Jet Impingement Reactor

Abstract

A jet impingement reactor is provided having a small spheroidal reaction chamber. The reaction chamber exhibits first and second fluid inlets arranged at opposing positions of the reaction chamber facing each other, each of the first and second fluid inlets comprising a nozzle. The distance between the nozzles is equal to or smaller than the diameter of the reaction chamber along the first central axis. Preferably, the nozzle is included in a fluid inlet connector reversibly insertable into the wall of the reaction chamber to provide the first and second fluid inlets. The invention further provides a method of mixing two fluids based on jet impingement using a reactor according to the invention.

Description

[Background technology]

[0001] Jet impingement reactors are fluid reactors for mixing fluids or for generating particulate fluids by impingement. They can be used, for example, for the production of nanoparticle fluids incorporating poorly water-soluble active ingredients. The functioning of these reactors is based on the use of two fluid streams (at least one of which typically contains the active ingredient) that are injected into the reactor cavity and impinge in a turbulent mixing zone, thereby generating nanoparticles. One of the main principles used in connection with jet impingement reactors is solvent / non-solvent precipitation, in which a first fluid containing the active ingredient dissolved in a suitable solvent is contacted with a non-solvent or anti-solvent under defined conditions to precipitate nanoparticles containing the active ingredient. If one of the solvents contains lipids, lipid nanoparticles can be produced, for example, with a jet impingement reactor that can subsequently be loaded with biologically active compounds, for example by pH shift.

[0002] The jet impingement reactor comprises a reaction chamber having two fluid inlets with nozzles that allow two fluids to be injected into the reaction chamber, typically at a pressure higher than ambient pressure. Through the first and second fluid inlets, two streams are injected so that they meet in the reaction chamber and form an impingement or mixing zone. An outlet is also provided for obtaining the resulting nanoparticle suspension.

[0003] An example of a jet impingement reactor is a microjet reactor as disclosed in EP 1165224. Such a microjet reactor has at least two nozzles or pinholes arranged opposite each other, each with associated pumps and supply lines to direct the liquids towards a common impingement point in a reaction chamber enclosed by a reactor housing. The reaction chamber comprises two bores that intersect each other and occur in a small cavity where the two fluids impinge, possibly without contacting the walls of this cavity. One of the bores contains two fluid inlets, while the second contains a further opening in the reactor housing through which a gas, evaporating liquid, cooling liquid or cooling gas can be introduced to maintain or cool the gaseous atmosphere in the reaction chamber. The other end of the second bore is provided with a further opening for removing the products obtained and excess gas from the reactor. Solvent / non-solvent precipitation in such a microjet reactor results in a dispersion of precipitated particles. This reactor requires an external source of gas or cooling liquid as a third fluid. However, the inventors have found that this setup is also associated with problems and drawbacks, such as foaming caused by the gas, or an undesirable accumulation of products at the gas inlet.

[0004] WO 2018 / 234217 discloses another jet impingement reactor with a housing surrounding a reaction chamber and a first fluid nozzle and a second fluid nozzle oriented in a same line. The second nozzle is arranged diametrically opposite the first fluid nozzle in the jet direction of the nozzle. The nozzles reach the reaction chamber and form an impingement zone in the form of a disk with each other. This reactor type has at least one rinsing fluid inlet arranged on the side of the first fluid nozzle and at least one product outlet arranged on the side of the second fluid nozzle and can be used for the continuous preparation of a fine particle fluid. Furthermore, the rinsing fluid guide structure is designed as a parallel channel on the side of the first fluid nozzle, which generates a rinsing fluid flow directed in the jet direction of the first fluid nozzle and guides the rinsing fluid in the direction of the impingement disk causing a slight deformation of the impingement disk. This transports the particles present in the formed nanoparticle fluid of the impingement disk from the impingement zone. Thus, the manufacturing process when carried out in a reactor as disclosed in WO 2018 / 234217 relies on the presence of rinse fluid directing structures and rinse fluid.

[0005] The quality and reproducibility of the nanoparticle fluid obtained depends, among other things, on the protocol of the production method as well as on the accuracy of the reactor. The protocol of the method can define different parameters such as, for example, the volumetric flow rates of the fluid streams injected through the nozzle, the ratio of these flow rates, the concentration of materials dissolved in the streams, or the temperature settings. These parameters can also be influenced by the reactor itself. The nozzle size, for example, affects the flow rate of the streams since its diameter allows only a certain amount of fluid to pass through the nozzle depending on the respective pressure of the streams.

[0006] Proper adaptation of parameters and selection of appropriate reactors for the production of nanoparticles is always a challenge in product and process development or process upscaling.

[0007] It is also known that the particle size distribution as well as the reproducibility of the results depend on the exact setting of the reactor, especially the nozzle, and on the exact control of the fluid flow. In order to achieve further improvements in terms of product particle size, particle size distribution or other quality parameters, improved jet impingement reactors are needed that allow better control of the process parameters. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] European Patent No. 1165224 [Patent Document 2] International Publication No. 2018 / 234217 Summary of the Invention [Problem to be solved by the invention]

[0009] Thus, there is a need for a system and method that provides the desired particle size distribution, morphology, and reduces the risk of undesired side reactions. Still further, there remains a need for a system and method that can be used continuously, for the production of large amounts of particulate fluids, and that is easy to set up, to achieve a cost-effective and uncomplicated manufacturing process that is reliable in terms of reproducibility and flexible when product or process development or upscaling of established manufacturing processes is performed. Another object is to provide a jet impingement reactor that is easy to clean and versatile in process development. A further object is to overcome one or more of the shortcomings of jet impingement reactors and related methods proposed in the prior art. These needs and objects are addressed by the invention disclosed herein. [Means for solving the problem]

[0010] In one aspect, the present invention provides a jet impingement reactor according to the main claim below. In particular, the jet impingement reactor comprises a reaction chamber defined by an inner surface of a reaction chamber wall, the reaction chamber having a substantially spheroidal overall shape, as described in more detail below. The reaction chamber comprises: (a) a first and a second fluid inlet, the first and the second fluid inlet being arranged at opposing positions on a first central axis of the reaction chamber facing each other, each of the first and the second fluid inlet comprising a nozzle; and (b) a fluid outlet arranged at a third position, the third position being located on a second central axis of the chamber, the second central axis being perpendicular to the first central axis. Furthermore, the distance between the nozzle of the first fluid inlet and the nozzle of the second fluid inlet is equal to or smaller than the diameter of the reaction chamber along the first central axis.

[0011] In a preferred embodiment, each nozzle has a downstream end substantially aligned with the inner surface of the chamber wall. Furthermore, the reaction chamber preferably does not include any further inlet or outlet openings. According to a further preferred form, each of the first and second fluid inlets is provided by a fluid inlet connector having an upstream end, a downstream end for holding a nozzle of the first or second fluid inlet, and a fluid conduit for conducting fluid from the upstream end to the downstream end, the downstream end of each fluid inlet connector being reversibly insertable into the chamber wall to provide the first and second fluid inlets.

[0012] In a further aspect, the present invention provides a method for mixing two fluids, the method comprising the steps of: (i) providing a jet impingement reactor according to the present invention; (ii) directing a first fluid stream into a reaction chamber through a first fluid inlet; and (iii) directing a second fluid stream into the reaction chamber through a second fluid inlet such that it impacts with the first fluid stream at an angle of about 180°.

[0013] In a preferred embodiment, the orifice of the first nozzle is larger than the orifice of the second nozzle and / or the flow rate of the first fluid is larger than the flow rate of the second fluid, and the pressure of the first fluid and the pressure of the second fluid may be adapted such that the first fluid stream and the second fluid stream have substantially the same kinetic energy when they enter the reaction chamber.

[0014] In a further aspect, the present invention relates to a method for manufacturing a jet impingement reactor by injection molding. In one embodiment, the jet impingement reactor, or at least the reactor wall, may be made from a thermoplastic polymer by injection molding, where a prefabricated inlet nozzle made of a hard non-thermoplastic material such as metal, glass or ceramic is inserted into the mold during the injection molding process, or mechanical or laser drilling is used to manufacture a nozzle on both sides of the reactor. [Brief description of the drawings]

[0015] [Figure 1] 1 shows, not to scale, a jet impingement reactor (1) according to an embodiment of the present invention. The reaction chamber (6) defined by the inner surface (2) of the chamber wall (3) is substantially spherical, except for two fluid inlets (4) and a fluid outlet (7). The fluid inlets (4) are located at opposite positions on a first central axis (x) of the reaction chamber (6) and face each other. Each of the fluid inlets (4) includes a nozzle (5), which in this embodiment is a flat orifice nozzle. The fluid outlet (7) is located on a second central axis (y) perpendicular to the first central axis (x). The distance (d) between the two nozzles (4) is substantially the same as the diameter of the spherical reaction chamber (6). [Diagram 2]FIG. 1 shows a fluid inlet connector (10) according to one embodiment of the present invention. The connector (10) has an upstream end (11), a downstream end (12) that holds a nozzle (13) downstream of the downstream end (12), and a fluid conduit (14) for conducting fluid from the upstream end (11) to the downstream end (12). The fluid inlet connector (10) provides a fluid inlet for a jet impingement reactor (not shown) according to the present invention and is designed to be reversibly insertable into the wall of said reactor. The figure is not to scale. [Diagram 3] 1 shows, also not drawn to scale, a fluid inlet connector (20) according to another embodiment of the invention, and designed to be reversibly insertable into the wall of a jet impingement reactor (not shown) according to the invention, such as to provide a fluid inlet. It has an upstream end (21), a downstream end (22) that holds a nozzle (23) downstream of the downstream end (22), and a fluid conduit (24) for conducting a fluid from the upstream end (21) to the downstream end (22). [Figure 4] 1 is a graphical depiction of particle size (Z-average diameter, nm) and polydispersity (PDI) characterized for lipid nanoparticles encapsulating poly(A) obtained as described in Example 3 at tested total flow rates of 1 mL / min, 5 mL / min, 15 mL / min, 40 mL / min and 280 mL / min. "300 / 300-5-2" corresponds to the characterization of particles produced using a jet impingement reactor equipped with a reactor chamber having a diameter of 5 mm and a pair of interchangeable fluid connectors having a 2 mm outlet and a nozzle with an orifice diameter of 300 nm, respectively. "200 / 100-2-1" corresponds to the characterization of particles produced using a jet impingement reactor equipped with a reactor chamber having a diameter of 2 mm and a pair of interchangeable fluid connectors having a 1 mm outlet and a nozzle with an orifice diameter of 200 μm and 100 μm for the first and second fluids, respectively. "T-shaped" corresponds to the characterization of particles produced using a T-shaped part (control). [Diagram 5]FIG. 5 is a graphical representation of the encapsulation efficiency (EE%) of Poly(A) determined for lipid nanoparticles prepared using different reactor configurations as described in Example 3 and FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] In one aspect, the present invention provides a jet impingement reactor, particularly a jet impingement reactor comprising a reaction chamber defined by an inner surface of a reaction chamber wall having a substantially spheroidal overall shape, as described in more detail below. The reaction chamber is further characterized by including (a) a first and a second fluid inlet, the first and the second fluid inlet being disposed at opposing positions on a first central axis of the reaction chamber facing each other, each of the first and the second fluid inlet including a nozzle, and (b) a fluid outlet disposed at a third position, the third position being located on a second central axis of the chamber, the second central axis being perpendicular to the first central axis. Furthermore, the distance between the nozzle of the first fluid inlet and the nozzle of the second fluid inlet is equal to or less than the diameter of the reaction chamber along the first central axis.

[0017] The inventors have found that the reactor of the present invention achieves substantial improvements over conventional jet reactors, particularly due to the substantially spheroidal overall shape of the reaction chamber and its small size, especially reflected in the relatively short distance between the fluid inlet nozzles. Without wishing to be bound by theory, it is believed that the spheroidal overall shape eliminates some of the deleterious effects of irregularly shaped reaction chambers known in the art, which have internal angles, edges or corners, and associated dead volume areas. It is believed that the small size and minimized distance between the fluid inlet nozzles enhances turbulent mixing of the fluids in the chamber and facilitates proper alignment of the nozzles on the same axis, such as achieving frontal impingement of the two fluids injected into the chamber by the nozzles.

[0018] As used herein, a substantially spheroidal overall shape means that at least a majority of the reaction chamber defined by the inner surface of the chamber wall has or resembles the shape of a sphere. For example, a portion of the cross section of a spheroid may be elliptical. In one preferred embodiment, all parts or portions of the reaction chamber or parts or portions of the inner surface of the chamber wall, except for those parts that hold or define the inlet or outlet openings, are substantially spheroidal or even spherical.

[0019] If the outlet opening, which is typically of relatively large diameter compared to the diameter of the nozzle or inlet opening, is understood as a deviation from the otherwise spherical shape of the reaction chamber, the shape of the reaction chamber can also be described as a spherical cap, also called a spherical dome. In a preferred embodiment, such a spherical cap has a height, a base, and a radius along a first central axis (i.e., where the two fluid inlets are located), the height is greater than the radius and the base is defined by the fluid outlet. In other words, the spherical dome formed by the reaction chamber has a larger volume than a corresponding hemisphere, which also means that the diameter of the outlet opening is smaller than the maximum diameter of the reaction chamber. In certain embodiments, the height of the dome is in the range of about 110% to about 170% of the radius. For example, the height may be about 120% to about 160% of the radius, such as about 120%, about 130%, about 140%, about 150%, or about 160% of the radius.

[0020] Another preferred feature of the reactor relates to the arrangement of the nozzles. As mentioned above, each of the first and second fluid inlets includes a nozzle, and in the assembled state of the reactor, the distance between the nozzle of the first fluid inlet and the nozzle of the second fluid inlet is equal to or smaller than the diameter of the reaction chamber along the first central axis. This is in contrast to some jet reactors known in the art that have retracted nozzles. In a preferred embodiment of the invention, the nozzles (more precisely their downstream ends) are not retracted or protruded into the reaction chamber, but are substantially aligned with the inner surface of the reaction chamber wall.

[0021] It is further preferred that the reaction chamber is provided with a fairly small internal volume, which also corresponds to a small distance between the nozzles when arranged according to the preferences explained above. As used herein, the distance between the first and second nozzles should be understood as the distance between the downstream ends (i.e. the ends of the nozzles facing the center of the reaction chamber). The preferred reaction chamber volume is less than about 0.5 mL, and the preferred distance between the nozzles is less than about 7 mm. In a particularly preferred embodiment, the reaction chamber has a volume of about 0.25 mL or less, and the distance between the nozzle of the first fluid inlet and the nozzle of the second fluid inlet is 5 mm or less. In a further preferred embodiment, the volume of the reaction chamber is about 0.2 mL or less, for example about 0.15 mL, and the distance between the two nozzles is about 4 mm or less. Even smaller dimensions, such as 1 mm, 2 mm, or 3 mm, may also be useful. In an embodiment in which the distance between the first and second nozzles is the same as the diameter of the reaction chamber along the first central axis, the distance between the nozzles as explained in the embodiment above herein also corresponds to the diameter of the chamber. For the sake of clarity, it should be noted that for the purposes of providing these preferences with respect to the volume of the reaction chamber, the respective values ​​are calculated under the assumption that the reaction chamber has a substantially spherical shape, regardless of the outlet opening. In other words, the outlet opening is not interpreted as forming the base of a spherical cap whose volume is smaller than the sphere from which it originates. If the outlet opening is to be understood as being planar so as to form the base of a spherical segment representing the volume of the reaction chamber, the values ​​in mL provided above should be adapted accordingly, taking into account the dimensions of the outlet opening.

[0022] In a further particularly preferred embodiment, the reaction chamber has no other inlet or outlet openings. In other words, the first and second fluid inlets and the fluid outlet represent the only openings of the reaction chamber provided in the chamber wall. This is also in contrast to some known jet impingement reactors, which show one or more additional inlets, such as an inlet for gases introduced into the reaction chamber or an outlet for degassing purposes. However, as the inventors have found, such additional inlets or outlets can also have a negative effect on the impingement process, leading to uncontrolled precipitation or accumulation of contamination at such additional openings, and the reactor according to the invention offers the advantages of better control over the interaction and mixing of the first and second fluids, improved cleanability and increased batch-to-batch consistency.

[0023] As used herein, a reactor having a reaction chamber with one or more additional inlet or outlet openings that are inactivated by a closing mechanism is also to be understood as a reactor whose reaction chamber has no further inlet or outlet openings other than the two essentially necessary inlet openings for the first and second fluids and an outlet opening for the fluid resulting from the mixing (and / or reaction) of the first and second fluids in the reaction chamber.

[0024] According to the basic concept of the jet impingement reactor, the reactor of the present invention should preferably be constructed and / or arranged to direct the first and second fluids into the reaction chamber so that the two fluids impinge or face-on against each other. This is particularly relevant for the precise positioning and orientation of the nozzles contained in the two fluid inlets. Thus, in a preferred embodiment, the jet impingement reactor is characterized in that the nozzles of the first and second fluid inlets are arranged to direct the first and second fluid streams along the first central axis towards the center of the chamber and allow the first and second fluid streams to impinge at an angle of about 180°. As used herein, impingement at an angle of about 180° may also be referred to as face-on impingement. In this context, the expression "about" means that the actual angle is sufficiently close to 180° to ensure that the impingement of the first and second liquid streams results in a rapid and highly turbulent fluid flow in the mixing zone so that complete mixing occurs within a very short time, for example typically within a few milliseconds.

[0025] As will be appreciated by those skilled in the art, and as further illustrated and explained in various embodiments relating to methods of using an impingement reactor described herein and below, the reactor of the present invention is constructed and / or arranged for mixing two fluids with one another, i.e., mixing of a first and a second fluid by frontal collision of a stream of a first fluid with a stream of a second fluid, the second fluid being different or not the same as the first fluid.

[0026] Thus, as described herein in any one or combination of its embodiments, the reaction chamber of the jet impingement reactor may include a first fluid inlet through which a first fluid flow is directed and a second fluid inlet through which a second fluid flow is directed, the second fluid being different or not the same as the first fluid, the first and second fluid inlets being arranged at opposite positions on a first central axis of the reaction chamber so as to face each other, and each of the first and second fluid inlets including a nozzle, the nozzle being arranged to direct the first fluid flow (i.e., the first fluid stream) and the second fluid flow (i.e., the second fluid stream) along the first central axis toward the center of the chamber, allowing the first and second fluid streams to collide at an angle of about 180°. In another particularly advantageous embodiment, the jet impingement reactor of the present invention is equipped with interchangeable nozzles. This allows for rapid screening of process parameters using the same reactor, thus accelerating product and process development efforts. This differs from prior art reactors that typically have non-removable or non-replaceable nozzles, i.e., nozzles that are glued, welded, crimped or heat-fitted so that they cannot be non-destructively disconnected from the reactor, so that testing of certain process parameters, especially testing of different nozzle diameters, requires the use of several reactors within each series of experiments. As used herein, nozzle diameter should be understood as the inner diameter of the nozzle opening, which may also be referred to as the pinhole size or diameter if the nozzle is a flat orifice nozzle. In other words, this embodiment provides a substantially increased versatility of the reactor.

[0027] In one embodiment, each of the first and second fluid inlets is provided by a fluid inlet connector having an upstream end, a downstream end that holds a nozzle of the first or second fluid inlet, and a fluid conduit for directing fluid from the upstream end to the downstream end, and the downstream end of each fluid inlet connector is reversibly insertable into the chamber wall to provide the first and second fluid inlets. According to this embodiment, the nozzle is replaceable in that a reversibly insertable inlet connector is provided that holds the nozzle. The nozzle may be fixedly fixed to the replaceable connector. As used herein, an inlet connector (or fluid inlet connector) may be any part having an upstream end, a downstream end, and an internal fluid conduit configured to provide a fluid connection between the upstream and downstream ends.

[0028] A further advantage of such a reactor configuration having interchangeable fluid inlet connectors (and thereby interchangeable nozzles) is that the reactor exhibits better cleanability and reduced cycle times.

[0029] In one embodiment, the fluid inlet connectors are secured to the chamber wall by releasable compression fittings. For example, the fluid inlet connectors providing the first and / or second fluid inlets are attached to the chamber wall by single ferrule fittings or double ferrule fittings. Other tight fittings capable of preventing leakage under high pressure are also useful as long as they are releasable.

[0030] In a preferred embodiment, the reactor comprises a fluid inlet connector having (i) an upstream segment comprising an upstream end of the fluid inlet connector and an upstream portion of a fluid conduit, and (ii) a downstream segment comprising a downstream end of the fluid inlet connector having a nozzle and a downstream portion of the fluid conduit, the diameter of the upstream portion of the fluid conduit being larger than the diameter of the downstream portion of the fluid conduit, in this context the diameter should be understood as the inner diameter.

[0031] The downstream portion may be shaped as or provided by a capillary having a diameter substantially smaller than that of the upstream portion. For example, in one embodiment, the diameter of the downstream portion is less than or equal to half the diameter of the upstream portion. In another embodiment, the diameter of the downstream portion is less than or equal to about 40% of the diameter of the upstream portion. Optionally, the upstream portion may be substantially longer than the downstream portion. For example, the ratio of the length of the upstream portion to the length of the downstream portion may be 5:1 or more, or 8:1 or more.

[0032] In one particular embodiment, the downstream end of the fluid inlet connector is externally conical and the chamber wall exhibits a corresponding cavity that is similarly conically shaped and dimensioned to receive the downstream end of the fluid inlet connector. Using this configuration facilitates the insertion of the fluid inlet connector into the reactor and at the same time facilitates proper alignment of the respective nozzles on the first central axis as described above. Preferably, the reactor is equipped with two fluid inlet connectors having essentially the same overall configuration, except that their nozzles may have different diameters.

[0033] The fluid inlet connector described herein represents one aspect of the present invention.

[0034] The nozzle may be of any type or shape that allows the first and second fluids to be injected into the reaction chamber in the form of a fluid stream using appropriate pressures. Useful pressure ranges are generally known to those skilled in the art.

[0035] In one preferred embodiment, the nozzle of the first and / or second fluid inlet is a planar orifice nozzle. In this embodiment, it is further preferred that both nozzles are planar orifice nozzles. As used herein, a planar orifice nozzle is a nozzle characterized by a simple orifice having an essentially simple (i.e. substantially cylindrical) through-hole shape, which may also be referred to as a pinhole in view of its small dimensions. Alternatively, the nozzle may be provided as a shaped orifice nozzle, as long as the selected shape results in the generation of a fluid stream capable of frontal impact with a second fluid stream in the reaction chamber at the respective operating pressure.

[0036] When a flat orifice nozzle is used, such a nozzle may be provided as a component made of a particularly hard material such as sapphire, ruby, diamond, ceramic, glass-ceramic, glass (such as borosilicate glass) or metal such as steel, for example stainless steel. In the case of steel, a steel quality having high hardness and low wear is preferably used, such as high-speed steel (HSS), which is an alloy steel containing carbide-forming elements such as tungsten, molybdenum, chromium, vanadium and cobalt, the total amount of alloying elements typically being in the range of about 10-25% by weight, or tungsten steel, also called hard alloy, with tungsten and cobalt being the main alloying elements.

[0037] If sapphire, ruby ​​or diamond nozzles are used, these may be prefabricated and inserted into the downstream end of the downstream part of the fluid inlet connector and fixed, for example by crimping. The tolerances of the nozzle, which depend on the prefabrication method, should be taken into account. If steel nozzles are used, it is useful to prepare the entire fluid inlet connector or at least its downstream part from the respective steel quality and then introduce the necessary orifice. In this way, the alignment of the nozzle with the first central axis can be further improved.

[0038] Nozzle diameters, i.e. the diameter of the nozzle orifice, are typically in the range of less than about 1 mm. Process development in the pharmaceutical field often involves the use of very expensive materials, and in particular in the development of nanoparticle forms of new chemical entities, new biological drugs, highly specialized colloidal carrier systems for advanced therapies, etc., it is necessary to minimize the volume of liquid used in process development. This is best achieved with even smaller nozzles, such as nozzles with orifices of 0.5 mm diameter or less, among others.

[0039] Thus, it is one of the preferred embodiments of the present invention that the jet impingement reactor as described above is characterized in that the nozzle of the first fluid inlet has a first orifice diameter and the nozzle of the second fluid inlet has a second orifice diameter, the first and / or second orifice diameter being in the range of 20 μm to 500 μm. Preferably, both the first and second orifice diameters are in the range of 20 μm to 500 μm, or in the range of about 50 μm to 500 μm. Also preferred are reactor configurations in which at least one of the orifice diameters is about 500 μm, about 400 μm, about 300 μm, about 200 μm, about 100 μm, about 50 μm, or about 20 μm, respectively. Even smaller diameters, for example less than 20 μm, can be considered.

[0040] In one particular embodiment, the diameter of the first and second nozzles (i.e., nozzle orifices) is the same, for example about 300 μm, about 200 μm, about 100 μm. Such a configuration seems to work well for some, but certainly not all, product applications. The inventors have found that for many processes based on jet impingement technology, the best results are achieved with a reactor according to the invention having two nozzles of different sizes. In other words, according to this further preferred embodiment, the first orifice diameter is larger than the second orifice diameter. Such an asymmetric nozzle configuration can be advantageous in various ways. For example, it can be used to minimize the introduction of solvents that are necessary for processing purposes but undesirable in the final product. It can also be used for the generation of two liquid streams with different flow rates but with similar kinetic energy as they are injected through the nozzles into the reaction chamber where they impinge. The possibility of operating with different nozzle diameters using one and the same reactor, especially reactors with interchangeable nozzles or fluid inlet connectors that can be easily replaced, substantially increases the versatility of the reactor according to the invention.

[0041] In one embodiment, the diameter of the first nozzle (i.e., its orifice) is at least 20% larger than the diameter of the second nozzle. In a further embodiment, the ratio of the first orifice diameter to the second orifice diameter is from about 1.2 to about 5. For example, the following nozzle pairs can be used, where the first value represents the approximate diameter of the first orifice and the second value represents the approximate diameter of the second orifice: 100 μm and 50 μm; 200 μm and 100 μm; 200 μm and 50 μm; 300 μm and 200 μm; 300 μm and 100 μm; 300 μm and 50 μm; 400 μm and 300 μm; 400 μm and 200 μm; 400 μm and 100 μm; 400 μm and 50 μm; 500 μm and 400 μm; 500 μm and 300 μm; 500 μm and 200 μm; 500 μm and 100 μm; 500 μm and 50 μm. Again, these pairs are non-limiting examples and other orifice diameter combinations may be useful depending on the particular product or process.

[0042] Furthermore, the inventors have found it useful to observe certain dimensional relationships in the configuration of the reactor, especially when small nozzles are used. As already mentioned, generally speaking, it is preferable for the reaction chamber to be small. In some processes, it has also been found useful to provide the reactor with a reaction chamber diameter of 100 times or less than the diameter of the nozzle orifice, or, when nozzles of different sizes are used, a chamber diameter of about 100 times or less than the diameter of the orifice diameter of the larger nozzle. For example, if the larger nozzle has an orifice diameter of 100 μm, according to this particular embodiment, the diameter of the reaction chamber is preferably about 10 mm or less. In one embodiment where the nozzle or the larger nozzle has an orifice diameter of 200-300 μm, the diameter of the reaction chamber along the first central axis is preferably in the range of 2-5 mm.

[0043] In a related embodiment, the ratio of the diameter of the reaction chamber along the first central axis to the diameter of the first orifice is in the range of 6 to 60. For example, according to this particular embodiment, if the diameter of the first orifice is about 200 μm, the diameter of the reaction chamber along the first central axis is in the range of about 1.2 mm to about 12 mm. However, reactors equipped with larger nozzles may require other dimensional considerations.

[0044] According to a further related embodiment, the ratio of the diameter of the reaction chamber along the first central axis to the diameter of the fluid outlet is in the range of about 1.2 to about 3. For example, according to this particular embodiment, a reaction chamber having a diameter of about 3 mm has an outlet diameter of about 1 mm to about 2.5 mm. In one preferred embodiment, the fluid outlet diameter is about 1 to 2 mm.

[0045] When selecting the outlet diameter, the nozzle orifice diameter should also be considered. For example, a small nozzle size (i.e., orifice), such as less than 100 μm, should be combined with a small fluid outlet diameter, such as less than 1 mm, to ensure that the pressure in the reaction chamber is high enough to support turbulent flow and rapid mixing of the two fluids. For example, when using two nozzles with 50 μm orifices, a fluid outlet diameter of 0.5 mm can be used. Based on the present disclosure and the guidance provided above, it will be apparent to one of skill in the art that further variations in dimensional factors may also be useful to accommodate specific product or process requirements.

[0046] Regarding the reactor material, and in particular the chamber wall material, various types of sufficiently hard and wear-resistant materials can be used. In some preferred embodiments, the reaction chamber wall (3) is made of a material selected from metal, glass, glass-ceramic, ceramic, and thermoplastic polymer.

[0047] An example of a particularly useful metal is stainless steel. Thus, in one preferred embodiment, the reactor of the present invention comprises a reaction chamber wall made of stainless steel. Depending on the type of product used in the manufacture of the reactor, carbide and coated alloys can also be used. Furthermore, it is also preferred that the inner surface of the chamber wall exhibits a smooth finish. A smooth finish can be characterized by a low Ra value, which represents the surface roughness. The Ra value represents the arithmetic mean roughness value from the amount of all values ​​when measuring the surface along the surface profile. According to one preferred embodiment, the inner surface of the reaction chamber wall exhibits a surface roughness of 0.8 Ra or less, where Ra is determined according to ISO4287:1997.

[0048] In an alternative but preferred embodiment, the jet impingement reactor comprises a reaction chamber wall made of a thermoplastic polymer or a material containing a thermoplastic polymer, such as a mixture of thermoplastic polymers or a mixture of thermoplastic polymers with additives such as colorants, antioxidants, antistatic agents, glass fibers, etc. The advantage of a reaction chamber wall made of a thermoplastic polymer or a material based on a thermoplastic polymer is that the reactor can potentially be manufactured by injection molding, which is a very cost-effective manufacturing method. Examples of potentially suitable thermoplastic polymers include, but are not limited to, polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU), and polyetherimide (PEI). In one embodiment, the thermoplastic polymer is selected from PTFE and PEEK.

[0049] In one embodiment, the jet impingement reactor comprises (i) a reaction chamber wall made of or including a thermoplastic polymer, and (ii) a fluid inlet nozzle (i.e., nozzles of the first and second fluid inlets). Optionally, the fluid inlet nozzle may be made of a material selected from metal, glass, glass-ceramic, and ceramic. The advantage of such an embodiment is that it combines a nozzle with a high degree of hardness and strength, and at the same time allows the reactor body, i.e., the reaction chamber wall, to be manufactured cost-effectively by injection molding. In these embodiments, the fluid inlet nozzle may be arranged either exchangeably or non-exchangeably with respect to the reaction chamber wall. If designed to be exchangeable, this brings the advantage that the jet impingement reactor is versatile and can be used with a high degree of flexibility for different products and processes. On the other hand, if designed to be non-exchangeable, this may bring the advantage of a very cost-effective manufacturing in that the nozzle can be pre-manufactured for or during the injection molding process in which the reactor body, i.e., at least the reaction chamber wall, is manufactured, and then inserted into the respective mold. In an alternative embodiment, the jet impingement reactor comprises (i) a reaction chamber wall made of or comprising a thermoplastic polymer, and (ii) fluid nozzles (i.e., first and second fluid inlet nozzles) obtained or manufactured, for example, by mechanical or laser drilling of the jet impingement reactor, on at least one or both sides of the reactor or reactor chamber wall.

[0050] A further aspect of the invention relates to the manufacture of the jet impingement reactor as described above. As described above, when the reactor is made of a thermoplastic polymer or a material comprising or based on a thermoplastic polymer, the reactor, or at least its body including the reaction chamber wall, can be made by injection molding. Thus, in some preferred embodiments, the jet impingement reactor is made by a method comprising a step of injection molding the reaction chamber wall.

[0051] In one embodiment, a method of manufacturing a jet impingement reactor having (a) a reaction chamber wall made of a thermoplastic polymer and (b) first and second fluid inlet nozzles made of a material selected from metal, glass, glass-ceramic, and ceramic includes the steps of: (i) providing a mold for molding the reaction chamber wall; (ii) providing a first fluid inlet nozzle and a second fluid inlet nozzle (4); (iii) inserting the nozzles into the mold; (iv) melting a thermoplastic polymer; and (v) injecting the molten thermoplastic polymer into the mold.

[0052] Examples of potentially suitable thermoplastic polymers that can be used in the context of the present invention have already been disclosed above. Further details regarding the method, such as the temperature at which the molten thermoplastic polymer can be injected into the mold, depend on the nature of the selected material, i.e. the thermoplastic polymer, and are generally known to those skilled in the art.

[0053] In a further aspect, the present invention provides a method based on the use of the reactor detailed above. In particular, the present invention discloses a method for mixing two fluids, the method comprising the steps of: (i) providing a jet impingement reactor as described above, (ii) directing a first fluid stream into a reaction chamber through a first fluid inlet, and (iii) directing a second fluid stream into the reaction chamber through a second fluid inlet such that it impacts with the first fluid stream at an angle of about 180°.

[0054] As used herein, a fluid is a liquid or gaseous material that flows or deforms continuously when exposed to shear stress.Preferably, the two fluids mixed according to the present invention are liquid materials, such as liquid solutions, suspensions or emulsions, most preferably liquid solutions.As used herein, the mixing of two fluids in a reactor can optionally further include other physical or chemical changes beyond simple mixing, such as precipitation, emulsification, complexation, self-assembly, or even chemical reactions, but all these optional processes are caused by the mixing of two liquids achieved by the use of the jet impingement reactor according to the present invention.

[0055] Operating a reactor under jet impingement conditions typically involves selecting an appropriate nozzle size as described above, and providing two fluid streams at a pressure or flow rate such that the fluids are injected through the nozzle towards the center of the reaction chamber where they ideally impinge forward.

[0056] When the reactor is configured with interchangeable fluid inlet connectors reversibly insertable into the chamber wall to provide the first and second fluid inlets, the method steps of providing the jet impingement reactor include the substeps of (i) selecting a first fluid inlet connector having a first nozzle and a second fluid inlet connector having a second nozzle, and (ii) inserting the first fluid inlet connector and the second fluid inlet connector into the chamber wall to provide a jet impingement reactor having the first and second fluid inlets. As explained above, the orifice diameter can be different between the first nozzle and the second nozzle.

[0057] In one preferred embodiment of the method, the first fluid stream comprises a dissolved active ingredient and the second fluid stream is a non-solvent or anti-solvent for the active ingredient, such that the collision and mixing of the two streams in the reaction chamber results in the precipitation of nanoparticles comprising the active ingredient. In one of the preferred embodiments, the first and second fluid streams are extruded through their respective fluid inlet nozzles at a pressure in the range of about 0.1 to about 120 bar. In this context, and unless the context indicates otherwise, pressure is expressed as gauge pressure, i.e., overpressure, or pressure difference relative to ambient (atmospheric) pressure, which is usually obtained from a pressure gauge in fluid communication with the respective fluids being measured. In a further preferred embodiment, the first and second fluid streams are extruded through their respective fluid inlet nozzles at a pressure in the range of about 1 to about 40 bar.

[0058] In a further preferred embodiment, each of the first and second fluid streams is directed to the reaction chamber at a flow rate in the range of about 1 to about 1000 mL / min. In this context, unless otherwise indicated, flow rates are provided for each individual stream. Other preferred ranges of flow rates are about 5 to about 500 mL / min and about 10 to about 300 mL / min, respectively.

[0059] It should be understood that the preferred flow rates, like the pressure preferences, are generally applicable and can therefore be combined with each other. In other words, there is also an option or further preference for the embodiment of the method in which the first and second fluids are directed through the respective nozzles to the reaction chamber at a pressure in the range of about 0.1 to about 120 bar, in particular at a pressure of about 1 to about 40 bar, and at a flow rate in the range of about 10 to 300 mL / min.

[0060] As mentioned above, according to one preferred embodiment of the jet impingement reactor, the two nozzles may have different pinhole sizes, i.e. the orifice of the first nozzle may be larger than the orifice of the second nozzle. In a related embodiment, the method of the invention is carried out with such a reactor equipped with two different nozzles. Alternatively or additionally, the flow rate of the first fluid may be larger than the flow rate of the second fluid. In a further preferred embodiment, the method is characterized in that (i) the orifice of the first nozzle is larger than the orifice of the second nozzle and / or (ii) the flow rate of the first fluid is larger than the flow rate of the second fluid, and the pressure of the first fluid and the pressure of the second fluid are adapted such that the first and second fluid streams have substantially the same kinetic energy when entering the reaction chamber.

[0061] In this regard, the kinetic energy may optionally be calculated according to the following formula: JPEG2024537965000002.jpg955where m is the mass of the flow per unit of volume and v is the velocity of the flow.

[0062] An advantage of working with two liquid streams having similar or even substantially the same kinetic energy is that the impact point in a spheroidal (i.e. symmetric) reaction chamber is at or near the center of the chamber, thus allowing better control of the impact process and eliminating the effects of uncontrolled impact points that may have various unknown or even undesirable effects on the process.

[0063] In some further preferred embodiments, the method includes the use of a first liquid that is an aqueous liquid and a second liquid that is an organic liquid. As used herein, an aqueous liquid should be understood as a liquid whose main solvent or liquid component is water. For example, an aqueous liquid may contain dissolved or suspended solids, but is nevertheless an aqueous liquid if its main (or most abundant by mass) liquid component is water. In other words, a buffered aqueous solution that contains a small amount of ethanol is clearly an aqueous liquid. In contrast, an organic liquid is a liquid whose main solvent or liquid component is an organic solvent or a combination of two or more organic solvents.

[0064] Again, this preferred embodiment can be combined with other preferences mentioned above. For example, it is also a preferred embodiment to carry out the method of the invention using a first fluid that is an aqueous liquid, a second fluid that is an organic liquid, a first nozzle having a larger orifice than the second nozzle, and directing the first and second fluids through the first and second nozzles, respectively, into the reaction chamber at a flow rate in the range of about 10-300 mL / min and a pressure in the range of 0.1-120 bar, in particular in the range of 1-40 bar, such that the first and second fluid streams collide forward, i.e. at an angle of about 180°. Preferably, the kinetic energy of the fluid streams is sufficiently similar to cause the streams to collide or impinge at or near the center of the reaction chamber.

[0065] The present invention, including several additional embodiments, options and preferences, is further illustrated by the following examples which should not be construed as limiting the scope of the invention. EXAMPLES

[0066] Example 1 Preparation of barium sulfate nanoparticles Barium sulfate nanoparticles were prepared using a jet impingement reactor according to the invention made of stainless steel. The reactor was equipped with two interchangeable fluid inlet connectors containing ruby ​​nozzles aligned on the same axis facing each other at an angle of about 180°. The internal volume of the reaction chamber was about 0.15 mL and the nozzle-to-nozzle distance (i.e., between their downstream ends) was about 3 mm.

[0067] The reactor was connected to an apparatus providing the vessels, pipes, pumps, valves, pressure gauges, thermometers and flow meters necessary to operate the reactor. The first fluid, fed to the reactor through a first nozzle, was an aqueous solution of barium chloride. The second fluid was sodium sulfate. As is known, barium and sulfate ions readily precipitate as barium sulfate.

[0068] Three sets of process parameters were tested (A, B and C) at a temperature of about 23° C. The parameters are shown in Table 1 below.

[0069] [Table 1]

[0070] The results showed that barium sulfate nanoparticles could be obtained with all three sets of process parameters. Example 2

[0071] Characterization of barium sulfate nanoparticles The barium sulfate nanoparticles prepared in Example 1 were characterized with respect to their particle size and the polydispersity of the particle size distribution. The particle size was obtained as the z-average of the hydrodynamic particle size using dynamic light scattering (DSL). Measurements were performed at room temperature immediately after the preparation of batches A, B and C, and were repeated after storage at room temperature for 48 hours. The results are shown in Table 2.

[0072] [Table 2]

[0073] The results show that the barium sulfate nanoparticles obtained according to the present invention were of high quality and sufficiently stable. Example 3

[0074] Preparation of poly(A) lipid nanoparticles Poly(A)-loaded lipid nanoparticles were prepared using jet impingement reactors according to the present invention made of stainless steel. Each reactor was equipped with two interchangeable fluid inlet connectors containing stainless steel (316L) nozzles aligned coaxially facing each other at an angle of about 180°, with the distance between the first and second nozzles being the same as the diameter of the reaction chamber along the first central axis.

[0075] Jet impingement reactors were tested, including reaction chambers with diameters along the first central axis of 2 mm and 5 mm. A 2 mm diameter reactor chamber with an outlet diameter of 1 mm was provided with a pair of interchangeable fluid inlet connectors, the first with a nozzle orifice diameter of 200 μm and the second with a nozzle orifice diameter of 100 μm (asymmetric reactor setup). A 5 mm diameter reactor chamber with an outlet diameter of 2 mm was provided with a pair of interchangeable fluid inlet connectors with a nozzle orifice diameter of 300 μm for both nozzles of the inlet connectors (symmetric reactor setup). As a control, a T-shaped part (PEEK, 0.020 inch, 500 / 500 μm) was used.

[0076] The preparation of poly(A)-loaded lipid nanoparticles was tested over different total flow rates (TFR, the sum of the flow rates of the first and second fluid streams) at a constant flow rate ratio of 3:1 for the ratio of the flow rate of the first fluid, i.e., the aqueous solution, to the flow rate of the second fluid, i.e., the organic solution. The composition of the first and second fluids and the total flow rates tested are listed in Table 3.

[0077] The reactor was connected to equipment providing the vessels, tubing, pumps, valves, pressure gauges, thermometers, and flow meters necessary to operate the reactor. Two equipment setups were used: a lab-scale equipment capable of handling approximate batches of about 1-10 mL volume and total flow rates of about 0.1-60 mL / min, and a pilot-scale equipment capable of handling larger batch volumes of about 50-1000 mL and total flow rates up to 500 mL / min. The lab-scale equipment was used to operate the reactor to test total flow rates of 1 mL / min, 5 mL / min, 15 mL / min, and 40 mL / min, and the pilot-scale equipment was used to operate the reactor at total flow rates of 40 mL / min and 280 mL / min.

[0078] [Table 3]

[0079] Product test samples were diluted in 10% ethanol with 50 mM citrate buffer (pH 6) immediately after sample collection. The diluted samples were dialyzed against PBS buffer (pH 7.4) with moderate magnetic stirring using a 3 mL cassette. The buffer was changed twice at 2-hour intervals and then left overnight before characterization by dynamic light scattering (DLS, Stunner) to evaluate lipid nanoparticle size and polydispersity index (PDI). Encapsulation efficiency (EE%) was analyzed using the Quant-iT™ RiboGreen™ RNA Assay Kit according to the manufacturer's protocol.

[0080] Particle size was found to be consistent across the two jet impingement reactor configurations and for T-piece generated particles at the total flow rates tested. No clear differences were found between particles generated in different devices but with the same reactor configuration. The PDI of the resulting particles was also low, even at lower total flow rates such as 5 mL / min, especially for the jet impingement reactor with a 2 mm diameter chamber (see Figure 4).

[0081] High encapsulation efficiency (EE%) of poly(A) was observed for particles prepared from the jet impingement reactor over the total flow rates tested, especially at total flow rates above 15 mL / min (see Figure 5 ).

[0082] In summary, these results demonstrate that the jet impingement reactor according to the present disclosure produces lipid nanoparticles that encapsulate payloads with desired particle size and PDI and have very high encapsulation efficiency across the configurations and flow rates tested.

Claims

1. 1. A jet impingement reactor (1) comprising a reaction chamber (6) defined by an inner surface (2) of a reaction chamber wall (3), said reaction chamber (6) having a substantially spheroidal overall shape, said chamber (6) comprising: (a) first and second fluid inlets (4), the first and second fluid inlets (4) being arranged at opposing positions on a first central axis (x) of the reaction chamber (6) so as to face each other, and each of the first and second fluid inlets (4) including a nozzle (5, 13, 23); (b) a fluid outlet (7) arranged at a third position, the third position being located on a second central axis (y) of the chamber (6), the second central axis (y) being perpendicular to the first central axis (x); Including, a distance (d) between the nozzle (5, 13, 23) of the first fluid inlet (4) and the nozzle (5, 13, 23) of the second fluid inlet (4) is equal to or smaller than a diameter of the reaction chamber (6) along the first central axis (x).

2. 2. The jet impingement reactor of claim 1, wherein the nozzles (5, 13, 23) of the first fluid inlet (4) and the nozzles (5, 13, 23) of the second fluid inlet (4) have downstream ends (12, 22), and the downstream ends (12, 22) of each nozzle (5, 13, 23) are substantially aligned with the inner surface (2) of the chamber wall (3) and / or the nozzles (5, 13, 23) are arranged to direct first and second fluid streams along the first central axis (x) towards a center of the chamber (6) and allow the first and second fluid streams to collide at an angle of approximately 180°.

3. (i) the reaction chamber (6) has the overall shape of a spherical cap having a height, a base, and a radius along the first central axis (x), the height being greater than the radius, and the base being defined by the fluid outlet (7); and / or (ii) essentially all of the inner surface (2) of the reaction chamber wall (3) is substantially spherical; and / or (iii) essentially all of the inner surface (2) of the reaction chamber wall (3) is substantially spherical, except for the portion of the inner surface (2) that is part of the first and / or second fluid inlet (4) or the fluid outlet (7); and / or (iv) the reaction chamber (6) has no other inlet or outlet openings; 3. The jet impingement reactor of claim 1 or 2.

4. 3. The jet impingement reactor of claim 1 or 2, wherein the reaction chamber (6) has a volume of 0.25 mL or less, and the distance (d) between the nozzle (5, 13, 23) of the first fluid inlet (4) and the nozzle (5, 13, 23) of the second fluid inlet (4) is 5 mm or less.

5. 3. The jet impingement reactor of claim 1, wherein each of the first and second fluid inlets (4) is provided by a fluid inlet connector (10, 20) having an upstream end (11, 21), a downstream end (12, 22) that holds the nozzle (5, 13, 23) of the first or second fluid inlet (4), and a fluid conduit (14, 24) for conducting fluid from the upstream end to the downstream end, the downstream end of each fluid inlet connector (10, 20) being reversibly insertable into the chamber wall (3) to provide the first and second fluid inlets (4).

6. The fluid inlet connector (10, 20) an upstream segment comprising the upstream end (11, 21) of the fluid inlet connector (10, 20) and the upstream portion of the fluid conduit (14, 24); and a downstream segment comprising the downstream end (12, 22) of the fluid inlet connector with the nozzle (5, 13, 23) and the downstream part of the fluid conduit (14, 24); 6. The jet impingement reactor of claim 5, wherein the diameter of the upstream portion of the fluid conduit (14, 24) is greater than the diameter of the downstream portion of the fluid conduit (14, 24).

7. 3. A jet impingement reactor according to claim 1 or 2, wherein the nozzles (5, 13, 23) of the first and / or second fluid inlets (4) are plain orifice nozzles (5, 13, 23).

8. 3. The jet impingement reactor according to claim 1 or 2, wherein the nozzle (5, 13, 23) of the first fluid inlet (4) has a first orifice diameter and the nozzle (5, 13, 23) of the second fluid inlet (4) has a second orifice diameter, and the first orifice diameter and / or the second orifice diameter is in the range of 20 μm to 500 μm.

9. 3. The jet impingement reactor of claim 1 or 2, wherein a ratio of a diameter of the reaction chamber (6) along the first central axis (x) to a diameter of the first orifice is in the range of 6 to 60.

10. 3. The jet impingement reactor according to claim 1 or 2, wherein the ratio of the diameter of the reaction chamber (6) along the first central axis (x) to the diameter of the fluid outlet (7) is in the range of 1.2 to 3.

11. 3. The jet impingement reactor according to claim 1 or 2, wherein the inner surface (2) of the reaction chamber wall (3) exhibits a surface roughness of 0.8 Ra or less, Ra being determined according to ISO 4287:1997.

12. Jet impingement reactor according to claim 1 or 2, wherein the reaction chamber wall (3) is made of a material selected from metal, glass, glass-ceramic, ceramic, and thermoplastic polymer.

13. 13. The jet impingement reactor of claim 12, wherein the thermoplastic polymer is selected from polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU), and polyetherimide (PEI).

14. 3. The jet impingement reactor according to claim 1 or 2, wherein the nozzle (5, 13, 23) of the first fluid inlet (4) and the nozzle (5, 13, 23) of the second fluid inlet (4) are made from a material selected from metal, glass, glass-ceramic, and ceramic.

15. 3. A method for making the jet impingement reactor of claim 1 or 2, comprising: the reaction chamber wall (3) is made of a thermoplastic polymer, the nozzle (5, 13, 23) of the first fluid inlet (4) and the nozzle (5, 13, 23) of the second fluid inlet (4) are made of a material selected from metal, glass, glass-ceramic and ceramic, and the method comprises: (i) providing a mould for forming said reaction chamber wall (3); (ii) providing the nozzle (5, 13, 23) of the first fluid inlet (4) and the nozzle (5, 13, 23) of the second fluid inlet (4); (iii) inserting the nozzle (5, 13, 23) of the first fluid inlet (4) and the nozzle (5, 13, 23) of the second fluid inlet (4) into the mould; (iv) melting the thermoplastic polymer; (v) injecting the molten thermoplastic polymer into the mold; 3. A method of making the jet impingement reactor of claim 1 or 2, comprising:

16. 1. A method of mixing two fluids, said method comprising: (i) providing a jet impingement reactor (1) according to claim 1 or 2; (ii) directing a first fluid stream through said first fluid inlet (4) into said reaction chamber (6); (iii) directing a second fluid stream through the second fluid inlet (4) into the reaction chamber (6) so that it impacts the first fluid stream at an angle of approximately 180°; 1. A method for mixing two fluids, comprising:

17. 17. The method of claim 16, wherein each of the first and second fluid streams is forced through the fluid inlet nozzle (5, 13, 23) at a pressure in the range of 0.1 to 120 bar, and each of the first and second fluid streams is directed into the reaction chamber (6) at a flow rate in the range of 1 to 1000 mL / min.

18. the orifice of said first nozzle (5, 13, 23) is larger than the orifice of said second nozzle (5, 13, 23), and / or the flow rate of the first fluid is greater than the flow rate of the second fluid; 20. The method of claim 17, wherein the pressure of the first fluid and the pressure of the second fluid are adapted so that the first fluid stream and the second fluid stream have substantially the same kinetic energy when they enter the reaction chamber.

19. 17. The method of claim 16, wherein the first fluid is an aqueous liquid and the second fluid is an organic liquid.

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