Systems and methods for solvent mixing in chromatography systems

Abstract

The solvent mixing system 400 includes a mixing tee 401, a centrifugal mixing path 403, and a low frequency blending mixer 405. The mixing tee has at least two solvent input ports 407 and a solvent output port 409 in fluid communication with each other. The centrifugal mixing path has a mixing path inlet in fluid communication with the solvent output port of the mixing tee. The centrifugal mixing path includes at least one coiled section 402 between the mixing path inlet and a mixing path outlet. The low frequency blending mixer is in fluid communication with the outlet of the centrifugal mixing path.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 017,154, filed April 29, 2020, entitled “SYSTEM AND METHOD FOR SOLVENTMIXING IN A CHROMATOGRAPHY SYSTEM”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to chromatography, and more particularly to systems and methods for mixing solvents within a chromatographic system. Background Technology

[0004] Generally, according to conventional techniques, different solvents within a chromatographic system can be mixed in a mixer with two input ports for receiving different solvent streams. Several challenges can arise when attempting to properly blend the solvent streams. If the solvents are not properly blended, some chromatographic peaks may fail to integrate. In dual-input mixers, voids can exist at the molten interface or in the bead bed of the mixing chamber, and these voids can cause solvent stratification and poor mixing. Although the mixing quality can be increased by using a higher-volume mixer, this may be impossible or undesirable in some cases. Therefore, there is a need for a highly efficient mixer that prevents stratification and does not require an increase in mixing volume. Summary of the Invention

[0005] Generally, embodiments of the present invention relate to mixing solvent streams within a chromatographic system. According to one aspect of this disclosure, a solvent mixing system is disclosed. The solvent mixing system includes a mixing tee having at least two solvent inlet ports and a solvent outlet port, the at least two solvent inlet ports and the solvent outlet port being in fluid communication with each other. The solvent mixing system also includes a centrifugal mixing path having a mixing inlet in fluid communication with the solvent outlet port of the mixing tee. The centrifugal mixing path includes at least one coiled section between the mixing path inlet and the mixing path outlet. The solvent mixing system also includes a low-frequency co-mixer in fluid communication with the outlet of the centrifugal mixing path. In some embodiments, the mixing tee has an internal mixing volume of about 0.045 μL. In some embodiments, the mixing tee is a small-volume first-in-first-out (FIFO) mixing point. In some embodiments, the mixing tee eliminates stratification of at least two solvent streams. In some embodiments, the centrifugal mixing path is corrugated and shaped to impart centrifugal force to a high-speed solvent mixture passing between the mixing path inlet and the mixing path outlet at a speed of about 150 inches / min to 17,000 inches / min. In some embodiments, the centrifugal mixing path has an inner diameter of approximately 0.0005 inches to 0.090 inches. In some embodiments, the low-frequency blending mixer is a single-inlet mixer. In some embodiments, the low-frequency blending mixer includes: a mixer inlet port in fluid communication with the outlet of the centrifugal mixing path; a first filter / retainer located downstream of the mixer inlet port; a mixing chamber; and a second filter / retainer located downstream of the mixing chamber. In some embodiments, the mixing chamber is a bead-filled mixing chamber. In some embodiments, the mixing chamber is a diffusion-bonded mixing chamber.

[0006] According to another aspect of this disclosure, a method for mixing solvent streams is disclosed. The method includes directing at least two solvent streams into a small-volume mixing tee. The method further includes mixing the solvent streams within the small-volume mixing tee to form a merged solvent stream. The method also includes directing the merged solvent streams through a coiled centrifugal mixing path to impart centrifugal force to the merged solvent streams. The method further includes further mixing the merged solvent streams using a low-frequency co-mixing mixer located downstream of the coiled centrifugal mixing path. In some embodiments, mixing the solvent streams within the small-volume mixing tee eliminates stratification of the at least two solvent streams. In some embodiments, directing the merged solvent streams through the coiled centrifugal mixing path imparts centrifugal force to the merged solvent streams at a speed of approximately 150 inches / minute to 17,000 inches / minute. In some embodiments, the centrifugal mixing path has an inner diameter of approximately 0.0005 inches to 0.090 inches. In some embodiments, the low-frequency co-mixing mixer is a single-inlet mixer. In some embodiments, mixing the combined solvent stream using a low-frequency blender includes: filtering the combined solvent stream using a first filter located downstream of the mixer inlet; mixing the combined solvent stream in a mixing chamber; and filtering the combined solvent stream using a second filter located downstream of the mixing chamber. In some embodiments, the mixing chamber is a bead-filled mixing chamber. In some embodiments, the mixing chamber is a diffusion-bonded mixing chamber with multiple channels to form a solvent mixture.

[0007] According to another aspect of this disclosure, a solvent mixing system is disclosed, comprising a small-volume first-in-first-out (FIFO) mixing tee with an internal mixing volume of approximately 0.045 μL. The mixing tee includes at least two solvent inlet ports and a solvent outlet port and is configured to eliminate stratification of at least two solvent flow streams, the at least two solvent inlet ports and the solvent outlet port being in fluid communication with each other. The system also includes a coiled centrifugal mixing path in fluid communication with the outlet port of the mixing tee and configured to impart centrifugal force to the merged solvent flow streams received from the mixing tee. The system further includes a low-frequency single-inlet blender in fluid communication with the outlet of the centrifugal mixing path and configured to further mix the merged solvent flow streams located downstream of the coiled centrifugal mixing path.

[0008] The various aspects of this disclosure provide one or more of the following advantages. The use of a mixing tee, a centrifugal mixing path, and a co-mixing mixer allows for the elimination of the integrated tee inlet at the co-mixing mixer, eliminates voids within the mixer, and prevents stratification. In some embodiments, the combination of a mixing tee and a final mixer with a much smaller internal volume can be used with a centrifugal mixing path to provide noise performance and mixing quality for a significantly larger mixer volume.

[0009] Other embodiments will become apparent from the following detailed description taken in conjunction with the accompanying drawings. However, it should be understood that the drawings are intended for illustrative purposes only and are not intended to define limitations of the invention. Attached Figure Description

[0010] To assist those skilled in the art in manufacturing and using the disclosed exemplary embodiments of the diffuser assembly, please refer to the accompanying drawings, in which:

[0011] Figure 1 An exemplary solvent mixing system according to an embodiment of the present disclosure is shown.

[0012] Figure 2 It is two mixers (including) according to the embodiments of this disclosure. Figure 1 A graph showing the baseline results of the solvent mixing system.

[0013] Figure 3A Two conventional systems and an embodiment according to this disclosure are shown. Figure 1 A comparison chart of the standard deviations of retention times for solvent mixing systems.

[0014] Figures 3B-3D Three different mixers according to embodiments of this disclosure are shown (including...) Figure 1 Comparison of baseline results for solvent mixing systems.

[0015] Figure 4 Another exemplary solvent mixing system according to an embodiment of this disclosure is shown.

[0016] Figure 5 An exemplary single-inlet mixer according to an embodiment of this disclosure is shown.

[0017] Figure 6 A flowchart illustrating an exemplary method for mixing solvent streams according to an embodiment of the present disclosure is provided. Detailed Implementation

[0018] This disclosure relates to solvent mixing within a chromatographic system. In some embodiments, the chromatographic system is a liquid chromatography system or a gas chromatography system. As mentioned above, some conventional mixers can use, for example, a 50 μL mixer with two input ports for mixing two solvents. If these solvents are effectively blended, the user can integrate the peaks on a UV detector with high resolution, ideally with a high signal-to-noise ratio. If the mixing performance is poor, some chromatographic peaks may not be integrated. In conventional dual-input mixers, voids may exist at the molten interface or at the bed in the bead mixing chamber, and these voids can cause solvent stratification and poor mixing. Although the mixing quality can be increased by using a larger volume mixer, this may be impossible or undesirable in all cases.

[0019] According to some embodiments, this disclosure relates to a solvent mixing system comprising a mixing tee, a centrifugal mixing path, and a mixer arranged in series with each other. Individually, each of these three components has some mixing capacity, and together they provide effective solvent mixing without stratification and without a significant increase in volume.

[0020] In some embodiments, the mixing tee operates at a small-volume first-in-first-out (FIFO) mixing point. This mixing point can eliminate solvent stratification. In one embodiment, the mixing tee can eliminate stratification within the combined analytes exiting the tee.

[0021] In some embodiments, the centrifugal mixing path may include a section of tube comprising one or more coils. As the centrifugal mixing tube passes through the coils, centrifugal force creates turbulence in the combined solvent flow, adding additional packing mixing. In some embodiments, diffusion-bonded components or other types of centrifugal mixing paths may be used instead of tubes. Any suitable path with the same or similar geometry may be used instead of a tube as a centrifugal mixing path.

[0022] In some embodiments, the blending mixer includes a bead mixer. Instead of using a dual-input mixer, the solvent is pre-combined and partially mixed at the mixing tee and centrifugal mixing path before entering the blending mixer's inlet. According to this embodiment, voids are no longer solvent stratification points due to premixing. In some embodiments, the blending mixer may include a diffusion-bonded mixing chamber with multiple pore channels to form a solvent blend.

[0023] When each of the mixing tee, centrifugal mixing path, and blending mixer is combined in series, the result is a solvent mixing system in which each component is complementary. In some embodiments, the mixing tee and the final mixer, which has a much smaller internal volume, can be used together with the centrifugal mixing path to create a solvent mixing system that offers significantly higher noise performance and mixing quality compared to a much larger mixer volume.

[0024] Figure 1 An exemplary solvent mixing system 100 according to an embodiment of the present disclosure is shown. In this embodiment, the solvent mixing system 100 includes a tee 101, a centrifugal mixing path 103, and a mixer 105, which are arranged in series with each other. Individually, each of these three components has some mixing capacity.

[0025] In some embodiments, the Mixing T-Join 101 operates at a small-volume, high-frequency First-In-First-Out (FIFO) mixing point. This mixing point eliminates solvent stratification. In one embodiment, at a flow rate of 0.5 mL / min (>10,000 packs / min), the Mixing T-Join 101 can have an internal mixing volume of about 0.045 μL. In some embodiments, the Mixing T-Join 101 has an internal mixing volume of about 0.005 μL to 3.000 μL and can cover a series of pipes with an inner diameter between about 0.003 inches and 0.060 inches, wherein the common length is about 0.045 inches. In some embodiments, depending on system constraints, the length can be between about 0.010 inches and 6 inches.

[0026] In some embodiments, the centrifugal mixing path 103 may include a section of tube comprising one or more coils 102. When the coils 102 of the centrifugal mixing path 103 pass through the centrifugal mixing path 103, centrifugal force creates turbulence in the combined solvent flow, adding additional packing mixing. In some embodiments, the combined solvent from the mixing tee 101 may be pumped at high speed through the centrifugal mixing path to promote turbulence and increase mixing. For example, the combined solvent flow from the mixing tee 101 may be pumped through the centrifugal mixing path 103 at a rate of approximately 150 inches / min to 17,000 inches / min. In some embodiments, the centrifugal mixing path 103 has an inner diameter of approximately 0.0005 inches to approximately 0.090 inches. In one particular embodiment, the inner diameter of the centrifugal mixing path is approximately 0.005 inches. In some embodiments, the mixer designs disclosed herein can be scaled to achieve low flow rates of approximately 10 μL / min or high flow rates of up to approximately 1,000 mL / min for applications.

[0027] In some embodiments, the blending mixer 105 includes a bead mixer with a bead bed and a single fluid inlet. Instead of using a dual-inlet mixer, the solvent is pre-combined and partially mixed at the mixing tee 101 and centrifugal mixing path 103 before entering the blending mixer 105. According to this embodiment, voids are no longer solvent stratification points due to premixing. In some embodiments, the blending mixer 105 may include a diffusion-bonding mixing chamber with multiple pore channels instead of a bead mixing chamber to form a solvent blend. In some embodiments, the blending mixer may be a low-frequency mixer capable of operating in the range of 0.5 cycles / min to 80.0 cycles / min. In one particular embodiment, the blending mixer may operate at approximately 10 cycles / min.

[0028] Figure 2 It is two mixers (including) according to the embodiments of this disclosure. Figure 1 The graph 200 shows the baseline results for the solvent mixing system. In this graph, the upper three traces 201, 203, and 205 correspond to three runs on a conventional mixing device without a tee / pipe / mixer assembly, while the lower trace 207 corresponds to the tee / pipe / mixer system of this disclosure. It can be seen in the graph that the bottom baseline trace 207 corresponding to the solvent mixing system of this disclosure has significantly reduced noise compared to the traces 201, 203, and 205 of the conventional system. This noise reduction can significantly improve peak integration. In this embodiment, the top three traces 201, 203, and 205 corresponding to the previous mixer system have significantly higher noise, especially in the time range between 12 and 20 minutes. According to these prior art techniques, if the chromatographic peak appears between 12 and 20 minutes, peak integration can be very difficult and the results can be compromised.

[0029] Figure 3A Two conventional systems and an embodiment according to this disclosure are shown. Figure 1 A comparison chart 300 shows the retention time standard deviations of the solvent mixing systems. The retention time standard deviations of systems using different styles of mixers are shown at 303, while those of another system using a different mixer are shown at 305. The retention time standard deviation of the tee / tube / mixer system of this disclosure is shown at 301. In this embodiment, it can be seen that the mixing system according to this disclosure, comprising a 50 μL mixing tee, a centrifugal mixing path, and a single-input mixer, exhibits a significantly lower retention time standard deviation 301. This reduction in retention time standard deviation is likely a result of the combination of the three elements disclosed herein, with performance enhanced by the single-input mixer. In this example, a flow rate of 0.2 mL / min is used for comparison.

[0030] Figures 3B-3D Three different mixers according to embodiments of this disclosure are shown (including...) Figure 1 Comparison of baseline results for solvent mixing systems. Figure 3B The baseline results for the first different system design are shown in the figure. Figure 3C The baseline results for the second different system are shown in the figure, and in Figure 3D The baseline results of the hybrid system according to this disclosure are shown. Although Figure 3B and Figure 3C The baselines shown are not necessarily noisy, but they are significantly unstable and include a large amount of drift. This makes peak integration difficult. In contrast, Figure 3D The baseline of the system of the present invention shown eliminates some of these unwanted behaviors.

[0031] Figure 4 Another exemplary solvent mixing system 400 according to an embodiment of the present disclosure is shown. In this embodiment, the solvent mixing system 400 includes a tee 401 arranged in series, a centrifugal mixing path 403 having a plurality of coils 402, and a mixer 405. In some embodiments, the mixing tee 401 operates as a small-volume, high-frequency first-in-first-out (FIFO) mixing point, wherein the internal mixing volume is about 0.045 μL. In some embodiments, the mixing tee 401 has an internal mixing volume of about 0.005 μL to 3.000 μL and can cover a series of pipes with an inner diameter between about 0.003 inches and 0.060 inches, wherein the common length is about 0.045 inches. In some embodiments, depending on system constraints, the length can be between about 0.010 inches and 6 inches. In this embodiment, the mixing tee 401 includes at least two solvent inlet ports 407 and a solvent outlet port 409 and is configured to eliminate stratification of at least two solvent flow streams, the at least two solvent inlet ports and the solvent outlet port being in fluid communication with each other.

[0032] Centrifugal mixing path 403 is in fluid communication with output port 409 and includes a plurality of coils 102 that impart centrifugal force to the combined solvent flow received from mixing tee 401. As the coils 402 of centrifugal mixing path 403 pass through, the centrifugal force creates turbulence in the combined solvent flow, adding additional packing mixing. In some embodiments, centrifugal mixing path 403 has an inner diameter of about 0.0005 inches to about 0.090 inches. In one particular embodiment, the inner diameter of centrifugal mixing path 403 is about 0.005 inches. Centrifugal mixing path 403 may include a single coil or multiple coils, depending on the application, and the number and compactness of the coils may depend on the solvent being mixed or other application-specific factors. In some embodiments, the combined solvent flow from mixing tee 401 may be pumped through centrifugal mixing path 403 at a rate of about 150 inches / minute to 17,000 inches / minute.

[0033] In some embodiments, the blending mixer 405 includes a low-frequency single-inlet mixer located downstream of a coiled centrifugal mixing path 403. In some embodiments, the blending mixer 405 may be a low-frequency mixer capable of operating in the range of 0.5 cycles / min to 80.0 cycles / min. In some embodiments, the blending mixer 405 may have a beaded or diffusion-bonded mixing chamber with multiple porous channels to form a solvent blend.

[0034] Figure 5 An exemplary single-inlet mixer 500 according to an embodiment of the present disclosure is shown. In this embodiment, the mixer 500 includes a single inlet 501 in fluid communication with a centrifugal mixing path. According to some embodiments, the inlet 501 may be made of titanium, stainless steel, or any suitable chemically compatible material. The mixer 500 also includes a first filter / retainer 503 located upstream of a mixing chamber 505 and a second filter / retainer 507 located downstream of the mixing chamber 505. In some embodiments, the mixer 500 may be a 100 μL mixer. According to some embodiments, the mixing chamber 505 may be a bead mixing chamber with multiple pore channels or a diffusion-bonded mixing chamber to form solvent blends. Without the need for a dual-inlet mixer, no stratification voids are created in the solvent flow.

[0035] Figure 6A flowchart illustrating an exemplary method 600 for mixing solvent flows according to an embodiment of the present disclosure is provided. In this particular embodiment, the method begins by directing at least two solvent flow streams 601 into a small-volume mixing tee. The method then proceeds to mix the solvent flow streams within the small-volume mixing tee 603 to form a merged solvent flow. In some embodiments, mixing the solvent flow streams within the small-volume mixing tee eliminates stratification of the solvent flow streams. In some embodiments, the mixing tee has an internal mixing volume of about 0.005 μL to 3.000 μL and may cover a series of pipes with an inner diameter between about 0.003 inches and 0.060 inches, wherein the common length is about 0.045 inches. In some embodiments, depending on system constraints, the length may be between about 0.010 inches and about 6 inches.

[0036] The method continues to guide the combined solvent flow 605 through a coiled centrifugal mixing path to impart centrifugal force to the combined solvent flow. In some embodiments, the centrifugal mixing path is corrugated and shaped to impart centrifugal force to the high-speed solvent mixture passing between the mixing path inlet and outlet at speeds of approximately 150 inches / min to 17,000 inches / min. In some embodiments, the centrifugal mixing path has an inner diameter of approximately 0.0005 inches to approximately 0.090 inches. In one exemplary embodiment, the inner diameter of the centrifugal mixing path is approximately 0.005 inches. In some embodiments, the mixer design disclosed herein can be scaled to achieve low flow rates of approximately 10 μL / min or high flow rates of up to approximately 1,000 mL / min for applications.

[0037] The method continues to further mix the combined solvent stream using a low-frequency blender located downstream of the coiled centrifugal mixing path. In some embodiments, the blender can operate in the range of 0.5 cycles / min to 80.0 cycles / min. In some embodiments, the blender is a single-inlet mixer operating at approximately 10 cycles / min. In some embodiments, further mixing the combined solvent stream using the blender includes filtering the solvent stream using a first filter located downstream of the mixer inlet port; mixing the solvent stream within a mixing chamber; and filtering the solvent stream using a second filter located downstream of the mixing chamber.

[0038] While exemplary embodiments have been described herein, it should be explicitly noted that these embodiments should not be construed as restrictive, but rather as including additions and modifications to the express description herein within the scope of the invention. Furthermore, it should be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and arrangements, even without departing from the spirit and scope of the invention.

[0039] The exemplary flowcharts are provided herein for illustrative purposes and are non-limiting examples of methods. Those skilled in the art will recognize that exemplary methods may include more or fewer steps than those shown in the exemplary flowcharts, and that operations in the exemplary flowcharts may be performed in a different order than those shown. Furthermore, although exemplary embodiments have been shown and described within this disclosure with reference to specific embodiments, those skilled in the art will understand that various substitutions and changes in form and detail may be made without departing from the scope of this disclosure. In addition, other aspects, features, and advantages are also within the scope of this disclosure.

Claims

1. A solvent mixing system, comprising: A mixing tee has at least two solvent inlet ports and a solvent outlet port, wherein the at least two solvent inlet ports and the solvent outlet port are in fluid communication with each other; A centrifugal mixing path having a mixing path inlet in fluid communication with the solvent output port of the mixing tee, the centrifugal mixing path including at least one coiled section between the mixing path inlet and the mixing path outlet; and A low-frequency blending mixer, the low-frequency blending mixer being in fluid communication with the outlet of the centrifugal mixing path, wherein the low-frequency blending mixer is a single-inlet mixer and the low-frequency blending mixer comprises: A mixer input port, which is in fluid communication with the outlet of the centrifugal mixing path; A first filter is located downstream of the mixer input port; Mixing chamber; and A second filter is located downstream of the mixing chamber.

2. The solvent mixing system according to claim 1, wherein the mixing tee has an internal mixing volume of 0.045 μL.

3. The solvent mixing system according to claim 1, wherein the mixing tee is a small-volume first-in-first-out mixing point.

4. The solvent mixing system of claim 1, wherein the mixing tee eliminates stratification of at least two solvent flow streams.

5. The solvent mixing system of claim 1, wherein the centrifugal mixing path is wavy and shaped to impart centrifugal force to the high-speed solvent mixture passing between the mixing path inlet and the mixing path outlet at a speed of 150 inches / minute to 17,000 inches / minute.

6. The solvent mixing system of claim 1, wherein the centrifugal mixing path has an inner diameter of 0.0005 inches to 0.090 inches.

7. The solvent mixing system of claim 1, wherein the mixing chamber is a bead-filled mixing chamber.

8. The solvent mixing system of claim 1, wherein the mixing chamber is a diffusion-bonded mixing chamber.

9. A method for mixing solvent streams, comprising: Guide at least two solvent flows to a small-volume mixing tee; The at least two solvent flows are mixed within the small-volume mixing tee to form a combined solvent flow; The combined solvent stream is guided through a coiled centrifugal mixing path to impart centrifugal force to the combined solvent stream; as well as The combined solvent stream is further mixed using a low-frequency blender located downstream of the coiled centrifugal mixing path, wherein the low-frequency blender is a single-inlet mixer, and wherein the low-frequency blender comprises: A mixer input port is in fluid communication with the outlet of the centrifugal mixing path; A first filter is located downstream of the mixer input port; Mixing chamber; and A second filter is located downstream of the mixing chamber.

10. The method of claim 9, wherein mixing the at least two solvent flows within the small-volume mixing tee eliminates stratification of the at least two solvent flows.

11. The method of claim 9, wherein guiding the combined solvent stream through the coiled centrifugal mixing path comprises applying centrifugal force to the combined solvent stream at a speed of 150 inches / minute to 17,000 inches / minute.

12. The method of claim 9, wherein the centrifugal mixing path has an inner diameter of 0.0005 inches to 0.090 inches.

13. The method of claim 9, wherein further mixing of the combined solvent streams using the low-frequency co-mixer comprises: The combined solvent stream is filtered using a first filter located downstream of the mixer input port; The combined solvent streams are mixed in a mixing chamber; as well as The combined solvent stream is filtered using a second filter located downstream of the mixing chamber.

14. The method of claim 13, wherein the mixing chamber is a bead-filled mixing chamber.

15. The method of claim 13, wherein the mixing chamber is a diffusion-bonded mixing chamber.

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