Mixing integrated device with double functions and mixing method

Abstract

The invention discloses a mixing integrated device with double functions and a mixing method, and belongs to the technical field of liquid chromatographs.The device is internally provided with mixing columns, the mixing columns comprise the first mixing column and the second mixing column, and the device further comprises a mixing column mounting base and two mixing column connecting joints; the two mixing columns are arranged in a connecting chamber formed by sealing the mixing column mounting base and the two mixing column connecting joints; a first interface and a second interface are respectively arranged in the two mixing column connecting joints, a first connecting channel is arranged between the two mixing columns, and the first interface, the first mixing column, the first connecting channel, the second mixing column and the second interface are sequentially communicated in series; the mixing column mounting base is further provided with a third connector, and the third connector communicates with the first connecting channel. According to the invention, the solvent effect in liquid chromatographic analysis can be efficiently eliminated, and the double mixing columns are integrated in the same device in series, so that the dead volume of a flow path can be effectively controlled, and the manufacturing cost can be reduced.

Description

Technical Field

[0001] This invention belongs to the field of liquid chromatography instrument technology, specifically relating to a dual-function integrated mixing device and mixing method. Background Technology

[0002] In liquid chromatography, samples are usually introduced into the column in solution form via an autosampler or injection system. There is usually a certain potential energy difference between the sample solution and the mobile phase. When the potential energy difference is too large, multiple solvents will diffuse from high potential energy to low potential energy in the column, thus forming a solvent effect.

[0003] Solvent effect is a classic technical challenge in liquid chromatography analysis. Essentially, it stems from the interfacial mass transfer imbalance caused by the mismatch in elution strength between the sample solvent and the chromatographic solvent. When a sample containing a high-diffusion-coefficient solvent (such as methanol or acetonitrile) enters a column primarily composed of a low-diffusion-coefficient solvent (such as an aqueous buffer), the following common phenomena occur: 1. Chromatographic peak distortion: The sample cannot be effectively focused at the column head, resulting in peak prolongation, bifurcation, or broadening; 2. Retention time drift: Local changes in the stationary phase equilibrium caused by solvents with high diffusion coefficients result in poor reproducibility of retention time. 3. Decreased separation efficiency: Peak shape distortion directly leads to a reduction in the separation efficiency of adjacent components.

[0004] According to the search, patent number "CN221405559U" discloses a connector for eliminating solvent effect, which includes a front connector, a twisted core tube and a rear connector connected in sequence. The twisted core tube has a hollow core cavity that extends along its axial direction and penetrates its two end faces. The hollow core cavity is twisted in shape as a whole.

[0005] However, the above devices have limited effectiveness in addressing solvent effects and cannot modulate the mobile phase. Summary of the Invention

[0006] In view of the shortcomings of the existing technology, the purpose of this invention is to solve the problem that it is difficult to eliminate the harmful effects of solvent effect in the existing liquid chromatography separation and analysis process.

[0007] This invention provides a dual-function hybrid integrated device, which includes a hybrid column, comprising a first hybrid column and a second hybrid column, a hybrid column mounting base, and two hybrid column connecting joints. The two hybrid columns are disposed within a sealed connecting cavity formed between the hybrid column mounting base and the two hybrid column connecting joints. The two hybrid column connecting joints are respectively provided with a first interface and a second interface, and a first connecting channel is provided between the two hybrid columns. The first interface, the first hybrid column, the first connecting channel, the second hybrid column, and the second interface are connected in series. The hybrid column mounting base is also provided with a third interface, which communicates with the first connecting channel.

[0008] Preferably, the first connection channel is disposed on the hybrid column mounting base.

[0009] The hybrid column includes an inner liner with a first through hole in the center, a sealing cap with a second through hole in the center, and a column core that is interference-fitted into the cavity inside the inner liner and the sealing cap.

[0010] Specifically, the sealing cap and the inner liner cover are combined to form a placement cavity for placing the core. The core and the placement cavity are interference fit. The inner liner cover has a first through hole at the center near the end face of the core for connecting the core with the first interface and the second interface. The sealing cap has a second through hole at the center for connecting the core with the first connection channel.

[0011] Preferably, the surface of the column core is provided with a mixing channel groove, which includes a front face channel, a cylindrical face channel and a rear face channel. The front face channel includes a liquid inlet end and a first connecting end. The cylindrical face channel includes an inlet end and an outlet end. The rear face channel includes a second connecting end and a liquid outlet end. Multiple second connecting channels are provided inside both ends of the column core. The first connecting end is connected to the inlet end of the cylindrical face channel through the second connecting channel. The second connecting end is connected to the outlet end of the cylindrical face channel through the second connecting channel.

[0012] Preferably, the front end flow channel is provided with an inlet end and a first connecting end, the rear end flow channel is provided with an outlet end and a second connecting end, the front end flow channel and the rear end flow channel are both spiral-shaped, and the cylindrical flow channel is spiral-shaped or unidirectional wave-shaped.

[0013] Preferably, the unidirectional square waveform is specifically a flow channel shape with a square wave-like curve that flows in one direction.

[0014] Preferably, the front end flow channel has an inlet end and multiple first connection ends; the rear end flow channel has an outlet end and multiple second connection ends; the cylindrical flow channel includes multiple independent flow channel groups, and each flow channel group has a connection structure of first splitting and then merging; the two ends of the cylindrical core are provided with multiple second connection channels; the two ends of each flow channel group of the cylindrical flow channel are respectively connected to the first connection end of the front end flow channel and the second connection end of the rear end flow channel through the second connection channels.

[0015] Preferably, the front end flow channel includes a first flow channel and two second flow channels, which are joined together to form an "I" shape. The center of the first flow channel is the liquid inlet, and the two ends of the second flow channels are first connecting ends. The rear end flow channel includes an eighth flow channel and two ninth flow channels, which are joined together to form an "I" shape. The center of the eighth flow channel is the liquid outlet, and the two ends of the ninth flow channels are second connecting ends.

[0016] Preferably, the connection structure of first splitting and then merging flows specifically includes a splitting channel, an intermediate channel and a merging channel connected in sequence. The splitting channel is one channel divided into multiple channels, and the merging channel is multiple channels merging into one channel. The intermediate channel includes multiple connecting channels for connecting the splitting channel and the merging channel.

[0017] Preferably, the cylindrical flow channel includes four flow channel groups. In a single independent flow channel group, the branching flow channel includes one third flow channel, two fourth flow channels, one tenth flow channel, and two eleventh flow channels. The intermediate flow channel includes four fifth flow channels. The merging flow channel includes two sixth flow channels, one seventh flow channel, two twelfth flow channels, and one thirteenth flow channel. One end of the third flow channel is connected to the first connecting end through a second connecting channel. The other end of the third flow channel is connected to two adjacent fourth flow channels through the tenth flow channel. The other end of each fourth flow channel is connected to two adjacent fifth flow channels through the eleventh flow channel. Each pair of adjacent fifth flow channels is connected to a sixth flow channel through the twelfth flow channel. Each pair of adjacent sixth flow channels is connected to a seventh flow channel through the thirteenth flow channel. The seventh flow channel is connected to the second connecting end through a second connecting channel.

[0018] Preferably, the inner wall of the mixing tank is provided with internal threads, and the mixing column connecting joint is provided with matching external threads.

[0019] Preferably, the materials of the hybrid column mounting base, hybrid column connecting joint, and hybrid column are all selected from PEEK plastic materials, PI plastic materials, and titanium alloys.

[0020] This invention effectively prevents the precipitation of iron ions when different organic phases flow through the column core by coating the column core surface or by directly selecting the column core material as a material with an iron ion content of less than 0.04%, such as PEEK, PI-type plastic materials, or titanium alloys. This avoids the serious interference of the precipitated iron ions on the results of downstream analysis and achieves inertization and residue-free operation.

[0021] All components of this invention can be manufactured using PEEK material, which can effectively reduce processing, maintenance and replacement costs, while also effectively preventing the precipitation of iron ions from the components, achieving multiple benefits.

[0022] This invention achieves a technological leap from "passive mixing" to "active control" through a systematic design of bidirectional mixing chamber integration, surface flow channel mixing column, and fully inert materials, resulting in advantages in mixing efficiency, residue control, and adaptability.

[0023] The present invention also provides a hybrid method, including the above-described hybrid integrated device with dual functions. The hybrid method includes three operating modes: Mode 1: A1 Sampling: By controlling the solenoid valve connected to the second interface, the second interface is connected to the autosampler, and at the same time, the chromatographic pump is controlled to draw the sample at the third interface, temporarily storing the sample in the second mixing column. A2 Switch to the analysis step: By controlling the solenoid valve connected to the second interface, the second interface is connected to the chromatographic column. By controlling the chromatographic pump through the third interface, the sample is pushed to the chromatographic column for subsequent processing through a low-diffusion solvent. Mode 2: B1 Sampling: By controlling the solenoid valve connected to the second interface, the second interface is connected to the autosampler, and at the same time, the chromatographic pump is controlled to draw in the first interface to temporarily store the sample in the first mixing column. B2 Switch to the analysis step: By controlling the solenoid valve connected to the second interface, the second interface is connected to the chromatographic column; B3 Mixing: A highly diffusive solvent is introduced into the mixing device through the first interface via a chromatographic pump, pushing the sample solution through the first mixing column to the second mixing column. At the same time, a low-diffusion solvent is pumped into the mixing device through the third interface via a chromatographic pump, so that the sample solution and the highly diffusive solvent are mixed with the low-diffusion solvent in the second mixing column, and the mixed sample solution is continued to be delivered to the chromatographic column for subsequent processing. Mode 3: C1 pre-filling: Low-diffusion solvent is introduced into the device through the third interface by a chromatography pump to fill the first and second mixing columns; C2 injection: By controlling the solenoid valve connected to the second interface, the second interface is connected to the automatic sampler for injection; C3 dilution: The solvent and sample in the device are drawn from the first interface by the chromatographic pump, so that the sample and the low diffusion solvent are mixed in sequence through the second mixing column and the first mixing column. The mixed sample solution is pushed to the first mixing column for temporary storage. C4 Switch to the analysis step: By controlling the solenoid valve connected to the second interface, the second interface is connected to the chromatographic column; C5 Secondary Mixing: A highly diffusive solvent is introduced into the mixing device through the first interface via a chromatographic pump, pushing the premixed sample solution through the first mixing column () to the second mixing column. At the same time, a low-diffusion solvent is pumped into the mixing device through the third interface via a chromatographic pump, so that the sample solution and the low-diffusion solvent are mixed twice in the second mixing column, and the sample solution after secondary mixing is delivered to the chromatographic column for subsequent processing.

[0024] Preferably, in step C3, a low-diffusion solvent is continuously pumped into the mixing device through the third interface by a chromatographic pump, and the delivery flow rate of the third interface is less than the suction flow rate of the first interface.

[0025] Compared with the prior art, the beneficial effects of the present invention are: 1. The innovative dual-mixer functional design of this invention: By setting up a first mixing column and a second mixing column and designing a first interface, a second interface, a third interface and a first connecting channel, the two mixing columns are cleverly connected to the liquid chromatography system. This dual-mixing column design improves the integration of the device and significantly reduces the volume of the mixer with the same function; the dual mixing chambers are integrated in series in the same device, which can effectively control the dead volume of the flow path and reduce the manufacturing cost.

[0026] 2. The dual-function integrated mixing device of the present invention allows the sample to undergo multiple stages of diffusion performance modulation with a low-diffusion solvent within the device, which can efficiently eliminate the solvent effect of the sample solvent in liquid chromatography analysis, thereby obtaining better chromatographic peak shape.

[0027] 3. The dual-function hybrid integrated device proposed in this invention has a simple structure, low processing cost, and is easy to install.

[0028] 4. The device of the present invention significantly reduces the processing difficulty of precision mixers by setting a spiral, unidirectional waveform and / or forced flow mixing channel structure on the core surface, and enables the mixer to have a sample storage function similar to a quantitative ring.

[0029] 5. The mixing method of the present invention first premixes the analytical sample with a low-diffusion reagent in a second mixer, then remixes and pre-stores the sample with the low-diffusion reagent in a first mixer, and then introduces a high-diffusion solvent through the first and second mixers in sequence, while simultaneously introducing a low-diffusion solvent into the dual mixers to achieve secondary mixing of different solvents with the sample. The solvent effect in liquid chromatography analysis is eliminated through the above mixing method.

[0030] 6. The device provided by the present invention integrates two functions: Function 1: Modulates the diffusion performance of the sample by introducing a low-diffusion solvent and mixing it with the sample multiple times and in multiple stages; Function 2: Modulates the mixing of two mobile phases by utilizing the mixing effect of the second mixing column.

[0031] The detailed structure of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0032] Figure 1 This is a three-dimensional schematic diagram of Embodiment 1 of the present invention; Figure 2 This is a cross-sectional schematic diagram of Embodiment 1 of the present invention; Figure 3 This is an exploded view of Embodiment 1 of the present invention; Figure 4 This is a three-dimensional schematic diagram of the core of Embodiment 1 of the present invention; Figure 5 This is a cross-sectional schematic diagram of the core of Embodiment 1 of the present invention; Figure 6 for Figure 4 A partial schematic diagram at point A; Figure 7 This is a three-dimensional schematic diagram of Embodiment 2 of the present invention; Figure 8 This is a three-dimensional schematic diagram of Embodiment 3 of the present invention; Figure 9 for Figure 8 A partial schematic diagram at point B.

[0033] Component names and corresponding numbers: 1. Mixing column mounting base; 11. First connecting channel; 12. Third interface; 2. First mixing column connecting joint; 21. First interface; 3. Second mixing column connecting joint; 31. Second interface; 4. Inner liner sleeve; 41. First through hole; 5. Column core; 51. Front end flow channel; 511. First flow channel; 512. Second flow channel; 513. Liquid inlet end; 514. First connecting end; 52. Rear end flow channel; 521. Eighth flow channel; 522. Ninth flow channel; 523. Liquid outlet end 524. Second connecting end; 525. Tenth flow channel; 526. Eleventh flow channel; 527. Twelfth flow channel; 528. Thirteenth flow channel; 53. Cylindrical flow channel; 531. Third flow channel; 532. Fourth flow channel; 533. Fifth flow channel; 534. Sixth flow channel; 535. Seventh flow channel; 54. Turbulent channel; 55. Second connecting channel; 551. Horizontal section; 552. Vertical section; 6. Sealing cap; 61. Second through hole; 7. Internal thread; 8. External thread; 9. First mixing column; 10. Second mixing column. Detailed Implementation

[0034] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. The components of the embodiments of the present invention described and shown in the accompanying drawings can generally be arranged and designed in various different configurations. The following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0035] Unless otherwise defined, the technical or scientific terms used in this disclosure shall have the ordinary meaning understood by a person skilled in the art to which this disclosure pertains. The words “comprising” or “including” and similar terms used in this disclosure mean that the element or object preceding the word covers the element or object listed after the word and its equivalents, without excluding other elements or objects. The words “connected” or “linked” and similar terms are not limited to physical or mechanical connections, but may also include electrical connections, whether direct or indirect. “Up,” “down,” “left,” “right,” etc., are used only to indicate relative positional relationships. When the absolute position of the described object changes, the relative positional relationship may also change accordingly. Example 1

[0036] like Figures 1-4As shown, this invention provides a dual-function integrated mixing device, including a mixing column mounting base 1, a first mixing column connection joint 2, and a second mixing column connection joint 3. The mixing column mounting base 1 has mixing grooves at both ends. The first mixing column connection joint 2 and the second mixing column connection joint 3 are respectively sealed with caps 6 on the mixing grooves at both ends of the mixing column mounting base 1, forming a first mixing chamber and a second mixing chamber. The first mixing chamber contains a first mixing column 9, and the second mixing chamber contains a second mixing column 10. The mixing columns are interference-fitted with the first and second mixing chambers. The first mixing column connection joint 2 has a first interface 21, and the second mixing column connection joint 3 has a second interface 31. A first connecting channel 11 is provided between the first mixing column 9 and the second mixing column 10. The mixing column mounting base 1 has a third interface 12, which communicates with the first connecting channel 11. In use, both the first interface 21 and the third interface 12 are connected to a chromatography pump, and the second interface 31 is connected to a high-pressure switching valve in the liquid chromatography system. The connection status of the second interface 31 with the injector and the chromatography column is switched according to the procedure. By controlling the suction and push of the chromatography pump and the flow channel connectivity of the high-pressure switching valve, the mixing process can be controlled. This allows for both premixing and secondary mixing and dilution of analytical samples containing high concentrations of highly diffusive reagents, as well as mixing two different mobile phases: highly diffusive solvents and low-diffusion solvents.

[0037] The first mixing column 9 and the second mixing column 10 can have different volume capacities. The mixing column can also be any commercially available mixer core that can achieve a mixing effect.

[0038] Specifically, the mixing column includes an inner liner 4, a column core, and a sealing cap 6. The sealing cap 6 and the inner liner 4 are combined to form a placement cavity for the column core. The column core and the placement cavity are interference-fitted. The inner liner 4 has a first through hole 41 at its center near the end face of the column core, for connecting the column core with the first interface 21 and the second interface 31. The sealing cap 6 has a second through hole 61 at its center, for connecting the column core with the first connecting channel 11. Solutions pumped in through the first interface 21, the second interface 31, and the third interface 12 can all be directly introduced into the column core, reducing the influence of components on the solution or solvent.

[0039] like Figures 1-4As shown, the surface of the core 5 is provided with a mixing channel groove, which includes a front face channel 51, a cylindrical face channel 53, and a rear face channel 52. The front face channel 51 includes a liquid inlet end 513 and a first connecting end 514. The cylindrical face channel 53 includes an inlet end and an outlet end. The rear face channel 52 includes a second connecting end 524 and a liquid outlet end 523. The first connecting end 514 is connected to the inlet end of the cylindrical face channel 53, and the second connecting end 524 is connected to the outlet end of the cylindrical face channel 53. By setting a mixing channel groove on the surface of the core 5, the purpose of mixing multiple solvent liquids in the mixing channel groove can be achieved. Moreover, in the design stage of the mixing channel groove, the dead volume of the mixing channel groove can be better controlled. The dead volume of the mixing channel groove can be controlled within 20-40uL. In this embodiment, it is specifically 23.6uL, which is much lower than the mixing dead volume of existing mixers with the same materials. Under the premise of ensuring the mixing effect, a smaller mixing dead volume delay volume is perfectly achieved.

[0040] Specifically, the front flow channel 51 is provided with an inlet end 513 and a first connecting end 514, and the rear flow channel 52 is provided with an outlet end 513 and a second connecting end 524. The front flow channel 51 and the rear flow channel 52 are spiral-shaped, and the cylindrical flow channel 53 is a unidirectional square wave shape surrounding the cylindrical surface. As different solvents flow along the cylindrical flow channel 53, at the flow channel corners, a mixing effect is achieved through the velocity difference between the inner and outer fluids (the outer fluid flows slower, the inner fluid flows faster) and multiple collisions and fusions. The unidirectional square wave shape specifically refers to a unidirectional flow channel with a square wave-shaped curve.

[0041] Specifically, the second connecting channel 55 includes a vertical section 552 and a horizontal section 551, which are perpendicular to each other. The right-angled shape of the second connecting channel 55 facilitates processing. Furthermore, when the solvent liquid transfers from the end face section in the mixing channel to the cylindrical channel 53, various solvent liquid components collide on the inner wall of the second connecting channel 55, enhancing the mixing effect. Simultaneously, since the second connecting channel 55 is located inside the core 5, it effectively avoids sealing and leakage problems during installation.

[0042] Specifically, the outer surface of the column core 5, the inner surface of the liner 43, and the inner surface of the sealing cap 62 are coated with stainless steel. This effectively prevents iron ions from precipitating into the solvent liquid under high pressure, and then following the solvent liquid into the chromatographic column and detector, affecting the analytical results. Alternatively, the mixing column mounting base 1, the first mixing column connection joint 2, the second mixing column connection joint 3, and the mixing column can be directly manufactured from materials with an iron ion content of less than 0.04%, such as PEEK plastics, PI plastics, or titanium alloys. This significantly reduces processing and maintenance costs while effectively preventing the precipitation of iron ions from the mixer components when the organic phase flows through the mixer. Example 2

[0043] like Figure 5 and Figure 6 As shown, this invention provides another dual-function integrated mixing device. Based on Embodiment 1, the shape of the cylindrical flow channel 53 is changed, making the cylindrical flow channel 53 a unidirectional spiral around the cylindrical surface. Different solvent liquids in the spiral flow channel, through centrifugal force, cause the fluid to collide with the flow channel wall. The different solvent liquid portions in the fluid will continuously move back and forth between the inner and outer walls of the flow channel, forming a mixing effect through the velocity difference between the inner and outer fluids. Furthermore, since the cylindrical flow channel 53 in this embodiment has fewer bends, it can also effectively reduce sample residue on the core 5. Example 3

[0044] like Figures 7-9 As shown, based on Embodiment 1, the shape of the mixing channel groove on the core 5 is changed to form Embodiment 3. The front end channel 51 of Embodiment 3 is provided with an inlet end 513 and multiple first connection ends 514; the rear end channel 52 is provided with an outlet end 513 and multiple second connection ends 524; the cylindrical channel 53 includes multiple sets of independent channel groups, and each channel group has a connection structure of first splitting and then merging. The two ends of the core 5 are provided with multiple second connection channels 55. The two ends of each channel group of the cylindrical channel 53 are connected to the first connection end 514 and the second connection end 524 respectively through the second connection channel 55.

[0045] The connection structure of the flow channel group is as follows: the flow channel is divided into upper and lower parts. The upper part is divided downward by a vertical direct current channel and connected to two vertical direct current channels. The two vertical direct current channels are then divided downward by themselves and connected to a total of four vertical direct current channels, forming a forced flow splitting structure where one channel becomes two channels and two channels become four channels. The lower part is symmetrical to the upper part, that is, a merging structure where four channels become two channels and two channels become one channel.

[0046] Specifically, in this embodiment, the front end flow channel 51 includes a first flow channel 511 and two second flow channels 512, which are joined to form an "I" shape. The center of the first flow channel 511 is the liquid inlet end 513, and the two ends of the second flow channels 512 are first connecting ends 514. The rear end flow channel 52 includes an eighth flow channel 521 and two ninth flow channels 522, which are joined to form an "I" shape. The center of the eighth flow channel 521 is the liquid outlet end 513, and the two ends of the ninth flow channels 522 are second connecting ends 524. The cylindrical flow channel 53 includes four sets of independent flow channels. Each set of independent flow channels includes a third flow channel 531, two fourth flow channels 532, four fifth flow channels 533, two sixth flow channels 534, a seventh flow channel 535, and a tenth flow channel 525. Two eleventh flow channels 526, two twelfth flow channels 527, and one thirteenth flow channel 528 are provided. One end of the third flow channel 531 is connected to the connection end of the second flow channel 512 through the second connecting channel 55. The other end of the third flow channel 531 is connected to two fourth flow channels 532 through the tenth flow channel 525. The end of each fourth flow channel 532 away from the third flow channel 531 is connected to two fifth flow channels 533 through the eleventh flow channel 526. The ends of each pair of fifth flow channels 533 away from the fourth flow channel 532 are connected to the same sixth flow channel 534 through the twelfth flow channel 527. The ends of the two sixth flow channels 534 away from the fifth flow channel 533 are merged and connected to the seventh flow channel 535 through the thirteenth flow channel 528. The end of the seventh flow channel 535 away from the sixth flow channel 534 is connected to the second connecting end 524 of the rear end flow channel 52 through the second connecting channel 55. The sample solution and mobile phase enter the first flow channel 511 through the inlet end 513. They are then forced to flow through the first two-way, second-to-four-way, fourth-to-eight-way, and eighth-to-sixteen-way flow channels. Then, they are forced to flow through the sixth-to-eight-way, eighth-to-four-way, fourth-to-two-way, and second-to-one-way flow channels. The different solvent liquids in the fluid are continuously dispersed and recombined in the flow channels, causing different solvent liquids to collide and merge, resulting in excellent mixing effect.

[0047] It is worth noting that, based on Embodiment 3 of the present invention, the number of the first connecting end 514 in the front face flow channel 51 and / or the number of the second connecting section in the rear face flow channel 52 are increased or decreased as needed to form different shapes; the number of flow channel groups in the cylindrical flow channel 53 is increased or decreased, and the number of times the flow is split and merged in each group of flow channels in the cylindrical flow channel 53 is increased or decreased. These changes in the flow channel structure are all variations of the present technical solution and are all within the protection scope of the present invention.

[0048] In addition, to enhance the mixing effect of the mixing channel, the corners of the mixing channel can be set to right angles to enhance the collision and mixing effect of the fluid in the channel. Example 4

[0049] The present invention also provides a hybrid method, used in conjunction with a dual-function hybrid integrated device provided in Embodiment 1, comprising three mode methods: Mode 1: A1 Sampling: By controlling the solenoid valve connected to the second interface 31, the second interface 31 is connected to the automatic sampler, and at the same time, the chromatographic pump is controlled to draw the sample at the third interface 12, and the sample is temporarily stored in the second mixing column 10. A2 Switch to the analysis step: By controlling the solenoid valve connected to the second interface 31, the second interface 31 is connected to the chromatographic column. By controlling the chromatographic pump through the third interface 12, the sample is pushed to the chromatographic column for subsequent processing through a low-diffusion solvent. Mode 2: B1 Sampling: By controlling the solenoid valve connected to the second interface 31, the second interface 31 is connected to the automatic sampler, and at the same time the chromatographic pump is controlled to draw in the first interface 21 to temporarily store the sample in the first mixing column 9. B2 Switch to the analysis step: By controlling the solenoid valve connected to the second interface 31, the second interface 31 is connected to the chromatographic column; B3 Mixing: A highly diffusive solvent is introduced into the mixing device through the first interface 21 via a chromatographic pump, pushing the sample solution through the first mixing column 9 to the second mixing column 10. At the same time, a low-diffusion solvent is pumped into the mixing device through the third interface 12 via a chromatographic pump, so that the sample solution and the highly diffusive solvent are mixed with the low-diffusion solvent in the second mixing column 10, and the mixed sample solution is continued to be delivered to the chromatographic column for subsequent processing. Mode 3: S1 Pre-filling: Low-diffusion solvent is introduced into the device through the third interface 12 via the chromatographic pump to fill the first mixing column and the second mixing column 10; S2 injection: By controlling the solenoid valve connected to the second interface 31, the second interface 31 is connected to the automatic sampler for injection; S3 Dilution: The solvent and sample in the device are drawn through the first interface 21 by the chromatographic pump, so that the sample and the low diffusion solvent are mixed in sequence through the second mixing column and the first mixing column 9. The mixed sample solution is pushed to the first mixing column for temporary storage. S4 Switch to the analysis step: By controlling the solenoid valve connected to the second interface 31, the second interface 31 is connected to the chromatographic column; S5 Secondary Mixing: A highly diffusive solvent is introduced into the mixing device through the first interface 21 via a chromatographic pump, propelling the premixed sample solution through the first mixing column 9 to the second mixing column 10. Simultaneously, a low-diffusion solvent is pumped into the mixing device through the third interface 12 via the chromatographic pump, causing the sample solution and the low-diffusion solvent to mix a second time within the second mixing column 10. The sample solution after secondary mixing is then delivered to the chromatographic column for subsequent processing. At the same time, the highly diffusive and low-diffusion solvents are mixed in the second mixing column 10 to form the mixed solvent required for chromatographic separation of the sample in the chromatographic column, thus achieving the function of mixing different mobile phases in traditional liquid chromatography.

[0050] Preferably, in step S3, a low-diffusion solvent is continuously pumped into the mixing device through the third interface 12 by a chromatography pump, and the delivery flow rate of the third interface 12 is less than the suction flow rate of the first interface 21.

[0051] Working process and principle: Based on the mixing device and mixing method provided above, this invention has the following three operating modes: Mode 1: When the sample to be analyzed has very low diffusivity, the high-pressure switching valve is connected to the second interface 31 and the autosampler. The chromatographic pump provides suction force at the third interface 12 to draw the sample solution into the second mixing column 10. Then, the high-pressure switching valve is connected to the second interface 31 and the chromatographic column. The chromatographic pump then pumps the low-diffusion solvent at the third interface 12 to push the sample solution and the low-diffusion solvent together into the chromatographic column for separation.

[0052] Mode 2: When the sample to be analyzed has a certain degree of diffusivity, firstly, the high-pressure switching valve is connected to the second interface 31 and the autosampler, and the chromatographic pump is used to draw the sample solution into the first mixing column 9 for temporary storage via the first interface 21. Then, the high-pressure switching valve is connected to the second interface 31 and the chromatographic column, and the chromatographic pump is used to pump a highly diffusive solvent into the first mixing column 9 via the first interface 21, pushing the sample solution towards the second mixing column 10. At the same time, the chromatographic pump is used to pump a low-diffusion solvent into the mixing device via the third interface 12, so that the sample solution mixes with the low-diffusion solvent in the second mixing column 10, thereby modulating the diffusivity of the sample solution. At the same time, the highly diffusive solvent and the low-diffusion solution also mix at the second mixing column 10, thereby modulating the subsequent mobile phase.

[0053] Mode 3: When the sample to be analyzed has extremely high diffusivity, firstly, the chromatography pump is controlled to pump a low-diffusivity solvent (pure water, buffered phosphate solution, etc.) into the first mixing column 9 and the second mixing column 10 through the third port 12. Then, the high-pressure switching valve is controlled to connect the autosampler and the second port 31, and the autosampler delivers the sample solution into the second mixing column 10 through the second port 31. At the same time, the chromatography pump is controlled to provide suction force outward through the first port 21, so that the sample solution passes through the second mixing column 10 and the first mixing column 9 in sequence and mixes with the low-diffusivity solvent. During this process, the chromatography pump can be controlled to continuously pump and replenish the low-diffusivity solvent through the third port 12. It is worth noting that the pumping flow rate of the third port 12 is less than the suction flow rate of the first port 21. Finally, the sample is temporarily stored in the first mixing column 9 to complete the sample analysis. The process involves a premixing procedure; then, a high-pressure switching valve is used to connect the second interface 31 and the chromatographic column. The chromatographic pump is controlled to pump a highly diffusive solvent (methanol, acetonitrile, etc.) into the first mixing column 9 via the first interface 21, propelling the premixed sample towards the second mixing column 10. Simultaneously, the chromatographic pump continues to pump a low-diffusion solvent into the mixing device via the third interface 12, allowing the sample solution to undergo a secondary mixing process with the low-diffusion solvent in the second mixing column 10. Simultaneously, the highly diffusive solvent and the low-diffusion solvent also mix in the second mixing column 10. This invention, by diluting the analytical sample containing a high concentration of highly diffusive reagent twice with a low-diffusion solvent, effectively reduces the solvent strength of the sample solution, bringing the sample solvent environment closer to the initial mobile phase. This prevents direct impact on the chromatographic column, completely eliminating the root cause of peak distortion and the harmful effects of solvent effects.

[0054] The above description is a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and concept of the present invention, should be covered within the scope of protection of the claims of the present invention.

Claims

1. A hybrid integrated device with dual functions, comprising a hybrid column (5) inside, characterized in that: The mixing column includes a first mixing column (9) and a second mixing column (10), and also includes a mixing column mounting base (1) and two mixing column connecting joints. The two mixing columns are arranged in a sealing connection chamber formed between the mixing column mounting base (1) and the two mixing column connecting joints. The two mixing column connecting joints are respectively provided with a first interface (21) and a second interface (31). A first connection channel (11) is provided between the two mixing columns. The first interface (21), the first mixing column (9), the first connection channel (11), the second mixing column (10), and the second interface (31) are connected in series. The mixing column mounting base (1) is also provided with a third interface (12), which is connected to the first connection channel (11).

2. The hybrid integrated device with dual functions according to claim 1, characterized in that: The mixing column includes an inner liner (4) with a first through hole (41) in the center, a sealing cap (6) with a second through hole (61) in the center, and a core (5) that is interference-fitted into the cavity inside the inner liner (4) and the sealing cap (6).

3. The hybrid integrated device with dual functions according to claim 1, characterized in that: The surface of the core (5) is provided with a mixing channel groove, which includes a front face channel (51), a cylindrical face channel (53) and a rear face channel (52). The front face channel (51) includes an inlet end (513) and a first connecting end (514). The cylindrical face channel (53) includes an inlet end and an outlet end. The rear face channel (52) includes a second connecting end (524) and an outlet end (523). Multiple second connecting channels (55) are provided inside both ends of the core (5). The first connecting end (514) is connected to the inlet end of the cylindrical face channel (53) through the second connecting channel (55). The second connecting end (524) is connected to the outlet end of the cylindrical face channel (53) through the second connecting channel (55).

4. A hybrid integrated device with dual functions according to claim 3, characterized in that: The front end flow channel (51) is provided with an inlet end (513) and a first connection end (514), and the rear end flow channel (52) is provided with an outlet end (523) and a second connection end (524). The front end flow channel (51) and the rear end flow channel (52) are both spiral-shaped, and the cylindrical flow channel (53) is spiral-shaped or unidirectional wave-shaped.

5. A hybrid integrated device with dual functions according to claim 3, characterized in that: The front end flow channel (51) is provided with an inlet end (513) and multiple first connection ends (514); the rear end flow channel (52) is provided with an outlet end (523) and multiple second connection ends (524); the cylindrical flow channel (53) includes multiple independent flow channel groups, and each flow channel group has a connection structure of first splitting and then merging. The two ends of each flow channel group of the cylindrical flow channel (53) are connected to the first connection end (514) of the front end flow channel (51) and the second connection end (524) of the rear end flow channel (52) respectively through the second connection channel (55).

6. A hybrid integrated device with dual functions according to claim 5, characterized in that: The front end flow channel (51) includes a first flow channel (511) and two second flow channels (512). The first flow channel (511) and the second flow channel (512) are joined together to form an "I" shape. The center of the first flow channel (511) is the liquid inlet end (513), and the two ends of the second flow channel (512) are the first connecting ends (514). The rear end flow channel (52) includes an eighth flow channel (521) and two ninth flow channels (522). The eighth flow channel (521) and the ninth flow channel (522) are joined together to form an "I" shape. The center of the eighth flow channel (521) is the liquid outlet end (513), and the two ends of the ninth flow channel (522) are the second connecting ends (524).

7. A hybrid integrated device with dual functions according to claim 5, characterized in that: The connection structure of first splitting and then merging flows specifically includes a splitting channel, an intermediate channel and a merging channel that are connected in sequence. The splitting channel is one channel divided into multiple channels, and the merging channel is multiple channels that merge into one channel. The intermediate channel includes multiple connecting channels for connecting the splitting channel and the merging channel.

8. A hybrid integrated device with dual functions according to claim 7, characterized in that: The cylindrical flow channel (53) includes four flow channel groups. In each independent flow channel group, the branch flow channel includes one third flow channel (531), two fourth flow channels (532), one tenth flow channel (525), and two eleventh flow channels (526); the intermediate flow channel includes four fifth flow channels (533); the merging flow channel includes two sixth flow channels (534), one seventh flow channel (535), two twelfth flow channels (527), and one thirteenth flow channel (528); one end of the third flow channel (531) is connected to the first connection end through the second connecting channel (55). (514) Connected, the other end of the third flow channel (531) is connected to two adjacent fourth flow channels (532) through the tenth flow channel, the other end of each fourth flow channel (532) is connected to two adjacent fifth flow channels (533) through the eleventh flow channel, each pair of adjacent fifth flow channels (532) is connected to a sixth flow channel (534) through the twelfth flow channel, each pair of adjacent sixth flow channels is connected to a seventh flow channel (535) through the thirteenth flow channel, and the seventh flow channel (535) is connected to the second connecting end (524) through the second connecting channel (55).

9. A hybrid integrated device with dual functions according to any one of claims 1-8, characterized in that: The hybrid column mounting base (1) is provided with an internal thread (7), and the hybrid column connecting joint is provided with a matching external thread (8).

10. A mixing method, characterized in that, Including a hybrid integrated device with dual functions as described in any one of claims 1-9, the hybrid method comprising three operating modes: Mode 1: A1 Sampling: By controlling the solenoid valve connected to the second interface (31), the second interface (31) is connected to the automatic sampler, and at the same time, the chromatographic pump is controlled to draw the sample at the third interface (12) to temporarily store the sample in the second mixing column (10). A2 Switch to the analysis step: By controlling the solenoid valve connected to the second interface (31), the second interface (31) is connected to the chromatographic column. By controlling the chromatographic pump through the third interface (12) to push the sample to the chromatographic column for subsequent processing through a low-diffusion solvent. Mode 2: B1 Sampling: By controlling the solenoid valve connected to the second interface (31), the second interface (31) is connected to the automatic sampler, and at the same time, the chromatographic pump is controlled to draw the sample in the first interface (21) to temporarily store the sample in the first mixing column (9); B2 Switch to the analysis step: By controlling the solenoid valve connected to the second interface (31), the second interface (31) is connected to the chromatographic column; B3 Mixing: A highly diffusive solvent is introduced into the mixing device through the first interface (21) via a chromatographic pump, pushing the sample solution through the first mixing column (9) to the second mixing column (10). At the same time, a low-diffusion solvent is pumped into the mixing device through the third interface (12) via a chromatographic pump, so that the sample solution and the highly diffusive solvent are mixed with the low-diffusion solvent in the second mixing column (10) one after the other, and the mixed sample solution is continued to be transported to the chromatographic column for subsequent processing. Mode 3: C1 pre-filling: Low-diffusion solvent is introduced into the device through the third port (12) by the chromatographic pump to fill the first mixing column (9) and the second mixing column (10). C2 injection: By controlling the solenoid valve connected to the second interface (31), the second interface (31) is connected to the automatic sampler for injection; C3 dilution: The solvent and sample in the device are drawn through the first interface (21) by the chromatographic pump, so that the sample and the low diffusion solvent are mixed in sequence through the second mixing column (10) and the first mixing column (9). The mixed sample solution is pushed to the first mixing column (9) for temporary storage. C4 Switch to the analysis step: By controlling the solenoid valve connected to the second interface (31), the second interface (31) is connected to the chromatographic column; C5 Secondary Mixing: A highly diffusive solvent is introduced into the mixing device through the first interface (21) via a chromatographic pump, pushing the premixed sample solution through the first mixing column (9) to the second mixing column (10). At the same time, a low-diffusion solvent is pumped into the mixing device through the third interface (12) via a chromatographic pump, so that the sample solution and the low-diffusion solvent are mixed twice in the second mixing column (10), and the sample solution after secondary mixing is delivered to the chromatographic column for subsequent processing.

11. The mixing method according to claim 10, characterized in that: In step C3, a low-diffusion solvent is continuously pumped into the mixing device through the third port (12) by a chromatographic pump, and the delivery pressure of the third port (12) is less than the suction pressure of the first port (21).

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