Static mixer

Abstract

A static mixing device for mixing a fluid, preferably a liquid, is provided. The mixer comprises a series of chambers (5, 8, 12, 15), a first chamber (5) of the series comprising a fluid inlet (4), and a last chamber (15) of the series comprising a fluid outlet (16), each chamber of the series, except the last chamber, being in fluid connection with a subsequent chamber, the fluid connection comprising a plurality of orifices (7, 10, 11, 14) interspersed along a flow direction, each subsequent orifice overlapping from a nearest point to the fluid inlet to a farthest point from the fluid inlet of a previous orifice, and being offset from the previous orifice along the flow direction.

Description

Technical Field

[0001] The present invention relates to a static mixer, and more specifically, to a mixer for liquids, especially aqueous liquids. Background Technology

[0002] Numerous designs for static mixers, particularly in-line static mixers, have been proposed for mixing two or more liquids that are simultaneously combined and then mixed in the flow path, as disclosed in US4222671. Further examples include, for instance, the device disclosed in US6629775, in which the flow entering the mixer is divided into partial flows with different flow path lengths and said partial flows are recombined. Other examples include the device disclosed in US20060285433, in which a swirling flow path induces mixing. Existing mixer designs operate with the mixed liquid occupying the entire flow path volume within the device, and therefore the residence time of the entire liquid mass within the mixer depends on the flow rate, cross-sectional area, and mixer length. These devices are often ineffective in mixing liquids delivered to the static mixer sequentially rather than simultaneously. Furthermore, these devices lack the ability to maintain a liquid-gas boundary within the device (when present), and tend to promote liquid aeration when bubbles are introduced into one or more inlet liquid flows. Summary of the Invention

[0003] According to a first aspect of the invention, a static mixing device (“mixer”) for mixing fluids, preferably liquids, is provided, comprising a series of multiple chambers, a first chamber of the series including a fluid inlet, and a last chamber of the series including a fluid outlet, each chamber in the series except the last chamber being fluidly connected to a subsequent chamber, the fluid connection including a plurality of orifices distributed along the flow direction, each subsequent orifice having its closest point to the fluid inlet overlapping with the farthest point of the preceding orifice from the fluid inlet, and being offset from the preceding orifice along the flow direction.

[0004] Preferably, each chamber is concentric, and most preferably has a circular cross-section. The chambers are preferably elongated along their longitudinal axis, have parallel chamber walls, and have a uniform cross-sectional area. Most preferably, the first chamber is the innermost chamber, and the last chamber is the outermost chamber.

[0005] Preferably, the mixer comprises an even number of chambers, and most preferably, concentric chambers. In many embodiments, four chambers are preferred.

[0006] Preferably, the mixer comprises a concentric tube with the inlet and outlet located at the same end of the tube. In some highly preferred embodiments, the gas outlet is located at the end of the mixer opposite to the inlet and outlet. Most preferably, the inlet and outlet are located at the bottom of the mixer, and the gas outlet is located at the top of the mixer.

[0007] In some embodiments, for a given chamber, along the longitudinal direction, the nearest point of each subsequent orifice to the inlet and the farthest point of the previous orifice from the inlet are aligned such that they form part of the same cross-section perpendicular to the axis of the chamber. Preferably, for a given chamber, along the longitudinal direction, the nearest point of each subsequent orifice to the inlet and the farthest point of the previous orifice from the inlet overlap by about 50% of the length of the subsequent orifice, preferably more than about 1% of the length of the subsequent orifice, for example, 5% to 25%. By ensuring that the liquid / gas boundary is at the same level within each chamber of the mixer and across each chamber, the overlap of the start and end points of each subsequent orifice enables the mixer to also function as a bubble trap. In many embodiments, the sum of the areas of the orifices of the first separator is between 5 and 20 times, preferably between 10 and 15 times, the cross-sectional area of ​​the inner chamber, and preferably, the sum of the areas of the orifices in the separator between two chambers is equal for all separators. In some preferred embodiments, the outer walls of the even-numbered chambers also include additional chamber outlets (not included in the orifice area calculation) located at the same end of the mixer as the inlet. The width of each additional chamber outlet is typically up to 25% of the total length of the perimeter of the chamber wall, preferably from 15% to 20%, and the total width of all additional chamber outlets is typically up to 50% of the length of the perimeter of the chamber wall, preferably from 30% to 40%. Most preferably, there are two additional chamber outlets located on opposite sides of the chambers. In many embodiments, the height of the additional chamber outlets is typically chosen to be 100% to 140% of the distance from the bottom of the chamber to the first orifice, for example, 110% to 130%. To prevent back pressure in the mixer, for each chamber, the total area of ​​the orifice plus any additional chamber outlets is chosen to be not less than the area of ​​the inlet.

[0008] The chamber is sealed except for the inlet, outlet, fluid connection to other chambers, and optional gas outlet (if present).

[0009] When the inlet is located at the bottom of the mixer, it is preferable that the area of ​​each orifice in the walls of all odd-numbered chambers fluidly connected to subsequent chambers increases along the direction away from the inlet end of the chamber from the mixer. Preferably, the distance from the first orifice to the fluid inlet end of the chamber is equal to the length of the first orifice of these chambers.

[0010] In some embodiments, the distance from the fluid inlet and outlet to the end of their respective chambers is within 1 / 10 of the total length of the chamber. In a preferred embodiment, the fluid inlet and outlet are located at the end of their respective chambers.

[0011] In many highly preferred embodiments, particularly when the inlet and outlet are located at the bottom of the mixer, the chamber wall between the even-numbered chamber and the subsequent odd-numbered chamber has two additional chamber outlets of equal area at the bottom of the fluid inlet end of the chamber. The combined area of ​​these outlets is advantageously between 10% and 50% of the fluid inlet area, preferably 20% to 35%, and most preferably 25% to 30%. The center points of the additional chamber outlets are advantageously 180 degrees (i.e., opposite) to each other and 90 degrees to the center of the subsequent orifices above these additional chamber outlets. The length of these additional chamber outlets is preferably equal to the distance from the first orifice in the wall of the preceding odd-numbered chamber to the end of the fluid inlet end of the chamber. All subsequent orifices in the even-numbered chamber wall preferably have the same increased length and distance to the fluid inlet end of the chamber as the orifices in the odd-numbered chamber wall. In a particularly preferred embodiment, the combined area of ​​all orifices (including any additional chamber outlets) within the chamber wall separating the two chambers is greater than the area of ​​the fluid inlet.

[0012] In some embodiments, all orifices have the same width, and in other such embodiments, for orifices in odd-numbered chambers, the length of each orifice increases along the chamber wall in the flow direction, preferably by a fixed amount for each subsequent orifice, and for orifices in even-numbered chambers, the length of each orifice decreases along the chamber wall in the flow direction, preferably by a fixed amount for each subsequent orifice. In other embodiments, all orifices have equal width and length.

[0013] Preferably, the orifice offset forms a spiral pattern along the flow direction. Most preferably, for all chambers, the orifice offset forms the same spiral pattern along the flow direction, including multiple, especially two, spiral patterns. For subsequent orifices, the offset angle from the centerline passing through the mixer and through the previous orifice is preferably selected to be 90 degrees for single or double spirals and 120 degrees for triple spirals. In these preferred embodiments, the orifices form discontinuous spiral patterns.

[0014] The orifice can have many different shapes, and is typically one or more of a circle, stadium shape, or rectangle. Most preferably, all orifices are stadium shape.

[0015] Most preferably, for a mixer comprising an even number of chambers (e.g., four chambers), first orifices along the longitudinal direction in the walls of all odd-numbered chambers fluidly connected to subsequent chambers are aligned such that they are not directed toward the fluid outlet. In many cases, for embodiments with a single helix, the first orifice is aligned 180 degrees to the direction of the center of the fluid outlet; for a double helix, both offsets are 90 degrees; and for a triple helix, one offset is 180 degrees relative to the fluid outlet, and the two offsets are 60 degrees relative to the fluid outlet. In some embodiments, where the same orifice pattern is used in the walls of each chamber fluidly connected to subsequent chambers, the orifices in the even-numbered chambers are aligned such that orifices equidistant from the fluid inlet end are 180 degrees to their matching orifices on the preceding odd-numbered chamber wall. This results in the alternating patterns of orifices and walls operating out of phase between the odd-numbered and even-numbered chamber walls as the fluid mass passes through the mixer along the main serpentine path.

[0016] In some embodiments, when the fluid is a liquid, the fluid level in the mixing device is determined by the inlet fluid pressure, which is derived from the device or method supplying flow to the mixing device against a compressible gas contained within a sealed mixing device. In other embodiments, when the fluid is a liquid, the liquid level in the mixing device is determined by sensing changes in the liquid level and regulating the gas pressure within the mixer, preferably the head space of the mixer, by, for example, venting or pressurizing the mixing device by opening or closing a gas outlet.

[0017] In a preferred embodiment, the liquid proportion in the mixer is less than 100% of the mixer volume, for example up to 95%, especially up to 80%, and in many embodiments operates at 10-75% of the mixer volume, a proportion typically determined by the liquid flow rate. The remainder of the mixer volume comprises compressible gas, typically air. Under these conditions, the residence time of the liquid in the mixer is independent of the flow rate, as an increased flow rate increases the liquid volume and compresses the gas.

[0018] It will be recognized that the volume and area of ​​the fluid inlet, chamber, and outlet (especially the fluid inlet) will be determined by the maximum desired flow rate. For example, in the research that led to this invention, it was found that a 15 mm diameter fluid inlet and a mixer with a total volume of 1 L were suitable for flow rates up to 1000 L / h.

[0019] In some embodiments, the total mixing chamber volume in L is selected to be no greater than 0.0015 times the maximum desired supply flow rate in L / h, and preferably at most 0.001 times the maximum desired supply flow rate in L / h.

[0020] In some embodiments, the width-to-height ratio of the outermost chamber of the mixing device is typically between 1:3 and 1:9, preferably between 1:5 and 1:8. In many preferred embodiments, the width-to-height ratio of the outermost chamber is between 1:3 and 1:6, more specifically about 1:5. In many embodiments, the cross-sectional area of ​​each subsequent chamber is greater than that of the preceding chamber. In some preferred embodiments having four chambers, the cross-sectional area of ​​the second chamber is typically between 2 and 4 times that of the first chamber, preferably about 2.5 to 3.25 times; the cross-sectional area of ​​the third chamber is typically between 1.2 and 2 times that of the second chamber; and the cross-sectional area of ​​the fourth chamber is typically at least 4 times that of the third chamber, for example between 5 and 15 times, preferably between 5 and 10 times.

[0021] In certain specific embodiments, the cross-sectional area of ​​the first chamber is 1.5-2.5 cm². 2 The cross-sectional area of ​​the second chamber is 4.5-6.2 cm². 2 The cross-sectional area of ​​the third chamber is 7.4-9 cm². 2 Furthermore, the cross-sectional area of ​​the fourth chamber is 37-50 cm². 2 Furthermore, in certain highly specific embodiments, the total volume of the mixer is selected to be 2.5-3 L.

[0022] The materials used in the construction of the mixer of the present invention are selected to be compatible with the fluid being mixed, and may include, for example, metals (e.g., stainless steel), polymers (e.g., polypropylene, polysulfone, and polycarbonate). In some preferred embodiments, the mixer forms part of a single-use flow path.

[0023] The fluids that can be mixed in the mixer of the present invention are preferably liquids, and more preferably two or more liquids with different chemical and / or physical properties. Most preferably, the liquid is an aqueous solution or an aqueous mixture comprising a water-soluble organic solvent, such as ethanol and ethylene glycol. In many embodiments, the liquid comprises an aqueous buffer solution and / or a salt solution, and is preferably a biotreatment solution, which optionally contains one or more biomolecules.

[0024] In many highly preferred embodiments, the mixed liquid comprises aliquots of liquids with different chemical or physical properties, which arrive at the inlet sequentially. The order in which the aliquots arrive at the inlet is typically determined by the operation of one or more flow controllers that allow the supply of liquid to flow out into a flow path leading to the inlet. Preferably, aliquots of 2, 3, 4, 5, 6, 7, or 8 or more, and most preferably 2, 3, or 4 liquids, are provided to the inlet in a predetermined order.

[0025] In many embodiments, the mixer of the present invention is used to smooth changes in the properties and / or composition of a liquid before it passes through the mixer, and to produce a substantially homogeneous liquid after passing through the mixer. It will be appreciated that, in addition to producing a mixture with a substantially constant composition, varying the proportion of aliquots entering the mixer over time can make it possible to produce a substantially homogeneous, smooth composition gradient or a smooth liquid composition profile after passing through the mixer.

[0026] The mixer according to the invention is advantageously used in apparatus for performing biological treatment operations, and such apparatus forms another aspect of the invention. Biological treatment operations that can be performed by said apparatus to achieve biological treatment operations include chromatography, virus inactivation, filtration, refolding, ultrafiltration, percolation, microfiltration, in-line conditioning, and refolding. In many embodiments, the in-line mixer is located downstream of the pump and upstream of the apparatus for performing the biological treatment operation.

[0027] Chromatographic operations that can be performed using the apparatus of the present invention include affinity chromatography, ion exchange (one or both of anion and cation exchange) chromatography, hydrophobic interaction chromatography (HIC), reversed-phase chromatography, expanded bed chromatography, mixed-mode chromatography, membrane chromatography, and size exclusion chromatography (SEC). In many embodiments, protein A affinity chromatography includes at least one of these unit operations. The apparatus for performing the chromatographic operations includes suitable chromatographic devices, such as membranes, fiber blocks, or columns. The number and sequence of chromatographic unit operations will be selected based on the properties of the target biomolecule.

[0028] Virus inactivation unit operations that can be performed using the device of the present invention typically include a storage container in which a liquid comprising the target biomolecule can be stored under certain conditions for a residence time sufficient to inactivate the virus. In some embodiments, the outlet and inlet of the device can be fluidly connected to create a recirculation loop. In one such embodiment, the device is configured to have a container or bag fluidly connected between a device inlet and a device outlet, and one of the device outlets is fluidly connected to one of the inlets of a multi-inlet flow controller. The container or bag between the device inlet and outlet, fluidly connected to a liquid feed inlet, is filled by a flow-giving device (typically a pump) or conditioned with at least one other liquid via at least one of the other multi-inlet flow controller inlets. In some embodiments, the container or bag is a mixing container or bag. When the solution comprising the target substance is conditioned with at least one additional liquid via at least one other inlet fluidly connected to the multi-inlet flow controller, the process liquid is recirculated through the inlet of the multi-inlet flow controller to the container or bag and back to the inlet of the multi-inlet flow controller.

[0029] Performable filtration unit operations include viral, depth and absolute filtration, ultrafiltration, percolation, and microfiltration. In many embodiments, the filtration unit operation includes a filter module between a device inlet and a device outlet. The filter module is flushed and tracked using at least two liquid supplies attached to the inlet of a multi-inlet flow controller, and a solution comprising the target molecules is fluidly connected to the feed inlet. Liquid treatment through the filter is achieved by a flow-giving device fluidly connected to and positioned downstream of the multi-inlet flow controller outlet and the feed inlet, and upstream of the filter module. The filter module typically employs a construction known in the field of biological treatment.

[0030] Viral filtration, deep filtration, and absolute filtration are well-known unit operations in the art and can be performed using the apparatus of this invention, typically using filter devices known in the field of biological processing. In many embodiments, one or more filter devices are placed between the inlet and outlet of the apparatus to perform a specific unit operation. In other embodiments, the filter device is located downstream of the apparatus outlet; in some embodiments, this allows the apparatus to perform a primary unit operation, such as chromatography, virus inactivation, TFF, viral filtration, or deep filtration, followed by a secondary filtration operation.

[0031] Tangential flow filtration (“TFF”) unit operations that can be performed using the device of the present invention include conventional recirculating TFF and single-pass TFF. In some embodiments, the outlet and inlet of the device may be fluidly connected to create a recirculation loop; one example is recirculating tangential flow filtration. In one embodiment, as known in the art, the device is configured to have a TFF module between the device inlet and the device outlet, the TFF module comprising a flat sheet, hollow fiber, or spiral wound membrane, and permeate from the TFF module is guided from one of the device outlets to a fluidly connected inlet on a container or bag, the container or bag comprising at least one inlet and one outlet. The outlet of the container or bag is fluidly connected to a liquid feed inlet. An auxiliary device is used to hold the container or bag at a constant level to supply feed or liquid into the container or bag via a second inlet fluidly connected to the container or bag. In another embodiment, the device is configured to have a TFF module between the device inlet and the device outlet, the TFF module comprising a flat sheet, hollow fiber, or spiral wound membrane, and permeate from the TFF module is fluidly connected from one of the device outlets back to one of the inlets of a multi-inlet flow controller valve. In some embodiments, the recirculation loop from the device outlet to its inlet includes a ruptured container or bag. A solution comprising the target substance or liquid is drawn into the recirculation loop through a liquid feed inlet by means of a flow-inducing device (typically a pump). Residue is recirculated through the TFF module, preferably through one of the inlets of a multi-inlet flow controller. The multi-inlet flow controller can be used to mix the residue with at least one other liquid. The operation of a recirculating TFF is well known in the art and is controlled by setting crossflow rates and transmembrane pressures.

[0032] In some embodiments, a single-pass TFF may be configured with a TFF module comprising a flat, hollow fiber, or spiral wound membrane between the “device” inlet and the “device” outlet, for example, as in the case of a single-pass TFF as described in WO2017 / 118835.

[0033] In some embodiments, a hybrid of single-pass and recirculating TFF can be used, wherein the residue generated using a variable flow valve downstream of the TFF module is returned to the supply container.

[0034] The mixer according to the invention can also be used in apparatus for preparing buffer solutions, particularly in biological processing operations. Methods for generating biomolecules, especially methods for reducing the proportion of one or more impurities in biomolecules, constitute one aspect of the invention.

[0035] When the mixer of the present invention is used in biological processing operations, the biomolecules that can be processed include, for example, pDNA; cell therapies, vaccines (e.g., viral vaccines), gene therapy products, sugars, and inclusion bodies (particularly including inclusion bodies of polypeptides, especially recombinant polypeptides).

[0036] pDNA can exist in one or more of several forms, such as supercoiled, linear, and open-circular (i.e., nicked or relaxed) isoforms. Supercoiled pDNA isoforms have a covalently closed circular form, and the pDNA is negatively supercoiled within the host cell by the action of the host enzyme system. In open-circular isoforms, one strand of the pDNA duplex breaks at one or more locations.

[0037] Methods for producing pDNA are well known in the art. pDNA can be natural or artificial, for example, a cloning vector carrying a foreign DNA insert. In many embodiments, pDNA is in the size range of 1 kilobase to 50 kilobases. For example, the interfering RNA encoded by pDNA is typically in the size range of 3 kilobases to 4 kilobases.

[0038] Polypeptides (especially recombinant polypeptides) include therapeutic proteins and peptides, including cytokines, growth factors, antibodies, antibody fragments, immunoglobulin-like polypeptides, enzymes, vaccines, peptide hormones, chemokines, receptors, receptor fragments, kinases, phosphatases, isomerases, hydrolases, transcription factors, and fusion polypeptides.

[0039] Antibodies include monoclonal antibodies, polyclonal antibodies, and biologically active antibody fragments, including any of the aforementioned multivalent and / or multispecific forms.

[0040] Naturally occurring antibodies typically consist of four polypeptide chains: two identical heavy (H) chains and two identical light (L) chains linked together by disulfide bonds. Each heavy chain includes a variable region (VL). H ) and constant region (C H ), C H The region, in its natural form, comprises three structural domains C H 1. C H 2 and C H 3. Each light chain includes a variable region (V). L ) and a constant region, which includes a structural domain C L .

[0041] V H and V L The region can be further subdivided into hypervariable regions known as complementary determinant regions (CDRs), and more conservative regions scattered throughout, known as framing regions (FRs). Each V H and V LIt consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0042] An expressible antibody fragment comprises a portion of a complete antibody that has the desired biological activity. Antibody fragments typically include at least one antigen-binding site. Examples of antibody fragments include: (i) having V... L C L V H and C H 1) Fab fragments of a structural domain; (ii) Fab derivatives, such as those in C H Fab' fragments with one or more cysteine ​​residues at the C-terminus of the 1 domain can form divalent fragments by disulfide bridging between two Fab derivatives; (iii) having V H and C H 1. Fd fragments of the structural domain; (iv) Fd derivatives, such as those in C H (v) An Fd derivative having one or more cysteine ​​residues at the C-terminus of the 1st domain; (v) A V-type antibody with a single arm. L and V H Fv fragments of structural domains; (vi) single-chain antibody molecules, such as single-chain Fv (scFv) antibodies, wherein V L and V H Domains are covalently linked; (vii) V without constant-region domains H or V L A domain polypeptide, which has a variable domain (V) with or without a constant region domain. H or V L Domain peptide) link (e.g., V) H -V H V H -V L or V L -V L (viii) Domain antibody fragments, such as those derived from V H Domain or V L Fragments composed of structural domains, and V H or V L Antigen-binding fragments of structural domains, such as isolated CDR regions; (ix) so-called "diabody" which includes two antigen-binding sites within the same polypeptide chain, such as those linked to a light chain variable domain (V). L Heavy chain variable structural domain (V) H (x) and so-called linear antibodies, which comprise a pair of tandem Fd fragments that together with complementary light chain polypeptides form a pair of antigen-binding regions.

[0043] Inclusion bodies are insoluble aggregates that form in the cytoplasm of bacterial cells (such as Escherichia coli), and most commonly include polypeptides, especially recombinant polypeptides. Attached Figure Description

[0044] This invention is based on reference Figure 1 and Figure 2 Please provide an explanation. Detailed Implementation

[0045] Figure 1 A cross-section through a mixer according to the invention is shown. The mixer comprises a housing formed by end plates 1 and 2 and sidewalls 3, the end plates 1 and 2 preferably being circular and the sidewalls 3 preferably being cylindrical. A fluid inlet 4 allows fluid to flow under pressure into a first chamber 5, which is preferably centrally located on the end plates 1 and 2. The wall 6 of the first chamber 5 is preferably cylindrical and concentric with the sidewalls 3. The wall includes a series of orifices 7 distributed along the flow direction, each subsequent orifice having its nearest point to the fluid inlet overlapping at least with the farthest point of the preceding orifice from the fluid inlet, and being offset from the preceding orifice along the flow direction. The orifices 7 allow a portion of the flow path to flow into a second chamber 8, which is preferably cylindrical and concentric with the sidewalls 3. The second chamber includes an inner wall formed by the wall 6 of the first chamber and includes an outer wall 9. The outer wall 9 of the second chamber includes a series of orifices 10 distributed along the flow direction, each subsequent orifice having its nearest point to the bottom plate 1 overlapping at least with the farthest point of the preceding orifice from the bottom plate 1, and includes a plurality of additional chamber outlets 11 terminating at the end plate 1. The orifices 10 and 11 allow a portion of the flow path to flow into a third chamber 12, preferably cylindrical and concentric with the sidewall 3. The third chamber includes an inner wall formed by the outer wall 9 of the second chamber and includes an outer wall 13. The outer wall of the third chamber 12 includes a series of orifices 14 distributed along the flow direction, each subsequent orifice having its “start” overlapping at least with the “end” of the preceding orifice and offset from the preceding orifice along the flow direction. The orifices 14 allow a portion of the flow path to flow into a fourth chamber 15, the fourth chamber 15 including an inner wall formed by the outer wall 13 of the third chamber and including the sidewall 3. The fourth chamber also includes an outlet 16 located at the end plate 1 and a gas release valve 17 located at the end opposite the outlet 16. In use, the mixer is preferably vertically oriented along the axes of chambers 5, 8, 12, and 15, such that end plate 1 is at the bottom and end plate 2 is at the top. In use, the main flow of fluid is away from end plate 1 in the first and third chambers 5 and 12, respectively, and toward end plate 1 in the second and fourth chambers 8 and 15, respectively.

[0046] Figure 2 It shows perpendicular to Figure 1The cross-section of the axes of chambers 5, 8, 12, and 15 of the mixer shown illustrates the concentric arrangement of chambers 5, 8, 12, and 15 and the walls 6, 9, 13, and 3 of the chambers. For clarity, the cross-section is shown as a section without orifices in any of the walls of the chambers.

[0047] The invention will be illustrated by the following examples without limitation.

[0048] Example 1 abbreviation : L rise L / h (liters per hour) min minutes mm s seconds TC Clover Fixture.

[0049] In the experimental study, a 1 M sodium chloride solution and water were used for dilution. The mixing chamber was tested on a biological treatment system as described in co-pending application WO2019 / 158906. The sodium chloride solution was connected to the first inlet, and water was connected to the final inlet, allowing the system to alternately select either inlet. The inlets were connected to the pump via a quaternary valve, which was controlled during the experiment to select either water or a sodium chloride / water mixture by repeatedly metering an aliquot of sodium chloride for 1 second and water for 3 seconds. Downstream of the pump, a conductivity sensor monitored the conductivity of the liquid before it entered the mixing chamber. A second conductivity sensor downstream of the mixing chamber monitored the final conductivity of the liquid.

[0050] The mixing apparatus used in this experiment employed a SpectrumLabs (now Repligen, USA) K06 hollow fiber shell (63 mm inner diameter, 3-inch TC end, 460 mm long, with two 35 mm diameter ports at 22.5 mm from each end), featuring a 3-inch TC end cap and a 3-inch TC bottom plate with a 15 mm diameter inlet at the center. The interior of the mixing apparatus was divided into four sections by three 460 mm long, progressively increasing diameter circular tubes. The inner tube, with an inner diameter of 15 mm and a wall thickness of 2.5 mm, connects to the mixing apparatus inlet via the bottom. The middle tube has an inner diameter of 32 mm and a wall thickness of 2.5 mm. Finally, the outer tube has an inner diameter of 50 mm and a wall thickness of 2.5 mm. This resulted in a total internal volume of 1.06 L for the mixing chamber. Each tube contains a spiral of stadium-shaped orifices starting 10 mm above the bottom, progressing clockwise. The starting point of the next orifice coincides with and thus slightly overlaps with the previous one, but is offset by 90 degrees when viewed along the tube. The length of each orifice increases by 2 mm, resulting in a final orifice length of 42 mm. The inner and outer upper orifices are 4 mm wide and aligned such that the shorter bottom orifice of each tube is 180 degrees away from the 35 mm diameter port at the bottom. A spiral orifice with a width of 3 mm is formed on the intermediate tube, and two additional openings are cut into the bottom of the tube. The midpoint of these two openings is at 90 degrees to the shortest bottom 3 mm wide orifice, and each opening is 10 mm high and 25 mm wide. The intermediate tube is aligned such that the shortest bottom orifice faces the 35 mm diameter port at the bottom.

[0051] The experiment began with pre-filling the chamber with liquid to 150 mm from the bottom. The pump rate was set to 20% of its maximum output, resulting in an average flow rate of 225 L / h, and the chamber was flushed with water for 2 minutes. Sodium chloride was then metered into the water at the described 1:4 ratio for 5 minutes. Conductivity data were recorded starting at 3 minutes to allow the chamber to exchange with the sodium chloride mixture and then equilibrate. The results of Example 1 are shown in... Figure 3 As shown in Table 1.

[0052] Example 2 Repeat the method of Example 1, but set the pump speed to 35% of its maximum output, thus obtaining an average flow rate of 395 L / h. The results of Example 2 are... Figure 4 As shown in Table 1.

[0053] Example 3 Repeat the method of Example 1, but set the pump speed to 50% of its maximum output to obtain an average flow rate of 560 L / h.

[0054] The result of Example 3 is Figure 5 As shown in Table 1.

[0055] Example 4 Using the mixing chamber and flow path described in Example 1, a conductivity gradient was generated with 0.23 M sodium chloride solution and water. Two gradients were run using a 4-second duty cycle and a pump speed set to 10% or 20% of maximum output. Each gradient was generated by running for 15 minutes from 0 to 100% sodium chloride. In practice, this required calculating the ratio of valve opening time between the water and sodium chloride inlets every 4 seconds. For example, initially the water valve was opened for a full 4 seconds, at 1 minute, the sodium chloride valve was opened for 0.27 seconds and the water valve for 3.73 seconds, and by 10 minutes, the sodium chloride valve was opened for 2.67 seconds and the water valve for 1.33 seconds. At the end of the gradient, the sodium chloride valve was opened for a full 4 seconds. The conductivity of the two gradient runs was measured after the mixing chamber and plotted on [plotting data]. Figure 6 middle.

[0056] The examples illustrate that the mixer of the present invention allows for the mixing of liquids delivered sequentially into the flow path over a specific time period. In most cases, a certain proportion of liquid is added to the total liquid volume, which is less than or equal to the liquid volume within the mixing chamber. For continuous operation, a duty cycle is used to allow two or more liquids to be repeatedly and sequentially delivered into the mixer.

[0057] In the mixer of the present invention, the retention volume in the mixer is surprisingly small for the range of flow rates used. Furthermore, the volume of the mixer is surprisingly very small compared to the volume of the liquid being mixed.

[0058] The mixer of the present invention can be used as a device for mixing two or more liquids, and also as a device for capturing and retaining bubbles from a liquid stream.

Claims

1. A static mixing device for mixing fluids, comprising a series of multiple chambers, a first chamber of the series including a fluid inlet, and a last chamber of the series including a fluid outlet, each chamber in the series except the last chamber being fluidly connected to a subsequent chamber, the fluid connection including a plurality of orifices distributed along a flow direction, each subsequent orifice having its closest point from the inlet to the fluid inlet overlapping with the farthest point of the preceding orifice from the fluid inlet, and offset from the preceding orifice along the flow direction, wherein, The static mixing device further includes a gas outlet located at the end of the mixing device opposite to the fluid inlet and the fluid outlet.

2. The mixing device according to claim 1, wherein, The fluid is a liquid.

3. The mixing device according to claim 1, wherein, Each chamber is concentric.

4. The mixing device according to claim 3, wherein, Each chamber has a circular cross-section.

5. The mixing device according to claim 1, wherein, The first chamber is the innermost chamber, and the last chamber is the outermost chamber.

6. The mixing apparatus according to any one of claims 1-5, wherein the mixing apparatus comprises an even number of chambers.

7. The mixing apparatus according to any one of claims 1-5, wherein the mixing apparatus comprises four chambers.

8. The mixing apparatus according to any one of claims 1-5, wherein, The inlet and outlet are located at the bottom of the mixing device.

9. The mixing apparatus according to any one of claims 1-5, wherein, For a given chamber, along the longitudinal direction, the nearest point of each subsequent orifice to the inlet and the farthest point of the previous orifice from the inlet are aligned such that they form part of the same cross section perpendicular to the axis of the chamber.

10. The mixing apparatus according to any one of claims 1-5, wherein, The fluid inlet is located at the bottom of the mixing device, and the area of ​​the orifices in the walls of all odd-numbered chambers fluidly connected to subsequent chambers increases along the direction of the chambers away from the inlet end of the mixing device.

11. The mixing apparatus according to any one of claims 1-5, comprising an even number of chambers, wherein, In all odd-numbered chambers that are fluidly connected to subsequent chambers, the first orifice along the longitudinal direction is aligned such that it is not directed toward the fluid outlet.

12. The mixing apparatus according to claim 11, wherein, In all odd-numbered chambers that are fluidly connected to subsequent chambers, the first orifice along the longitudinal direction is aligned 180 degrees to the direction of the center of the fluid outlet.

13. The mixing apparatus according to any one of claims 1-5, wherein, The inlet and outlet are located at the bottom of the mixing device, and the chamber wall between the even-numbered chamber and the subsequent odd-numbered chamber has two initial orifices of equal cross-sectional area at the bottom of the fluid inlet end of the chamber, wherein the center points of the initial orifices are aligned with each other at 180 degrees.

14. A method for mixing two or more fluids, the method comprising passing the fluids through a mixing apparatus according to any one of claims 1-13.

15. The method of claim 14, wherein, The fluid is an aqueous solution, and the method includes steps in a biological treatment operation.

16. The method of claim 15, wherein, The method is included in methods for producing biomolecules.

17. An apparatus for performing biological treatment operations, the apparatus comprising a mixing apparatus according to any one of claims 1-13.

18. A method for producing biomolecules, the method comprising processing the biomolecules in a biological processing operation using the apparatus of claim 17.

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