Dynamic monitoring chromatographic column with built-in phased array ultrasonic detection and ultraviolet detection module capable of automatically ascending and descending

Abstract

The invention discloses a dynamic monitoring chromatographic column with a built-in phased array ultrasonic detection and ultraviolet detection module capable of automatically ascending and descending, which comprises a chromatographic column body filled with a filler, a hollow short shaft is arranged in the chromatographic column body, a long shaft is arranged in the hollow short shaft, the long shaft extends out of the hollow short shaft into the resin filler, and the long shaft is connected with the chromatographic column body. A liquid inlet distributor is mounted on the outer surface of the hollow short shaft, phased array ultrasonic detectors are mounted on the liquid inlet distributor, a plurality of flexible phased array ultrasonic detectors are uniformly arranged on the outer surface of the chromatographic column body along the height direction of the chromatographic column body, an eluent ultraviolet (UV) detection module is arranged at the end part of the long shaft, and an automatic lifting ultrasonic detection module is arranged at the top end of the chromatographic column body. According to the invention, the filler distribution in the axial direction and the radial direction of the chromatographic column is monitored in real time, and a phased array ultrasonic imaging technology and a fusion technology of axial imaging along the chromatographic column and radial imaging at different axial heights are combined to superpose the three-dimensional imaging of the filler in the whole chromatographic column, so that the filling uniformity of the chromatographic filler is more accurately judged.

Description

Technical Field

[0001] The present invention belongs to the technical field of biopharmaceutical separation and purification, and particularly relates to a dynamic monitoring chromatography column with a phased array ultrasonic detection and ultraviolet detection module that can automatically lift and lower inside. Background Art

[0002] To improve the separation efficiency of liquid chromatography in a chromatography column, the following aspects are mainly considered: (1) reducing the flow rate of the mobile phase; (2) reducing the amount of the stationary phase; (3) reducing the particle size of the stationary phase; (4) selecting a mobile phase with low viscosity; (5) appropriately increasing the column temperature, etc. During the chromatographic separation process, various factors are interrelated and restricted. Only by tracking and calculating the column efficiency value and continuously researching and practicing one's own analysis method can the optimal working conditions be found.

[0003] The invention patent (CN111841076A) discloses an industrial device for ultrasonic enhanced column chromatography separation and purification, belonging to the technical field of new device for column chromatography separation and purification in the fields of chemical engineering, food, pharmaceuticals, etc. It can improve the working efficiency and effect of the column packing, adsorption, and elution processes. In particular, it can increase the number of times the adsorption filler can be reused and reduce the amount of eluent used. The advantage of this invention patent is that it only utilizes the kinetic energy of ultrasonic waves, but has not utilized the principle that ultrasonic waves can form images, nor has it utilized ultrasonic non-destructive testing technology to detect the uniformity of the packing of the filler.

[0004] The invention patent (CN116496343A) discloses a visualization deep filtration system, which includes: a full-automatic protein purification analyzer with a UV sensor and a chromatography column position, and a filter membrane package. The inlet and outlet of the filter membrane package are respectively connected to two column position valves of the protein purification analyzer. The main feature of this invention is that a pH sensor and a conductivity sensor are arranged at the flow-through cell, and the UV sensor is arranged on the pipeline. However, this invention patent does not set relevant sensors inside the chromatographic / chromatography column, nor does it detect the uniformity of the packing of the chromatographic filler and the UV detection situation of the eluent in the filler layer in real time.

[0005] The invention patent (CN212680149U) discloses a fluorescence real-time monitoring chromatography column device, which is provided with a plurality of chromatography inlet pipes at intervals on one side wall of the chromatography column, and a chromatography light source device of the same height is arranged on the side wall of the chromatography column opposite to the chromatography inlet pipe, which can adjust the proportion of the mobile phase in real time and reduce the waste of the mobile phase. However, this invention patent is only applicable to a transparent glass chromatography column, and fluorescence detection belongs to qualitative judgment, not quantitative judgment.

[0006] There is no relevant technical monitoring of the actual packing uniformity of the stationary phase inside the chromatography column and the elution effect of the mobile phase. In most cases, it relies on manual experience and improved packing technology solutions (such as dynamic axial compression column technology, etc.) to improve the chromatography separation effect, and cannot determine the operation control of processes such as feeding and gradient elution according to the characteristics inside the resin adsorption column, so as to more agilely adapt to process parameter adjustment and improve the separation efficiency. Summary of the Invention

[0007] In view of the problems existing in the prior art, the purpose of the present invention is to provide a dynamic monitoring chromatography column with a built-in automatically liftable phased array ultrasonic detection and ultraviolet detection module. Through phased array ultrasonic three-dimensional imaging analysis of the chromatographic packing inside the chromatography column and on-line ultraviolet UV detection analysis of the eluent, it can ensure that the chromatographic packing inside the chromatography column is evenly packed, the concentration and flow rate of the eluent are appropriate, thereby greatly reducing the solvent usage amount of the eluent, more targeted improving the column efficiency of the chromatographic column, making full use of the existing chromatographic packing raw materials, reducing the frequency of replacing the chromatographic packing, and reducing the production cost of chromatography / column chromatography.

[0008] To achieve the above purpose, the technical solution of the present invention is as follows: A dynamic monitoring chromatography column with a built-in automatically liftable phased array ultrasonic detection and ultraviolet detection module, including a chromatography column body filled with packing. A hollow short shaft is arranged inside the chromatography column body, a long shaft is arranged inside the hollow short shaft, and the long shaft extends out of the hollow short shaft into the resin packing. A liquid inlet distributor is installed on the outer surface of the hollow short shaft. A phased array ultrasonic detector for real-time monitoring of the packing distribution in the axial direction of the chromatography column is installed on the liquid inlet distributor. A plurality of flexible phased array ultrasonic detectors for real-time monitoring of the packing distribution in the radial direction of the chromatography column are evenly arranged on the outer surface of the chromatography column body along its height direction. An eluent ultraviolet UV detection module for real-time on-line sampling and analysis of the elution effect is arranged at the end of the long shaft. An automatic lift ultrasonic detection module for enabling the phased array ultrasonic detector and the eluent ultraviolet UV detection module to lift out of sync is arranged at the top of the chromatography column body. The automatic lift ultrasonic detection module is built with a phased array ultrasonic signal processing module. The automatic lift ultrasonic detection module is connected to the eluent ultraviolet UV detection module through a signal line.

[0009] Furthermore, the eluent ultraviolet UV detection module includes a UV module annular channel and an ultraviolet UV detection module. At least four UV detection points are arranged in the radial direction of the UV module annular channel. A transparent sampling pipeline is arranged at each UV detection point position. The transparent sampling pipeline is fixed along the connection shaft of the ultraviolet UV detection module. The transparent sampling pipeline is arranged in a wall-attached manner between the UV module annular channel. An ultraviolet UV detection module is arranged inside the UV module annular channel. Each transparent sampling pipeline is communicated with the UV module channel.

[0010] Further, a magnetic induction loop circuit is provided in the annular channel of the UV module for receiving an external electrical control signal to continuously switch-control the magnetic induction magnetic field; a magnetic induction electrical circuit is provided in the ultraviolet UV detection module for receiving an external electrical control signal to continuously switch-control the magnetic induction magnetic field.

[0011] Further, the annular channel of the UV module is in a sealed state and is not communicated with external solvents and fillers; the material of the annular channel of the UV module at at least four UV detection points is a transparent material with high ultraviolet transmittance.

[0012] Further, it includes an ultraviolet light source module, and the ultraviolet generating unit of the ultraviolet light source module is communicated with the conduction optical fiber inside the transparent sampling pipeline.

[0013] Further, it includes a sampling cell auxiliary module, and a vacuum source or a nitrogen source controlled by a solenoid valve is built in the sampling cell auxiliary module and is communicated with the transparent sampling pipeline through a pipeline.

[0014] Further, both the phased array ultrasonic detector and the flexible phased array ultrasonic detector adopt phased array probes, and the phased array probe of the phased array ultrasonic detector is integrated on the liquid inlet distributor plate of the chromatographic column body.

[0015] Further, the automatic lifting ultrasonic detection module includes a first automatic lifting mechanism and a second automatic lifting mechanism. The first automatic lifting mechanism includes a first motor, a first gear and a first rack. The first motor is installed on the top of the chromatographic column body, the output shaft of the first motor is installed with the first gear, the first gear meshes with the first rack, and the first rack is connected with a hollow short shaft, so that the phased array probe of the phased array ultrasonic detector is lifted.

[0016] Further, the second automatic lifting mechanism includes a second motor, a second gear and a second rack. The second motor is installed at the top end of the chromatographic column body, the second gear is installed on the output shaft of the second motor, the second gear meshes with the second rack, and the second rack is connected with a long shaft, so that the eluent ultraviolet UV detection module is lifted.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) A phased array ultrasonic device is provided inside the chromatographic column body of the present invention to real-time monitor the packing distribution in the axial direction of the chromatographic column. A plurality of flexible phased array ultrasonic detectors are provided on the outer surface of the chromatographic column body along its height direction for real-time monitoring of the packing distribution in the radial direction of the chromatographic column. Combined with the phased array ultrasonic imaging technology, the fusion technology of axial imaging along the chromatographic column and radial imaging at different axial heights can be used to superimpose a three-dimensional image of the packing inside the entire chromatographic column, so as to more accurately judge the problem of uniform packing of the chromatographic packing, and specifically improve the overall column efficiency through processes such as compaction and regeneration of the chromatographic packing. 2) Inside the chromatography column body of the present invention, there is resin packing, and an eluent ultraviolet (UV) detection module is provided inside the resin packing to analyze the elution effect in real time and online, which can effectively reduce the consumption of the eluent and improve the elution effect of the active ingredient. 3) The high-speed inspection function of the built-in sampling ultraviolet (UV) detection module of the present invention can perform high-speed UV detection on the eluent in at least four or more sampling pools, improving the breadth and real-time performance of the detection. 4) The present invention is mainly applied to large-diameter large-scale chromatography column sites. On the one hand, through processes such as regeneration, the characteristics of the packing are fully utilized to improve the separation effect. On the other hand, through the real-time online UV detection function, the usage amount of the eluent solvent is effectively reduced, and the energy consumption for subsequent solvent recovery is also reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the overall schematic diagram of the chromatography column with a built-in dynamic monitoring module of the present invention; Figure 2 is the top view of the chromatography column with a built-in phased array ultrasonic detection module of the present invention; Figure 3 is the top view of the chromatography column with a built-in eluent ultraviolet (UV) detection module of the present invention.

[0019] Figure 4 is the structural sectional view of the automatic lifting ultrasonic detection module of the present invention.

[0020] In the figure: 1. Automatic lifting ultrasonic detection module; 2. Built-in phased array ultrasonic detector; 3. External flexible phased array ultrasonic detector; 4. Eluent ultraviolet (UV) detection module; 5. Chromatography column body; 6. Phased array probe; 7. Sampling pool auxiliary module; 8. Ultraviolet light source module; 9. Optical fiber; 10. Ultraviolet (UV) detection module; 11. UV module annular channel; 12. Transparent sampling pipeline; 13. Hollow short shaft; 14. Long shaft; 15. Liquid inlet distributor; 16. Gear 1; 17. Rack 1; 18. Gear 2; 19. Rack 2. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0021] The following further describes the present invention in conjunction with the accompanying drawings of the specification and embodiments, but the protection scope of the present invention is not limited thereto.

[0022] Since the material of the chromatographic column / chromatography column cylinder is usually stainless steel and is in a closed environment, in order to facilitate the detection of the packing uniformity of the packing along the axial and radial directions of the cylinder, the present invention proposes a dynamic monitoring chromatography column with a built-in automatically liftable phased array ultrasonic detection and ultraviolet detection module. Please refer to Figure 1, the chromatography column includes a chromatography column body 5 filled with packing material. Inside the chromatography column body 5, there is a hollow short shaft 13. Inside the hollow short shaft 13, there is a long shaft 14. The long shaft 14 extends out of the hollow short shaft 13 into the resin packing material. A liquid inlet distributor 15 is installed on the outer surface of the hollow short shaft 13.

[0023] Please refer to Figures 2-4 , a phased array ultrasonic detector 2 for real-time monitoring of the packing distribution in the axial direction of the chromatography column is installed on the liquid inlet distributor 15. Along the height direction of the outer surface of the chromatography column body 5, several flexible phased array ultrasonic detectors 3 for real-time monitoring of the packing distribution in the radial direction of the chromatography column are evenly arranged. At the end of the long shaft 14, there is an eluent ultraviolet UV detection module 4 for real-time online sampling and analysis of the elution effect. At the top of the chromatography column body 5, there is an automatic lifting ultrasonic detection module 1 for enabling the phased array ultrasonic detector 2 and the eluent ultraviolet UV detection module 4 to lift and lower out of sync. The automatic lifting ultrasonic detection module 1 incorporates a phased array ultrasonic signal processing module to output phased array ultrasonic image signals in real time. The automatic lifting ultrasonic detection module 1 is connected to the eluent ultraviolet UV detection module 4 through a signal line.

[0024] The automatic lifting ultrasonic detection module 1 can automatically increase or decrease the insertion depth of the phased array ultrasonic detector according to external operation requirements. It also integrates modules such as a signal processor for ultrasonic signals to output phased array ultrasonic image signals in real time.

[0025] When the chromatographic packing is filled or regenerated, the built-in phased array ultrasonic detector 2 descends to the contact surface with the chromatographic packing. Then, ultrasonic signals are emitted through the phased array ultrasonic detector 2. After being processed by the processor, the ultrasonic detection situation of the chromatographic packing along the axial direction is obtained, thereby judging whether the packing is filled evenly. At the same time, combined with the external flexible phased array ultrasonic detector 3 outside the chromatography column, the ultrasonic detection of the packing filling situation in the radial direction of the chromatographic packing at different heights is carried out, thereby judging whether the packing is filled evenly. Combining phased array ultrasonic imaging technology, the fusion technology of axial imaging and radial imaging at different axial heights along the chromatography column can superimpose a three-dimensional image of the packing inside the entire chromatography column, so as to more accurately judge the problem of even filling of the chromatographic packing and improve the overall column efficiency through processes such as compacting and regenerating the chromatographic packing.

[0026] Both the phased array ultrasonic detector 2 and the flexible phased array ultrasonic detector 3 use phased array probes 6. Among them, the phased array probe 6 of the phased array ultrasonic detector 2 is integrated on the plate of the liquid inlet distributor 15 of the chromatography column body 5.

[0027] The automatic lifting ultrasonic detection module 1 includes an automatic lifting mechanism 1 and an automatic lifting mechanism 2. The automatic lifting mechanism 1 includes a motor 1, a gear 1 16 and a rack 1 17. The motor 1 is installed at the top of the chromatography column body 5. The output shaft of the motor 1 is installed with the gear 1 16. The gear 1 16 meshes with the rack 1 17. The rack 1 17 is connected to the hollow short shaft 13, so that the phased array probe 6 of the phased array ultrasonic detector 2 is lifted and lowered.

[0028] The automatic lifting mechanism 2 includes a motor 2, a gear 2 18 and a rack 2 19. The motor 2 is installed at the top end of the chromatography column body 5. The gear 2 18 is installed on the output shaft of the motor 2. The gear 2 18 meshes with the rack 2 19. The rack 2 19 is connected to the long shaft 14, so that the eluent ultraviolet UV detection module 4 is lifted and lowered to judge the elution effect of the packing at different heights.

[0029] The eluent ultraviolet UV detection module 4 includes a UV module annular channel 11 and an ultraviolet UV detection module 10. At least four UV detection points are arranged in the radial direction of the UV module annular channel 11. A transparent sampling pipeline 12 is arranged at each UV detection point. The transparent sampling pipeline 12 is fixed along the connecting shaft of the ultraviolet UV detection module 10. The transparent sampling pipeline 12 is arranged in a wall-attached manner between the UV module annular channel 11. The ultraviolet UV detection module 10 is arranged in the UV module annular channel 11. Each transparent sampling pipeline 12 communicates with the UV module channel 11.

[0030] The transparent sampling pipeline 12 is fixed along the connecting shaft of the eluent ultraviolet UV detection module 4 and is communicated with the vacuum source or nitrogen source controlled by the built-in solenoid valve of the sampling pool auxiliary module 7 to meet the requirements of sucking and discharging the solvent in the sampling pipeline.

[0031] The UV module annular channel 11 is provided with a magnetic induction annular electrical circuit for receiving external electrical control signals to continuously switch control the magnetic induction magnetic field; the ultraviolet UV detection module 10 is provided with a magnetic induction electrical circuit for receiving external electrical control signals to continuously switch control the magnetic induction magnetic field.

[0032] The UV module annular channel 11 is in a sealed state and does not communicate with external solvents and packings; the material of the UV module annular channel 11 at at least four UV detection points is made of a transparent material with high ultraviolet transmittance.

[0033] A dynamic monitoring chromatography column of the present invention with a built-in phased array ultrasonic detection and ultraviolet detection module that can be automatically lifted includes an ultraviolet light source module 8. The ultraviolet generating unit of the ultraviolet light source module 8 is communicated with the conduction optical fiber 9 inside the transparent sampling pipeline 12.

[0034] The dynamic monitoring chromatography column of the present invention with a built-in phased array ultrasonic detection and ultraviolet detection module capable of automatic lifting further includes a sampling pool auxiliary module 7. The sampling pool auxiliary module 7 has a vacuum source or nitrogen source controlled by an electromagnetic valve and is connected to a transparent sampling pipeline 12 through a pipeline. The sampling pool auxiliary module 7 has functions such as nitrogen back blowing, vacuum pumping, and UV detection signal output to complete on-line sampling and analysis work.

[0035] When the ultrasonic detection analyzes that the chromatographic packing is uniform, an eluent ultraviolet (UV) detection module 4 for real-time on-line sampling and analyzing the elution effect can be used inside the packing, and in combination with an external ultraviolet light source module 8 and a sampling pool auxiliary module 7. The sampling pool auxiliary module 7 has functions such as nitrogen back blowing, vacuum pumping, and UV detection signal output to complete on-line sampling and analysis work.

[0036] When the on-line sampling starts to work, the sampling pool auxiliary module 7 first fills a certain amount of nitrogen into the transparent sampling tube 12 to ensure the update of the eluent in the transparent sampling tube 12, and then controls the electromagnetic valve to switch to the vacuum source to appropriately suck a certain amount of the eluent inside the packing for real-time on-line sampling and analysis.

[0037] When the transparent sampling tube 12 meets the detection conditions, turn on the ultraviolet light source of the ultraviolet light source module 8 and send it to the UV transparent detection point of the UV module annular channel 11 through a conductive optical fiber 9. According to the positioning signal, the ultraviolet (UV) detection module 10 automatically performs rapid UV detection at four UV detection points respectively, so as to transmit data to an external signal receiving module in real time for judging whether the solvent elution effect under the current working condition reaches the expected purpose. The high-speed inspection function of the built-in ultraviolet (UV) detection module 10 can perform high-speed UV detection on the eluent in at least four or more transparent sampling tubes, improving the breadth and real-time performance of the detection.

Claims

1. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can be automatically raised and lowered, comprising a chromatography column body (5) filled with filler, a hollow short shaft (13) is provided inside the chromatography column body (5), a long shaft (14) is provided inside the hollow short shaft (13), the long shaft (14) extends from the hollow short shaft (13) to the inside of the resin filler, and a liquid inlet distributor (15) is installed on the outer surface of the hollow short shaft (13), characterized in that The liquid inlet distributor (15) is provided with a phased array ultrasonic detector (2) for real-time monitoring of the distribution of fillers in the axial direction of the chromatography column; the outer surface of the chromatography column body (5) is evenly provided with a plurality of flexible phased array ultrasonic detectors (3) for real-time monitoring of the distribution of fillers in the radial direction of the chromatography column along its height direction; the end of the long axis (14) is provided with an eluent ultraviolet UV detection module (4) for real-time online sampling and analysis of elution effects; the top of the chromatography column body (5) is provided with an automatic lifting ultrasonic detection module (1) for asynchronously lifting the phased array ultrasonic detector (2) and the eluent ultraviolet UV detection module (4); the automatic lifting ultrasonic detection module (1) has a built-in phased array ultrasonic signal processing module; and the automatic lifting ultrasonic detection module (1) is connected to the eluent ultraviolet UV detection module (4) via a signal line.

2. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can automatically rise and fall according to claim 1, characterized in that The eluent ultraviolet UV detection module (4) comprises a UV module annular channel (11) and an ultraviolet UV detection module (10); at least four UV detection points are arranged in the radial direction of the UV module annular channel (11); a transparent sampling pipe (12) is arranged at each UV detection point; the transparent sampling pipe (12) is fixed along a connecting axis of the ultraviolet UV detection module (10); the transparent sampling pipe (12) and the UV module annular channel (11) are arranged adjacent to the wall; an ultraviolet UV detection module (10) is arranged in the UV module annular channel (11); and each transparent sampling pipe (12) is connected to the UV module channel (11).

3. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can automatically rise and fall according to claim 2, characterized in that The UV module annular channel (11) is provided with a magnetic induction annular electrical circuit for receiving an external electrical control signal to continuously switch the magnetic induction magnetic field; the ultraviolet UV detection module (10) is provided with a magnetic induction electrical circuit for receiving an external electrical control signal to continuously switch the magnetic induction magnetic field.

4. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can automatically rise and fall according to claim 3, characterized in that The UV module annular channel (11) is in a sealed state and is not in communication with external solvents and fillers; the material of the UV module annular channel (11) at at least four UV detection points is a transparent material with high ultraviolet transmittance.

5. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can automatically rise and fall according to claim 4, characterized in that It comprises an ultraviolet light source module (8), wherein an ultraviolet light generating unit of the ultraviolet light source module (8) is connected to a conducting optical fiber (9) inside a transparent sampling pipe (12).

6. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can automatically rise and fall according to claim 5, characterized in that It comprises a sampling pool auxiliary module (7), wherein a vacuum source or a nitrogen source controlled by a built-in solenoid valve in the sampling pool auxiliary module (7) is connected to a transparent sampling pipeline (12) through a pipeline.

7. The dynamic monitoring chromatography column with built-in phased array ultrasonic detection and ultraviolet detection modules that can be automatically raised and lowered according to claim 1, characterized in that The phased array ultrasonic detector (2) and the flexible phased array ultrasonic detector (3) both use a phased array probe (6), wherein the phased array probe (6) of the phased array ultrasonic detector (2) is integrated on a plate of a liquid inlet distributor (15) of a chromatography column body (5).

8. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can automatically rise and fall according to claim 7, characterized in that The automatic lifting ultrasonic detection module (1) comprises an automatic lifting mechanism 1 and an automatic lifting mechanism 2, wherein the automatic lifting mechanism 1 comprises a motor 1, a gear 1 (16) and a rack 1 (17), wherein the motor 1 is mounted on the top of the chromatography column body (5), the output shaft of the motor 1 is mounted with a gear 1 (16), the gear 1 (16) is meshed with the rack 1 (17), and the rack 1 (17) is connected to the hollow short shaft (13), so that the phased array probe (6) of the phased array ultrasonic detector (2) is lifted and lowered.

9. A dynamic monitoring chromatography column with a built-in phased array ultrasonic detection and ultraviolet detection module that can automatically rise and fall according to claim 8, characterized in that The second automatic lifting mechanism comprises a second motor, a second gear (18) and a second rack (19); the second motor is mounted on the top of the chromatography column body (5); the second gear (18) is mounted on the output shaft of the second motor; the second gear (18) is meshed with the second rack (19); the second rack (19) is connected to the long shaft (14), so that the eluent ultraviolet UV detection module (4) is lifted and lowered.

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