Multi-channel crystallization process rapid screening method combined with microflow imaging analysis

Abstract

The invention discloses a multi-channel crystallization process rapid screening method combined with microflow imaging analysis, which comprises the following steps: S1, lifting an upper sealing cover, putting into six crystallization glass beakers, and adding raw materials and solvents into the respective beakers; s2, lowering an upper sealing cover, connecting external circulation of a high-low temperature circulator to a temperature control tank, starting a magnetic stirrer and temperature control through program control, and starting dissolution; s3, after dissolution is completed, cooling crystallization is achieved by reducing the temperature or solvent-out crystallization is achieved by adding a poor solvent into a feeding opening in the upper portion; and S4, after the crystals are separated out, starting an automatic sampling program, and carrying out wet particle size and particle shape detection on the crystal recrystallization sample of each channel to obtain morphology results under different experimental conditions. According to the invention, real-time monitoring of particle morphology in a wet environment can be realized, disturbance of the whole process to a crystallization system is minimum, real'lossless' monitoring is realized, and the method has the advantages of high time resolution, resource saving and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the chemical industry field, in particular to a multi-channel crystallization process rapid screening method combined with micro-flow imaging analysis. BACKGROUND

[0002] Traditional crystallization process screening methods usually use single batch experiments. This method not only takes a long time, but also is difficult to comprehensively evaluate the influence of various parameters on the crystallization process. In addition, due to the limitation of experimental conditions, the traditional method also has great limitations in parameter adjustment and optimization.

[0003] In recent years, with the development of automation technology and high-throughput experimental equipment, multi-channel crystallization process screening has gradually become a research hotspot. This method can significantly improve experimental efficiency and shorten process development cycle by conducting multiple experiments simultaneously. However, existing multi-channel crystallization technology still faces some problems, such as how to accurately control the experimental conditions of each channel, and how to quickly and accurately evaluate the quality of the crystalline product.

[0004] It is particularly noteworthy that the existing multi-channel crystallization technology lacks an effective solution for real-time monitoring of particle morphology during the crystallization process. Traditional morphology analysis usually uses offline sampling detection, and conventional particle analysis techniques have obvious limitations: laser diffraction method can only provide equivalent spherical diameter data and cannot obtain morphology information; microscope method needs to analyze the sample after filtering, washing and drying, etc. This process not only takes time but also has a lag, and more importantly, the sample processing process will cause secondary changes in particles (such as fragmentation, aggregation, continued growth or dissolution, etc.), making the measurement results unable to truly reflect the particle state during the crystallization process.

[0005] In the existing technical literature, there are few reports on the application of multi-channel crystallization and micro-flow imaging analysis, especially the lack of technical solutions for combining automatic sampling systems with wet particle morphology analysis for real-time monitoring of the crystallization process. Existing technologies mainly focus on temperature control, stirring systems or simple turbidity monitoring, and cannot obtain dynamic change information of particle morphology. SUMMARY

[0006] The present application aims to solve the shortcomings of traditional crystallization process screening methods and provides a multi-channel crystallization process rapid screening method combined with micro-flow imaging analysis by combining modern automation and measurement technology.

[0007] The present application achieves the above-mentioned purpose by the following technical solutions:

[0008] The present application provides a multi-channel crystallization process rapid screening method combined with micro-flow imaging analysis, comprising the following steps:

[0009] Step S1, lift the upper cover, put six crystal glass beaker, raw materials and solvent into the respective beaker;

[0010] Step S2, lower the upper cover, connect the external circulation of high and low temperature circulator on the temperature control tank, start the magnetic stirrer and temperature control through program control, and begin to dissolve;

[0011] Step S3, after waiting for the completion of dissolution, realize the cooling crystallization by reducing the temperature or realize the solvent-out crystallization by adding poor solvent through the upper feeding port;

[0012] Step S4, after the crystal precipitates, start the automatic sampling program, detect the wet particle size and shape of the crystal recrystallization sample of each channel, and obtain the morphology results under different experimental conditions.

[0013] As a preferred embodiment of the present application, the upper cover in step S1 is controlled to be lifted and lowered by a stepping motor, and each glass beaker is placed in a temperature control tank.

[0014] As a preferred embodiment of the present application, the temperature control tank in step S2 adopts an integrated jacket design, which is different from the independent temperature control unit in the prior art. The jacket structure of the present application can provide a more uniform temperature field, ensure the synchronization and consistency of the six channels during temperature cycling, and is particularly suitable for the study of crystallization systems which are less sensitive to temperature but sensitive to other parameters.

[0015] As a preferred embodiment of the present application, the magnetic stirrer in step S2 is placed below the temperature control tank and has six independent motors driven, which can realize different speed adjustment and integrated control in the general control program.

[0016] As a preferred embodiment of the present application, step S3 provides two differentiated crystallization induction methods: one is to realize the precise control of supersaturation through programmed temperature reduction; the other is to realize linear increase, exponential increase or pulse addition and other addition modes through the anti-solvent addition controlled by the metering pump. The two methods can be used alone or in combination to form a differentiated regulation strategy for crystal morphology. No matter which crystallization method is adopted, the dynamic evolution information of particle characteristics can be obtained through subsequent real-time wet morphology analysis.

[0017] As a preferred embodiment of the present application, the automatic sampling procedure in step S4 is completed by an automatic sampling system including two injection pumps (a main pump and an auxiliary pump) working alternately, an eight-way electromagnetic switching valve, a sampling pipeline, and a waste liquid tank. One end of the sampling pipeline is connected to the sampling port on the upper cover, and the other end is connected to the image analysis system through the eight-way switching valve for wet particle size and shape detection of the crystallization samples in each channel. The eight-way electromagnetic switching valve is a high-precision electromagnetic eight-way switching valve, in which six ports are connected to six crystallization units, responsible for switching the sampling of different crystallizers, the seventh port is connected to a cleaning liquid for cleaning the residual substances in the pipeline, and the eighth port is connected to a waste liquid tank. Through programmed control, the sample flow direction of different channels is accurately switched, ensuring that the samples are not mixed and cross-contaminated, and the switching time is less than 100 ms.

[0018] The image analysis system used in the present application is another key innovation point different from the prior art:

[0019] The working principle of the image analysis system: the system is composed of a liquid cell assembly, a high-precision telecentric zoom lens, a blue pulsed light source, and a high-resolution CMOS camera, forming a closed-loop system with shooting and analysis integrated. Unlike traditional laser diffraction and static microscopy methods, this technology directly images and analyzes suspended particles in the original solution environment, maintaining the original state of the particles and avoiding changes in particle characteristics during sample processing.

[0020] The liquid cell assembly is an optical flow cell specially designed for suspended particle detection, with a parallel light path structure inside, and the flow channel thickness can be adjusted within the range of 50 μm to 600 μm to meet the measurement needs of particles in different size ranges. The internal flow channel geometry is optimized to ensure uniform dispersion of particles during measurement without breaking or aggregation.

[0021] It needs to be noted that the solvent content in the crystallizer should not be too small, at least to meet the amount that can be extracted for detection, about 15 ml, and at most not more than 100 ml.

[0022] Dynamic image capture technology: the system uses a high-speed CMOS camera (120 million pixels, resolution 4096x3000) combined with stroboscopic illumination, with a pulse width of up to 1 microsecond, which can effectively avoid motion artifacts, clearly capture particle images in a flowing state, and ensure that the images are clear and representative.

[0023] Multi-dimensional morphology parameter extraction algorithm: the system uses image processing algorithms specified in ISO-13322-2:2006 and GB / T 21649.2-2017 standards to extract up to 30 kinds of morphology parameters from the captured particle images, mainly including:

[0024] Particle size parameters (15 kinds): area, perimeter, convex hull perimeter, equivalent area diameter, equivalent perimeter diameter, inner diameter, Legendre ellipse long / short axis, Feret maximum / minimum diameter, Feret conjugate diameter, geodesic length, thickness, minimum circumscribed circle diameter, average diameter, skeleton length, etc.

[0025] Particle shape parameters (16 kinds): ellipticity, aspect ratio, elongation, straightness, irregularity, compactness, spread, curl, circularity, solidity, concavity, convexity, ISO shape factor, bluntness, satellite index, average gray level, etc.

[0026] Weight factors (2 kinds): number and volume, supporting data statistics and distribution expression according to different weights

[0027] Crystallization kinetics correlation analysis: the system is equipped with professional data processing software, which can realize various statistical chart display (bar distribution chart, scatter chart, etc.), establish a quantitative relationship model between process parameters (temperature, stirring rate, cooling rate, etc.) and particle morphology parameters, and provide a scientific basis for crystallization mechanism research and process optimization.

[0028] The beneficial effects of the present application are: 1. Methodological innovation automation is realized, the online analysis of wet morphology is combined with multi-channel crystallization screening, a complete "crystallization-sampling-analysis-reflow" closed loop system is formed, the limitations of traditional multi-channel screening which only focuses on temperature, turbidity and other conventional parameters are broken through, real-time dynamic monitoring of particle morphology characteristics is realized, the measurement range can be from 300 nm to 1000 μm, covering the particle size range of most crystallization processes.

[0029] 2. Real-time monitoring of particle morphology in a wet environment is realized, which is different from traditional dry analysis or simple online particle size measurement. Through the special design of the microfluidic circulation system and the dynamic image analysis technology, high-quality morphology information can be obtained under the condition of maintaining the original ecological state of the particles, the key laws of the evolution of particle characteristics in the crystallization process are revealed, the system automatically identifies the adhered particles on the lens, avoids repeated counting, and ensures the accuracy of the data.

[0030] 3. Non-destructive testing capability: the disturbance of the whole sampling-analysis-reflow process to the crystallization system is minimal, realizing true "non-destructive" monitoring, especially suitable for crystallization systems sensitive to shear. The sampling pipeline is made of corrosion-resistant polytetrafluoroethylene material, ensuring chemical compatibility and good adaptability to various organic and inorganic solvents.

[0031] 4. High time resolution: the system can realize high-frequency morphology data acquisition (the shortest interval can reach 1 minute), which can capture transient changes in the crystallization process, such as secondary nucleation, crystal dissolution, morphology transformation and other key phenomena. Real-time presentation of particle size distribution and particle count can continuously monitor and record the change process of the sample.

[0032] 5. Resource saving: Compared with traditional single batch experiment, the system can obtain multiple experimental data under the same material consumption, and further reduces the material loss through sample reflux design, especially suitable for crystallization research of valuable raw materials. The sample recovery rate can reach 100%, greatly improving the material utilization efficiency and experimental economy. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 It is a schematic diagram of the overall structure of the present application;

[0034] Figure 2 It is a schematic diagram of the structure of the crystallization screening unit of the present application;

[0035] Figure 3 It is a schematic diagram of the structure of the connection of the crystallization screening unit of the present application and the image analysis system;

[0036] Figure 4 It is a schematic diagram of the upper cover structure of the present application;

[0037] Figure 5 It is a schematic diagram of the software interface of the present application

[0038] In the figure: 1-solvent feeding port, 2-sampling port, 3-anti-solvent feeding port, 4-crystallizer tank, 5-stepping motor, 6-upper cover, 7-eight-way switching valve, 8-injection pump, 9-liquid material area, 10-magnetic stirrer, 11-control panel, 12-temperature control machine box, 13-temperature control medium conveying pipeline, 14-sampling pipeline, 15-waste liquid barrel, 16-liquid pool assembly, 17-CMOS camera, 18-particle size and shape instrument, 19-magnetic stirring paddle. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical scheme and advantages of the present application more clear, the implementation method of the present application will be described in detail below in combination with the drawings and examples, so that the realization process of how to apply technical means to solve technical problems and achieve technical effects can be fully understood and implemented.

[0040] In the following description, many specific details are set forth in order to provide a thorough understanding of the present application, however, the present application can also be implemented in other ways different from those described herein, therefore, the protection scope of the present application is not limited by the specific embodiments disclosed below.

[0041] As shown in the accompanying Figures 1-5 The present embodiment provides a multi-channel crystallization process rapid screening method combined with micro-flow imaging analysis, including the following steps:

[0042] Step S1, lift the upper cover 6, put six crystalline glass beakers, add raw materials and solvents into the respective beakers;

[0043] Step S2, lower the upper cover 6, connect the external circulation of the high and low temperature circulators to the temperature control tank, start the magnetic stirrer 10 and temperature control through program control, and begin dissolution;

[0044] Step S3, after waiting for the completion of dissolution, realize cooling crystallization by lowering the temperature or realize solvent-out crystallization by adding an undesirable solvent through the upper feeding port;

[0045] Step S4, after the crystallization, start the automatic sampling program, and detect the wet particle size and shape of the crystal recrystallization sample in each channel to obtain the morphology results under different experimental conditions.

[0046] As a preferred embodiment of the present application, the upper cover 6 in step S1 is controlled to be lifted and lowered by a stepping motor 5, and each glass beaker is placed in a temperature control tank.

[0047] As a preferred embodiment of the present application, the temperature control tank in step S2 adopts an integrated jacket design, which is different from the independent temperature control unit in the prior art. The jacket structure of the present application can provide a more uniform temperature field, ensure the synchronization and consistency of the six channels during temperature cycling, and is particularly suitable for the study of crystallization systems that are less sensitive to temperature but sensitive to other parameters.

[0048] As a preferred embodiment of the present application, the magnetic stirrer 10 in step S2 is placed below the temperature control tank and has six independent motors for driving and realizing different speed adjustments, which are integrated in the total control program.

[0049] As a preferred embodiment of the present application, step S3 provides two differentiated crystallization induction methods: one is to realize precise control of supersaturation through programmed temperature reduction; the other is to realize linear increase, exponential increase or pulse addition and other addition modes through the addition of anti-solvent controlled by a metering pump. These two methods can be used alone or in combination to form a differentiated regulation strategy for crystal morphology. Regardless of which crystallization method is used, the dynamic evolution information of the particle characteristics can be obtained through subsequent real-time wet morphology analysis.

[0050] As preferred embodiments of the present application, the automatic sampling procedure in step S4 is performed by an automatic sampling system, which includes two injection pumps 8 (a main pump and an auxiliary pump) working alternately, an eight-way electromagnetic switching valve, a sampling pipeline 14 and a waste liquid tank 15. One end of the sampling pipeline 14 is connected to the sampling port 2 on the upper cover 6, and the other end is connected to the image analysis system through the eight-way switching valve 7 for wet particle size and shape detection of the crystallization samples in each channel.

[0051] As shown in Figures 2-4 , the present embodiment also provides a multi-channel crystallization process rapid screening device combined with a particle size and shape instrument, which includes a crystallization screening unit and an image analysis system, and the image analysis system is located beside the crystallization screening unit. As shown in Figure 1 , the crystallization screening unit of the multi-channel crystallization process rapid screening device combined with a particle size and shape instrument of the present application includes a main box body, an upper cover 6, a six-channel crystallization unit, a temperature control system, a six-site magnetic stirrer 10 and an automatic sampling system. The upper cover 6 is connected to the top of the main box body, the six-channel crystallization unit is placed on the top of the main box body and connected to the temperature control system, the six-site magnetic stirrer 10 is located below the six-channel crystallization unit, and the automatic sampling system connects the six-channel crystallization unit and the image analysis system.

[0052] As preferred embodiments of the present application, the main box body adopts a frame structure design and includes an upper and lower two-layer platform. The upper layer platform is a temperature control tank area for placing the six-channel crystallization unit, and the lower layer platform is a supporting plate supporting the six-channel crystallization unit above, and the lower layer platform below is used for protecting and storing internal motors and electrical circuits. Six crystallization containers are evenly distributed in the temperature control tank, and each container is connected with the temperature measurement and sampling system pipeline above.

[0053] As preferred embodiments of the present application, the upper cover 6 is supported by two liftable supports and placed directly above the crystallization tank, and the feeding port and the sampling port 2 are arranged on the upper cover 6. The feeding port has four, and the sampling port 2 has one, arranged in a 212 arrangement (solvent feeding port 1, sampling port 2, anti-solvent feeding port 3). The upper cover 6 is controlled to rise and fall by a stepping motor 5 and integrated in the overall control program. Through these feeding ports and the sampling port 2, solvent or sample can be added during the experiment without affecting the stability of the crystallization environment. A liquid material area 9 is also arranged beside the upper cover 6, which is used to supply solvent and anti-solvent to the six-channel crystallization unit.

[0054] As a preferred embodiment of the present application, the six-channel crystallization unit comprises six sets of crystallizer tanks 4 and temperature control tanks. The crystallizer tanks 4 are used to place standard specification crystallization glass beakers, and the temperature control tanks are jacketed structures connected to a temperature control system. The crystallizer specifications of the six-channel crystallization unit are divided into multiple types, and each is matched with an upper cover 6, which is suspended by a central perforation with a magnetic stirring paddle 19 driven by a bottom magnetic stirrer 10.

[0055] As a preferred embodiment of the present application, the temperature control system comprises a high-low temperature circulator and a temperature measurement unit. The high-low temperature circulator comprises a control panel 11, a temperature control cabinet 12, and a temperature control medium delivery pipeline 13. The control panel 11 is installed on the temperature control cabinet 12, and the temperature control cabinet 12 delivers temperature control medium to the temperature control tanks through the temperature control medium delivery pipeline 13. The high-low temperature circulator is connected to the temperature control tanks through external circulation to control the temperature inside the crystallizer. The temperature measurement unit comprises a temperature measurement probe placed inside the crystallizer tank 4 to transmit temperature signals to the temperature control cabinet 12.

[0056] As a preferred embodiment of the present application, the six-site magnetic stirrer 10 is placed below the temperature control tank and has six independent motor drives that can achieve different speed adjustments and are integrated into the overall control program. The six-site magnetic stirrer 10 is used to control the magnetic stirring paddle 19 to stir the crystallizers in the crystallization unit.

[0057] As a preferred embodiment of the present application, the automatic sampling system connects the six-channel crystallization unit with the image analysis system to form a complete integrated system. The automatic sampling system comprises two alternating injection pumps 8 (main pump and auxiliary pump), an eight-way electromagnetic switching valve, a sampling pipeline 14, and a waste liquid tank 15. One end of the sampling pipeline 14 is connected to the sampling port 2 on the upper cover 6, and the other end is connected to the image analysis system through the eight-way switching valve 7 for wet particle size and shape detection of each channel's crystallization sample. The eight-way electromagnetic switching valve is a high-precision electromagnetic drive eight-way switching valve, six ports of which are connected to six crystallization units to switch the sampling of different crystallizers, the seventh port is connected to a cleaning liquid for cleaning residual substances in the pipeline, and the eighth port is connected to the waste liquid tank 15. Through programmed control, the sample flow direction of different channels is accurately switched to ensure that the samples are not mixed and cross-contaminated, and the switching time is less than 100 ms.

[0058] As a preferred embodiment of the present application, the two injection pumps 8 of the automatic sampling system work alternately to achieve uninterrupted liquid sampling to ensure the fluidity of the sample during wet optical particle size detection. After the detection is completed, the excess mother liquor is pushed back into the crystallizer.

[0059] As Figure 3As shown, the image analysis system comprises a particle size and shape analyzer 18 and a computer. The particle size and shape analyzer 18 is used for high-definition imaging of particles, analysis of particle size and shape and the like, and is connected to the computer through a data line. The computer is used for data analysis, storage and display of relevant parameters.

[0060] As a preferred embodiment of the present application, the particle size and shape analyzer 18 comprises a liquid cell assembly 16, a high-precision telecentric zoom lens, a blue pulsed light source and a high-resolution CMOS camera 17. The liquid cell assembly 16 is disposed between the high-resolution CMOS camera 17 and the blue pulsed light source. The high-precision telecentric zoom lens is combined with the high-resolution CMOS camera 17 to perform high-definition imaging of particles. The entire system is placed inside the particle size and shape analyzer 18. The bottom and side of the liquid cell assembly 16 are provided with an inlet and an outlet. The inlet is connected to an eight-way switching valve 7, and the outlet is connected to a syringe pump 8.

[0061] As a preferred embodiment of the present application, the liquid cell assembly 16 comprises replaceable clamps. The clamps have five different thicknesses to choose from: 50 μm, 100 μm, 200 μm, 400 μm and 600 μm, which are suitable for detection of particles in different size ranges. The liquid cell assembly 16 is a module of the imaging area. The thickness of the clamp in the liquid cell assembly 16 determines the maximum size of the particles flowing through. Particles larger than the thickness of the clamp in the liquid cell assembly 16 cannot pass through the imaging area.

[0062] As a preferred embodiment of the present application, the computer is configured with a special software for controlling the particle size and shape analyzer 18. The software includes data acquisition and data processing functions, which can process the collected images and extract particle size and shape parameters. The data processing function of the software can perform binaryzation processing on the images, identify the contours of the particles, and then calculate the particle size, circularity and other physical parameters of each particle according to certain equivalent modes.

[0063] The software interface will be shown in Figure 4 . The software includes a custom instruction control module, a real-time data display module, a particle morphology analysis module and a report generation module. The custom instruction control module supports multiple instructions, including PUMP instructions, CLEAN instructions, RESET instructions, VALVE instructions and other operation instructions. The real-time data display module is used to display particle number, particle size distribution, online statistics and concentration distribution information. The particle morphology analysis module can process the collected images, extract and analyze more than 30 particle size and shape parameters.

[0064] Specific operation steps

[0065] Test 1: Multi-channel cooling crystallization experiment

[0066] (1) Put the crystallization raw materials and solution with different mass ratio into six crystallizers, lower the cover, start the magnetic stirring and temperature control system,

[0067] (2) Raise the temperature to the set value, let the crystallization raw materials dissolve completely,

[0068] (3) Rapidly lower the temperature to the specified crystallization temperature,

[0069] (4) Start the crystallization in the crystallizer, open the automatic sampling, and detect the wet particle size and shape of the crystallization samples in the six channels,

[0070] (5) The image analysis system analyzes the particle shape data, and takes out the six crystallizers for unified cleaning.

[0071] Test 2: Multi-channel solvent crystallization experiment

[0072] (1) Put the crystallization raw materials and solution with different mass ratio into six crystallizers, lower the cover, start the magnetic stirring and temperature control system,

[0073] (2) Raise the temperature to the set value, let the crystallization raw materials dissolve completely,

[0074] (3) Control to the set crystallization temperature, and add the specified anti-solvent from the feeding port,

[0075] (4) Start the crystallization in the crystallizer, open the automatic sampling, and detect the wet particle size and shape of the crystallization samples in the six channels,

[0076] (5) The image analysis system analyzes the particle shape data, and takes out the six crystallizers for unified cleaning. Detailed working process of the device

[0077] 1. Forward continuous conveying stage

[0078] Double pump cooperation: the phase difference of the piston movements of the main pump and the auxiliary pump is 180°, and they are synchronously driven by the electromagnetic controller. The main pump is in the discharge state (the valve port is switched to the B state, and the pump cavity is connected with the outlet), and the liquid is conveyed to the eight-way valve through the main pipeline. The auxiliary pump is in the suction state at the same time (the valve port is switched to the A state, and the inlet is connected with the pump cavity), and the liquid is extracted from the liquid storage tank.

[0079] Eight-way valve control: after receiving the liquid discharged by the main pump, the eight-way valve is programmed to switch to the target crystallization channel (port 1-6), and the liquid is directed to the specified reaction cavity. The switching action is driven by the electromagnetic drive, and the time consumption is <100 ms, which ensures uninterrupted conveying.

[0080] Switching logic: when the main pump completes the discharge stroke, the auxiliary pump immediately switches to the discharge state (valve port B), and the main pump switches to the suction state (valve port A), realizing the alternate output of the double pumps. The eight-way valve is synchronously switched to the next target channel, forming a seamless continuous flow.

[0081] 2、Reverse delivery phase

[0082] Flow reversal: By adjusting the double pump valve port switching sequence, the main pump is in the suction stage (valve port A), and the auxiliary pump discharges liquid into the main pipeline in the reverse direction through the eight-way valve, and the eight-way valve switches to the reverse target port (such as a waste liquid collector). The direction of piston movement does not change, and only the flow direction is reversed by adjusting the valve state.

[0083] Application scenario: suitable for post-reaction waste liquid recovery, pipeline reverse flushing and other needs.

[0084] 3、Multi-channel cleaning phase

[0085] Cleaning liquid injection: the eight-way valve switches to the seventh port (cleaning liquid inlet), and the double pumps cooperatively discharge cleaning liquid to sequentially flush each crystallization channel. The cleaning process is controlled by the program, and each channel is independently flushed to avoid residue.

[0086] Waste liquid discharge: after cleaning is completed, the eight-way valve switches to the eighth port (waste liquid collector), and the double pumps reversely discharge waste liquid to ensure pipeline cleanliness.

[0087] 4、System cutoff state

[0088] Safety block: the double pumps pause movement, both valves switch to A state (the inlet is connected to the pump cavity, and the outlet is closed), and the eight-way valve synchronously closes all outlet ports, forming a double physical cutoff to prevent liquid leakage or backflow.

[0089] Core points:

[0090] 1、Double pump-eight way valve dynamic cooperative control,

[0091] Integrate the double pump with a phase difference of 180° with the eight-way electromagnetic valve, and realize millisecond-level synchronization (<100ms) of pump action-valve switching-channel distribution through programmed timing control, breaking through the bottleneck of large switching delay and high flow pulsation of traditional multi-pump systems.

[0092] Timing accuracy: the mechanical-electronic control cooperation problem of double pump piston movement and eight-way valve electromagnetic drive needs to be solved, and the PID closed-loop feedback control algorithm is adopted to ensure that the switching error is <1ms.

[0093] Sealing guarantee: the eight-way valve adopts a multi-layer ceramic-polymer composite sealing structure with a pressure resistance of >1MPa, avoiding cross-contamination of multiple channels.

[0094] 2、No pulsation continuous flow generation (core advantage)

[0095] Phase complementary principle: the double pumps alternately discharge, and the pulsation waveform of a single pump is eliminated by flow superposition, realizing a main pipeline flow fluctuation rate of <±2% (better than the traditional single pump of ±20%).

[0096] The present application has the advantages of: the design realizes the pulsation-free delivery without buffer for the first time in the microfluidic field, simplifies the system structure, and reduces the maintenance cost.

[0097] 3, flow direction-channel bidirectional programmable

[0098] Flow flexibility: forward and reverse flow can be realized by adjusting the valve switching logic, without physical modification of the pipeline, and adapting to complex processes (such as cyclic reaction, gradient generation).

[0099] Multi-channel isolation: eight-way valve integrates cleaning and waste liquid port, combined with programmed switching, to ensure independent operation of the six crystallization channels, with cross-contamination rate <0.01%.

[0100] Although the present application has been described with reference to the explanatory embodiments thereof, the above-described embodiments are merely preferred embodiments of the present application, and the embodiments of the present application are not limited to the above-described embodiments, and it should be understood that those skilled in the art can design many other modifications and embodiments, which will fall within the scope and spirit of the principles disclosed in the present application.

Claims

1. A rapid screening method of multi-channel crystallization process combined with micro-flow imaging analysis, comprising the following steps: Step S1, lifting the upper cover (6), putting six crystallization glass beakers, adding raw materials and solvents into the respective beakers; Step S2, lowering the upper cover (6), connecting the external circulation of high and low temperature circulators to the temperature control tank, starting the magnetic stirrer (10) and temperature control through program control, and starting dissolution; Step S3, after waiting for the completion of dissolution, realizing cooling crystallization by reducing temperature or realizing solvent-out crystallization by adding an undesirable solvent through the upper feeding port; Step S4, after the crystallization, starting the automatic sampling program, detecting the wet particle size and shape of the crystal recrystallization sample of each channel, and obtaining the morphology results under different experimental conditions.

2. The method according to claim 1, wherein the method is characterized by, The upper cover (6) in step S1 is controlled to be lifted and lowered by a stepping motor (5), and each glass beaker is placed in a temperature control tank.

3. The method of claim 1, wherein the method is a rapid screening method for multi-channel crystallization process combined with microfluidic imaging analysis. The temperature control tank in step S2 adopts an integrated jacket design, which can provide a more uniform temperature field and ensure the synchronization and consistency of the 6 channels during temperature cycling.

4. The method of claim 1, wherein the method is a rapid screening method for multi-channel crystallization process combined with microfluidic imaging analysis. The magnetic stirrer (10) in step S2 is placed below the temperature control tank and has six independent motor drives, which can realize different speed adjustments.

5. The method of claim 1, wherein the method is a rapid screening method for multi-channel crystallization process in combination with microfluidic imaging analysis. The cooling crystallization in step S3 realizes the precise control of supersaturation through programmed cooling.

6. The method of claim 1, wherein the method is a rapid screening method for multi-channel crystallization process in combination with microfluidic imaging analysis. The solvent-out crystallization in step S3 is the addition of an anti-solvent controlled by a metering pump, which can realize linear increase, exponential increase or pulse addition modes.

7. The method of claim 1, wherein the method is a rapid screening method for multi-channel crystallization process in combination with microfluidic imaging analysis. The automatic sampling program in step S4 completes the related operations through an automatic sampling system, which includes two injection pumps (8) working alternately, an eight-way electromagnetic switching valve, a sampling pipeline (14) and a waste liquid tank (15). One end of the sampling pipeline (14) is connected to the sampling port (2) on the upper cover (6), and the other end is connected to the image analysis system through the eight-way switching valve (7) for wet particle size and shape detection of the crystallization sample of each channel.

8. The method of claim 1, wherein the method is a rapid screening method for multi-channel crystallization process in combination with microfluidic imaging analysis. The eight-way switching valve (7) adopts a high-precision electromagnetic eight-way switching valve, in which six ports are connected to six crystallization units, responsible for switching the extraction of different crystallizers, the seventh port is connected to a cleaning liquid for cleaning residual substances in the pipeline, and the eighth port is connected to the waste liquid tank (15); through programmed control, the sample flow direction of different channels is accurately switched, ensuring that the samples are not mixed and cross-contaminated, and the switching time is <100 ms.

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