Disposable reactor for mixing two liquids

Abstract

A jet impingement reactor is disclosed having a housing made of a polymeric material, the housing comprising at least two housing parts fixed to each other. The housing encloses a substantially spherical reaction chamber (2) having at least two fluid inlets (3, 4) and a fluid outlet (6) provided by a nozzle (5). Also provided are methods of manufacturing the reactor based on injection molding, as well as the use of the reactor for the sterile manufacture of a sterile liquid pharmaceutical composition, in particular a composition comprising nanoparticles (e.g., lipid nanoparticles).

Description

Background Art

[0001] Jet impact reactors are fluid reactors used to mix fluids or generate particulate fluids by collision. For example, they can be used to produce nanoparticle fluids containing active ingredients with poor water solubility. The function of these reactors is based on the use of two fluid streams, at least one of which usually contains the active ingredient, which are injected into the reactor cavity and collide in a turbulent mixing zone to produce nanoparticles. One of the main principles used in jet impact 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 with the help of a jet impact reactor, for example, the lipid nanoparticles can then be loaded with biologically active compounds by pH changes.

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

[0003] An example of a jet impact reactor is a microfluidic reactor as disclosed in EP 1165224 B1. Such a microfluidic reactor has at least two nozzles or pinholes facing each other, each of which has an associated pump and feed line for directing liquid to a common collision point in a reaction chamber surrounded by a reactor housing (having a metal body). The reaction chamber contains two holes that intersect each other and form a small cavity in which two fluids collide, possibly without contacting the cavity wall. When one of the holes accommodates two fluid inlets, the second hole accommodates another opening in the reactor housing, through which gas, evaporating liquid, cooling liquid or cooling gas can be introduced to maintain the gas environment in the reaction chamber or for cooling. Another opening is provided at the other end of the second hole for discharging the resulting product and excess gas from the reactor. In addition, this reactor also requires an external gas source or cooling liquid source as a third fluid, so it may be more complicated and not so simple for producing particles under sterile conditions. The reactor or reactor housing is also made of metal, so its manufacture, assembly and cleaning between uses will require specific processes.

[0004] WO 2018 / 234217 A1 discloses another jet impact reactor, having a shell (surrounding a reaction chamber), a first fluid nozzle and a second fluid nozzle oriented in a colinear manner. In the injection direction of the nozzle, the second nozzle is located directly opposite the first fluid nozzle. The nozzles extend into the reaction chamber and form a disc-shaped collision zone with each other. This type of reactor has at least one flushing 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 to continuously prepare a particle fluid. In addition, the flushing fluid guiding structure is designed as a parallel channel on the side of the first fluid nozzle, which generates a flushing fluid flow guided along the injection direction of the first fluid nozzle, and introduces the flushing fluid into the direction of the collision disk, causing the collision disk to deform slightly. In this way, the particles present in the nanoparticle fluid formed by the collision disk are taken away from the collision zone. When carried out in a reactor such as that disclosed in WO 2018 / 234217 A1, the production process depends on the presence of a flushing fluid guiding structure and a flushing fluid, which also increases the complexity, cost and time required for manufacturing the reactor itself, as well as cleaning between uses, making rapid and small batch production more difficult, especially when used for sterile production of nanoparticles.

[0005] The quality and reproducibility of the nanoparticle fluid obtained depends on the scheme of the production method and the accuracy of the reactor, etc. The scheme of the method can define different parameters, such as the volume flow rate of the fluid stream injected by the nozzle, the ratio of these flow rates, the concentration of dissolved components in the stream or the temperature setting. These parameters may also be affected by the reactor itself. For example, the nozzle size can affect the flow rate of the stream because its diameter only allows a certain amount of fluid to pass through the nozzle, which depends on the respective pressure of the stream. In product and process development or upgrading, it is always a challenge to properly adjust the nanoparticle production parameters and select a suitable reactor.

[0006] It is also known that the particle size distribution and the reproducibility of the results depend on the precise setting of the reactor (especially the precise setting of the nozzle) and the precise control of the fluid flow. In order to further improve the particle size, particle size distribution or other quality parameters of the product, it is necessary to improve the jet impact reactor so as to better control the process parameters.

[0007] Therefore, there is a need for a jet impact reactor that can be used not only to produce nanoparticles with ideal particle size distribution and morphology and reduce the risk of adverse side reactions, but also to achieve efficient and rapid small-batch production, especially in the form of ready-to-use or sterilizable disposable hardware, which reduces the need for sterilization or complex cleaning protocols between batch production, thereby improving production efficiency. Another object is to provide a flow impact reactor that can be easily manufactured in a cost-effective and reproducible manner. Yet another object is to overcome one or more disadvantages of the jet impact reactors and related methods proposed in the prior art. These needs and purposes are all addressed in the invention disclosed herein. Summary of the invention

[0008] In a first aspect, the present disclosure relates to a jet impact reactor (1), comprising a reaction chamber (2), the reaction chamber having a substantially spherical shape, wherein the spherical shape is interrupted by: (a) a first fluid inlet (3) and a second fluid inlet (4), wherein the first fluid inlet (3) and the second fluid inlet (4) are arranged at relative positions on a first central axis (x) of the reaction chamber (2) so as to point towards each other, and wherein each of the first fluid inlet (3) and the second fluid inlet (4) is provided by a nozzle (5); and (b) a fluid outlet (6), arranged at a position located on a second central axis (y) of the reaction chamber (2), the second central axis (y) being perpendicular to the first central axis (x). The reactor (1) further comprises a first fluid conduit (7), a second fluid conduit (8) and a third fluid conduit (9), wherein the first fluid conduit (7) and the second fluid conduit (8) are arranged to guide the first fluid to the first fluid inlet (3), the second fluid to the second fluid inlet (4), and wherein the third fluid conduit (9) is arranged to guide the third fluid in the downstream direction from the fluid outlet (6), the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber (2). The reactor (1) is further characterized in that it comprises at least two parts fixed to each other: wherein a first part (121, 171, 181) is made of a polymer material and comprises at least a part of the first fluid conduit (7) or the second fluid conduit (8) and at least a hemispherical part of the reaction chamber (2); and a second part (132, 172, 182) which is at least partially insertable into the first part (121, 171, 181), the second part comprising the fluid outlet (6).

[0009] Another aspect relates to a method of manufacturing a reactor (1) or a first component (121, 171, 181), the method comprising the step of injection molding the first component (121, 171, 181). Other aspects presented in the present disclosure relate to the use of such a reactor in the aseptic manufacture of a sterile liquid pharmaceutical composition, and an apparatus for aseptically manufacturing a sterile liquid pharmaceutical composition, the apparatus comprising a reactor. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 A cross-sectional view of an embodiment of a first component (121) of a jet impact reactor is shown.

[0011] Figure 2 A cross-sectional view of an embodiment of a second component (132) of a jet impact reactor is shown, wherein the second component is designed to Figure 1 The first component (121) is shown to be compatible with and insertable into the first cavity (21) of the first component (121).

[0012] Figure 3 A cross-sectional view of an embodiment of a connecting member (33) is shown, wherein the connecting member is designed to be connected to Figure 1 The first component (121) is used together with the above-mentioned first component.

[0013] Figure 4 A cross-sectional view of an embodiment of a jet impact reactor (1) is shown, the reactor comprising Fig.12 The first component (121) shown, and Figure 2 The second component (132) and two Figure 3 The connecting part (33) is shown.

[0014] Figure 5 A cross-sectional view of a specific embodiment of a substantially spherical reaction chamber (2) is shown, the reaction chamber being formed by a first component (121) and an at least partially inserted second component (132); only portions of the first component (121) and the second component (132) are shown.

[0015] Figure 6 A cross-sectional view of an embodiment of a first component (171) of a jet impact reactor is shown.

[0016] Figure 7 A cross-sectional view of an embodiment of a jet impact reactor (1) is shown, the reactor comprising Figure 6 The first component (171) is shown, as well as the second component (172) and two connecting components (73).

[0017] Figure 8 A cross-sectional view (not drawn to scale) of another embodiment of a jet impact reactor (1) is shown, comprising a first part (181) secured to a second part (182), and two connecting parts (83).

[0018] Fig. 9An enlarged cross-sectional view of a specific embodiment of a substantially spherical reaction chamber (2) is shown, the reaction chamber being formed by a first component (181) and a partially or fully inserted second component (182); only portions of the first component (181) and the second component (182) are shown.

[0019] Fig.10 A cross-sectional perspective view (A) of a first component (181) and a cross-sectional perspective view (B) of the first component (181) secured to a second component (182) are shown.

[0020] Fig.11 Particle size graphical depiction (mean diameter (nm), Figure A) and polydispersity index graphical depiction (PDI, Figure B) of the PLGA nanoparticle characteristics obtained using polymer jet impact reactors according to the present invention (A, B and C) and using a comparative stainless steel reactor (M) as described in Example 1 are shown.

[0021] Fig.12 Particle size graphical depiction (mean diameter (nm), Figure A) and polydispersity index graphical depiction (PDI, Figure B) of the characteristics of liposome nanoparticles obtained using polymer reactors according to the present invention (A, B and C) and using a comparative stainless steel reactor (M) as described in Example 2 are shown.

[0022] Fig.13 A cross-sectional view of an alternative example of a jet impact reactor (1) is depicted, said reactor comprising a housing (10) made of a polymer material, the housing consisting of two parts (11, 12) fixed to each other.

[0023] Fig.14 Describes Fig.13 A perspective view of a second housing part (12) of a housing (10) of a jet impact reactor (1) is shown.

[0024] Fig.15 Describes Fig.13 A perspective view of a first housing part (11) of a housing (10) of a jet impact reactor (1) is shown.

[0025] Fig.16 A cross-sectional view of another alternative embodiment of a jet impact reactor (1) is depicted, said reactor comprising a housing (40) consisting of two parts (41, 42) fixed to each other.

[0026] Fig.17 Describes Fig.16 A perspective cross-sectional view of a first housing component (41) of a housing (40) is shown.

[0027] Fig.18 Describes Fig.16A cross-sectional view of a second housing component (42) of a housing (40) is shown.

[0028] Fig.19 Describes Fig.16 A perspective view of a second housing component (42) of a housing (40) is shown.

[0029] Fig. 20 A cross-sectional view of another example of an alternative jet impact reactor (1) is depicted, said reactor comprising a housing (80) consisting of two parts (81, 82) fixed to each other.

[0030] Fig.21 Describes Fig. 20 A cross-sectional perspective view of a first housing component (81) of a housing (80) is shown.

[0031] Fig. 22 Describes Fig. 20 A cross-sectional view of a second housing component (82) of a housing (80) is shown.

[0032] Fig.23 Describes Fig. 20 A perspective view of a second housing component (82) of the housing (80) is shown. DETAILED DESCRIPTION

[0033] According to a first aspect of the present invention, there is provided a jet impact reactor comprising a reaction chamber having a substantially spherical shape, the spherical shape being interrupted by (a) a first fluid inlet and a second fluid inlet and (b) a fluid outlet. The first fluid inlet and the second fluid inlet are arranged at relative positions on a first central axis of the reaction chamber so as to point to each other, and each of the first fluid inlet and the second fluid inlet is provided by a nozzle. The fluid outlet is arranged at a position located on a second central axis (perpendicular to the first central axis) of the reaction chamber (6). The reactor further comprises a first fluid conduit, a second fluid conduit and a third fluid conduit, wherein the first fluid conduit and the second fluid conduit are arranged for directing a first fluid to the first fluid inlet, directing a second fluid to the second fluid inlet, and wherein the third fluid conduit is arranged for directing a third fluid in a downstream direction from the fluid outlet, the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber. In addition, the reactor comprises at least two components fixed to each other: a first component, made of a polymer material, and comprising at least a portion of the first fluid conduit or the second fluid conduit and at least one hemispherical portion of the reaction chamber; and a second component, at least partially insertable into the first component, the second component comprising the fluid outlet. Optionally, the second component is also made of a polymer material.

[0034] The reactor is assembled from at least two parts fixed to each other and is particularly suitable for aseptically manufacturing small batches of liquid compositions from at least two liquid matrices as a disposable reactor. The inventors have found that, as described herein, manufacturing the reactor from two parts can use an efficient manufacturing process, such as injection molding at least the first part of the reactor, and if the second part is also made of a polymer material, it is also possible to perform injection molding. Alternative methods for manufacturing reactors with a roughly spherical reaction chamber require special tools and are less efficient. In addition, as disclosed herein, the design of the reactor assembled from at least two potential moldable parts enables the reactor to be equipped with a nozzle, the position and orientation accuracy of the nozzle is particularly high, and the size accuracy of the first fluid inlet and the second fluid inlet potentially provided by the nozzle may also be high. Another advantage is versatility: for example, using the same molding tool for manufacturing the first part, and then using (for example) laser drilling to add the first fluid inlet and the second fluid inlet of the desired size, a reactor with a variety of different fluid inlet sizes can be manufactured. In addition, adjusting the outlet geometry does not require the modification of the first part. It has also been found that the reactor represents a static mixing device which is easily installed in an apparatus suitable for mixing two fluid flows, wherein the fluid flows are driven by external gas pressure, such as disclosed in WO 2023 / 079039 A1.

[0035] Some of these advantages may be particularly evident for those embodiments in which the first and second fluid conduits are designed to be relatively short (as explained in more detail below), so that each nozzle location is well suited for high-precision tools and processes during manufacturing. For example, if the nozzle orifice is introduced by mechanical precision drilling or laser drilling, the drilling tool can be close to the nozzle location, thereby minimizing tolerances.

[0036] In a broader sense, the reactor according to the present disclosure also solves the problem of providing a suitable device that can cost-effectively and aseptically (aseptic) or sterilely (sterile) manufacture small batches of liquid products, such as liquid pharmaceutical compositions for injection obtained by mixing two or more liquid matrices, because the reactor is essentially polymeric and can be designed as a disposable processing device while meeting all precision requirements. Compared with metal body reactors, as a disposable and cost-effective manufacturing and production device, and as a modular system, the reactor according to the present disclosure can be advantageously used as a flexible process development tool. For example, different nozzle orifice sizes can be easily tested, as well as various different compositions of fluid matrices.

[0037] The key features of the reactor are now described in more detail.

[0038] As mentioned above, the reactor is a jet impact reactor. In the context of the present invention, a jet impact reactor is a static mixing device having a reaction chamber, the reaction chamber having at least two fluid inlets provided by a nozzle, the nozzle allowing two fluids (particularly two liquids) to be injected into the reaction chamber at a pressure generally higher than the ambient pressure. Through the inlets, the fluid streams are injected to collide (i.e. impact each other) in the reaction chamber, which may produce rapid, intense and turbulent mixing. According to a general preference, the fluid is a liquid. According to a further general preference, the two fluids or liquids mixed in the reactor are different from each other, and the result of the mixing is to obtain a third fluid or liquid.

[0039] The first component is made of polymer material and represents the main part of the reactor shell, because it at least contains most of the reaction chamber and the first inlet and the second inlet. As used herein, being made of polymer material does not exclude the presence of a certain amount of non-polymer material. In other words, the statement of "being made of polymer material" should be understood as being mostly or mainly made of polymer. For example, the first component can include certain structures, such as identification tags that are not polymers themselves. In addition, the main material constituting the first component can be (e.g., thermoplastic) polymer material, which also contains one or more additives, such as glass fiber, ceramic filler, plasticizer, antioxidant, colorant, antibacterial agent, antistatic agent, UV stabilizer, flame retardant, etc. In some preferred embodiments, at least the first component and the second component of the reactor as disclosed herein are based on polymer material or are substantially made of it, and the material optionally includes one or more additives. In some embodiments, the reactor is substantially composed of the first component and the second component as described herein, and wherein the first component and the second component are both made of polymer material.

[0040] As used herein, a reaction chamber is a chamber within a reactor that provides space for two fluids to contact each other to mix or react. Typically, the shape and internal dimensions of a reaction chamber are required to be different from, for example, a simple T-shaped or Y-shaped component, which is essentially composed of two (or three) pipes connected together, and its inner lumen forms a T-shaped or Y-shaped flow path. For example, a reaction chamber preferably includes at least one diameter that is larger than its fluid inlet diameter.

[0041] According to this aspect of the invention, the overall shape of the reaction chamber is spherical, wherein the spherical shape is interrupted by a fluid inlet and a fluid outlet. As will be appreciated by those skilled in the art, the spherical overall shape of the reaction chamber in the device does not necessarily represent a perfect sphere. Minor deviations, such as deviations within the manufacturing tolerance range, or small features that improve manufacturability, are still within the "spherical" expression. Therefore, the overall shape of the reaction chamber may also be described as spherical. The spherical overall shape refers to at least a large portion of the reaction chamber defined by the inner surface of the reaction chamber wall that is at least similar to a sphere. For example, the sphere may be formed so that some of its cross-sections are strictly elliptical, rather than circular in a perfect sphere. In one embodiment, all or parts of the reaction chamber or the inner surface of the reaction chamber wall, except those parts that define the inlet or outlet, or the small planar wall parts as described below, are substantially spherical or spherical.

[0042] In this case, a fluid inlet refers to an opening, orifice or interruption in or in the wall of a reaction chamber to allow fluid to enter the reaction chamber. Both the first fluid inlet and the second fluid inlet are provided by a nozzle. For example, if the nozzle is a simple flat-hole nozzle comprising a narrow hole or inner cavity having an upstream end and a downstream end, the downstream end of the hole or inner cavity forms the fluid inlet. More generally, a "nozzle" refers to a device or device component suitable for controlling the direction, speed and / or other characteristics of a fluid flow and comprising at least one fluid path, while an "inlet" refers primarily to the cross-section of the fluid path at the downstream end of such a nozzle, unless the context dictates that these expressions have different meanings. Preferably, the downstream end of the nozzle providing the first fluid inlet and the second fluid inlet is substantially flush with the wall of the reaction chamber.

[0043] Optionally, the reactor may have one or more additional fluid inlets. For example, the third fluid inlet and the fourth fluid inlet may be arranged to provide another fluid collision point, or to form a common fluid collision point with the first fluid inlet and the second fluid inlet. However, in a generally preferred embodiment, the first fluid inlet and the second fluid inlet are the only fluid inlets of the reactor.

[0044] As described above, the first fluid inlet and the second fluid inlet are arranged at relative positions on the first central axis of the reaction chamber to point to each other. Preferably, the nozzles providing the first fluid inlet and the second fluid inlet are oriented to point to each other at an angle of about 180°. This orientation enables the two fluid streams to be injected into the reaction chamber in a manner such that they collide head-on or hit each other at an angle of about 180°, depending on the pressure and / or velocity of the fluid streams.

[0045] Fluid outlet should be understood as an opening in the reaction chamber wall, which is suitable for allowing fluid to leave the reaction chamber. As previously mentioned, the fluid outlet is located on the second central axis of the reaction chamber, and the second central axis is perpendicular to the first central axis on which the fluid inlet is arranged. For example, when the reactor is running, the first central axis can have a substantially horizontal orientation, and the second central axis can have a substantially vertical orientation. In addition, the orientation of the reactor when running can make the fluid outlet be arranged in the upper position of the reaction chamber, so that the direction of fluid flow in the reaction chamber is at least partially opposite to gravity.

[0046] As described above, the first fluid conduit and the second fluid conduit are arranged to guide the first fluid to the first fluid inlet, and guide the second fluid to the second fluid inlet. In other words, the first fluid flow and the second fluid flow are supplied to the reaction chamber through these fluid conduits. In this case, the fluid conduit is a three-dimensional structure including an internal fluid path, and the internal fluid path provides a fluid connection between the upstream end and the downstream end of the corresponding fluid conduit. The third fluid conduit is suitable for the third fluid produced by the mixing or reaction of the first fluid and the second fluid to be derived from the reaction chamber in the downstream direction. For the avoidance of doubt, the downstream direction may be an upward or anti-gravity flow direction, depending on the orientation of the reactor.

[0047] According to one of the key features of the reactor disclosed herein, the reactor is composed of at least two parts fixed to each other. In this case, the fixation between the parts can be separable or releasable (i.e., without damage), or permanent. The first part comprises at least a portion of the first fluid conduit or the second fluid conduit and at least one hemispherical portion of the reaction chamber. The second part comprises at least a fluid outlet, and in some embodiments, comprises a portion of the reaction chamber. In some embodiments, the first part also comprises or is suitable for accommodating two nozzles providing a first fluid inlet and a second fluid inlet, as described below.

[0048] For example, if the first cavity is slightly tapered, the second component may be secured to the first component by forcing it partially or fully into the first cavity. This may not require any additional fastening means. The polymer material from which at least the first component and optionally the second component are made typically has a certain degree of elasticity to maintain contact between the two components.

[0049] In other embodiments, the first and second components may be held together by fastening means such as screws, or they may be bonded or fused together. Alternatively or in addition, they may be held together by snap-fit ​​or press-fit features provided on the first or second components, or more preferably both the first and second components. For example, suitable snap-fit ​​or press-fit features may include flanges and matching grooves, such as a flange provided in the contact surface of the first component and a corresponding groove provided in the contact surface of the second component for accommodating the flange, or vice versa. Optionally, at least one of the materials used to provide such flanges or grooves should have a certain degree of flexibility or elasticity. In some preferred embodiments, the first and second components are press-fit, and preferably there are no additional fastening means.

[0050] In some embodiments, the first component may include one or more insertion guides to facilitate insertion of the second component in a defined orientation relative to the first component. Vice versa, the second component shaped and adapted to be insertable into the first component may include complementary insertion guides or insertion features that ensure insertion and mating in the correct orientation relative to the first component. For example, in one embodiment, one or more protrusion features are provided on the contact surface of the second component, which are complementary to one or more complementary shaped grooves or recesses arranged in the first component.

[0051] Optionally, additional features may be used to ensure that the first component and the second component are not only securely fixed to each other, but also that the contact between the two components is tight enough to even prevent fluid from leaking from the reactor. For example, a gasket may be provided between the first component and the second component to seal the contact between the two components. In other embodiments, there is no gasket between the first component and the second component.

[0052] In some embodiments, one of the two components is overmolded onto the other, which can be considered similar to welding, because heat is used to partially soften or melt the material at the desired contact surface of at least one of the two components to fuse that surface with the corresponding contact surface of the other of the two components. Overmolding may be a useful technique if at least one of the two housing components is made of a polymer material that can be formed by melt injection or injection molding. In some embodiments, more than one means or method can be used to permanently or non-permanently secure the two housing components together.

[0053] In some embodiments, the reactor or reactor housing consists essentially of a first component and a second component. In other words, the body of the reactor consists only of the two parts described herein. Those skilled in the art will appreciate that this does not exclude the possibility of auxiliary structures or functional components associated with the housing. Non-limiting examples of such other components include fastening devices, such as screws, bolts, Luer connectors, or nuts; identification devices, such as RFID chips or QR codes; or sensors, such as temperature probes; washers, etc.

[0054] As described above, the first part of the reactor comprises at least a portion of the first fluid conduit or the second fluid conduit and at least one hemispherical portion of the substantially spherical reaction chamber. In this case, the hemispherical portion is a portion of the reaction chamber that contains or surrounds a portion of the reaction chamber having a hemispherical shape. In some preferred embodiments, the first component comprises a portion that is larger than a hemisphere, such as at least about 55% or at least about 60% of the internal volume of the reaction chamber, the internal volume being calculated based on the approximate spherical shape formed by the reaction chamber wall without being interrupted by the fluid inlet and fluid outlet, and optionally other minor deviations from the spherical shape of the reaction chamber wall. In another preferred embodiment, the first component of the reactor comprises about 50% of the internal volume of the reaction chamber, the internal volume being calculated based on the approximate spherical shape formed by the reaction chamber wall without being interrupted by the fluid inlet, fluid outlet, or non-spherical wall protrusions or recesses.

[0055] The second component including the fluid outlet is designed to be at least partially insertable into the first component. In a related embodiment, the first component is shaped to include a cavity (hereinafter referred to as the first cavity) for accommodating the second component by insertion (i.e., at least partially inserted), and the second component is shaped and adapted to be insertable (i.e., at least partially insertable) into the first cavity.

[0056] The first cavity can be shaped for insertion. For example, its surface can be cylindrical, elliptical or conical. In this case, elliptical should be understood as a cylindrical overall shape, but with one or more slight deviations from a perfect cylindrical shape. In this case, the tapered elliptical should be tapered so that its upstream end (i.e., located at the reaction chamber) is narrower than the downstream end. The shape of the second component or at least its insertable portion can advantageously match the shape of the first cavity.

[0057] In some preferred embodiments, the second component comprises: an upstream end, comprising a fluid outlet of the reaction chamber and a portion of the reaction chamber; a downstream end; and a third fluid conduit, wherein the third fluid conduit fluidically connects the upstream end with the downstream end. In this particular case, a portion of the reaction chamber is understood so that the second component also provides a portion of the reaction chamber wall. Such a wall portion generally surrounds the fluid outlet and, when inserted into the first cavity, is flush with the complementary portion of the reaction chamber wall provided by the first component. In terms of size, the portion of the reaction chamber wall provided by the second component can, for example, account for about 2% to about 25% of the surface of the reaction chamber wall, or optionally about 5% to about 20%, respectively. In other embodiments, the portion of the reaction chamber wall provided by the second component is between 5% and 50% of the surface of the reaction chamber wall. In another embodiment, the second component of the reactor comprises at most 50% of the internal volume of the reaction chamber, the internal volume being calculated based on the approximately spherical shape formed by the reaction chamber wall without the interruption of the fluid outlet or any non-spherical wall element (e.g., a recess or a protruding portion). In addition, the portion of the reaction chamber wall provided by the second component can be shaped as a spherical region. In this case, the spherical area refers to the surface of the spherical segment excluding the base.

[0058] In another preferred embodiment, the second component is fully insertable into the first cavity. In a related embodiment, the downstream end of the second component is flush with the surface of the first component surrounding the first cavity.

[0059] In some embodiments, the downstream end of the second component may be fitted with or may include a connector for securing tubing or pipes, such as a Luer connector or a barbed connector or a barbed fitting.

[0060] As described above, at least the first component of the reactor is made of a polymer material. In some preferred embodiments, the first component is at least mainly made of a thermoplastic polymer material, wherein the thermoplastic polymer material preferably comprises polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile-butadiene-styrene copolymer (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU) or polyetherimide (PEI). In some embodiments, both the first component and the second component are at least mainly made of such a thermoplastic polymer material.

[0061] In this case, being made mainly of thermoplastic polymer materials does not exclude the presence of small amounts of one or more non-thermoplastic materials or non-polymer materials. In other words, the thermoplastic polymer material is the main component of the respective component, even if it is not the only component. In this case, "mainly" means that the thermoplastic polymer material accounts for the largest proportion of the composition by weight and / or determines the physical properties of the composition. For example, the material composition of the respective component contains sufficient thermoplastic polymer material to ensure that the entire material composition behaves as a thermoplastic material and can be thermoformed, for example, by injection molding or melt injection.

[0062] In some preferred embodiments, the first component or the first component and the second component are at least mainly made of PEEK. For example, an unfilled grade of PEEK consisting essentially only of polymers can be used. Alternatively, a PEEK grade with one or more fillers (e.g., glass fibers or carbon fibers) can be used.

[0063] Examples of other optional additives that may be used include, but are not limited to, ceramic fillers, plasticizers, antioxidants, colorants, antimicrobial agents, antistatic agents, UV stabilizers, flame retardants, etc. In some embodiments, both the first component and the second component of the housing as disclosed herein are based on or substantially made of a thermoplastic polymer material (optionally including one or more additives).

[0064] In some embodiments, the first fluid conduit and the second fluid conduit each have a longitudinal center axis that overlaps with the first center axis (x) of the reaction chamber. In addition, the third fluid conduit can have a longitudinal center axis that overlaps with the second center axis (y) of the reaction chamber. In this case, the longitudinal center axis of the fluid conduit should be understood as the longitudinal center axis of the conduit lumen. In fact, the fluid flow direction in each conduit provided by these embodiments is the same as the fluid flow direction flowing into or out of the reaction chamber, that is, the flow direction in the conduit or between the reaction chamber and each conduit does not change.

[0065] According to some other embodiments, the first fluid conduit and / or the second fluid conduit has a lumen having an upstream portion and a downstream portion, wherein the upstream portion is cylindrical or elliptical, and wherein the diameter of the upstream portion is much larger than the diameter of the downstream portion. In this case, much larger means at least about 20% larger, and optionally at least about 50% larger, than the diameter of the downstream portion. In this case, the diameter of the fluid conduit is understood to be the inner diameter, i.e., the diameter of the lumen cross section of the corresponding portion or section of the fluid conduit.

[0066] In some other embodiments, the downstream portions of the first fluid conduit and the second fluid conduit each have a downstream end, and the downstream ends form the first fluid inlet and the second fluid inlet, respectively, or coincide with both. In other words, the two fluid inlets of the reaction chamber are provided by the downstream ends of the downstream portion or section of the fluid conduit. Therefore, as described above, the downstream portion or at least its downstream end can also be understood as a part of the nozzle structure that provides the fluid inlet; and the nozzle can be understood as provided by the downstream portion of the fluid conduit.

[0067] In some embodiments, the downstream portion or section of the first fluid conduit and the second fluid conduit is tapered toward or away from its downstream end. In some other preferred embodiments, the downstream portion is substantially cylindrical. In this case, substantially cylindrical should be understood to encompass elliptical cylindrical shapes with slight deviations from a perfect cylinder, which is usually caused by a laser drilling or micro-drilling process. For example, laser drilling can make the downstream conduit portion substantially cylindrical, and the diameter of one end may be slightly different from the diameter at its other end, but generally not more than about 2-5% (the percentage is based on the smaller diameter).

[0068] As previously described, one advantage of the present invention is that the location on the reaction chamber housing where the first and second fluid conduits and the reaction chamber fluid inlet are arranged is easily accessible, which makes processes such as laser drilling or micro-drilling more feasible. The inventors have also found that a downstream portion that is substantially cylindrical in shape does not appear to have any significant effect on the flow of the first and second fluids in terms of flow resistance compared to a conical shape. This is particularly true if the narrow cylindrical downstream portion is relatively short, such as less than about 1 mm, or not more than about 0.5 mm, such as about 0.2 mm to about 0.5 mm, such as about 0.3 mm. In some embodiments, the inner cavity diameter of the cylindrical downstream portion or section of the first and second fluid conduits is independently substantially the same as the diameter of the fluid inlet that coincides with their downstream ends.

[0069] In some other embodiments, the inner cavity of the first fluid conduit and the second fluid conduit further comprises an intermediate portion between the upstream portion and the downstream portion, wherein the intermediate portion is tapered toward the downstream portion. If the downstream portion is also tapered, the intermediate portion and the downstream portion may optionally have different taper angles.

[0070] In the case where the nozzle providing the first fluid inlet and the second fluid inlet is a part of the first component, these embodiments are particularly useful. As discussed above, the first fluid inlet and the second fluid inlet are each provided by a nozzle. In principle, there are various different options for the properties of these nozzles. In some preferred embodiments, the nozzle (at least one of them) is integral with the first component of the reactor that accommodates them. In this case, being integral means that the nozzle is an integral part of the component and is made of the same material. For example, if the nozzle is designed as a flat hole nozzle, it can be directly introduced into the corresponding housing component by precision drilling or laser drilling. In other embodiments, the nozzle can be introduced by wire overmolding.

[0071] In some other embodiments, the nozzle providing the first fluid inlet or the second fluid inlet is an insert contained in the first part of the reactor. It is worth noting that the insert, regardless of its material, is not integral with the housing part. Optionally, the nozzle provided as an insert is made of the same material as the first part into which it is inserted. Alternatively, the nozzle can be made of a material different from the first part.

[0072] For example, if the nozzle is provided as an insert, the nozzle may be shaped to contain or consist of a cylindrical conduit. Such a nozzle would therefore be a flat-orifice nozzle. It is further preferred for this embodiment that both nozzles are flat-orifice nozzles. As used herein, a flat-orifice nozzle is a nozzle characterized by a simple orifice, the shape of which is essentially a simple (i.e., essentially cylindrical) through-hole, which may also be referred to as a pinhole in view of its small size. Alternatively, the nozzle may also be configured as a shaped-orifice nozzle, provided that the selected shape is capable of generating a fluid stream that is capable of head-on collision with a second fluid stream in the reaction chamber at the corresponding operating pressure.

[0073] If an insertable flat-bore nozzle is used, such a nozzle can be provided as a component made of a particularly hard material, such as sapphire, ruby, diamond, ceramic, glass ceramic, glass (e.g. borosilicate glass) or metal, such as steel (e.g. stainless steel). In the case of steel, preference is given to using a steel that is hard and has low abrasiveness: for example high-speed steel (HSS), which is an alloy steel containing carbide-forming elements (e.g. tungsten, molybdenum, chromium, vanadium and cobalt), the total amount of alloying elements usually being in the range of about 10-25 wt %; or tungsten steel, also known as hard alloy, in which tungsten and cobalt are the main alloying elements. The nozzle can be prefabricated, inserted into the first part of the reactor and fixed, for example by crimping or gluing.

[0074] Thus, in some embodiments, the downstream portion of the lumen of the first fluid conduit and / or the second fluid conduit is also cylindrical or substantially cylindrical.Such downstream portion may coincide with the lumen of the cylindrical nozzle insert.

[0075] As mentioned above, in some preferred embodiments, regardless of its shape, i.e., whether cylindrical or conical, the downstream portion of the lumen of the first fluid conduit and / or the second fluid conduit has a downstream end that coincides with the corresponding fluid inlet. In addition, the downstream end may advantageously be flush with the reaction chamber wall. The downstream portion of the lumen, or at least its downstream end, may be understood as a part or feature of the corresponding nozzle.

[0076] In some embodiments, the lumen of the first fluid conduit and / or the second fluid conduit, more preferably the lumen of each of the first fluid conduit and the second fluid conduit, is substantially cylindrical, elliptical or slightly conical, wherein the cone angle is constant over the lumen length. In this case, the diameter of the lumen at its downstream end can be significantly larger than the diameter of the first fluid inlet or the second fluid inlet. As described above, the fluid inlet is provided by a nozzle. This is in contrast to a simple T-shaped or Y-shaped mixer, which is substantially composed of two (or three) pipes connected together, whose lumen forms a T-shaped or Y-shaped flow path, and the lumen diameter of each pipe is uniform until the connection forming the fluid mixing zone is uniform. One of the functions of the nozzle is to control the direction and increase the speed of the fluid flow when it enters the reaction chamber through the nozzle. In order to enhance the nozzle effect and reduce any influence of the fluid conduit geometry, it is further preferred that the lumen diameter of the upstream end of the first fluid conduit and the second fluid conduit is at least twice the larger diameter of the first fluid inlet and the second fluid inlet. In related embodiments, the diameter of the lumen of the first fluid conduit and / or the second fluid conduit at its upstream end is at least five times, or optionally at least ten times, the diameter of the first fluid inlet or the second fluid inlet, respectively. In some embodiments, the lumen of each of the first fluid conduit and / or the second fluid conduit is cylindrical or elliptical cylindrical and has a downstream portion including a downstream end that coincides with the fluid inlet, wherein the lumen diameter of each downstream portion of the first fluid conduit and / or the second fluid conduit is independently substantially the same as the fluid inlet diameter (also referred to herein as the orifice diameter).

[0077] The first fluid conduit and / or the second fluid conduit may also include a connector disposed at its upstream end. In this case, a connector is understood to be a shaped feature that can facilitate connection with a correspondingly shaped feature of, for example, a tubing end component. Examples of connectors that may be useful include male or female Luer connectors (also called Luer tips), A pipe fitting or connector, a plug-in connector or coupler with an undercut, such as a quick connector. Similarly, the third fluid conduit can feature a connector disposed at its downstream end. The type of connector on the first, second, and third body conduits can be independently selected, and in some embodiments are of the same type, but in other embodiments may be different from each other.

[0078] In some other embodiments, the diameter range of the fluid inlet provided by the first nozzle and / or the second nozzle is about 20 μm to about 600 μm. The diameter of the fluid inlet provided by the nozzle can also be referred to as the orifice diameter of the nozzle. In some embodiments, the orifice diameter range of the first nozzle and the second nozzle is 20 μm to 500 μm, or about 50 μm to 600 μm or about 50 μm to 500 μm. In other embodiments, the orifice diameter range of the first nozzle and the second nozzle is about 50 μm to 450 μm, or 100 μm to 450 μm. In a particularly preferred embodiment, the maximum orifice diameter of one or two nozzles is not more than 500 μm, or less than 500 μm. In other reactor configurations, at least one orifice diameter is about 600 μm, about 500 μm, about 400 μm, about 300 μm, about 200 μm, about 100 μm, about 50 μm or about 20 μm, respectively. Optionally, smaller diameters are contemplated, such as diameters below 20 μm.

[0079] In some embodiments, the fluid inlet diameter (ie, orifice diameter) of the first and second nozzles is the same, such as about 400 μm, about 300 μm, about 200 μm, or about 100 μm. This configuration appears to work well for some, but certainly not all, jet impingement processes.

[0080] For many processes based on jet impact technology, the best results can be obtained by a reactor according to the invention having two nozzles with different orifice diameters, i.e. the nozzles provide a first fluid inlet and a second fluid inlet with different diameters. For example, according to this further preferred embodiment, the first orifice diameter may be larger than the second orifice diameter. Such an asymmetric nozzle configuration may have advantages in various respects: for example, it may be used to control the introduction of solvents that are required for processing purposes but are not required in the final product. It may also be used to generate two liquid streams that have different flow rates but similar kinetic energies when injected through the nozzles into the reaction chamber (wherein they collide).

[0081] In one embodiment, the diameter of the first fluid inlet (i.e., the first nozzle orifice) is at least 20% larger than the diameter of the second fluid inlet. In another embodiment, the ratio of the first orifice diameter to the second orifice diameter is from about 1.2 to about 5, or in the range of about 1.2 to 2. There are also some preferred embodiments, wherein the diameter of the first fluid inlet (i.e., the first orifice) ranges from about 200 μm to about 500 μm, or from about 200 to 400 μm, and wherein the diameter of the second fluid inlet (i.e., the second orifice) ranges from about 50 μm to about 200 μm.

[0082] For example, the following nozzle pairs may be used, wherein 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 150 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; 400μm and 100μm; 400μm and 50μm; 500μm and 400μm; 500μm and 300μm; 500μm and 200μm; 500μm and 100μm; 500μm and 50μm; 600μm and 500μm; 600μm and 400μm; 500μm and 300μm; 500μm and 200μm; 500μm and 100μm; 500μm and 50μm. Again, these nozzle pairs are non-limiting examples, and other orifice diameter combinations may also be useful depending on the specific product or process.

[0083] In general, the reaction chamber provided by the jet impact reactor according to the present disclosure, and in some embodiments, the reaction chamber provided by the combination and fixation of the first shell member and the second shell member, is small. In some embodiments, a reactor is provided, the reaction chamber diameter of which does not exceed 100 times the diameter of the nozzle orifice (i.e., the inlet opening), or, if nozzles of different sizes are used, the reaction chamber diameter is not greater than about 100 times the diameter of the larger nozzle orifice. For example, if the diameter of the larger fluid inlet is 100 μm, then according to this specific embodiment, the diameter of the reaction chamber is preferably about 10 mm or less. In one embodiment, when the diameter of the nozzle or the larger inlet opening is between 200 and 300 μm, the diameter range of the reaction chamber along the first central axis is preferably 2 to 5 mm.

[0084] In a related embodiment, the ratio of the diameter of the reaction chamber along the first central axis to the diameter of the first fluid inlet is in the range of 6 to 60. For example, according to this specific embodiment, if the diameter of the first fluid inlet is about 200 μm, the diameter of the reaction chamber along the first central axis will be in the range of about 1.2 mm to about 12 mm. However, reactors equipped with larger nozzles may need to consider other dimensions.

[0085] According to another related embodiment, the ratio of the diameter of the reaction chamber along the first central axis to the fluid outlet diameter ranges from about 1.2 to about 3. For example, according to this specific embodiment, the fluid outlet diameter of a reaction chamber having a diameter of about 3 mm will be about 1 mm to 2.5 mm. In a preferred embodiment, the fluid outlet diameter is about 1 to 2 mm.

[0086] When selecting the inlet diameter, the fluid outlet diameter should also be considered. For example, a small nozzle orifice or fluid inlet diameter (e.g., less than 100 μm) should be combined with a small fluid outlet diameter (e.g., less than 1 mm) to ensure that the pressure in the reaction chamber is high enough to support turbulence and rapid mixing of the two fluids during reactor operation. For example, when two nozzles with an orifice of 50 μm are used, a fluid outlet diameter of 0.5 mm can be used. Based on the above disclosure and guidance, it will be clear to those skilled in the art that further changes in dimensional factors may also be useful to meet certain product or process requirements.

[0087] As mentioned above, the key feature of the reactor is the substantially spherical or spherical shape of the reaction chamber. In some preferred embodiments, the spherical shape of the reaction chamber is interrupted only by the first and second fluid inlets and the fluid outlet. In other words, only the required inlet and outlet are exceptions or interruptions to the otherwise completely spherical inner surface of the reaction chamber wall.

[0088] In some other embodiments, the spherical shape of the reaction chamber is interrupted only by the first and second fluid inlets, the fluid outlet, and one or two small facet wall portions, each of which has an area smaller than the area of ​​the fluid outlet. Such small facet wall portions may be minor artifacts and are another minor deviation from the overall spherical shape of the reaction chamber. For example, the planar wall portions may be provided by the first component as protrusions of the first component, and the second component may have recesses for accommodating these protrusions. In some other embodiments, the spherical shape of the reaction chamber is as shown in FIG. Figure 7 , Figure 8 , Fig. 9 or Fig.10 As shown in any of the embodiments shown.

[0089] As understood herein, the term "planar wall portion" refers to a wall portion whose shape deviates from a perfect spherical cap shape, and the portion may have an overall flat or at least partially flat shape. In some embodiments, the planar wall portion is provided as a protruding portion of the first component, the distal end of which is generally planar and features two right-angled corners. Non-limiting examples of planar wall portions are Figure 5 , Fig. 9 and Fig.10 shown.

[0090] In an alternative embodiment, one or more planar wall portions may be provided as protruding portions of the second component, and the first component may have one or more recesses for accommodating them. In a preferred embodiment, the planar wall portion is integral with the first component and is made of the same material.

[0091] In a particular embodiment, the spherical shape of the reaction chamber is interrupted by the first and second fluid inlets, the fluid outlet and two or at least two planar wall portions, each planar wall portion independently having an area smaller than the fluid outlet area. As mentioned above, such planar wall portions are small and represent only a minor deviation from the overall spherical shape of the reaction chamber.

[0092] In some preferred embodiments, the first component provides a substantially hemispherical wall portion, on which two planar wall portions are arranged as protruding portions on a large arc or large circle of the wall portion. The dimensions of the planar wall portions can be selected independently, or in other words, the dimensions of each of the at least two planar wall portions can be different. Alternatively, the dimensions of the at least two planar wall portions can be substantially the same.

[0093] In case the first component comprises two planar wall portions, the two portions are preferably arranged at diametrically opposite positions relative to the spherical shape of the reaction chamber.In some embodiments, the first planar wall portion and the second planar wall portion are arranged at opposite positions along the first central axis (x) of the reaction chamber.

[0094] A second part of the reactor comprising a fluid outlet and a portion of the reaction chamber is complementary to the first part so that the two parts can be fixed to each other to form a substantially spherical reaction chamber of the jet impact reactor. In some embodiments, the second part comprises at least two recesses, namely a first recess and a second recess that are complementary to the first part, i.e., the two recesses are arranged on the second part, which are shaped or adapted to accommodate two planar protrusions comprised by the first part so that the two parts are fixed together to form the reaction chamber of the jet impact reactor. In some alternative embodiments, the features of the recesses and the small facet wall protrusions relative to the first part and the second part can be interchanged.

[0095] In order to supply the first fluid and the second fluid to the first fluid conduit and the second fluid conduit, respectively, the first part of the reactor may include a connector, such as a buckle connector or a Luer connector, so that an external supply tube or pipe can be connected to the first part of the reactor to establish a fluid connection with the fluid conduits. In some preferred embodiments, these connections are achieved by connecting components that can be partially inserted into the first part of the reactor.

[0096] In some related embodiments, the first component includes a second cavity and a third cavity, wherein each of the second cavity and the third cavity is configured to accommodate a connection component for directing the first fluid or the second fluid from an upstream fluid supply source to the first fluid conduit or the second fluid conduit, respectively. Such a connection component may have an upstream end, a downstream end, and a fluid conduit extending from the upstream end to the downstream end; wherein at least the downstream end is insertable into the second cavity or the third cavity so that the fluid conduit of the connector is in fluid communication with the inner cavity of the first fluid conduit or the second fluid conduit of the reactor. The upstream end of the connection component may have a connector for fixing a pipe or a pipeline, such as a Luer connector or a connector with a buckle or a connector with a buckle.

[0097] In some embodiments, the connecting component is characterized by an outer circular groove at or near its downstream end for holding an O-ring seal to seal the connecting component to the first part of the housing. In some related embodiments, the connecting component may include one or more (e.g., two) or more such outer circular grooves at or near the downstream end for holding an O-ring seal to seal the connecting component to the first housing part. Optionally, it is contemplated to use additionally or alternatively other means (e.g., external means) suitable for, for example, releasably holding and sealing the connecting component to the first part of the reactor.

[0098] In some embodiments, the connecting component is also made of a polymer material, such as any polymer material or material combination described herein with reference to the first component and / or the second component of the jet impact reactor. In some embodiments, the connecting component is made of the same polymer material as the first component and / or the second component.

[0099] The lumen of the connecting component can form a part of the first fluid or second fluid flow path from the fluid supply source arranged further upstream to the first fluid conduit or second fluid conduit of the reactor, and the connecting component can include an upstream part or section and a downstream part or section, and the diameters of the two parts are different. For example, the lumen diameter of the upstream part can be greater than the lumen diameter of the downstream part. In other embodiments, the upstream part and the downstream part are indistinguishable and have the same diameter. In some embodiments, the lumen of the connecting component can be substantially cylindrical. In other embodiments, the lumen diameter of the upstream part can be less than the lumen diameter of the downstream part. In a related embodiment, the lumen diameter difference between the upstream section and the downstream section can gradually change, that is, the lumen is a tapered elliptical cylinder. In one embodiment, the lumen can be shaped as a tapered elliptical cylinder so that the lumen diameter of the upstream part of the connecting component is smaller, but gradually expands to the lumen diameter of the downstream end of the connecting component. The cone angle is preferably smaller. For example, the diameter difference between the upstream end and the downstream end of the lumen of the connecting component is not more than 0.5%, not more than 1% or not more than 5%. In other related embodiments, the difference in lumen diameter between the upstream portion and the downstream portion can be stepped or segmented.

[0100] In some embodiments, the lumen diameter of the connecting component can be the same as the lumen diameter of the upstream portion of the first fluid conduit and / or the second fluid conduit of the reactor. In other embodiments, the lumen diameter of the downstream portion or section of the connecting component that forms a portion of the first and second fluid flow paths to the first and second fluid conduits of the reactor is substantially the same as the lumen diameter of the upstream portion of the first or second fluid conduit of the reactor. In other embodiments, the lumen diameter of the connecting component or the lumen diameter of the downstream portion or section of the connecting component is different, for example, can be greater than or less than the lumen diameter of the first or second fluid conduit of the reactor.

[0101] The reactor may be designed in a substantially symmetrical manner with respect to the fluid characteristics upstream of the nozzle providing the first fluid inlet and the second fluid inlet. For example, the shape and size of the first fluid conduit and the second fluid conduit may be substantially the same, the shape and size of the second cavity may match the shape and size of the third cavity, and the connecting components insertable into the respective cavities may also be the same or similar in design.

[0102] Alternatively, the inner diameter of the fluid conduit of the connecting component for insertion into the second cavity and supplying the (first) fluid to the reactor may be greater than the diameter of the connecting component designed for insertion into the third cavity. To prevent assembly errors in this case, the shape or size of the downstream ends of the connecting components may also differ from each other, so that the connecting component can only be (partially) inserted into the correct cavity.

[0103] In other aspects, the present invention provides: (a) a reactor housing having the features of the first component as described above; (b) a connecting component as described above; and (c) a component having the features of the second reactor component as described above.

[0104] In another aspect, the invention provides a first part of a reactor as described above, optionally comprising any feature or combination of features disclosed as part of an optional or preferred embodiment in the context of the detailed disclosure of the reactor.

[0105] In another aspect, the present invention provides a method for making a reactor as described above. The method comprises the step of injection molding a first component. As described above, the first component will generally provide a major portion of the reactor housing. Optionally, the method may comprise the steps of: (a) injection molding the first component; (b) injection molding the second component; and (c) fixing the first component and the second component to each other. In some embodiments, the fixing step (c) comprises or consists of partially or completely inserting the second component into the first cavity of the first component.

[0106] Alternatively, the method may include the steps of: (a) injection molding a first component; and (b) overmolding a second component on the first component; or vice versa: (a) injection molding a second component; and (b) overmolding the first component on the second component. In some embodiments, the molding step (a) further includes forming a first fluid inlet and a second fluid inlet in the first component.

[0107] In certain embodiments, the method may include the step of inserting a preformed nozzle into the first component, which may be performed before or after the first and second components are secured to each other, or before the overmolding step, if any.

[0108] Alternatively, and according to some other preferred embodiments, the first fluid inlet and / or the second fluid inlet is generated by a step of mechanical micro-drilling or laser drilling of the first component. The step may be performed before or after step (c), i.e. before or after the first component and the second component are fixed to each other. According to some other preferred embodiments, wherein the diameters of the first fluid inlet and the second fluid inlet are different and are generated by laser drilling, the larger of the two inlets is first made, and then the smaller inlet is made by laser drilling, wherein the laser beam generating the smaller inlet is guided through the already existing larger inlet. In this way, precise alignment of the fluid inlet on the first central axis (x) of the reaction chamber can be achieved.

[0109] Optionally, the smaller entrance can be drilled completely through the larger entrance. In some alternative preferred embodiments, a very small hole can be initially drilled through the larger entrance to mark the location of the smaller entrance, and then subsequent drilling is performed from the opposite side (i.e., not through the larger entrance) to generate a smaller entrance with the desired diameter. This procedure can also be used to generate two entrances of the same diameter.

[0110] This method of manufacturing a jet impact reactor including a housing made of a polymer material can provide a more efficient manufacturing process; for example, it is contemplated that in some embodiments, although the same mold or molding tool can be used to manufacture the components, different reactors can be manufactured by simply adjusting the drilling step to adjust the first fluid inlet and / or the second fluid inlet diameter. In some embodiments, it is also contemplated that the reactor components and optional connecting components can be manufactured solely by injection molding without mechanical drilling, laser drilling, or machining to generate the first fluid inlet and / or the second fluid inlet.

[0111] In a related aspect, the present disclosure also provides a method of manufacturing a connecting component such as described above, which can be fixed to a jet impact reactor for supplying a first fluid and a second fluid from an upstream fluid supply source to a first fluid conduit and a second fluid conduit of the jet impact reactor. The method comprises the step of injection molding the connecting component. In some embodiments, the inner cavity of the connecting component can be provided by mechanical drilling or machining the connecting component.

[0112] Another aspect of the invention relates to the use of a reactor. In some particularly preferred embodiments, the reactor is used for aseptic manufacture of a sterile liquid pharmaceutical composition. The sterile liquid pharmaceutical composition may contain nanoparticles, such as lipid nanoparticles, which are common, for example, in the case of nucleic acid-based therapeutic or prophylactic drugs. In some embodiments, the sterile liquid pharmaceutical composition may contain liposomes, which are nanoparticles, generally in the form of spherical vesicles, composed of phospholipids and containing at least one lipid bilayer.

[0113] More specifically, such use may include the following steps: i) fluidly connecting a first fluid conduit to an upstream supply source of a first fluid through a first connecting component; (ii) fluidly connecting a second fluid conduit to an upstream supply source of a second fluid different from the first fluid through a second connecting component; and (iii) allowing the first fluid to flow from the first fluid supply source into the reactor at a first flow rate, while allowing the second fluid to flow from the second fluid supply source into the reactor at a second flow rate, thereby mixing the first fluid and the second fluid in the reaction chamber to form a third fluid that leaves the reaction chamber through the fluid outlet. The third fluid representing a mixture or reaction product of the first fluid and the second fluid will then leave the reactor through the fluid outlet and the third fluid conduit provided by the second component. Those skilled in the art will understand that such use may also be expressed as a process or method, i.e., a process or method comprising the above steps (i) to (iii). In addition, those skilled in the art will also understand that the order of steps (i) and (ii) is not critical, and step (iii) is performed after steps (i) and (ii). In some processes, depending on the type of material prepared using the reactor, the first flow rate and the second flow rate may be similar or even substantially the same. In many other processes (generally also including the manufacture of lipid nanoparticles for nucleic acid-based therapeutic drugs or preventive drugs), different volumes of the first fluid and the second fluid must be mixed, which requires that the first flow rate and the second flow rate are different. For example, a larger volume of a first fluid representing an aqueous liquid optionally containing an active ingredient (e.g., a nucleic acid construct) may need to be mixed with a smaller volume of a second fluid representing a lipid organic solution capable of forming lipid nanoparticles. Therefore, in some preferred embodiments, the first flow rate is greater than the second flow rate; preferably, in this process, the diameter of the first fluid inlet is also larger than the diameter of the second fluid inlet.

[0114] In yet another aspect, the present invention provides an apparatus for aseptically manufacturing a sterile liquid pharmaceutical composition, the apparatus being characterized in that it comprises a jet impact reactor as disclosed herein.

[0115] The following numbered bullet list is an embodiment included in the present disclosure:

[0116] 1. A jet impact reactor (1) comprising a reaction chamber (2), the reaction chamber having a substantially spherical shape, wherein the spherical shape is interrupted by:

[0117] (a) a first fluid inlet (3) and a second fluid inlet (4), wherein the first fluid inlet (3) and the second fluid inlet (4) are arranged at relative positions on a first central axis (x) of the reaction chamber (2) so as to point to each other, and wherein each of the first fluid inlet (3) and the second fluid inlet (4) is provided by a nozzle (5); and

[0118] (b) a fluid outlet (6) arranged at a position located on a second central axis (y) of the reaction chamber (2), wherein the second central axis (y) is perpendicular to the first central axis (x);

[0119] The reactor (1) further comprises a first fluid conduit (7), a second fluid conduit (8) and a third fluid conduit (9), wherein the first fluid conduit (7) and the second fluid conduit (8) are arranged to direct a first fluid to the first fluid inlet (3), and a second fluid to the second fluid inlet (4), and wherein the third fluid conduit (9) is arranged to direct a third fluid from the fluid outlet (6) in a downstream direction, the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber (2);

[0120] The reactor (1) comprises at least two parts fixed to each other: a first part (121, 171, 181) made of a polymer material and comprising at least a portion of the first fluid conduit (7) or the second fluid conduit (8) and at least one hemispherical portion of the reaction chamber (2); and a second part (132, 172, 182) which is at least partially insertable into the first part (121, 171, 181), the second part comprising the fluid outlet (6).

[0121] 2. A reactor (1) according to item 1, wherein the first component (121, 171, 181) is shaped to include a first cavity (21) for accommodating the second component (132, 172, 182) by insertion, and wherein the second component (132, 172, 182) is shaped and suitable for being inserted into the first cavity (21).

[0122] 3. The reactor (1) according to item 1 or 2, wherein the first cavity (21) is cylindrical, elliptical or conical.

[0123] 4. The reactor (1) according to any of the above items, wherein the second component (132, 172, 182) comprises:

[0124] - an upstream end (24) comprising the fluid outlet (6) and a portion of the reaction chamber (2) (16);

[0126] - a downstream end (25); and

[0127] - said third fluid conduit (9) fluidly connecting said upstream end (24) with said downstream end (25).

[0128] 5. The reactor (1) according to any one of the above items, wherein the second component (132, 172, 182) can be completely inserted into the first cavity (21).

[0129] 6. A reactor (1) according to any of the above items, wherein the first component (121, 171, 181) is at least mainly made of a thermoplastic polymer material; wherein the thermoplastic polymer material preferably comprises polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile-butadiene-styrene copolymer (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU) or polyetherimide (PEI).

[0130] 7. A reactor (1) according to any of the above items, wherein the first fluid conduit (7) and the second fluid conduit (8) both have a longitudinal central axis that coincides with the first central axis (x) of the reaction chamber (2), and wherein the third fluid conduit (9) has a longitudinal central axis that coincides with the second central axis (y) of the reaction chamber (2).

[0131] 8. A reactor (1) according to any of the above items, wherein the first fluid conduit (7) and / or the second fluid conduit (8) has an inner cavity (28), the inner cavity having an upstream part (29a) and a downstream part (29c), wherein the upstream part (29a) is cylindrical or elliptical and has a diameter that is much larger than the diameter of the downstream part (29c).

[0132] 9. A reactor (1) according to item 8, wherein the downstream portions (29c) of the first fluid conduit (7) and the second fluid conduit (8) both have downstream ends, which respectively form the first fluid inlet (3) and the second fluid inlet (4) or coincide with them.

[0133] 10. The reactor (1) according to item 9, wherein the downstream portion (29c) is tapered towards its downstream end.

[0134] 11. The reactor (1) according to any one of items 1 to 8, wherein the downstream portion (29c) is substantially cylindrical.

[0135] 12. A reactor (1) according to any of the above items, wherein the inner cavity (28) of each of the first fluid conduit (7) and the second fluid conduit (8) further comprises an intermediate portion (29b) between the upstream portion (29a) and the downstream portion (29c), wherein the intermediate portion (29b) is tapered toward the downstream portion (29c).

[0136] 13. The reactor (1) according to item 12, wherein the conical middle portion (29b) and the conical downstream portion (29c) have different conical angles.

[0137] 14. The reactor (1) according to any of the preceding items, wherein the nozzle (5) is provided by the downstream portion (29c).

[0138] 15. A reactor (1) according to any one of items 8 to 14, wherein the nozzle (5) providing the first fluid inlet (3) or the second fluid inlet (4) is integral with the first part (121, 171, 181) of the reactor (1).

[0139] 16. The reactor (1) according to any one of items 8 to 14, wherein the nozzle (5) providing the first fluid inlet (3) or the second fluid inlet (4) is an insert.

[0140] 17. The reactor (1) according to item 16, wherein the insert is made of metal.

[0141] 18. The reactor (1) according to any of the above items, wherein the diameter of the first fluid inlet (3) and the second fluid inlet (4) ranges from about 50 μm to about 600 μm.

[0142] 19. The reactor (1) according to any of the above items, wherein the diameter of the first fluid inlet (3) is different from the diameter of the second fluid inlet (4).

[0143] 20. The reactor (1) according to item 18 or 19, wherein the diameter of the first fluid inlet (3) ranges from about 200 μm to about 500 μm, and wherein the diameter of the second fluid inlet (4) ranges from about 50 μm to about 200 μm.

[0144] 21. The reactor (1) according to any of the preceding items, wherein the spherical shape of the reaction chamber (2) is interrupted only by the first fluid inlet (3), the second fluid inlet (4) and the fluid outlet (6).

[0145] 22. A reactor (1) according to any one of items 1 to 20, wherein the spherical shape of the reaction chamber (2) is interrupted only by the first fluid inlet (3) and the second fluid inlet (4), the fluid outlet (6) and a planar wall portion (31) having an area smaller than the area of ​​the fluid outlet (6).

[0146] 23. A reactor (1) according to item 22, wherein the planar wall portion (31, 319) is provided by the first component (121) as a protruding portion of the first component (121), and wherein the second component (132, 172, 182) has a recess (32) for accommodating the protruding portion.

[0147] 24. A reactor (1) according to any one of items 1 to 20, wherein the spherical shape of the reaction chamber (2) is interrupted only by the first fluid inlet (3) and the second fluid inlet (4), the fluid outlet (6) and at least two planar wall portions (31, 319), each planar wall portion independently having an area smaller than the area of ​​the fluid outlet (6), wherein the first planar wall portion and the second planar wall portion are arranged at relative positions on the first central axis (x) of the reaction chamber (2).

[0148] 25. A reactor (1) according to item 24, wherein the at least two planar wall portions (31, 319) are provided by the first component (121, 171, 181) as protruding portions of the first component (121), and wherein the second component (132, 172, 182) has a first recess and a second recess (32, 329) suitable for accommodating the protruding portions.

[0149] 26. A reactor (1) according to any of the above items, wherein the first component (121, 171, 181) comprises a second cavity (8) and a third cavity (9), wherein each of the second cavity (8) and the third cavity (9) is formed to accommodate a connecting component (33, 73, 83), and the connecting component is used to guide the first fluid or the second fluid from an upstream fluid supply source to the first fluid conduit (7) or the second fluid conduit (8), respectively.

[0150] 27. The reactor (1) according to item 26, wherein the connecting component (33, 73, 83) has an upstream end (34, 74, 84), a downstream end (35, 75, 85) and a fluid conduit (36, 76, 86) extending from the upstream end (34, 74, 84) to the downstream end (35, 75, 85), wherein at least the downstream end (35, 75, 85) can be inserted into the second cavity (22) or the third cavity (23), so that the fluid conduit (36, 76, 86) of the connecting component (33, 73, 83) is in fluid communication with the inner cavity of the first fluid conduit (7) or the second fluid conduit (8) of the reactor (1).

[0151] 28. A reactor (1) according to item 27, wherein the upstream end (34, 74, 84) of the connecting part (33, 74, 83) has a connector (37, 77, 87) for fixing a pipe or a pipeline, such as a Luer connector or a connector or connector with a barb.

[0152] 29. A reactor (1) according to any one of items 26 to 28, wherein the connecting component (33, 73, 83) is characterized by an outer circular groove (38, 78, 88) at or near its downstream end (35, 75, 85) for retaining an O-ring seal (39, 79) to seal the connecting component (33, 73, 83) to the first component (121, 171, 181) of the reactor (1).

[0153] 30. The first part (121, 171, 181) of the reactor (1) as defined in any of the preceding items.

[0154] 31. A method for manufacturing the first component (121, 171, 181) of the reactor (1) described in any one of items 1 to 29 or the reactor (1) described in item 30, comprising the step of injection molding the first component (121, 171, 181).

[0155] 32. The method according to item 31, wherein the step of injection molding the first component (121, 171, 181) includes forming the first fluid inlet (3) and the second fluid inlet (4).

[0156] 33. The method according to item 31, wherein the first fluid inlet (3) and the second fluid inlet (4) are formed by a step of micro drilling or laser drilling.

[0157] 34. Use of the reactor (1) according to any one of items 1 to 29 for the aseptic manufacture of a sterile liquid pharmaceutical composition.

[0158] 35. The use according to item 34, comprising:

[0159] (i) fluidly connecting the first fluid conduit (7) to an upstream supply source of a first fluid via a first connecting member (33, 73, 83);

[0160] (ii) fluidly connecting the second fluid conduit (8) to an upstream supply source of a second fluid different from the first fluid via a second connecting member (33, 73, 83);

[0161] (iii) allowing the first fluid to flow from the first fluid supply source into the reactor (1) at a first flow rate, and allowing the second fluid to flow from the second fluid supply source into the reactor (1) at a second flow rate, so that the first fluid and the second fluid are mixed in the reaction chamber (2) to form a third fluid, and the third fluid leaves the reaction chamber (1) through the fluid outlet (6).

[0162] 36. The use according to item 35, wherein the first flow rate is greater than the second flow rate, and wherein the diameter of the first fluid inlet (3) is greater than the diameter of the second fluid inlet (4).

[0163] 37. The use according to items 34 to 36, wherein the liquid pharmaceutical composition comprises lipid nanoparticles.

[0164] Alternative jet impact reactors provided by fixing or constructing alternative components are also provided in the present disclosure. Figures 13 to 23 The following numbered list also relates to alternative jet impact reactor embodiments:

[0165] 1. A jet impact reactor (1) comprising a housing (2) made of a polymer material, said housing enclosing a reaction chamber (2), said reaction chamber having a substantially spherical shape, wherein said spherical shape is interrupted only by:

[0166] (a) at least a first fluid inlet (3) and a second fluid inlet (4), wherein the first fluid inlet (3) and the second fluid inlet (4) are arranged at relative positions on a first central axis (x) of the reaction chamber (2) so as to point towards each other, and wherein each of the first fluid inlet (3) and the second fluid inlet (4) is provided by a nozzle (5); and

[0167] (b) a fluid outlet (6) arranged at a position located on a second central axis (y) of the reaction chamber (2), wherein the second central axis (y) is perpendicular to the first central axis (x);

[0168] The reactor (1) further comprises a first fluid conduit (7), a second fluid conduit (8) and a third fluid conduit (9), wherein the first fluid conduit (7) and the second fluid conduit (8) are arranged to direct a first fluid to the first fluid inlet (3), and a second fluid to the second fluid inlet (4), and wherein the third fluid conduit (9) is arranged to direct a third fluid from the fluid outlet (6) in a downstream direction, the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber (2);

[0169] The housing is composed of at least two parts fixed to each other, wherein a first part (11, 41, 81) contains at least a major part of the first fluid conduit (7) or the second fluid conduit (8), and a second part (12, 42, 82) contains at least one of the nozzles (5).

[0170] 2. A reactor according to item 1, wherein the first component comprises at least a major portion of each of the first fluid conduit, the second fluid conduit and the third fluid conduit.

[0171] 3. A reactor according to item 1 or 2, wherein the first component is shaped to include a cavity for accommodating the second component by insertion.

[0172] 4. The reactor according to any of the above items, wherein the second component is shaped and suitable for insertion into the first component.

[0173] 5. A reactor according to item 3 or 4, wherein the forming of the first component includes an insertion guide (51, 91) for accommodating the second component in a specific orientation, and / or wherein the forming of the second component includes an insertion guide (52, 92) for inserting the second component into the cavity of the first component in a specific orientation relative to the first component.

[0174] 6. A reactor according to any of the above items, wherein the second part comprises at least a major part of the reaction chamber.

[0175] 7. A reactor according to any of the above items, wherein the second component comprises the fluid outlet.

[0176] 8. The reactor according to any of the above items, wherein the second component comprises the first fluid inlet and the second fluid inlet.

[0177] 9. The reactor according to any of the above items, wherein the second part comprises the entire reaction chamber.

[0178] 10. The reactor according to any of the above items, wherein the second component comprises a smaller portion of at least one of the first fluid conduit, the second fluid conduit and the third fluid conduit.

[0179] 11. The reactor according to any of the above items, wherein the housing essentially consists of the first part and the second part.

[0180] 12. A reactor according to any of the above items, wherein the first component and the second component are fixed together by one or more fastening devices; optionally, wherein the first component and the second component are held together by fastening devices in the form of screws.

[0181] 13. A reactor according to any of the preceding items, wherein the first component is overmolded on the second component, or wherein the second component is overmolded on the first component.

[0182] 14. The reactor according to any of the preceding items, wherein the first component and / or the second component is at least mainly made of a thermoplastic polymer material.

[0183] 15. A reactor according to item 14, wherein the thermoplastic polymer material comprises polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile-butadiene-styrene copolymer (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU) or polyetherimide (PEI).

[0184] 16. A reactor according to any of the above items, wherein the first component and / or the second component comprises one or more snap-fit ​​or press-fit features (98, 108) for holding the first component and the second component together.

[0185] 17. The reactor according to any of the above items, further comprising a gasket located between the first component and the second component.

[0186] 18. A reactor according to any of the above items, wherein the first fluid conduit and the second fluid conduit both have a longitudinal central axis that coincides with the first central axis (x) of the reaction chamber.

[0187] 19. A reactor according to any of the above items, wherein the third fluid conduit has a longitudinal central axis that coincides with the second central axis (y) of the reaction chamber.

[0188] 20. A reactor according to any of the above items, wherein the first fluid conduit and / or the second fluid conduit has an inner cavity (13, 14) extending from the upstream end to the downstream end of the conduit, and the inner cavity is cylindrical or tapered toward the downstream end.

[0189] 21. A reactor according to item 20, wherein the diameter of the inner cavity of the first fluid conduit and / or the second fluid conduit at its downstream end is at least ten times the diameter of the first fluid inlet or the second fluid inlet, respectively.

[0190] 22. A reactor according to item 20 or 21, wherein the inner cavity of the first fluid conduit and / or the second fluid conduit has a tapered upstream section and a tapered downstream section, wherein the taper angle of the downstream section exceeds the taper angle of the upstream section.

[0191] 23. A reactor according to any of the above items, wherein the first fluid conduit and / or the second fluid conduit has an upstream end, and the upstream end includes a connector (27, 37, 57, 97).

[0192] 24. A reactor according to any of the above items, wherein the third fluid conduit comprises an inner cavity (15) having an upstream end and a downstream end, wherein the upstream end coincides with the fluid outlet (6) of the reaction chamber.

[0193] 25. A reactor according to any of the preceding items, wherein the nozzle (5) providing the first fluid inlet or the second fluid inlet is integral with the first part or the second part of the housing.

[0194] 26. A reactor according to any one of items 1 to 25, wherein the nozzle providing the first fluid inlet or the second fluid inlet is an insert received in the first or second part of the housing.

[0195] 27. A reactor according to item 26, wherein the nozzle is made of a different material than the component into which it is inserted.

[0196] 28. A reactor according to any of the preceding items, wherein the nozzle providing the first fluid inlet or the second fluid inlet is shaped as a cylindrical pipe.

[0197] 29. The reactor according to any of the above items, wherein the diameter of the first fluid inlet and the second fluid inlet ranges from about 50 μm to about 600 μm.

[0198] 30. The reactor according to any of the above items, wherein the diameter of the first fluid inlet is different from the diameter of the second fluid inlet.

[0199] 31. A reactor according to any of the above items, wherein the ratio of the diameter of the reaction chamber (2) along the first central axis (x) to the diameter of the first fluid inlet is in the range of 6 to 60.

[0200] 32. A reactor according to any of the above items, wherein the ratio of the diameter of the reaction chamber (2) along the first central axis (x) to the diameter of the fluid outlet (6) ranges from about 1.2 to 3.

[0201] 33. A method of manufacturing a reactor as described in items 1 to 32, comprising the step of injection molding the first part and / or the second part of the shell.

[0202] 34. The method according to item 33, wherein the first fluid inlet and / or the second fluid inlet are generated by mechanical drilling or laser drilling of the first part and / or the second part of the housing.

[0203] 35. Use of the reactor according to items 1 to 32 for the aseptic manufacture of a sterile liquid pharmaceutical composition.

[0204] 36. The use according to item 35, wherein the liquid pharmaceutical composition comprises lipid nanoparticles.

[0205] 37. An apparatus for aseptically manufacturing a sterile liquid pharmaceutical composition, the apparatus comprising a reactor as described in items 1 to 32.

[0206] Detailed description of the drawings

[0207] Figure 1A cross-sectional view (not drawn to scale) of an embodiment of a first component (121) of a jet impact reactor is shown, the first component comprising a first fluid conduit (7) and a second fluid conduit (8) or at least a portion of each conduit. In addition, it comprises or accommodates a portion of a substantially spherical reaction chamber (2). The portion provided by the first component (121) comprises more than one hemispherical segment or portion of the reaction chamber (2). Also shown are a first fluid inlet (3) and a second fluid inlet (4), which are arranged at relative positions on a first central axis of the reaction chamber (2) so as to point to each other, through which the first fluid and the second fluid jet can enter the reaction chamber (2) so as to collide or impact head-on with each other. Each of the first fluid inlet (3) and the second fluid inlet (4) is provided by a nozzle (5). The first component (121) also has a first cavity (21), which is an elliptical cylinder, slightly tapered, and is shaped to accommodate the second reactor component by insertion. The first fluid conduit (7) and the second fluid conduit (8) each have an inner cavity, the inner cavity having an upstream portion (29a), a downstream portion (29c), and an intermediate portion (29b) therebetween, the intermediate portion being tapered toward the downstream portion (29c). In addition, the downstream portion (29c) is tapered toward the respective fluid inlet (3, 4), the taper angle being different from the taper angle of the intermediate portion (29b). The downstream end of the downstream portion (29c) coincides with the respective fluid inlet (3, 4). The upstream portion (29a) of each fluid conduit (7, 8) has a cylindrical shape. The first component (121) further comprises a second cavity (22) and a third cavity (23), each cavity being shaped to accommodate a connecting component for directing a first fluid or a second fluid from an upstream fluid supply source to the first fluid conduit (7) or the second fluid conduit (8), respectively.

[0208] Figure 2 A cross-sectional view (not drawn to scale) of an embodiment of a second component (132) of a jet impact reactor is shown, the second component being designed to Figure 1 The first component (121) is shown to be compatible and insertable into the first cavity (21) of the first component (121). The second component (132) comprises an upstream end (24) and a downstream end (25). The inner cavity between the two ends represents a third fluid conduit (9), which fluidically connects the upstream end (24) with the downstream end (25). The upstream end (24) is designed to provide a portion (16) of the reaction chamber wall in its inserted state and includes a fluid outlet (6).

[0209] Figure 3 A cross-sectional view (not drawn to scale) of an embodiment of a connecting member (33) is shown, the connecting member being designed to be used with Figure 1The first component (121) is matched with the first component (121) shown and is used to guide the first fluid or the second fluid from the upstream fluid supply source to the first fluid conduit (7) or the second fluid conduit (8) of the first component (121). The connecting component (33) has an upstream end (34), a downstream end (35) and a fluid conduit (36) extending from the upstream end (34) to the downstream end (35). It is formed so that at least the downstream end (35) can be inserted into the second cavity (22) or the third cavity (23) of the first component (121). In addition, the connecting component (33) is characterized by an outer circular groove (38) at its downstream end (35) for retaining an O-ring seal (39) to seal the connecting component (33) in Figure 1 The first part (121) is shown. Another outer groove is arranged at the downstream end (35) and further upstream of the first outer groove (38) to hold another O-ring seal. The upstream end (34) of the connecting part (33) has a connector (37) or joint with an undercut for fixing a pipe or pipeline.

[0210] Figure 4 A cross-sectional view of an embodiment of a jet impact reactor (1) is shown, the reactor comprising Figure 1 The first component (121) shown, and Figure 2 The second component (132) and two Figure 3 The connecting part (33) is shown. The second part (132) is fully inserted into the first cavity (21). The downstream end (35) of the connecting part (33) is inserted into the second cavity (22) and the third cavity (23) arranged in the first part (121) of the reactor (1). The upstream end (24) of the second part (132) now provides a part of the wall of the reaction chamber (2) and the fluid outlet (6). For a description of other features shown, please refer to Figure 1 , Figure 2 and Figure 3 .

[0211] Figure 5 A cross-sectional view of a specific embodiment of a substantially spherical reaction chamber (2) formed by a first component (121) and a partially or fully inserted second component (132) is shown; only a portion of the first component (121) and the second component (132) are shown. The small planar wall portion (31) of the reaction chamber wall is provided by the first component (121). The second component (132) has a recess (32) which accommodates the protrusion forming the planar wall portion (31).

[0212] Figure 6A cross-sectional view (not drawn to scale) of another embodiment of a first component (171) of a jet impact reactor is shown, the first component comprising a first fluid conduit (7) and a second fluid conduit (8) or at least a portion of each conduit. In addition, it contains or accommodates a portion of a substantially spherical reaction chamber (2), the portion representing a substantially hemispherical segment or about 50% of the reaction chamber (2). A first fluid inlet (3) and a second fluid inlet (4) are also shown, which are arranged in relative positions on a first central axis of the reaction chamber (2) so as to point to each other, through which the first fluid and the second fluid jet can enter the reaction chamber (2) so as to collide or impact with each other head-on. Each of the first fluid inlet (3) and the second fluid inlet (4) is provided by a nozzle (5). The first component (171) also has a first cavity (21), which is an elliptical cylinder, slightly tapered, and is shaped to accommodate the second reactor component by insertion. The first fluid conduit (7) and the second fluid conduit (8) each have an inner cavity, the inner cavity having an upstream portion (29a), a downstream portion (29c) and an intermediate portion (29b) therebetween. The intermediate portion (29b) of the inner cavity is tapered toward the downstream portion (29c). In the depicted embodiment, the inner cavity downstream portion (29c) of the first fluid conduit (7) and the second fluid conduit (8) is elliptical or cylindrical, and its inner cavity diameter is significantly smaller than the inner cavity diameter of the upstream portion (29b), for example, less than half the diameter of the inner cavity upstream portion (29b). The downstream end of the downstream portion (29c) coincides with the corresponding fluid inlet (3, 4), that is, the inner cavity diameter of the downstream portion (29c) is substantially the same as the orifice diameter of the corresponding fluid inlet (3, 4). The upstream portion (29a) of each fluid conduit (7, 8) has a cylindrical shape. The first component (171) further comprises a second cavity (22) and a third cavity (23), each cavity being shaped to receive a connection component for directing the first fluid or the second fluid from an upstream fluid supply source to the first fluid conduit (7) or the second fluid conduit (8), respectively.

[0213] Figure 7 A cross-sectional view (not drawn to scale) of an embodiment of a jet impact reactor (1) is shown, the reactor comprising Figure 6A first component (171) is shown, as well as a second component (172) and two connecting components (73). The second component (172) is fully inserted into the first cavity (21) of the first component (171). The second component (172) comprises an upstream end (24) and a downstream end (25). The inner cavity between these two ends represents a third fluid conduit (9), which fluidically connects the upstream end (24) of the second component (172) with the downstream end (25). The upstream end (24) is designed to provide a portion (16) of the wall of a substantially spherical reaction chamber (2) and a fluid outlet (6) in its inserted state. The portion of the substantially spherical reaction chamber (2) provided by the second component (172) can provide up to 50% of the internal volume of the reaction chamber (2), the internal volume being calculated based on the substantially spherical shape formed by the reaction chamber wall without being interrupted by the fluid inlet (3, 4) and the fluid outlet (6) and optionally any other features (not shown) that may interrupt the spherical shape.

[0214] The downstream ends (75) of the two connecting parts (73) are inserted into the second cavity (22) and the third cavity (23) arranged in the first part (171) of the reactor (1). The two connecting parts (73) are used to guide the first fluid or the second fluid from the upstream fluid supply source to the third cavity (23) arranged in the first part (171) of the reactor (1). Figure 6 The first fluid conduit (7) or the second fluid conduit (8) of the first component (171) is shown. The connecting component (73) has an upstream end (74), a downstream end (75) and a fluid conduit (76) extending from the upstream end (74) to the downstream end (75). It is shaped so that at least the downstream end (75) can be inserted into the second cavity (22) or the third cavity (23) of the first component (121).

[0215] As shown in the figure, the fluid conduit (76) of the connecting component (73) has different inner cavity diameters in its upstream portion or section (744) and its downstream portion or section (755). As shown in the figure, the inner cavity diameter of the upstream portion (744) is greater than the diameter of the downstream portion (755). The length of the downstream portion (755) of the connecting component (73) coaxial with the first central axis (x) approximately corresponds to the portion of the connecting component that can be inserted or inserted into the second cavity (22) or the third cavity (23) of the first reactor component (171).

[0216] Furthermore, the connecting part (73) is characterized by at least one outer groove (78) at its downstream end (75) for holding an O-ring seal (79) for sealing the connecting part (73) to the first part (171). A further outer groove is arranged upstream of the first outer groove (78) for holding another O-ring seal. The upstream end (74) of the connecting part (73) has an undercut connector (77) or fitting for fixing a pipe or pipeline.

[0217] Figure 8A cross-sectional view (not drawn to scale) of another embodiment of a jet impact reactor (1) is shown, the reactor comprising a first part (181) fixed to a second part (182) and two connecting parts (83). The second part (182) is completely inserted into the first cavity (21) of the first part (181). The second part (182) comprises an upstream end (24) and a downstream end (25). The inner cavity between these ends represents a third fluid conduit (9), which fluidically connects the upstream end (24) of the second part (182) with the downstream end (25). The upstream end (24) is designed to provide a portion (16) of the wall of a substantially spherical reaction chamber (2) and a fluid outlet (6) in its inserted state. The portion of the spherical reaction chamber provided by the second component (182) can be at most 50% of the internal volume of the reaction chamber (2), which is calculated based on the basic spherical shape formed by the reaction chamber wall without the interruption of the fluid inlet, fluid outlet (6) and any small non-spherical elements (not shown) that may protrude or be recessed from the reaction chamber wall.

[0218] The downstream ends (85) of the two connecting parts (83) are inserted into the second cavity (22) and the third cavity (23) arranged in the first part (181) of the reactor (1). The two connecting parts (83) are used to guide the first fluid or the second fluid from the upstream fluid supply source to the first fluid conduit (7) or the second fluid conduit (8) of the first part (181). Figure 6 , with reference to the similar first fluid conduit (7) and second fluid conduit (8). The connecting component (83) has an upstream end (84), a downstream end (85) and a fluid conduit (86) extending from the upstream end (84) to the downstream end (85). It is shaped so that at least the downstream end (85) can be inserted into the second cavity (22) or the third cavity (23) of the first component (181).

[0219] The fluid conduit (86) of the connecting member (83) has different inner cavity diameters at its upstream portion or section (844) and its downstream portion or section (855). As shown, the inner cavity diameter of the upstream portion (844) is smaller than the diameter of the downstream portion (855). The inner cavity is tapered, that is, it gradually expands from a smaller inner cavity diameter at the upstream end (84) to a larger inner cavity diameter at the downstream end (85). The connecting member (83) is characterized by at least one outer circular groove (88) at its downstream end (75) for retaining an O-ring seal (not shown) to seal the connecting member (82) to the first member (181). Another outer circular groove is arranged at the downstream end (85) and further upstream of the first outer circular groove (88) to retain another O-ring seal. The upstream end (84) of the connecting member (83) has a connector (87) or joint with an undercut for fixing a pipe or pipeline.

[0220] Fig. 9A cross-sectional perspective enlarged view (not drawn to scale) of a specific embodiment of a substantially spherical reaction chamber (2) is shown, the reaction chamber being formed by a first component (181) and a second component (182) partially or completely inserted therein; only a portion of the first component (181) and the second component (182) are shown. A faceted wall portion (319) of the reaction chamber wall is provided by the first component (181). As shown, a fluid inlet (3) is included in the first component (181) and is arranged about a first central axis (x, not shown, see Figure 8 ). In this embodiment, the first component (181) and the second component (182) are connected at the arc of the substantially spherical reaction chamber (2), that is, at the circular intersection of the reaction chamber (2) and the plane passing through the spherical center point at the first central axis (x). The small face wall portion (319) is characterized by a protruding portion of the first component (181), which arises from and extends beyond the arc of the substantially spherical reaction chamber. The second component (182) provides a portion of the substantially spherical reaction chamber wall, a fluid outlet (6) and a recess (329) that accommodates the protruding portion of the first component (181) that forms the planar wall portion (319).

[0221] Fig.10 A cross-sectional perspective view (A) of a first component (181) and a cross-sectional perspective view (B) of the same first component (183) secured to a second component (182) are shown. The first component (181) comprises a fluid inlet (3) at the bottom of a planar wall portion (319) and a first cavity (21) for inserting the second component (182). As shown in view (A), the planar wall portion (319) is a small protrusion created by the hemispherical chamber portion provided by the first component (181). An insertion guide (109a) is also shown, which in this embodiment is shown as a recess arranged at the downstream end of the first cavity (21). For other features of the first component (181), see Figure 8 or Fig. 9 , similar features see Figure 6 .

[0222] View (B) shows the inserted second component (182), including an insertion guide feature (109b), such as a protrusion or undercut complementary to the insertion guide (109a) of the first component (181), to ensure that the second component (182) is correctly inserted and fixed to the first component (181), that is, the second component (182) is correctly oriented relative to the first component (181). The first component (181) and the second component (182) are fixed to each other to form a basically spherical reaction chamber (2), and the planar wall portion (319) is accommodated by a complementary recess (329, not shown) arranged in the reaction chamber wall portion (16) provided by the second component (182). The second component also provides a fluid outlet (6). For other features, please refer to Figure 8 , Fig. 9 and Figure 6 .

[0223] Fig.11 A graphical depiction of the particle size (mean diameter (nm); Figure A) and polydispersity index (PDI; Figure B) characteristics of PLGA nanoparticles obtained using polymer jet impact reactors (A, B, and C) according to the present invention and obtained using a stainless steel reactor (M) as described in Example 1 is shown. The mean particle size of the PLGA nanoparticles obtained was less than about 200 nm. The average PDI measured for the PLGA nanoparticles was less than 0.2.

[0224] Fig.12 A graphical depiction of the particle size (mean diameter (nm); Figure A) and polydispersity index (PDI; Figure B) characteristics of liposomal nanoparticles obtained using a polymer reactor (A, B and C) or a stainless steel reactor (M) according to the present invention as described in Example 2 is shown. The mean particle size of the liposomal nanoparticles obtained was less than about 40 nm. The average PDI measured for the liposomal nanoparticles was less than 0.1.

[0225] Fig.13A cross-sectional view (not drawn to scale) of an alternative embodiment of a jet impact reactor (1) is depicted, the reactor comprising a housing (10) made of a polymer material, the housing consisting of two parts (11, 12) fixed to each other, wherein the first housing part (11) comprises at least a major part of a second fluid conduit (14), at least a major part of a third fluid conduit (9), and a part of a wall of a reaction chamber (2). The second housing part (12) comprises the remaining part forming the wall of the reaction chamber (2) and the first fluid conduit (7). The reaction chamber wall is divided so that approximately half of the reaction chamber wall, including a fluid inlet (4) and half of the fluid outlet (6), is formed by the first housing part, and the other half of the reaction chamber wall, the other fluid inlet (3) and the other half of the fluid outlet (6) are accommodated in the second housing part (12). The contact area between the first part and the second part comprises a segment extending through the center of the reaction chamber along a second central axis (y), which segment may have a vertical orientation when the reactor is in operation, i.e. in the operating orientation of the reactor. The housing (10) encloses a reaction chamber (2) having a substantially spherical shape, the spherical shape being interrupted only by a first fluid inlet (3) and a second fluid inlet (4) and (b) a fluid outlet (6). The first fluid inlet (3) and the second fluid inlet (4) are arranged at relative positions on a first central axis (x) of the reaction chamber so as to point to each other, and each of the first fluid inlet and the second fluid inlet is provided by a nozzle (5). The fluid outlet (6) is arranged at a position located on a second central axis (y) of the reaction chamber, the second central axis being perpendicular to the first central axis (x). The first fluid conduit (7), the second fluid conduit (8) and the third fluid conduit (9) each have an inner cavity, the inner cavities of the first fluid conduit (13) and the second fluid conduit (14) each have a longitudinal axis coinciding with the first central axis (x) of the reaction chamber, and extend from an upstream end to a downstream end fluidically connected to the nozzle (5), the inner cavity (15) of the third fluid conduit having an upstream end and a downstream end, the upstream end coinciding with the fluid outlet (6) of the reaction chamber. Therefore, a first fluid conduit and a second fluid conduit are arranged in the reactor for directing the first fluid to the first fluid inlet and directing the second fluid to the second fluid inlet, and a third fluid conduit is arranged for directing a third fluid from the fluid outlet in a downstream direction, the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber.

[0226] Fig.14 A perspective view (not drawn to scale) of the second housing member (12) is depicted, as shown in FIG. Fig.13The second shell part (12) comprises a first fluid conduit (7) and approximately half of the wall forming a reaction chamber (2), the reaction chamber being hemispherical in shape and interrupted only by a fluid inlet (3) and approximately half of the fluid outlet (6). The shell (12) further comprises a first fluid conduit (7) and a plurality of fastening means (26), the first fluid conduit having a connector (27) at its upstream end, the fastening means being in the form of, for example, a cavity adapted or shaped to accommodate complementary or corresponding fastening means (e.g. a screw, or a push-fit or snap-fit ​​peg (not shown)) for fixing the shell part to the first shell part (11, not shown).

[0227] If there are multiple fastening devices, such as the fastening devices shown in this figure and subsequent figures for securing two shell components together, they should not be construed as being limited to or necessarily representing the same or single type of fastening devices. Instead, as contemplated herein, the fastening devices or configurations at each indicated position can be independently selected or constructed, and in some embodiments, different devices can be used at each of the positions. Similarly, the connectors shown in this figure and any of the subsequent figures should be understood to be exemplary and not limited to the shapes and forms shown. Instead, it should be understood that the selection of connectors at each position can be independently adjusted based on the requirements or preferences for connecting the fluid conduit and fluid outlet to other components, devices or instruments that may be associated with the use and operation of the jet impact reactor.

[0228] Fig.15 Describes Fig.13 A perspective view (not drawn to scale) of a first shell component (11) of an alternative jet impact reactor (1) shell (10) is shown. As shown, the first shell component (11) provides approximately half of the reaction chamber (2) wall, which is hemispherical in shape and is interrupted only by the fluid inlet (4) and approximately half of the fluid outlet (6). The shell (11) also includes a third fluid conduit (9) (having a formed feature in the form of a connector (37) at its downstream end) and a second fluid conduit (8). As shown, the second fluid conduit (8) also includes a formed connector (37) arranged at its upstream end. A fastening device (36) is also shown, such as in the form of a cavity, which is shaped or suitable for accommodating a complementary fastening device (not shown), such as a screw or a press-fit or snap-fit ​​feature, such as a pin, for fixing the shell to the second shell component (12, not shown).

[0229] Fig.16A cross-sectional view (not drawn to scale) of another example of an alternative jet impact reactor (1) is depicted, the reactor comprising a housing (40) made of a polymer material, the housing consisting of two mutually fixed parts (41, 42). The first housing part (41) comprises a major portion of each of the first fluid conduit (7) and the second fluid conduit (8), the major portion of which does not include the downstream end of the conduit; and the first housing part also comprises the entire third fluid conduit (9) and a small portion of the reaction chamber (2) wall including the fluid outlet (6). The first housing part (41) is shaped to include a cavity suitable for accommodating the second part by insertion. As shown in the figure, the second housing part (42) is shaped to fit and be inserted into the first housing part (41). The second housing part (42) comprises the downstream ends of the first fluid conduit (7) and the second fluid conduit (8) and the corresponding fluid inlet (3, 4), the nozzle (5) and the major portion of the reaction chamber (2) wall. The first fluid inlet (3) and the second fluid inlet (4) are arranged at relative positions on the first central axis (x) of the reaction chamber (2), and the reaction chamber is formed by inserting and fixing the second shell component (42) into the first shell component (41). The fluid outlet (6) is arranged at a position located on the second central axis (y) of the reaction chamber, and the second central axis is perpendicular to the first central axis (x). The first fluid conduit (7), the second fluid conduit (8) and the third fluid conduit (9) each have an inner cavity, and the inner cavity (13) of the first fluid conduit and the inner cavity (14) of the second fluid conduit respectively have a longitudinal axis coinciding with the first central axis (x) of the reaction chamber, and extend from an upstream end to a downstream end connected to the nozzle (5) fluid, and the inner cavity (15) of the third fluid conduit has an upstream end and a downstream end, and the upstream end coincides with the fluid outlet (6) of the reaction chamber. Therefore, a first fluid conduit and a second fluid conduit are arranged in the reactor for directing the first fluid to the first fluid inlet and directing the second fluid to the second fluid inlet, and a third fluid conduit is arranged for directing a third fluid from the fluid outlet in a downstream direction, the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber.

[0230] Fig.17 Describes Fig.16A perspective cutaway view (not drawn to scale) of the first housing member (41). The first housing member (41) comprises a major portion of each of the first fluid conduit (7) and the second fluid conduit (8), the major portion of which does not include the downstream end of the conduit; and also comprises the entire third fluid conduit (9) and a small portion of the reaction chamber (2) wall including the fluid outlet (6). As shown, the housing (41) comprises a cavity shaped and adapted to accommodate a second housing member (42, not shown), the shaping also providing an insertion guide (51) for inserting the second housing member in an intended and specific orientation relative to the first housing member (41) to form the housing (40). The inner cavities (13, 14, 15) of the first fluid conduit (7), the second fluid conduit (8) and the third fluid conduit (9) are each cylindrical. The first fluid conduit and the second fluid conduit (7, 8) also comprise a connector (57) which facilitates further connection to a correspondingly shaped feature, such as a pipe end or another connector. The first housing part (41) also includes a fastening means (56) in the form of a cavity, adapted or shaped to accommodate complementary fastening means (not shown), such as screws or press-fit or snap-fit ​​pins, which can be used to secure the first housing part (41) to the second housing part (42, not shown).

[0231] Fig.18 Describes Fig.16 A cross-sectional view of a second housing part (42) of a housing (40) is shown. The second housing part (42) comprises the downstream ends of the first fluid conduit (7) and the second fluid conduit (8), the respective fluid inlets (3, 4) and the nozzle (5) and a major portion of the reaction chamber (2) wall. As used herein, a major portion of the reaction chamber wall refers to more than 50% of the surface area of ​​the reaction chamber wall. The nozzle (5) is integral with the housing part, and the diameters of the fluid inlet (3) and the fluid inlet (4) are different, although in other embodiments, the diameters of the fluid inlet (3) and the fluid inlet (4) may be the same.

[0232] Fig.19 Describes Fig.16 A perspective view of a second shell component (42) of the shell (40) shown. The second shell component (42) is shaped to be insertable into the first shell component (41, not shown), and the shaping also provides an insertion guide (52) so that the component can only be inserted in a specific orientation relative to the first shell component (41) to form the shell (40). The shell (42) also includes a fastening means (76) in the form of a cavity, suitable or shaped to receive a complementary fastening means, such as a screw or a press-fit or snap-fit ​​pin, for fixing the two shell components together to form the shell (40) of the jet impact reactor (1).

[0233] Fig. 20A cross-sectional view (not drawn to scale) of another example of an alternative jet impact reactor (1) is depicted, the reactor comprising a housing (80) consisting of two mutually fixed parts (81, 82). The first housing part (81) comprises: a major portion of each of the first fluid conduit (7) and the second fluid conduit (8), the major portion of which does not include the downstream end of the conduit; and a major portion of the third fluid conduit (9), the major portion of which does not include the upstream end of the conduit coinciding with the fluid outlet (6) of the reaction chamber (2). In addition, the first housing part (81) is shaped to include a cavity suitable for accommodating the second housing part (82) by insertion. The second housing part (82) is shaped to fit the first housing part (81) and is inserted into the first housing part (81). The second housing part (82) comprises the entire reaction chamber (2), a small portion of the upstream end of the fluid outlet (6) and the third fluid outlet (9), as well as the downstream ends of the first fluid conduit (7) and the second fluid conduit (8) and the respective nozzles (5) (having respective fluid inlet openings) (see Fig.10 ). The nozzle providing the fluid inlet is arranged at a relative position on the first central axis (x) of the reaction chamber (2), and the reaction chamber is formed by inserting and fixing the second shell component (82) into the first shell component (81). The fluid outlet (6) is arranged at a position located on the second central axis (y) of the reaction chamber, and the second central axis is perpendicular to the first central axis (x). The first fluid conduit (7), the second fluid conduit (8) and the third fluid conduit (9) each have an inner cavity, the inner cavity (13) of the first fluid conduit and the inner cavity (14) of the second fluid conduit respectively have a longitudinal axis coinciding with the first central axis (x) of the reaction chamber, and extend from an upstream end to a downstream end connected to the nozzle (5) fluid, and the inner cavity (15) of the third fluid conduit has an upstream end and a downstream end. The upstream end coincides with the fluid outlet (6) of the reaction chamber (2). Therefore, a first fluid conduit (7) and a second fluid conduit (8) are arranged in the reactor (1) for directing a first fluid to a first fluid inlet provided by the nozzle (5), directing a second fluid to a second fluid inlet provided by the nozzle (5), and a third fluid conduit (9) is arranged for directing a third fluid from the fluid outlet in a downstream direction, the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber (2).

[0234] Fig.21 Describes Fig. 20A cutaway perspective view (not drawn to scale) of a first housing component (81) of a housing (80) is shown. The first housing component (81) comprises a major portion of each of a first fluid conduit (7) and a second fluid conduit (8), the major portion of which excludes the downstream end of the conduit; and a major portion of a third fluid conduit (9), the major portion of which excludes the upstream end of the conduit coinciding with the fluid outlet (6) of the reaction chamber (2). As shown, the housing (81) comprises a cavity shaped and adapted to receive a second housing component (82, not shown), the shaping also providing an insertion guide (91) for inserting the second housing component (82) in a particular orientation relative to the first housing component (81) to form the housing (80), and providing a flange / groove shaping corresponding to a snap-fit ​​or press-fit feature (98) to allow for fixation to the second housing component (82). The inner cavities (13, 14, 15) of the first fluid conduit (7), the second fluid conduit (8) and the third fluid conduit (9) are each cylindrical. The first and second fluid conduits (7, 8) further comprise a connector (97) which facilitates further connection to a correspondingly shaped feature, such as a pipe end or another connector. The first housing component (81) further comprises a fastening means (96) in the form of a cavity, shaped and adapted to receive a complementary fastening means, such as a screw, or a press-fit or snap-fit ​​pin (not shown), which can be used to secure the first housing component (41) to the second housing component (82, not shown).

[0235] Fig. 22 Describes Fig. 20 A cross-sectional view (not drawn to scale) of a second shell component (82) of a reactor shell (80) is shown. The second shell component (82) comprises the downstream ends of the first fluid conduit (7) and the second fluid conduit (8), the nozzle (5) and the corresponding fluid inlets (3, 4), the overall reaction chamber (2) (which is substantially spherical in shape and is interrupted only by the first fluid inlet (3) and the second fluid inlet (4), the fluid outlet (6), and a small portion (i.e., less than 50% of the fluid path length) of the upstream end of the fluid conduit (9) coinciding with the fluid outlet (6). The nozzle (5) is integral with the shell component, and the first fluid inlet (3) and the second fluid inlet (4) have different diameters, although in other embodiments, the first fluid inlet (3) and the second fluid inlet (4) have the same diameter. Also shown are snap-fit ​​or press-fit features in the form of flange and groove formations adapted to mate with corresponding features in the first shell component (81) for securing the second shell component (82) to the first shell component (81).

[0236] Fig.23 Describes Fig. 20A perspective view (not drawn to scale) of a second shell component (82) of the shell (80) shown. The second shell component (82) is shaped to be insertable into the first shell component (81, not shown), and the shaping also provides an insertion guide (92) so that the component can be inserted in an intended and specific orientation relative to the first shell component (81) to form the shell (80). The second shell component (82) also includes a snap-fit ​​or press-fit feature (108) in the form of a flange and groove formation, which is suitable for matching with a corresponding feature in the first shell component (81) for securing the component to the first shell component (81). The second shell component (82) also includes a fastening device (116), such as a cavity, suitable for receiving a screw, also for securing the two shell components together to form the shell (80) of the jet impact reactor (1).

[0237] Reference numerals list

[0238] 1 Jet impact reactor

[0239] 2 Reaction chamber

[0240] 3 First fluid inlet

[0241] 4 Second fluid inlet

[0242] 5 Nozzle

[0243] 6 Fluid outlet

[0244] 7 First fluid conduit

[0245] 8 Second fluid conduit

[0246] 9 Third fluid conduit

[0247] 121, 171, 181 Part 1

[0248] 132, 172, 182 Second part

[0249] 16 Reaction chamber wall part

[0250] 21 First cavity

[0251] 22 Second cavity

[0252] 23 Third cavity

[0253] 24 Upstream end of second component

[0254] 25 Downstream end of second component

[0255] 28 Fluid conduit lumen

[0256] 29a Upstream part of the lumen

[0257] 29b Middle part of the inner cavity

[0258] 29c Downstream part of the lumen

[0259] 31,319 Planar wall portion of reaction chamber

[0260] 32,329 recess

[0261] 33, 73, 83 Connecting parts

[0262] 34, 74, 84 Upstream end of connection part

[0263] 35, 75, 85 Connecting component downstream end

[0264] 744, 844 Connecting parts upstream

[0265] 755, 855 Connecting components downstream

[0266] 36, 76, 86 Fluid conduits for connecting components

[0267] 37, 77, 87 Connectors or joints for connecting components

[0268] 38, 78, 88 round slot

[0269] 39, 79 O-ring seals

[0270] 10, 40, 80 housing

[0271] 11, 41, 81 First housing part

[0272] 12, 42, 82 Second housing component

[0273] 13. First fluid conduit lumen

[0274] 14. Second fluid conduit lumen

[0275] 15 Third fluid conduit lumen

[0276] 51, 52, 91, 92, 109a, 109b Insertion guide

[0277] 26, 36, 56, 76, 96, 116 fastening devices

[0278] 27, 37, 57, 97 connectors

[0279] 98, 108 snap-fit ​​or press-fit feature

[0280] x First central axis

[0281] y Second central axis

[0282] The following examples are used to illustrate the present invention, but should not be construed as limiting the scope of the present invention.

[0283] Example

[0284] Example 1

[0285] The impact jet reactor according to the present invention is assembled from a first component and a second component as defined in the claims (both made of polymer materials and equipped with connecting components as disclosed herein) for preparing model PLGA (polylactic acid-co-glycolic acid, also known as polylactic acid-co-glycolic acid) nanoparticles. In order to evaluate the reproducibility, three reactors (A, B and C) of the same specifications were assembled and tested. As a further control and comparison, a jet impact reactor made of stainless steel and of the same specifications as described in WO 2023 / 025736 A1 was tested. Each reactor is connected to an instrument that provides the containers, pipes, pumps, valves, pressure gauges, flow meters, and thermometers required to operate the reactor and produce nanoparticles. As shown in the table below, PLGA nanoparticles were prepared using substantially the same reactor geometry and process parameters. The dimensions provided are manufacturing specifications, not measured values.

[0286]

[0287] The resulting nanoparticle samples were collected and treated with 0.1% polysorbate 20 ( 20) in a deionized water solution was diluted 1:1 to a solvent concentration of 10%, and then dynamic light scattering (DLS) measurements were performed to measure the particle size of the nanoparticles and the polydispersity index (PDI) of the particle size distribution. DLS measurements were performed at a scattering angle of 90° using a Zetasizer Nano ZS90 (Malvern Panalytical). The production runs of each of polymer reactors A, B, C and the comparative stainless steel reactor M were performed three times.

[0288] Results: Fig.11 As shown in the figure, it is found that the particle size of the PLGA nanoparticles produced by the polymer impact jet reactor according to the present invention is similar to the particle size of the nanoparticles produced under the same conditions using a stainless steel reactor M with the same specifications. It is also found that the produced particles have a low PDI (polydispersity index), i.e., less than a threshold value of 0.2, indicating that high-quality nanoparticles with a narrow particle size distribution are produced. In addition, it is found that the PLGA nanoparticles obtained from the three polymer reactors A, B and C have similar nanoparticle particle sizes and PDI, indicating that the production, assembly and assembly methods of these reactors have good reproducibility and robustness.

[0289] Example 2

[0290] The impinging jet reactor according to the present invention is assembled from a first component and a second component as defined in the claims (both made of polymer materials and equipped with connecting components as defined in the present invention) for preparing model liposome nanoparticles. Compared with the model PLGA particles prepared in Example 1, liposomes are more complex because they are spherical vesicles composed of amphiphilic lipids, containing at least one lipid bilayer generally surrounding an aqueous core.

[0291] To assess reproducibility, three reactors of identical specifications (A, B and C - different from the samples used in Example 1) were assembled and tested for liposome production. As a further control and comparison, a jet impact reactor made of stainless steel and of identical specifications as described in WO 2023 / 025736A1 was also tested in parallel. Each reactor was connected to an instrument that provided the containers, tubing, pumps, valves, pressure gauges, flow meters, and thermometers required to run the reactor and produce nanoparticles. As shown in the table below, liposomes were prepared using essentially the same reactor geometry and process parameters. Again, the dimensions provided are manufacturing specifications, not measurements:

[0292]

[0293] Production runs of each of polymer reactors A, B, C and the comparative stainless steel reactor M were performed three times at room temperature.

[0294] The liposome samples were collected and diluted with PBS buffer (same as fluid 2) immediately after production to an ethanol concentration of 16.5% in the sample, and then subjected to dynamic light scattering (DLS) measurements to measure the particle size and the polydispersity index (PDI) of the particle size. The DLS measurements were performed 10 minutes or less after sample collection and dilution, and the DLS measurements were performed using a Zetasizer Ultra (Malvern Panalytical) at a scattering angle of 173°.

[0295] Results: Fig.12 As shown in the figure, it is found that the liposome nanoparticles produced by the polymer impact jet reactor according to the present invention have a small particle size similar to the liposome nanoparticles produced under the same conditions using a stainless steel reactor M with the same specifications. It is also found that the particles produced have a low PDI (polydispersity index) of less than 0.1, which indicates that high-quality nanoparticles with a very narrow particle size range distribution are produced. In addition, it is found that the liposome nanoparticles produced by each of the three separate polymer reactors A, B and C have similar nanoparticle particle sizes and PDIs, indicating good reproducibility and robustness in the manufacture, assembly and assembly of the reactor components.

Claims

1. A jet impact reactor comprising a reaction chamber having a substantially spherical shape, wherein the spherical shape is interrupted by: (a) a first fluid inlet and a second fluid inlet, wherein the first fluid inlet and the second fluid inlet are arranged at opposite positions on a first central axis of the reaction chamber so as to point toward each other, and wherein each of the first fluid inlet and the first fluid inlet is provided by a nozzle; and (b) a fluid outlet arranged at a position located on a second central axis of the reaction chamber, the second central axis being perpendicular to the first central axis; The reactor further comprises a first fluid conduit, a second fluid conduit and a third fluid conduit, wherein the first fluid conduit and the second fluid conduit are arranged to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and wherein the third fluid conduit is arranged to direct a third fluid in a downstream direction from the fluid outlet, the third fluid being formed by mixing or reacting the first fluid and the second fluid in the reaction chamber; wherein the reactor comprises at least two parts fixed to each other: a first part, made of a polymer material and comprising at least a portion of the first fluid conduit or the second fluid conduit and at least one hemispherical portion of the reaction chamber; and a second component at least partially insertable into the first component, the second component comprising the fluid outlet.

2. The reactor according to claim 1, wherein the first component is shaped to include a first cavity for accommodating the second component by insertion, and wherein the second component is shaped and adapted to be insertable into the first cavity.

3. The reactor according to claim 1 or 2, wherein the first cavity is cylindrical, elliptical or conical.

4. A reactor according to any preceding claim, wherein the second component comprises - an upstream end comprising said fluid outlet and a portion of said reaction chamber; - downstream end; as well as - said third fluid conduit fluidly connecting said upstream end with said downstream end.

5. A reactor according to any preceding claim, wherein the second component is fully insertable into the first cavity.

6. A reactor according to any of the preceding claims, wherein the first component is at least mainly made of a thermoplastic polymer material; wherein the thermoplastic polymer material preferably comprises polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile-butadiene-styrene copolymer (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU) or polyetherimide (PEI).

7. A reactor according to any preceding claim, wherein the longitudinal central axes of the first fluid conduit and the second fluid conduit each coincide with the first central axis of the reaction chamber, and wherein the longitudinal central axis of the third fluid conduit coincides with the second central axis of the reaction chamber.

8. A reactor according to any preceding claim, wherein the first fluid conduit and / or the second fluid conduit has an inner cavity having an upstream portion and a downstream portion, wherein the upstream portion is cylindrical or elliptical and has a diameter that is much larger than the diameter of the downstream portion.

9. A reactor according to claim 8, wherein the downstream portions of the first and second fluid conduits each have a downstream end, the downstream ends forming or coinciding with the first and second fluid inlets, respectively.

10. The reactor of claim 9, wherein the downstream portion tapers toward its downstream end.

11. A reactor according to any one of claims 1 to 8, wherein the downstream portion is generally cylindrical.

12. A reactor according to any preceding claim, wherein the lumen of each of the first and second fluid conduits further comprises an intermediate portion between the upstream portion and the downstream portion, wherein the intermediate portion tapers towards the downstream portion.

13. The reactor of claim 12, wherein the tapered middle portion and the tapered downstream portion have different tapered angles.

14. A reactor according to any preceding claim, wherein the nozzle is provided by the downstream portion.

15. A reactor according to any one of claims 8 to 14, wherein the nozzle providing the first fluid inlet or the second fluid inlet is integral with the first part of the reactor.

16. A reactor according to any one of claims 8 to 14, wherein the nozzle providing the first fluid inlet or the second fluid inlet is an insert.

17. The reactor of claim 16, wherein the insert is made of metal.

18. A reactor according to any preceding claim, wherein the first and second fluid inlets have diameters ranging from about 50 μm to about 600 μm.

19. A reactor according to any preceding claim, wherein the diameter of the first fluid inlet is different to the diameter of the second fluid inlet.

20. The reactor of claim 18 or 19, wherein the diameter of the first fluid inlet ranges from about 200 μm to about 500 μm, and wherein the diameter of the second fluid inlet ranges from about 50 μm to about 200 μm.

21. A reactor according to any preceding claim, wherein the spherical shape of the reaction chamber is interrupted only by the first and second fluid inlets and the fluid outlet.

22. A reactor according to any one of claims 1 to 20, wherein the spherical shape of the reaction chamber is interrupted only by the first and second fluid inlets, the fluid outlet and a planar wall portion having an area smaller than the area of ​​the fluid outlet.

23. A reactor according to claim 22, wherein the planar wall portion is provided by the first component as a protruding portion of the first component, and wherein the second component has a recess for accommodating the protruding portion.

24. A reactor according to any one of claims 1 to 20, wherein the spherical shape of the reaction chamber is interrupted only by the first fluid inlet and the second fluid inlet, the fluid outlet and at least two planar wall portions, each planar wall portion independently having an area smaller than the fluid outlet area, wherein the first planar wall portion and the second planar wall portion are arranged at relative positions on the first central axis of the reaction chamber.

25. A reactor according to claim 24, wherein the at least two planar wall portions are provided by the first component as protruding portions of the first component, and wherein the second component has a first recess and a second recess adapted to accommodate the protruding portions.

26. A reactor according to any preceding claim, wherein the first component comprises a second cavity and a third cavity, wherein each of the second cavity and the third cavity is shaped to accommodate a connecting component for directing the first fluid or the second fluid from an upstream fluid supply source to the first fluid conduit and the second fluid conduit, respectively.

27. A reactor according to claim 26, wherein the connecting component has an upstream end, a downstream end and a fluid conduit extending from the upstream end to the downstream end, wherein at least the downstream end can be inserted into the second cavity or the third cavity, so that the fluid conduit of the connecting component is in fluid communication with the inner cavity of the first fluid conduit or the second fluid conduit of the reactor.

28. The reactor according to claim 27, wherein the upstream end of the connecting part has a connector for fixing a pipe or a tube, such as a Luer connector or a barbed connector or fitting.

29. A reactor according to any one of claims 26 to 28, wherein the connection component features an external circumferential groove at or near its downstream end for retaining an O-ring seal to seal the connection component to the first component of the reactor.

30. The first component of the reactor as defined in any one of the preceding claims.

31. A method of manufacturing the first part of the reactor of any one of claims 1 to 29 or the reactor of claim 30, comprising the step of injection molding the first part.

32. The method of claim 31 , wherein the step of injection molding the first component includes forming the first fluid inlet and the second fluid inlet.

33. The method of claim 31, wherein the first fluid inlet and the second fluid inlet are formed by the steps of micro-drilling or laser drilling.

34. Use of a reactor according to any one of claims 1 to 29 for the aseptic manufacture of a sterile liquid pharmaceutical composition.

35. The use according to claim 34, comprising: (i) fluidly connecting the first fluid conduit to an upstream supply source of a first fluid via a first connecting member; (ii) fluidly connecting the second fluid conduit to an upstream supply source of a second fluid different from the first fluid via a second connecting member; (iii) allowing the first fluid to flow from the first fluid supply source into the reactor at a first flow rate, and simultaneously allowing the second fluid to flow from the second fluid supply source into the reactor at a second flow rate, thereby mixing the first fluid and the second fluid in the reaction chamber to form a third fluid that leaves the reaction chamber through the fluid outlet.

36. The use according to claim 35, wherein the first flow rate is greater than the second flow rate, and wherein the diameter of the first fluid inlet is greater than the diameter of the second fluid inlet.

37. The use according to claims 34 to 36, wherein the liquid pharmaceutical composition comprises lipid nanoparticles.

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