obtained by a sampling device, and the obtained intermediate is formed into a solution to be tested; The solution to be tested enters the quantitative device, and a set amount of sample is taken out through the quantitative device and sent to the gas chromatography detection device; Performing gas chromatography analysis on the sample through a gas chromatography detection device to obtain a gas chromatography analysis result; Determine whether the intermediate is qualified based on the gas chromatography analysis results.

7. The detection method of the intermediate detection system in the production process of chemical raw materials as claimed in claim 6, characterized in that: When one intermediate storage tank is connected to multiple sampling devices, multiple portions of intermediates in the intermediate storage tank are obtained through the multiple sampling devices to form multiple portions of solutions to be tested; a set amount of sample is taken from each portion of the solution to be tested; Perform gas chromatography analysis on each sample through a separate gas chromatography detection device to obtain a gas chromatography analysis result of each sample; when the gas chromatography analysis results of all samples are qualified, the intermediate is judged to be qualified.

8. The detection method of an intermediate detection system in a chemical raw material drug production process according to claim 6, characterized in that: The qualified intermediates are put into qualified product tanks for storage; The intermediates judged as unqualified are placed in a defective product tank for storage, or are placed in the production process from which the intermediates were obtained for reprocessing.

9. The detection method of an intermediate detection system in a chemical raw material drug production process according to claim 6, characterized in that: For a sampling device connected to multiple intermediate storage tanks, the sampling device obtains an intermediate of a chemical raw material drug in an intermediate storage tank, and after completing a gas chromatography analysis of the intermediate by a gas chromatography detection device, the sampling device obtains an intermediate of a chemical raw material drug in another intermediate storage tank.

10. The detection method of an intermediate detection system in a chemical raw material drug production process according to claim 6, characterized in that: When 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 the diluent is sent to the quantitative device. The diluent coming out of the quantitative device enters the gas chromatography detection device to clean the sampling device, the quantitative device and the gas chromatography detection device.

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