Real-time quantitative calibration spectrum online detection device and use method

Abstract

The invention discloses a real-time quantitative calibration spectrum on-line detection device and a use method thereof, a standard substance with a known concentration is accurately injected into a mixer and is mixed with a reaction liquid on line, and then a spectrum detector obtains spectrum absorption data of the mixed liquid; on the basis of the spectral absorption intensity linear superposition relation between the standard substance and the reaction liquid and the metering relation between the target product and the injected target product, online correction is carried out, and finally the concentration value of the target product is obtained. The online standard sample injection and dynamic online calibration technology is introduced, so that the problems of low quantitative precision, manual sampling lagging and the like in chemical reaction monitoring are solved, and the online standard sample injection and dynamic online calibration technology is particularly suitable for the fields of photochemical synthesis, continuous pharmacy and the like with strict process analysis timeliness requirements.

Description

Technical Field

[0001] The present invention relates to the technical field related to chemical process analysis, and in particular to a real-time quantitative calibration spectrum online detection device and a use method thereof. Background Art

[0002] In fields such as chemical synthesis and pharmaceutical manufacturing, real-time and accurate reaction process monitoring is crucial for optimizing conditions and ensuring quality. Spectroscopic analysis techniques such as UV-Vis and near-infrared spectroscopy have become core tools for online monitoring of reaction progress in process analytical technology (PAT) due to their non-destructive, fast response, and rich information.

[0003] However, existing spectroscopy-based online detection technologies still have significant drawbacks when applied to complex dynamic reaction systems. This problem is particularly prominent in scenarios where timeliness is extremely important, such as photochemical synthesis, continuous flow chemistry, and continuous pharmaceutical manufacturing. Traditional methods require regular interruption of the reaction process, manual sampling, and offline analysis (such as HPLC and GC-MS), and then calibration of the online spectral model based on this. This method is cumbersome and time-consuming, causing monitoring data lags and disrupting reaction continuity, which can easily lead to product failure in fast or sensitive reaction systems. For example, it has poor adaptability to dynamic systems. In dynamic systems such as continuous flow reactors, changes in parameters such as flow rate and mixing efficiency affect the stability of spectral measurements, but existing online spectroscopy technologies lack an effective mechanism to actively correct the impact of dynamic factors on quantitative results in real time.

[0004] In cutting-edge fields like photochemical synthesis and continuous pharmaceutical manufacturing, rapid reactions, sensitive conditions, and stringent requirements for product purity and yield necessitate process analysis technologies with second- or even millisecond-level responses and accurate and reliable data. Therefore, developing an online detection method and device that can automatically and accurately calibrate spectral quantitative results in real time, overcome standard curve drift, avoid manual intervention lag, and adapt to dynamic reaction systems has become a key issue in this field, crucial for promoting the application of advanced production models. Summary of the Invention

[0005] The purpose of the present invention is to provide a real-time quantitative calibration chemical reaction online detection device and method of use. By introducing a standard solution in real time for dynamic calibration, the device overcomes the problems of manual calibration lag in traditional spectral detection technology, achieves real-time, high-precision online detection of target products in complex dynamic reaction systems, and meets the needs of chemical synthesis, pharmaceutical and other fields for precise control of reaction processes. The technical solution of the present invention is as follows: A real-time quantitative calibration spectrum online detection device comprises a reactor, a constant flow pump, a six-way valve, a mixer, a spectrum detector, a two-position three-way valve, a real-time quantitative calibration component and a data processing system; the constant flow pump is connected to the reactor and the six-way valve via a pipeline; the real-time quantitative calibration component is connected to the six-way valve via a pipeline; the mixer is connected to the six-way valve and the spectrum detector via a pipeline; the two-position three-way valve and the spectrum detector are connected via a pipeline; and the data processing system is connected to the spectrum detector, the constant flow pump, the six-way valve and the metering pump via a data line.

[0006] Furthermore, the real-time quantitative calibration component includes the six-way valve, a metering pump and a standard solution system, and the metering pump is connected to the six-way valve and the standard solution system through a pipeline; when the detection starts, the metering pump pumps the standard solution out of the standard solution system, passes through the six-way valve, enters the mixer, and after mixing with the reaction solution, the mixed solution flows into the spectral detector through the pipeline for detection.

[0007] Furthermore, the spectrum detector is one of an ultraviolet detector, a near-infrared detector or a Raman spectrum detector, or multiple detectors may be used.

[0008] Furthermore, the standard solution system contains a raw material standard solution or a product standard solution, or uses both a raw material standard solution and a product standard solution.

[0009] Furthermore, the maximum flow rate of the constant flow pump is 10 ml / min; the maximum flow rate of the metering pump is 5 ml / min, and the flow rate accuracy is ±1%; the spectral detector is an ultraviolet dual-wavelength detector, which detects raw materials and products respectively; the six-way valve has three core passages, namely the mobile phase direct current passage, the sample loading passage and the sample injection passage, and injection is achieved by switching the Load / Inject state; multiple real-time quantitative calibration components can be added between the constant flow pump and the mixer as needed.

[0010] Furthermore, the spectrum detector adopts a dual-wavelength mode for detecting the reaction liquid. The target product has a stronger absorption at wavelength A than other substances in the reaction liquid, and the reactant has a stronger absorption at wavelength B than other substances in the reaction liquid.

[0011] A method for using a real-time quantitative calibration spectral online detection device. The online detection device extracts the reaction liquid from the reactor through a constant flow pump, and flows it through the detection cell of the real-time quantitative calibration component and the spectral detector. The spectral signal is collected by a data processing system and calculated to obtain the real-time changes in the composition of the reactor. The specific steps are as follows: Step 1: Turn on the spectrum detector for preheating; Step 2: The constant flow pump pumps the reaction solution out of the reactor, passes through a six-way valve, and enters the mixer. At the same time, the metering pump pumps the standard solution from the standard solution system out through a six-way valve and enters the mixer. After mixing with the reaction solution, the mixed solution flows into the spectrum detector through a pipeline. After the reaction solution flows out of the spectrum detector, it passes through a two-position three-way valve to select whether to flow directly out or flow back into the reactor. Step 3: As the mixed solution flows through the spectral detector, the spectral detection module collects spectral absorption data of the mixed solution in real time. The data processing system establishes a dynamic correction model based on the linear superposition relationship between the spectral absorption data of the mixed solution and the spectral absorption data of the standard solution, combined with the metering parameters of the standard injection volume and the mixing ratio. The dynamic correction model is then used to perform online calibration of the spectral absorption signal of the target product to calculate the real-time concentration value of the target product. Step 4: After the test is completed, the mixed liquid flows back into the reactor or into the waste liquid tank as needed.

[0012] Furthermore, after the reaction solution is mixed online with a standard solution of known concentration by an online detection device, the spectral absorption data of the mixed solution is obtained by a spectral detector. A dynamic correction model is established through a linear superposition relationship with the spectral absorption data of the standard solution, combined with the metering parameters of the standard injection amount and the mixing ratio. The spectral absorption signal of the target product is then calibrated online using the dynamic correction model to calculate the real-time concentration value of the target product. The dynamic correction model is established by the following formula: in is the absorption strength of the mixed system, is the concentration of the reaction solution, is the concentration of the standard, is the molar absorptivity, which can be obtained by algorithm.

[0013] Furthermore, in step 1, the preheating time is 10 to 20 minutes.

[0014] Furthermore, in step 2, the concentration of the standard is 10% to 120% of the expected concentration range of the target product.

[0015] The present invention has the following beneficial effects: 1. By introducing online standard sample injection and dynamic online calibration technology, it solves problems such as low quantitative accuracy and manual sampling lag in chemical reaction monitoring, making it particularly suitable for fields such as photochemical synthesis and continuous pharmaceutical manufacturing, where timeliness of process analysis is strictly required. 2. The present invention can automatically calibrate spectral quantitative results in real time with high precision, overcome standard curve drift, avoid manual intervention lag, and adapt to dynamic reaction systems, thereby ensuring reaction continuity. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Schematic diagram of the structure of the detection device of the present invention; 1-reactor, 2-constant flow pump, 3-six-way valve, 4-mixer, 5-spectral detector, 6-two-position three-way valve, 7-metering pump, 8-standard solution system, 9-data processing system, 10-real-time quantitative calibration component. DETAILED DESCRIPTION

[0017] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0018] Combine Figure 1 Shown: Example 1 The reactor 1, constant flow pump 2, six-way valve 3, mixer 4, spectral detector 5, two-position three-way valve 6, and real-time quantitative calibration component 10 (including a metering pump and a standard solution system, in this embodiment, a product standard solution is used). The standard solution system is a system consisting of a storage bottle and the corresponding standard solution, and is connected in the above manner to form an online detection device.

[0019] The maximum flow rate of the constant flow pump is set to 8 ml / min, the maximum flow rate of the metering pump is set to 3 ml / min, and the spectral detector uses an ultraviolet dual-wavelength detector, whose wavelength A is set to the characteristic absorption wavelength of the target product, and the wavelength B is set to the characteristic absorption wavelength of the reactant.

[0020] The specific steps are as follows: Step 1: Preheat the spectrum detector for 15 minutes; Step 2: Start the constant flow pump to pump the reaction solution out of the reactor at a flow rate of 5 ml / min, which enters the mixer through the six-way valve. Simultaneously, start the metering pump to pump the product standard solution out at a flow rate of 1 ml / min, which enters the mixer through the six-way valve to mix with the reaction solution. The mixed solution then flows into the spectrum detector. A two-position three-way valve controls the reaction solution to flow out of the spectrum detector and back into the reactor. Step 6: The spectrum detector collects the spectrum absorption data of the mixed solution at wavelength A and wavelength B in real time. The data processing system uses the standard injection volume and mixing ratio parameters, combined with the formula in is the absorption strength of the mixed system, is the concentration of the reaction solution, is the concentration of the standard, is the molar absorptivity coefficient.

[0021] Establish a dynamic correction model to perform online calibration on the spectral absorption signal of the target product and calculate the real-time concentration value of the target product; After the test is completed, the mixed liquid is controlled to flow into the waste liquid tank through a two-position three-way valve.

[0022] In the above scheme, the molar absorptivity coefficient k is obtained by fitting the experimental data of the standard concentration gradient by the least squares method.

[0023] The above-mentioned chemical reaction online monitoring system has all the advantages of the above-mentioned chemical reaction online monitoring method, which will not be described in detail here.

[0024] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

[0025] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A real-time quantitative calibration spectrum online detection device, characterized by: The invention comprises a reactor (1), a constant flow pump (2), a six-way valve (3), a mixer (4), a spectrum detector (5), a two-position three-way valve (6), a real-time quantitative calibration component (10) and a data processing system (9); the constant flow pump (2) is connected to the reactor (1) and the six-way valve (3) through a pipeline; the real-time quantitative calibration component is connected to the six-way valve (3) through a pipeline; the mixer (4) is connected to the six-way valve (3) and the spectrum detector (5) through a pipeline; the two-position three-way valve (6) and the spectrum detector (5) are connected through a pipeline; the data processing system (9) is connected to the spectrum detector (5), the constant flow pump (2), the six-way valve (3) and the metering pump (7) through a data line.

2. The real-time quantitative calibration spectrum online detection device according to claim 1, characterized in that: The real-time quantitative calibration component (10) includes the six-way valve (3), a metering pump (7) and a standard solution system (8), and the metering pump (7) is connected to the six-way valve (3) and the standard solution system (8) through a pipeline; when the detection starts, the metering pump (7) pumps the standard solution in the standard solution system (8) out through the six-way valve (3) and into the mixer (4). After mixing with the reaction solution, the mixed solution flows into the spectrum detector (5) through the pipeline for detection.

3. The real-time quantitative calibration spectrum online detection device according to claim 1, characterized in that: The spectrum detector is one of an ultraviolet detector, a near infrared detector or a Raman spectrum detector.

4. The real-time quantitative calibration spectrum online detection device according to claim 2, characterized in that: The standard solution system includes a raw material standard solution or a product standard solution, or uses both the raw material standard solution and the product standard solution.

5. The real-time quantitative calibration spectrum online detection device according to claim 4, characterized in that: The maximum flow rate of the constant flow pump (2) is 10 ml / min; the maximum flow rate of the metering pump (6) is 5 ml / min, and the flow rate accuracy is ±1%; the spectrum detector (5) is an ultraviolet dual-wavelength detector, which detects the raw materials and products respectively; the six-way valve (3) has three core paths, namely, a mobile phase direct current path, a sample loading path and a sample injection path, and injection is achieved by switching the Load / Inject state; multiple real-time quantitative calibration components (10) can be added between the constant flow pump (2) and the mixer (4) as needed.

6. The real-time quantitative calibration spectrum online detection device according to claim 5, characterized in that: The spectrum detector (5) adopts a dual-wavelength mode for detecting the reaction liquid. The target product has a stronger absorption at wavelength A than other substances in the reaction liquid, and the reactant has a stronger absorption at wavelength B than other substances in the reaction liquid.

7. The method for using the real-time quantitative calibration spectrum online detection device according to claim 1, characterized in that: The online detection device extracts the reaction liquid in the reactor (1) through a constant flow pump (2), and flows it through the detection pool of the real-time quantitative calibration component (10) and the spectrum detector (5). The spectrum signal is collected by the data processing system (9) and then calculated to obtain the real-time changes in the composition in the reactor (1). The specific steps are as follows: Step 1: Turn on the spectrum detector (5) to preheat; Step 2: The constant flow pump (2) pumps the reaction liquid out of the reactor (1), passes through the six-way valve (3), and enters the mixer (4); at the same time, the metering pump (7) pumps the standard solution in the standard solution system (8), passes through the six-way valve (3), and enters the mixer (4). After mixing with the reaction liquid, the mixed solution flows into the spectrum detector (5) through the pipeline; after the reaction liquid flows out of the spectrum detector (5), it passes through the two-position three-way valve to select whether to flow out directly or flow back to the reactor (1). Step 3: When the mixed solution flows through the spectral detector, the spectral detection module collects the spectral absorption data of the mixed solution in real time. The data processing system (9) establishes a dynamic correction model based on the linear superposition relationship between the spectral absorption data of the mixed solution and the spectral absorption data of the standard solution, combined with the metering parameters of the standard injection volume and the mixing ratio. The dynamic correction model is then used to perform online calibration on the spectral absorption signal of the target product, and the real-time concentration value of the target product is calculated. Step 4: After the test is completed, the mixed liquid flows back into the reactor or into the waste liquid tank as needed.

8. The method for using the real-time quantitative calibration spectrum online detection device according to claim 7, characterized in that: After the reaction solution is mixed online with a standard solution of known concentration by an online detection device, spectral absorption data of the mixed solution is obtained by a spectral detector. A dynamic correction model is established based on a linear superposition relationship with the spectral absorption data of the standard solution, combined with the metering parameters of the standard injection amount and the mixing ratio. The spectral absorption signal of the target product is then calibrated online using the dynamic correction model to calculate the real-time concentration value of the target product; The dynamic correction model is established by the following formula: in is the absorption strength of the mixed system, is the concentration of the reaction solution, is the concentration of the standard, is the molar absorptivity coefficient.

9. The method for using the real-time quantitative calibration spectrum online detection device according to claim 7, characterized in that: In step 1, the preheating time is 10 to 20 minutes.

10. The method for using the real-time quantitative calibration spectrum online detection device according to claim 7, characterized in that: In step 2, the concentration of the standard is 10% to 120% of the expected concentration range of the target product.

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